@article {pmid40369385, year = {2025}, author = {Manohar, PM and Peterson, LM and Jenkins, IC and Wu, QV and Kurland, BF and Novakova-Jiresova, A and Muzi, M and Chen, DL and Specht, JM and Dintzis, S and Kinahan, PE and Mankoff, DA and Linden, HM}, title = {[18 F]-Fluoroestradiol PET (FES-PET) and [18 F] Flurodeoxyglucose PET (FDG-PET) Imaging May Aid in Managing Therapy in Patients with Metastatic Lobular Breast Cancer.}, journal = {Molecular imaging and biology}, volume = {}, number = {}, pages = {}, pmid = {40369385}, issn = {1860-2002}, abstract = {AIM: This study examines the combination of FES-PET and FDG-PET as complementary imaging for detection of metastatic ILC.<br><br>METHODS: We retrospectively evaluated FES and FDG uptake in patients with metastatic ILC from an estrogen receptor (ER) positive primary tumor. We classified lesions into three categories (FES high/FDG low, FES high/FDG high, FES low/FDG low) using SUVmax cut-off values of 1.5 for FES and 5.0 for FDG. Qualitative evaluation included examination of the difference in the extent of disease between FES and FDG.<br><br>RESULTS: Of the 38 patients, 82% had FES uptake in all tumor sites identified by FDG, with 18% lacking FES uptake in at least one lesion. Mean (range)&#xa0;SUVmax&#xa0;for FES and FDG was 4.0 (0.67-10.6) and 4.6 (1.3-12.5), respectively.&#xa0;The majority of ILC patients (25/38), had lesions with FES high/FDG low uptake, consistent with the strongly ER&#x2009;+&#x2009;indolent nature of ILC. Patients with disease classified as FES high/FDG low had longer median overall survival (OS) (3.2&#xa0;years) and progression-free survival (PFS) (1.5&#xa0;years) than FES high/FDG high (OS&#x2009;=&#x2009;2.1&#xa0;years and PFS&#x2009;=&#x2009;0.46&#xa0;years). The median overall OS for all patients was 3.0&#xa0;years (95% CI 2.5, 4.8) and PFS of 1.3&#xa0;years (95% CI 0.6, 2.5). 8 patients (21%) had qualitatively more extensive disease by FES-PET.<br><br>CONCLUSIONS: Our findings suggest that both FES-PET and FDG-PET can identify metastatic ILC and be useful in detecting the pattern and extent of disease. The imaging combination provides additional information for prognosis and clinical decision making, balancing suitability for endocrine therapy and aggressiveness/indolence of disease.}, }
@article {pmid40368142, year = {2025}, author = {Friedman, RK and Heath, AS and Huffman, JE and Baker, JT and Hasbani, NR and Gagliano Taliun, SA and Chen, MH and Howard, TE and Lewis, JP and Pankratz, N and Patil, S and Reiner, AP and Thibord, F and Yanek, LR and Yao, J and Chen, HH and Curran, JE and Faraday, N and Guo, X and Wheeler, MM and Ryan, KA and Zhou, X and Cho, K and Almasy, L and Auer, PL and Becker, LC and Wilson, PWF and Boerwinkle, E and O'Connell, JR and Rich, SS and Samuels, DC and ,  and ,  and ,  and Blangero, J and Fornage, M and Kooperberg, C and Mathias, RA and Mitchell, BD and Rotter, JI and Johnson, AD and Smith, NL and Coban-Akdemir, ZH and Below, JE and Morrison, AC and Johnsen, JM and de Vries, PS}, title = {Genetic study of von Willebrand factor antigen levels ≤ 50 IU/dL identifies variants associated with increased risk of VWD and bleeding.}, journal = {Journal of thrombosis and haemostasis : JTH}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtha.2025.04.029}, pmid = {40368142}, issn = {1538-7836}, abstract = {BACKGROUND: von Willebrand disease (VWD) is a common inherited bleeding disorder caused by low levels or activity of circulating von Willebrand factor (VWF). Genetic susceptibility to VWF antigen (VWF:Ag) below normal (≤50 IU/dL) in the general population is underexplored.<br><br>METHODS: To identify genetic variants influencing VWF:Ag levels &#x2264;50 IU/dL, we performed a genome-wide association study in 926 cases with VWF:Ag levels &#x2264;50 IU/dL and 12,846 controls from 7 studies from the TOPMed program. We then examined whether genome-wide significant findings were also associated with clinical diagnosis of VWD in 5 biobanks with 708 VWD cases and 1,286,069 controls, and with 6 bleeding and thrombotic disorders in FinnGen.<br><br>RESULTS: Variants at two loci were associated (P<5&#xd7;10[-9]) with VWF:Ag levels &#x2264;50 IU/dL: ABO and VWF. The VWF index variant, p.Tyr1584Cys, is a rare (0.22%) missense variant with odds ratio (OR) of 78.58, while the ABO index variant is a common intronic variant with a smaller effect (OR=2.52). Notably, both VWF (OR=7.16) and ABO (OR=1.57) variants were also associated (P<0.025) with diagnosed VWD. Among p.Tyr1584Cys heterozygotes, the penetrance of VWF:Ag levels &#x2264;50 IU/dL was 24.2% and the penetrance of diagnosed VWD was 0.3%. p.Tyr1584Cys was associated (P<0.0042) with increased odds of heavy menstrual bleeding (OR=1.27), iron deficiency anemia (OR=1.55), and intrapartum hemorrhage (OR=2.20), but decreased odds of deep vein thrombosis (OR=0.54).<br><br>CONCLUSIONS: While p.Tyr1584Cys currently has conflicting interpretations of pathogenicity, our results suggest that it is a low penetrance pathogenic variant that contributes to VWF:Ag levels &#x2264;50 IU/dL, bleeding, and VWD.}, }
@article {pmid40368025, year = {2025}, author = {Park, ER and Kirchhoff, AC and Mitchell, CO and Durieux, N and Foor, A and Kuhlthau, K and Perez, GK and Ards, L and Alston, S and Armstrong, GT and Vaca Lopez, PL and McDonald, A and Nolan, VG and Levy, DE and Leisenring, WM and Galbraith, AA and Nathan, PC and Vukadinovich, C and Cooper, CL and Donelan, K}, title = {Assessing the effect of virtual navigation interventions to improve health insurance literacy and decrease financial burden in cancer survivors: The HINT II study protocol.}, journal = {Contemporary clinical trials}, volume = {}, number = {}, pages = {107952}, doi = {10.1016/j.cct.2025.107952}, pmid = {40368025}, issn = {1559-2030}, abstract = {BACKGROUND: Childhood cancer survivors often face high healthcare costs to monitor and manage new or lasting effects of their treatment. Enhancing survivors' health insurance literacy (HIL) - the knowledge, ability, and confidence in enrolling in and navigating health plans - is vital for minimizing financial burden. Few studies have assessed the effect of a health insurance navigation program on improving HIL among survivors. We present the protocol for an ongoing randomized controlled trial (RCT) assessing the effectiveness of two health insurance navigation programs (HINT-S and HINT-A) on improving HIL, financial burden, out-of-pocket costs, and healthcare utilization for adult survivors of childhood cancer.<br><br>METHODS: This three-arm RCT assesses the effectiveness of two digitally delivered health insurance navigation interventions and enhanced usual care (EUC) on improving HIL at six and 12&#x202f;months in a national cohort of childhood cancer survivors. While HINT-S is composed of five synchronous, navigator-led sessions, HINT-A is an asynchronous, prerecorded set of five videos. EUC participants receive only a health insurance informational booklet. Financial burden, medical out-of-pocket costs, and healthcare utilization (receipt of preventive care, recommended screenings/vaccinations, and acute care) are assessed at 12&#x202f;months. Moderators to the interventions' effectiveness will be investigated, as well as implementation outcomes (feasibility, acceptability, appropriateness, fidelity, and cost-effectiveness).<br><br>CONCLUSIONS: There is a strong need for interventions to improve cancer survivors' HIL, helping them navigate the complexity of the U.S. healthcare system. This trial will elucidate the potential effectiveness and implementation of health insurance navigation programs that may benefit many cancer survivors.<br><br>TRIAL REGISTRATION: NCT05527392.}, }
@article {pmid40367160, year = {2025}, author = {Stepanov, I and Gottshall, NR and Ahmadianyazdi, A and Sinha, D and Lockhart, EJ and Nguyen, TNH and Hassan, S and Horowitz, LF and Yeung, RS and Gujral, TS and Folch, A}, title = {Low-cost robotic manipulation of live microtissues for cancer drug testing.}, journal = {Science advances}, volume = {11}, number = {20}, pages = {eads1631}, pmid = {40367160}, issn = {2375-2548}, mesh = {Humans ; *Robotics/economics/instrumentation ; Drug Screening Assays, Antitumor/methods/economics/instrumentation ; *Antineoplastic Agents/pharmacology ; *Neoplasms/drug therapy/pathology ; Lab-On-A-Chip Devices ; }, abstract = {The scarcity of human biopsies available for drug testing is a paramount challenge for developing therapeutics, disease models, and personalized treatments. Microtechnologies that combine the microscale manipulation of tissues and fluids offer the exciting possibility of miniaturizing both disease models and drug testing workflows on scarce human biopsies. Unfortunately, these technologies presently require microfluidic devices or robotic dispensers that are not widely accessible. We have rapidly prototyped an inexpensive platform based on an off-the-shelf robot that can microfluidically manipulate live microtissues into/out of culture plates without using complicated accessories such as microscopes or pneumatic controllers. The robot integrates complex functions with a simple, cost-effective, and compact construction, allowing placement inside a tissue culture hood for sterile workflows. We demonstrated a proof-of-concept cancer drug evaluation workflow of potential clinical utility using patient tumor biopsies with multiple drugs on 384-well plates. Our user-friendly, low-cost platform promises to make drug testing of microtissues broadly accessible to pharmaceutical, clinical, and biological laboratories.}, }
@article {pmid40366394, year = {2025}, author = {Hardy, S and Chhan, CB and Davis, AR and McGuire, AT}, title = {Viral Entry.}, journal = {Current topics in microbiology and immunology}, volume = {}, number = {}, pages = {}, doi = {10.1007/82_2025_300}, pmid = {40366394}, issn = {0070-217X}, abstract = {Epstein-Barr virus chiefly infects B cells and epithelial cells but is capable of infecting other cell types in the human host. Host cell entry is a complex process mediated by several viral glycoproteins that define tropism and mediate membrane fusion. This chapter will review what is known about the function of viral glycoproteins in the entry process, explore the nature of interactions between viral glycoproteins and host cell receptors, and highlight gaps in knowledge about the entry process that remain to be filled.}, }
@article {pmid40365909, year = {2025}, author = {Levy, JA and Kazemian, E and Ramin, C and Loroña, NC and Nadri, M and Gasho, JO and Silos, KD and Nikolova, AP and Dey, D and Siegel, EM and Gigic, B and Hardikar, S and Byrd, DA and Toriola, AT and Ose, J and Li, CI and Shibata, D and Ulrich, CM and Tamarappoo, BK and Atkins, KM and Figueiredo, JC}, title = {Subclinical Atherosclerosis and Cardiovascular Events Among Patients With Colorectal Cancer.}, journal = {Cancer medicine}, volume = {14}, number = {10}, pages = {e70938}, pmid = {40365909}, issn = {2045-7634}, support = {P30CA042014//National Cancer Institute of the National Institutes of Health/ ; R01CA160684//National Cancer Institute of the National Institutes of Health/ ; R01CA189184//National Cancer Institute of the National Institutes of Health/ ; R01CA207371//National Cancer Institute of the National Institutes of Health/ ; R01CA215134//National Cancer Institute of the National Institutes of Health/ ; R01CA254108//National Cancer Institute of the National Institutes of Health/ ; R03CA270473//National Cancer Institute of the National Institutes of Health/ ; U01CA206110//National Cancer Institute of the National Institutes of Health/ ; U01CA246659//National Cancer Institute of the National Institutes of Health/ ; }, mesh = {Humans ; Male ; Female ; *Colorectal Neoplasms/complications/epidemiology/therapy ; Middle Aged ; Aged ; Prospective Studies ; *Atherosclerosis/epidemiology/etiology ; *Cardiovascular Diseases/epidemiology/etiology ; Risk Factors ; Positron Emission Tomography Computed Tomography ; Coronary Vessels/diagnostic imaging ; }, abstract = {BACKGROUND: Prior studies have documented that patients with colorectal cancer (CRC) are at an increased risk of cardiovascular disease (CVD).<br><br>OBJECTIVES: To examine coronary artery calcium (CAC) as a marker of subclinical atherosclerosis and its association with major adverse cardiovascular events (MACE) in patients with CRC across the cancer treatment trajectory.<br><br>METHODS: Adults with newly diagnosed CRC were enrolled in the prospective ColoCare study from 2017 to 2024. CAC was measured from routine diagnostic computed tomography (CT) and positron emission tomography-CT scans at CRC diagnosis until 5&#x2009;years post-diagnosis. Atherosclerosis was defined as the presence of CAC. We used multivariable-adjusted Fine and Gray models to assess the association between CAC and MACE risk, accounting for competing risks.<br><br>RESULTS: Among 300 CRC patients, the most common CVD risk factors at cancer diagnosis were hypertension (37%), hyperlipidemia (24%), and diabetes (14%). During follow-up (median&#x2009;=&#x2009;5.3&#x2009;years), 75 (25%) individuals experienced MACE: stroke (3%), new/worsening HF (9%), HF exacerbation requiring hospitalization (2%), coronary revascularization (3%), and death (19%). Among individuals with imaging at baseline (n&#x2009;=&#x2009;101), 37 (36.6%) had CAC, and statins were not prescribed in 11 (55.0%) patients with moderate/high CAC. For those with serial imaging (n&#x2009;=&#x2009;61), 31.1% showed worsening CAC and 3% developed new CAC. Baseline CAC conferred a higher risk of MACE (HR&#x2009;=&#x2009;4.79; 95% CI: 1.05-21.75, p&#x2009;=&#x2009;0.04) after accounting for cancer-related deaths as a competing risk.<br><br>CONCLUSIONS: Subclinical atherosclerosis and MACE are common among patients with CRC. Integrating CAC from routine cancer imaging can identify patients who may benefit from cardio-preventive treatment.}, }
@article {pmid40365115, year = {2025}, author = {Restar, AJ and Lucas, R and Nfn, S and Alpert, AB and Phipps, A and Wang, G and Operario, D and Radix, A and van der Merwe, LA and Lindström, S and Everhart, A and Gamarel, KE and Streed, CG}, title = {Underinvested, Under-Referred, and Underserved: Applying a Gender Equity Continuum Framework in Cancer Control Continuum Programs and Policies to Expand to Transgender and Nonbinary Populations.}, journal = {JCO oncology advances}, volume = {2}, number = {1}, pages = {e2400023}, pmid = {40365115}, issn = {2994-9750}, abstract = {Gender-inclusive and gender-specific approaches are critically needed in cancer control continuum services to recognize and meet the needs of transgender and nonbinary (trans) populations. Current research, programs, and policies largely cater to cisgender populations and subscribe to a binary, gendered cisnormative ideology, both within health care systems and insurance policies, leaving trans people's cancer prevention and treatment needs neglected. Such disparities can be attributed to the significant gap in funding and research to address trans cancer prevention and treatment. We discuss the research, program, and policy implications of cisnormative practices and provide recommendations for promoting gender-inclusive and specific services across the cancer control continuum with the goal of eliminating cancer disparities and improving cancer outcomes for people of all gender groups, including trans populations.}, }
@article {pmid40364978, year = {2025}, author = {Alavattam, KG and Dickson, BM and Hirano, R and Dell, R and Tsukiyama, T}, title = {ChIP-seq Data Processing and Relative and Quantitative Signal Normalization for Saccharomyces cerevisiae.}, journal = {Bio-protocol}, volume = {15}, number = {9}, pages = {e5299}, pmid = {40364978}, issn = {2331-8325}, abstract = {Chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) is a widely used technique for genome-wide analyses of protein-DNA interactions. This protocol provides a guide to ChIP-seq data processing in Saccharomyces cerevisiae, with a focus on signal normalization to address data biases and enable meaningful comparisons within and between samples. Designed for researchers with minimal bioinformatics experience, it includes practical overviews and refers to scripting examples for key tasks, such as configuring computational environments, trimming and aligning reads, processing alignments, and visualizing signals. This protocol employs the sans-spike-in method for quantitative ChIP-seq (siQ-ChIP) and normalized coverage for absolute and relative comparisons of ChIP-seq data, respectively. While spike-in normalization, which is semiquantitative, is addressed for context, siQ-ChIP and normalized coverage are recommended as mathematically rigorous and reliable alternatives. Key features • ChIP-seq data processing workflow for Linux and macOS integrating data acquisition, trimming, alignment, processing, and multiple forms of signal computation, with a focus on reproducibility. • ChIP-seq signal generation using siQ-ChIP to quantify absolute IP efficiency-providing a rigorous alternative to spike-in normalization-and normalized coverage for relative comparisons. • Broad applicability demonstrated with Saccharomyces cerevisiae (experimental) and Schizosaccharomyces pombe (spike-in) data but suitable for ChIP-seq in any species. • In-depth notes and troubleshooting guide users through setup challenges and key concepts in basic bioinformatics, data processing, and signal computation. Graphical overview Flowchart depicting ChIP-seq data processing steps covered in this protocol.}, }
@article {pmid40364850, year = {2025}, author = {Rubinstein, S and Mohsin, A and Banerjee, R and Ma, W and Mishra, S and Kwok, M and Yang, P and Warner, JL and Cowan, AJ}, title = {Summarizing clinical evidence utilizing large language models for cancer treatments: a blinded comparative analysis.}, journal = {Frontiers in digital health}, volume = {7}, number = {}, pages = {1569554}, pmid = {40364850}, issn = {2673-253X}, abstract = {BACKGROUND: Concise synopses of clinical evidence support treatment decision-making but are time-consuming to curate. Large language models (LLMs) offer potential but they may provide inaccurate information. We objectively assessed the abilities of four commercially available LLMs to generate synopses for six treatment regimens in multiple myeloma and amyloid light chain (AL) amyloidosis.<br><br>METHODS: We compared the performance of four LLMs: Claude 3.5, ChatGPT 4.0; Gemini 1.0 and Llama-3.1. Each LLM was prompted to write synopses for six regimens. Two hematologists independently assessed accuracy, completeness, relevance, clarity, coherence, and hallucinations using Likert scales. Mean scores with 95% confidence intervals (CI) were calculated across all domains and inter-rater reliability was evaluated using Cohen's quadratic weighted kappa.<br><br>RESULTS: Claude demonstrated the highest performance in all domains, outperforming the other LLMs in accuracy: mean Likert score 3.92 (95% CI 3.54-4.29); ChatGPT 3.25 (2.76-3.74); Gemini 3.17 (2.54-3.80); Llama 1.92 (1.41-2.43);completeness: mean Likert score 4.00 (3.66-4.34); GPT 2.58 (2.02-3.15); Gemini 2.58 (2.02-3.15); Llama 1.67 (1.39-1.95); and extentofhallucinations: mean Likert score 4.00 (4.00-4.00); ChatGPT 2.75 (2.06-3.44); Gemini 3.25 (2.65-3.85); Llama 1.92 (1.26-2.57). Llama performed considerably poorer across all the studied domains. ChatGPT and Gemini had intermediate performance. Notably, none of the LLMs registered perfect accuracy, completeness, or relevance.<br><br>CONCLUSION: Claude performed at a consistently higher level than other LLMs, all tested LLMs required careful editing from a domain expert to become usable. More time will be needed to determine the suitability of LLMsto independently generate clinical synopses.}, }
@article {pmid40364846, year = {2025}, author = {Battisti, P and Ykema, MR and Kasal, DN and Jennewein, MF and Beaver, S and Weight, AE and Hanson, D and Singh, J and Bakken, J and Cross, N and Fusco, P and Archer, J and Reed, S and Gerhardt, A and Julander, JG and Casper, C and Voigt, EA}, title = {A bivalent self-amplifying RNA vaccine against yellow fever and Zika viruses.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1569454}, pmid = {40364846}, issn = {1664-3224}, mesh = {Animals ; *Zika Virus/immunology ; *Zika Virus Infection/prevention &amp; control/immunology ; Antibodies, Neutralizing/immunology/blood ; Mice ; *Yellow fever virus/immunology ; Antibodies, Viral/immunology/blood ; *Yellow Fever/prevention &amp; control/immunology ; Mice, Inbred C57BL ; Cricetinae ; *Viral Vaccines/immunology ; Female ; Mesocricetus ; CD8-Positive T-Lymphocytes/immunology ; *Yellow Fever Vaccine/immunology ; Immunogenicity, Vaccine ; }, abstract = {INTRODUCTION: Yellow fever (YFV) and Zika (ZIKV) viruses cause significant morbidity and mortality, despite the existence of an approved YFV vaccine and the development of multiple ZIKV vaccine candidates to date. New technologies may improve access to vaccines against these pathogens. We previously described a nanostructured lipid carrier (NLC)-delivered self-amplifying RNA (saRNA) vaccine platform with excellent thermostability and immunogenicity, appropriate for prevention of tropical infectious diseases.<br><br>METHODS: YFV and ZIKV prM-E antigen-expressing saRNA constructs were created using a TC-83 strain Venezuelan equine encephalitis virus-based replicon and complexed with NLC by simple mixing. Monovalent and bivalent vaccine formulations were injected intramuscularly into C57BL/6 mice and Syrian golden hamsters, and the magnitude, durability, and protective efficacy of the resulting immune responses were then characterized.<br><br>RESULTS AND DISCUSSION: Monovalent vaccines established durable neutralizing antibody responses to their respective flaviviral targets, with little evidence of cross-neutralization. Both vaccines additionally elicited robust antigen-reactive CD4[+] and CD8[+] T cell populations. Notably, humoral responses to YFV saRNA-NLC vaccination were comparable to those in YF-17D-vaccinated animals. Bivalent formulations established humoral and cellular responses against both viral targets, commensurate to those established by monovalent vaccines, without evidence of saRNA interference or immune competition. Finally, both monovalent and bivalent vaccines completely protected mice and hamsters against lethal ZIKV and YFV challenge. We present a bivalent saRNA-NLC vaccine against YFV and ZIKV capable of inducing robust and efficacious neutralizing antibody and cellular immune responses against both viruses. These data support the development of other multivalent saRNA-based vaccines against infectious diseases.}, }
@article {pmid40360879, year = {2025}, author = {Wang'ondu, RW and Ashcraft, E and Chang, TC and Roberts, KG and Brady, SW and Fan, Y and Evans, W and Relling, MV and Crews, KR and Yang, J and Yang, W and Pounds, S and Wu, G and Devidas, M and Maloney, K and Mattano, L and Schore, RJ and Angiolillo, A and Larsen, E and Salzer, W and Burke, MJ and Loh, ML and Jeha, S and Pui, CH and Inaba, H and Cheng, C and Mullighan, CG}, title = {Heterogeneity of IKZF1 genomic alterations and risk of relapse in childhood B-cell precursor acute lymphoblastic leukemia.}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, pmid = {40360879}, issn = {1476-5551}, support = {P30 CA021765 and R35 CA197695//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; U10 CA98543, U10 CA180886, U10 CA98413, U10 CA180899, U24 CA114766, U24-CA196173//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; CA015704//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; American Society of Hematology Minority Hematology Fellow award//American Society of Hematology (ASH)/ ; }, abstract = {Genomic alterations of IKZF1 are common and associated with adverse clinical features in B-progenitor acute lymphoblastic leukemia (B-ALL). The relationship between the type of IKZF1 alteration, B-ALL genomic subtype and outcome are incompletely understood. B-ALL subtype and genomic alterations were determined using transcriptome and genomic sequencing, and SNP microarray analysis in 688 pediatric patients with B-ALL in the St. Jude Total Therapy XV and 16 studies. IKZF1 alterations were identified in 115 (16.7%) patients, most commonly in BCR::ABL1 (78%) and CRLF2-rearranged, BCR::ABL1-like B-ALL (70%). These alterations were associated with 5-year cumulative incidence of relapse (CIR) of 14.8 ± 3.3% compared to 5.0 ± 0.9% for patients without any IKZF1 alteration (P < 0.0001). In separate multivariable analyses adjusting for genetic subtype groups and other factors, IKZF1 deletions of exons 4-7 (P = 0.0002), genomic IKZF1[plus] with any IKZF1 deletion (P = 0.006) or with focal IKZF1 deletion (P = 0.0007), and unfavorable genomic subtypes (P < 0.005) were independently adverse prognostic factors. Associations of genomic IKZF1[plus] and exon 4-7 deletions with adverse outcomes were confirmed in an independent cohort. The type of IKZF1 alteration, together with the subtype, are informative for risk stratification and to predict response in patients with B-ALL.}, }
@article {pmid40359708, year = {2025}, author = {Gouda, MA and Voss, MH and Tawbi, H and Gordon, M and Tykodi, SS and Lam, ET and Vaishampayan, U and Tannir, NM and Chaves, J and Nikolinakos, P and Fan, A and Lee, R and McDermott, D and Shapiro, GI and Gandhi, L and Bhatia, S and Katragadda, V and Meric-Bernstam, F}, title = {A phase I/II study of the safety and efficacy of telaglenastat (CB-839) in combination with nivolumab in patients with metastatic melanoma, renal cell carcinoma, and non-small-cell lung cancer.}, journal = {ESMO open}, volume = {10}, number = {5}, pages = {104536}, doi = {10.1016/j.esmoop.2025.104536}, pmid = {40359708}, issn = {2059-7029}, abstract = {BACKGROUND: Telaglenastat (CB-839) is a glutaminase 1 inhibitor that targets the dysregulation in glutamine metabolism in cancer cells and the tumor microenvironment. Preclinical data suggested that the combination of telaglenastat with programmed cell death protein 1 (PD-1) or programmed cell death-ligand 1 (PD-L1) antibodies can lead to enhanced immune response against cancer.<br><br>PATIENTS AND METHODS: We designed a phase I/II trial to investigate the safety and efficacy of telaglenastat combined with nivolumab in patients with advanced solid tumors. Dose escalation was carried out using a 3 + 3 design with two dose levels for telaglenastat (600 mg and 800 mg twice daily). Nivolumab was given at a fixed dose of 240 mg by intravenous infusion on days 1 and 15 of a 28-day cycle in all patients. Expansion in phase II was planned using Simon's two-stage design in disease- and prior therapy-specific cohorts.<br><br>RESULTS: We included a total of 118 patients across different cohorts. The most frequently reported adverse events were fatigue (42.4%; n = 50), nausea (39%; n = 46), and photophobia (32.2%; n = 38). In the response-assessable analysis set (including 107 patients in dose expansion and recommended phase II dose of dose escalation), the overall response rate (ORR) was 8.4% (n = 9). The ORR was 24% in 25 patients with clear-cell renal cell carcinoma (ccRCC) who were checkpoint inhibitor-na&#xef;ve, 5.9% in 17 patients with ccRCC after nivolumab, 0% in 9 patients with ccRCC after other prior anti-PD-1/PD-L1, 5.4% in 37 patients with melanoma after anti-PD-1/PD-L1, and 0% in 19 patients with non-small-cell lung cancer after anti-PD-1/PD-L1.<br><br>CONCLUSIONS: Telaglenastat in combination with nivolumab was generally well tolerated. The combination did not show a pattern of efficacy across different study cohorts.}, }
@article {pmid40359110, year = {2025}, author = {Gen, R and Addetia, A and Asarnow, D and Park, YJ and Quispe, J and Chan, MC and Brown, JT and Lee, J and Campbell, MG and Lapointe, CP and Veesler, D}, title = {SARS-CoV-2 nsp1 mediates broad inhibition of translation in mammals.}, journal = {Cell reports}, volume = {44}, number = {5}, pages = {115696}, doi = {10.1016/j.celrep.2025.115696}, pmid = {40359110}, issn = {2211-1247}, abstract = {Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) non-structural protein 1 (nsp1) promotes innate immune evasion by inhibiting host translation in human cells. However, the role of nsp1 in other host species remains elusive, especially in bats-natural reservoirs of sarbecoviruses with a markedly different innate immune system than humans. We reveal that nsp1 potently inhibits translation in Rhinolophus lepidus bat cells, which belong to the same genus as known sarbecovirus reservoir hosts. We determined a cryoelectron microscopy structure of nsp1 bound to the R. lepidus 40S ribosomal subunit, showing that it blocks the mRNA entry channel by targeting a highly conserved site among mammals. Accordingly, we found that nsp1 blocked protein translation in mammalian cells from several species, underscoring its broadly inhibitory activity and conserved role in numerous SARS-CoV-2 hosts. Our findings illuminate the arms race between coronaviruses and mammalian host immunity, providing a foundation for understanding the determinants of viral maintenance in bat hosts and spillover.}, }
@article {pmid40358923, year = {2025}, author = {Yorke, AA and Schandorf, MT and Quaye, ANM and Twum, PT and Sengupta, B and Nkansah-Poku, K and Kplorfia, JA and Fagestrom, J}, title = {Empowering young minds through STEM education: Engaging high schoolers in Ghana through medical physics.}, journal = {Journal of applied clinical medical physics}, volume = {}, number = {}, pages = {e70126}, doi = {10.1002/acm2.70126}, pmid = {40358923}, issn = {1526-9914}, abstract = {PURPOSE: To promote diversity in Science, Technology, Engineering, and Mathematics (STEM), an educational presentation and hands-on session was organised to raise awareness of STEM career opportunities among high school girls to introduce the students to the field of medical physics.<br><br>MATERIALS AND METHODS: The study involved 65 first-year Senior High School girls, aged 13-16, pursuing general science in Accra, Ghana. This initiative, organised by the Girls Excellence Movement (GEM) in collaboration with a United States (US) institution, implemented the "heroes in radiation oncology" program, which included a relatable presentation and hands-on experience in simulation to treatment planning activities. The program's effectiveness was assessed through pre-and post-assessment surveys, and a thematic analysis of student feedback.<br><br>RESULTS: Participants' awareness of career fields showed an interest in traditional healthcare professions (92%) and engineering (73.8%), with minimal medical physics awareness (12.3%). Post-presentation survey showed a significant change in participants' perception of medical physics 87.3%. Thematic analysis revealed increased awareness, understanding, and interest, dispelled misconceptions about radiation safety, and highlighted the interdisciplinary nature and career opportunities. The presentation was successful in inspiring participants and expanding their perspectives on medical physics.<br><br>CONCLUSION: The program raised awareness of medical physics among participants, many of whom were previously unfamiliar with the field. Participants reported a newfound understanding of the interdisciplinary nature of medical physics, its connections to biology, mathematics, and engineering.This program can easily be reproduced in community and school outreaches.}, }
@article {pmid40358803, year = {2025}, author = {Krisch, JM and Ermoian, RP and Indelicato, DJ and Lee, JY and Perentesis, JP and Perkins, SM and Laack, NN and Chang, JH and MacEwan, IJ and Wolden, SL and Wang, D and Yock, TI and Aridgides, PD}, title = {Outcomes following radiation therapy for embryonal tumor with multilayered rosettes (ETMR): results from the Pediatric Proton/Photon Consortium Registry (PPCR).}, journal = {Journal of neuro-oncology}, volume = {}, number = {}, pages = {}, pmid = {40358803}, issn = {1573-7373}, abstract = {PURPOSE: Embryonal tumor with multilayered rosettes (ETMR) is a rare pediatric CNS embryonal tumor with poor survival. The Pediatric Proton/Photon Consortium Registry (PPCR) was queried for outcomes data from prospectively consenting pediatric patients with ETMR treated with proton radiation therapy (RT).<br><br>METHODS: 20 patients (2013-2021) at 9 institutions had ETMR; 2 with prior RT were excluded from statistical analyses (PPCR ETMR, N&#x2009;=&#x2009;18). Overall Survival (OS) and Event Free Survival (EFS) analyses were performed using the Kaplan-Meier method and log-rank values. Median follow-up was calculated using the reverse Kaplan-Meier method.<br><br>RESULTS: Median age at RT was 3.0 years (1.7-12.2); median follow-up was 55.5 months (2.6-119.4). 8 patients (44%) expired and 6 patients (33%) are surviving&#x2009;&#x2265;&#x2009;55 months. 11 (61%) patients received systemic therapy with stem cell support. The majority (89%) had focal RT (median dose 54&#xa0;Gy), while 2 patients received craniospinal irradiation (CSI, 30.6-36&#xa0;Gy). 4-year OS and EFS were 59.6% and 54.2%, respectively. Local control (LC) at 4 years was 81%. No differences in OS or EFS were observed for receipt of systemic therapy with stem cell support (p&#x2009;=&#x2009;0.361, p&#x2009;=&#x2009;0.57), progression prior to RT (p&#x2009;=&#x2009;0.127, p&#x2009;=&#x2009;0.18), or surgery to RT&#x2009;&#x2265;&#x2009;200 days (p&#x2009;=&#x2009;0.35, p&#x2009;=&#x2009;0.254). Symptomatic radionecrosis was not reported.<br><br>CONCLUSION: Focal proton RT provided effective local control as part of multimodality therapy for ETMR, with encouraging survival for this rare and often infant age tumor. Outcomes for CSI were limited to 2 patients treated upfront, and 1 patient receiving salvage CSI for disseminated relapse after focal RT who is surviving&#x2009;>&#x2009;1 year.<br><br>TRIAL REGISTRATION: DFCI protocol 12-103, clinicaltrials.gov NCT01696721, date of registration 9/27/2012.}, }
@article {pmid40357548, year = {2025}, author = {Blair, KM and Bohinc, DJ and Bane, KL and Warnock, M and Abuaita, B and Gura, C and Grinsztejn, E and Marshall, SH and Wilson, BM and Bonomo, RA and Tambralli, A and Knight, JS and O'Riordan, MX and Lawrence, DA and Stavrou, EX and Sandkvist, M}, title = {Acinetobacter Baumannii Secreted Protease CpaA Inhibits Factor XII-Mediated Bradykinin Generation and Neutrophil Activation.}, journal = {Circulation research}, volume = {}, number = {}, pages = {}, doi = {10.1161/CIRCRESAHA.124.324764}, pmid = {40357548}, issn = {1524-4571}, abstract = {BACKGROUND: FXII (coagulation factor XII) is best known for its roles in the contact and kallikrein-kinin pathways. FXII is converted to its active enzyme (FXIIa [activated factor XII]) by PKa (plasma kallikrein) or its unique ability to autoactivate on bacterial or other biologic surfaces. In vivo, FXIIa initiates the intrinsic coagulation pathway and promotes inflammation by reciprocal activation of prekallikrein, which cleaves HK (high-molecular-weight kininogen) to liberate bradykinin. CpaA (coagulation targeting metallo-endopeptidase of A baumannii) is a secreted metalloprotease identified in a human clinical isolate of Acinetobacter baumannii that cleaves FXII at O-linked glycosylated sites, inhibiting contact activation. While CpaA facilitates a modest in vivo fitness advantage in mice, the role of CpaA in human infection remains unclear. As such, the objectives of this study were to characterize the structural details of the interaction between CpaA, FXII, and the KKSs (kallikrein-kinin systems) and to determine the downstream consequences on thromboinflammatory responses.<br><br>METHODS: The effect of purified CpaA on the coagulant activity of FXII and the generation of bradykinin was characterized. Neutrophil signaling, flow cytometry, and functional assays were performed to define how CpaA-mediated cleavage of FXII affects innate immune functions. Bacterial killing by human neutrophils was performed with wild-type and mutant A baumannii strains lacking CpaA.<br><br>RESULTS: We found that CpaA cleaves both FXII zymogen and FXIIa but not beta Factor XII. However, cleavage of FXIIa by CpaA does not significantly inhibit its clotting activity, demonstrating that CpaA does not inactivate FXIIa, but rather prevents activation of zymogen FXII. CpaA also cleaves HK, resulting in reduced kallikrein activation and bradykinin generation. We previously identified that zymogen FXII interacts with the urokinase receptor on neutrophils and upregulates neutrophil activation. Here, we demonstrate that CpaA cleaves neutrophil FXII, resulting in reduced Akt2 phosphorylation, chemotaxis, oxidative burst, and neutrophil extracellular trap formation. Importantly, CpaA decreases the human neutrophil killing efficiency of A baumannii in culture.<br><br>CONCLUSIONS: These data identify a role for FXII in responding to bacterial infection and suggest that by inhibiting the contact and KKSs and impairing neutrophil activation, CpaA may blunt the innate immune response and help prevent the elimination of A baumannii from the human host.}, }
@article {pmid40357217, year = {2025}, author = {Kuczmarski, TM and Lynch, RC}, title = {Optimizing therapy for relapsed/refractory classic Hodgkin lymphoma in the era of PD-1 blockade.}, journal = {HemaSphere}, volume = {9}, number = {5}, pages = {e70110}, pmid = {40357217}, issn = {2572-9241}, }
@article {pmid40355027, year = {2025}, author = {Phelan, R and Rotz, S and Dandoy, CE and Auletta, JJ and Badia, P and Bhatt, NS and Ballard, SA and Blacken, R and Daraiseh, NM and Desmond, C and Dunseath, C and Epling, P and Flesch, L and Huber, J and Jenssen, K and Kapadia, M and Kent, G and Klunk, A and Kusnier, K and Lehmann, L and Liberio, N and Maier, S and Myers, KC and O'Connor, G and Pai, A and Tarquini, S and Fitch, TJ and Hartley, D}, title = {Multicenter Study on Caregiver Experiences in Pediatric Hematopoietic Stem Cell Transplantation: Part II. Treatment Challenges, Communication Barriers, and Caregiver-Driven Approaches to Mitigation.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.04.012}, pmid = {40355027}, issn = {2666-6367}, abstract = {Hematopoietic stem cell transplantation (HSCT) is a life-saving yet complex treatment for pediatric patients that introduces significant physical, emotional, and logistical challenges for caregivers. This multicenter, prospective qualitative longitudinal study explored caregiver experiences across four time points: pre-transplant (n=47), 30 days post-transplant (n=43), 100 days post-transplant (n=34), and six months post-transplant (n=26). Forty-nine caregivers participated in semi-structured interviews, which were transcribed and thematically analyzed. This manuscript encompasses the following themes that emerged from the interviews: treatment-related side effects and complications, communication gaps, and the impact of the COVID-19 pandemic. Caregiver priorities evolved over time, shifting from managing acute complications such as pain, infections, mucositis, and medication administration to addressing longer-term concerns like developmental delays, nutritional rehabilitation, and psychosocial adaptation. Caregivers reported challenges such as information overload, inconsistent messaging, and limited preparation for transitions in care. They employed various strategies to cope, including advocacy, peer support, and the use of healthcare team resources. These findings highlight the importance of stage-specific, tailored interventions to support caregivers throughout the HSCT journey. Clear communication, accessible education, and coordinated multidisciplinary care are essential to fostering caregiver resilience and improving patient and family-centered outcomes.}, }
@article {pmid40350587, year = {2025}, author = {Sala, M and Roos, CR and Kober, H and Bricker, JB and Stern, CM and Plutchik, J and John, M and Haeny, AM and Feldman, JM and Aslan, M and Hay, JL and Forman, EM}, title = {Combining Cognitive-Behaviour Therapy With Mindfulness Training in a Digital Intervention for Binge Eating Disorder: A Single-Session Pilot Trial.}, journal = {European eating disorders review : the journal of the Eating Disorders Association}, volume = {}, number = {}, pages = {}, doi = {10.1002/erv.3204}, pmid = {40350587}, issn = {1099-0968}, support = {K23AT012126/AT/NCCIH NIH HHS/United States ; }, abstract = {OBJECTIVE: Delivering a single-session treatment digitally can offer increased accessibility. We developed and tested a single-session digital intervention for binge-eating disorder (BED) combining cognitive behavioural therapy (CBT) and mindfulness training.<br><br>METHOD: English-speaking adults who met criteria for BED were recruited nationally. Participants completed a 60-min digital single-session intervention for BED. Our primary outcome was to evaluate initial acceptability (usability, overall satisfaction, engagement, visual appeal of content, understandability of programme material, desire to continue the programme, and overall helpfulness) and feasibility (intervention completion). We also evaluated changes in binge eating episodes, assessed via the Eating Disorder Examination Questionnaire (EDE-Q) objective binge eating episodes question, and eating disorder symptoms, assessed via the EDE-Q and Binge Eating Scale (BES). Acceptability measures were administered immediately after the completion of the digital module, while the BES and EDE-Q were administered at pre-treatment and at 1-month follow-up.<br><br>RESULTS: All participants (N&#xa0;=&#xa0;21) completed the intervention. Ratings for acceptability were excellent, with averages above a four on a five-point Likert scale on ratings for all dimensions. Participants reported large and significant decreases in binge eating episodes (d&#xa0;=&#xa0;0.86) and BES scores (d&#xa0;=&#xa0;0.91) as well as medium and significant decreases in global eating disorder symptoms at 1-month follow-up (d&#xa0;=&#xa0;0.55).<br><br>DISCUSSION: Results from this pilot suggest promising acceptability and feasibility for a single session of Mindful Courage for BED. This single session also appears to be preliminarily efficacious in reducing binge eating.}, }
@article {pmid40349288, year = {2025}, author = {Mauro, M and Radich, J and Jain, P and Sequeira, D and Bellanti, F and Douer, D}, title = {Pharmacokinetic profile of novel reduced-dose Danziten[™] (nilotinib tablets) versus Tasigna[®] (nilotinib capsules): in vivo bioequivalence and population pharmacokinetic analysis.}, journal = {Cancer chemotherapy and pharmacology}, volume = {95}, number = {1}, pages = {56}, pmid = {40349288}, issn = {1432-0843}, mesh = {Humans ; Therapeutic Equivalency ; Male ; Female ; Tablets ; Adult ; Capsules ; *Pyrimidines/pharmacokinetics/administration &amp; dosage ; Food-Drug Interactions ; Biological Availability ; Models, Biological ; Middle Aged ; Young Adult ; Fasting ; Cross-Over Studies ; Dose-Response Relationship, Drug ; Administration, Oral ; }, abstract = {PURPOSE: To evaluate single dose pharmacokinetics (PK) of novel reduced-dose film coated Danziten[™] (nilotinib tablets) using a population PK approach, establish bioequivalence vs. Tasigna[®] (nilotinib capsules) and investigate food effects on PK of both formulations.<br><br>METHODS: A population PK model evaluating nilotinib capsules (300 or 400&#xa0;mg) or tablets (142 or 190&#xa0;mg) was developed using data from 14 single&#xa0;dose studies and >&#x2009;30,000 plasma samples from healthy men and women. Steady-state nilotinib concentration-time profiles following twice&#xa0;daily dosing with various treatment and food conditions were simulated using a randomly sampled dataset of 50 subjects.<br><br>RESULTS: PK was characterized by a 2-compartment model with linear elimination and zero-order absorption with lag time. Bioequivalence was met for all steady state exposure metrics for both doses under fasted conditions. A milligram strength for nilotinib tablets&#x2009;~&#x2009;50% lower than that for capsules resulted in bioequivalent nilotinib exposures. Administration with a low-fat meal under modified fasting conditions increased the bioavailability (BA) of 142&#xa0;mg and 190&#xa0;mg nilotinib tablets by 26.0% and 29.3%, respectively, vs. fasting; values for 300&#xa0;mg and 400&#xa0;mg capsules were 56.8% and 60.7%. Administration with a high-fat meal under modified fasting conditions increased the BA of 142 and 190&#xa0;mg nilotinib tablets by 48.6% and 52.2%, respectively; values for 300 and 400&#xa0;mg capsules were 180.6% and 183.3%.<br><br>CONCLUSION: Nilotinib tablets 142 and 190&#xa0;mg provide bioequivalent exposures to 300&#xa0;mg and 400&#xa0;mg capsules under fasted conditions and substantially smaller effects of food on exposure.}, }
@article {pmid39670372, year = {2025}, author = {Ramwala, OA and Lowry, KP and Hippe, DS and Unrath, MPN and Nyflot, MJ and Mooney, SD and Lee, CI}, title = {ClinValAI: A framework for developing Cloud-based infrastructures for the External Clinical Validation of AI in Medical Imaging.}, journal = {Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing}, volume = {30}, number = {}, pages = {215-228}, doi = {10.1142/9789819807024_0016}, pmid = {39670372}, issn = {2335-6936}, mesh = {Humans ; *Cloud Computing ; *Algorithms ; *Computational Biology ; Female ; *Artificial Intelligence ; *Diagnostic Imaging/standards/statistics &amp; numerical data ; Workflow ; Mammography/statistics &amp; numerical data/standards/methods ; Breast Neoplasms/diagnostic imaging ; Validation Studies as Topic ; }, abstract = {Artificial Intelligence (AI) algorithms showcase the potential to steer a paradigm shift in clinical medicine, especially medical imaging. Concerns associated with model generalizability and biases necessitate rigorous external validation of AI algorithms prior to their adoption into clinical workflows. To address the barriers associated with patient privacy, intellectual property, and diverse model requirements, we introduce ClinValAI, a framework for establishing robust cloud-based infrastructures to clinically validate AI algorithms in medical imaging. By featuring dedicated workflows for data ingestion, algorithm scoring, and output processing, we propose an easily customizable method to assess AI models and investigate biases. Our novel orchestration mechanism facilitates utilizing the complete potential of the cloud computing environment. ClinValAI's input auditing and standardization mechanisms ensure that inputs consistent with model prerequisites are provided to the algorithm for a streamlined validation. The scoring workflow comprises multiple steps to facilitate consistent inferencing and systematic troubleshooting. The output processing workflow helps identify and analyze samples with missing results and aggregates final outputs for downstream analysis. We demonstrate the usability of our work by evaluating a state-of-the-art breast cancer risk prediction algorithm on a large and diverse dataset of 2D screening mammograms. We perform comprehensive statistical analysis to study model calibration and evaluate performance on important factors, including breast density, age, and race, to identify latent biases. ClinValAI provides a holistic framework to validate medical imaging models and has the potential to advance the development of generalizable AI models in clinical medicine and promote health equity.}, }
@article {pmid40347455, year = {2025}, author = {Schenk, JM and Gulati, R and Beatty, SJ and Plymate, S and Lin, DW and Dash, A and Porter, MP and Vandoren, M and Wright, JL and Neuhouser, ML}, title = {Reduced adipose tissue with limited loss of lean mass after weight loss: results from the Prostate Active Lifestyle Study.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djaf113}, pmid = {40347455}, issn = {1460-2105}, abstract = {Adiposity reduction has both cancer-specific and overall health benefits for patients with overweight or obesity. However, the indiscriminate loss of lean mass accompanying weight loss remains a concern for older cancer patients. Body composition was evaluated in the Prostate Active Lifestyle Study, a randomized controlled weight loss trial targeting caloric restriction and increased physical activity among patients with prostate cancer (PCa) and overweight or obesity on active surveillance. Compared to control, the intervention statistically significantly decreased total fat (-3.4%; 95%CI: -5.3%, -1.5%), android fat (-2.0%; 95%CI: -3.6%, -0.4%), and visceral adipose tissue mass (-613 g; 95%CI: -894 g, -331 g) (all 2-sided p < .001) with no difference in lean mass (p = .70) and a statistically significant increase in lean-to-fat ratio (0.40; 95%CI: 0.06, 0.73; 2-sided p = .02). Weight loss interventions incorporating diet and physical activity among patients with PCa and overweight or obesity can yield statistically significant reductions in adiposity while limiting lean mass loss.}, }
@article {pmid40346049, year = {2025}, author = {Pasvolsky, O and Dima, D and Feng, L and Dong, W and Richards, T and Davis, JA and Afrough, A and Vazquez-Martinez, M and Sannareddy, A and Goel, U and Banerjee, R and Khouri, J and Cervoni, F and Gaballa, MR and Lieberman-Cribbin, A and Rana, MS and Julian, K and Ferreri, CJ and Shune, L and DeJarnette, S and Bhurtel, E and Susanibar Adaniya, S and Portuguese, A and Hosoya, H and Mikkilineni, L and Kaur, G and Rossi, A and Herr, MM and Schrum, D and Lin, C and Raza, S and Lin, Y and Midha, S and Omar, N and Atarsh, S and McGuirk, J and Sborov, D and Voorhees, P and Anwer, F and Alsina, M and Freeman, C and Garfall, AL and Razzo, BM and Sidana, S and Cowan, AJ and Anderson, LD and Hansen, DK and Richard, S and Patel, KK and Lee, HC and Grajales-Cruz, A}, title = {Outcomes of elderly patients with relapsed refractory multiple myeloma (RRMM) treated with teclistamab: a multicenter study from the U.S. Multiple Myeloma Immunotherapy Consortium.}, journal = {Blood cancer journal}, volume = {15}, number = {1}, pages = {92}, pmid = {40346049}, issn = {2044-5385}, support = {P30 CA016672/CA/NCI NIH HHS/United States ; R01 CA281756/CA/NCI NIH HHS/United States ; NCI Grant P30 CA016672//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; NCI (R01CA281756-01A1)//U.S. Department of Health &amp; Human Services | NIH | NIH Clinical Center (Clinical Center)/ ; }, mesh = {Humans ; *Multiple Myeloma/drug therapy/mortality/pathology ; Aged ; Male ; Female ; Aged, 80 and over ; Middle Aged ; Retrospective Studies ; *Antibodies, Bispecific/therapeutic use/adverse effects/administration &amp; dosage ; Treatment Outcome ; United States ; Adult ; *Antineoplastic Agents, Immunological/therapeutic use/adverse effects ; Age Factors ; }, abstract = {Teclistamab, a BCMA-directed bispecific antibody, received regulatory approval for relapsed/refractory multiple myeloma (RRMM) based on the MajesTEC-1 study. Despite the fact that myeloma is primarily a cancer of elderly adults, only 15% of MajesTEC-1 participants (n = 24) were ≥75 years old. In this multicenter retrospective study, we report real-world outcomes of a large cohort of older RRMM patients treated with teclistamab. Of 385 analyzed patients, 83 (22%) were in the older group (age ≥75) and 302 (78%) in the younger group (age <75). Compared to the younger group, the older group had less adverse baseline disease characteristics, including a lower incidence of high-risk cytogenetics (44.6% vs. 57.9%, p = 0.03) and extramedullary disease (22% vs. 40%, p = 0.02). There were no significant differences in rates of any-grade CRS (52% vs. 59%, p = 0.27), any-grade ICANS (19% vs. 13%, p = 0.12), and overall response rate (62% vs. 53%, p = 0.17) between the older and younger groups. In multivariable analysis, age was not significantly associated with survival outcomes. Our findings suggest that teclistamab is safe and efficacious in well-selected patients ≥75 years old, and advanced age alone should not preclude teclistamab administration.}, }
@article {pmid40346033, year = {2025}, author = {Mihalas, AB and Arora, S and O'Connor, SA and Feldman, HM and Cucinotta, CE and Mitchell, K and Bassett, J and Kim, D and Jin, K and Hoellerbauer, P and Delegard, J and Ling, M and Jenkins, W and Kufeld, M and Corrin, P and Carter, L and Tsukiyama, T and Aronow, B and Plaisier, CL and Patel, AP and Paddison, PJ}, title = {KAT5 regulates neurodevelopmental states associated with G0-like populations in glioblastoma.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {4327}, pmid = {40346033}, issn = {2041-1723}, support = {R01 CA295090/CA/NCI NIH HHS/United States ; R01 CA190957/CA/NCI NIH HHS/United States ; S10 OD026919/OD/NIH HHS/United States ; R01CA190957//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P30 CA015704/CA/NCI NIH HHS/United States ; R01NS119650//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R35 GM139429/GM/NIGMS NIH HHS/United States ; T32CA080416//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R21 CA232244/CA/NCI NIH HHS/United States ; R01 NS119650/NS/NINDS NIH HHS/United States ; P30CA15704//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; T32 CA080416/CA/NCI NIH HHS/United States ; }, mesh = {*Glioblastoma/pathology/genetics/metabolism ; Humans ; *Histone Acetyltransferases/metabolism/genetics ; *Brain Neoplasms/pathology/genetics/metabolism ; Cell Line, Tumor ; Neoplastic Stem Cells/metabolism/pathology ; Animals ; Gene Expression Regulation, Neoplastic ; Neural Stem Cells/metabolism ; Mice ; Cell Proliferation ; Proto-Oncogene Proteins c-myc/metabolism/genetics ; }, abstract = {Quiescence cancer stem-like cells may play key roles in promoting tumor cell heterogeneity and recurrence for many tumors, including glioblastoma (GBM). Here we show that the protein acetyltransferase KAT5 is a key regulator of transcriptional, epigenetic, and proliferative heterogeneity impacting transitions into G0-like states in GBM. KAT5 activity suppresses the emergence of quiescent subpopulations with neurodevelopmental progenitor characteristics, while promoting GBM stem-like cell (GSC) self-renewal through coordinately regulating E2F- and MYC- transcriptional networks with protein translation. KAT5 inactivation significantly decreases tumor progression and invasive behavior while increasing survival after standard of care. Further, increasing MYC expression in human neural stem cells stimulates KAT5 activity and protein translation, as well as confers sensitivity to homoharringtonine, to similar levels to those found in GSCs and high-grade gliomas. These results suggest that the dynamic behavior of KAT5 plays key roles in G0 ingress/egress, adoption of quasi-neurodevelopmental states, and aggressive tumor growth in gliomas.}, }
@article {pmid40344957, year = {2025}, author = {Rugo, HS and Bardia, A and Gradishar, WJ and Hamilton, EP and Hurvitz, SA and Jhaveri, K and Mahtani, R and Tolaney, SM}, title = {Expert consensus on treating HR+/HER2- metastatic breast cancer based on real-world practice patterns observed in the RETRACT survey of US oncologists.}, journal = {Breast (Edinburgh, Scotland)}, volume = {82}, number = {}, pages = {104485}, doi = {10.1016/j.breast.2025.104485}, pmid = {40344957}, issn = {1532-3080}, abstract = {Hormone receptor-positive, HER2-negative metastatic breast cancer (HR+/HER2-mBC) is incurable, but recent progress has been made in developing new treatment options and the treatment landscape is rapidly shifting. There are published recommendations for treatment choices and sequencing to help guide oncologists in treating HR+/HER2-mBC, but little evidence has been published regarding real-world practice patterns. The REal-world TReatment patterns And Considerations of Toxicity in HR+/HER2-mBC (RETRACT) survey was designed to evaluate real-world practice patterns in the testing and management of this disease by US oncologists. The survey questions were answered via an online platform and the data were anonymized before analysis. A total of 150 oncologists practicing at academic and community centers completed the survey. The results showed this sample of oncologists largely followed recommended best practices for testing biomarkers, selecting treatments, and managing adverse events. However, several items did show substantial minorities of oncologists not in alignment with recommendations in areas including the definition and treatment of visceral crisis, ideal treatment for patients with endocrine resistance, the routine use of next-generation sequencing for biomarker testing, and the use of prophylactic measures for treatment-related adverse events in patients receiving alpelisib.}, }
@article {pmid40344546, year = {2025}, author = {Check, DK and Li, Z and Shibeika, S and Sloan, CE and Sitlinger, A and Zullig, LL and Graf, SA and Blalock, DV}, title = {Receipt of Alcohol Screening, Brief Intervention, and Treatment Among US Adults With and Without a History of Cancer.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2401030}, doi = {10.1200/OP-24-01030}, pmid = {40344546}, issn = {2688-1535}, abstract = {PURPOSE: Many cancer survivors consume alcohol above recommended limits, increasing their risk of recurrence, second cancers, and cancer-related mortality. Alcohol screening, brief intervention, and referral to treatment (SBIRT) is a guideline-recommended strategy for reducing unhealthy alcohol consumption among adult primary care patients. To our knowledge, no prior studies have evaluated SBIRT's reach among cancer survivors.<br><br>METHODS: We conducted a cross-sectional study of adults who completed the National Survey on Drug Use and Health from 2015 to 2022. We examined past-year receipt of alcohol screening and-among respondents who endorsed unhealthy alcohol use-brief intervention and treatment. All outcomes were examined among cancer survivors and those with no cancer history. We used modified Poisson regression to assess the associations of cancer history with each outcome, adjusting for sociodemographic characteristics.<br><br>RESULTS: The cohort included 86,410 respondents with no history of cancer and 9,963 cancer survivors. The percentages of respondents endorsing past-year receipt of alcohol screening (approximately 40%), brief intervention (approximately 8%), and treatment (approximately 2%) were similarly low in both groups. After adjustment, there was a small but statistically significant difference in alcohol screening, with cancer survivors more likely than people without a history of cancer to receive alcohol screening (adjusted risk ratio [aRR], 1.07; 95% CI, 1.02 to 1.13). Among those with unhealthy alcohol use, cancer survivors were no more or less likely than people without a history of cancer to receive brief alcohol intervention (aRR, 1.00; 95% CI, 0.93 to 1.07) or alcohol treatment (aRR, 0.92; 95% CI, 0.47 to 1.69).<br><br>CONCLUSION: Results reveal an important opportunity to improve SBIRT uptake across the board and especially for cancer survivors, who are at increased risk of alcohol-related adverse health effects and, potentially, more motivated to change cancer-related health behaviors.}, }
@article {pmid40343485, year = {2025}, author = {Yang, H and Luo, K and Peters, BA and Wang, Y and Zhang, Y and Daviglus, M and Pirzada, A and Cordero, C and Yu, B and Burk, RD and Kaplan, R and Qi, Q}, title = {Diet, Gut Microbiota, and Histidine Metabolism Toward Imidazole Propionate Production in Relation to Type 2 Diabetes.}, journal = {Diabetes care}, volume = {}, number = {}, pages = {}, doi = {10.2337/dc24-2816}, pmid = {40343485}, issn = {1935-5548}, support = {R01DK119268/DK/NIDDK NIH HHS/United States ; R01HL140976/HL/NHLBI NIH HHS/United States ; }, abstract = {OBJECTIVE: To examine associations of serum imidazole propionate (ImP), histidine, and their ratio with incident type 2 diabetes (T2D) and related dietary and gut microbial factors in U.S. Hispanic/Latino people.<br><br>RESEARCH DESIGN AND METHODS: In the Hispanic Community Health Study/Study of Latinos, we evaluated serum ImP, histidine, and ImP-to-histidine ratio at baseline (2008-2011) and their cross-sectional associations with dietary intake and prospective associations with incident T2D over &#x223c;12 years (n = 4,632). In a subsample with gut microbiota data during a follow-up visit (2016-2018), we examined gut microbial species associated with serum ImP and their potential interactions with dietary intake.<br><br>RESULTS: Serum ImP and ImP-to-histidine ratio were positively associated with incident T2D (hazard ratio [95% CI] = 1.17 [1.00-1.36] and 1.33 [1.14-1.55], respectively, comparing highest and lowest tertiles), whereas histidine was inversely associated with incident T2D (hazard ratio = 0.75 [95% CI 0.64-0.86]). A higher amount of fiber intake was associated with lower serum ImP level and ImP-to-histidine ratio, whereas histidine intake was not associated with serum ImP level in the overall sample. Fifty-three bacterial species, including 19 putative ImP producers, were associated with serum ImP. Histidine intake was positively associated with serum ImP and ImP-to-histidine ratio only in participants with a high ImP-associated gut microbiota score (P = 0.03 and 0.02, respectively, for interaction). The associations of fiber intake with serum ImP and ImP-to-histidine ratio were partly mediated by ImP-associated gut microbiota (proportion mediated = 31.4% and 19.8%, respectively).<br><br>CONCLUSIONS: This study suggested an unfavorable relationship between histidine metabolism toward ImP production, potentially regulated by dietary intake and gut microbiota, and risk of T2D in U.S. Hispanics/Latino people.}, }
@article {pmid40342410, year = {2025}, author = {Zhang, T and Gentry, CA and Kuderer, NM and Lyman, GH and Ng, B and Michailidou, D}, title = {Association of SSRI and SNRI use with incidence of cardiovascular events in veterans with giant cell arteritis and polymyalgia rheumatica.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1509941}, pmid = {40342410}, issn = {1664-3224}, mesh = {Humans ; *Polymyalgia Rheumatica/drug therapy/epidemiology/complications ; Male ; Female ; Aged ; *Giant Cell Arteritis/drug therapy/epidemiology/complications ; *Selective Serotonin Reuptake Inhibitors/therapeutic use/adverse effects ; Incidence ; Veterans ; *Serotonin and Noradrenaline Reuptake Inhibitors/therapeutic use/adverse effects ; *Cardiovascular Diseases/epidemiology/etiology ; Aged, 80 and over ; Middle Aged ; United States/epidemiology ; }, abstract = {The leading cause of death in patients with giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) is cardiovascular disease. The objective of this study was to determine whether the use of selective serotonin reuptake inhibitors (SSRI) and serotonin norepinephrine reuptake inhibitors (SNRI) in veterans with GCA and PMR could have a cardio-modulatory effect as compared to nonuse. Patients with GCA and PMR were identified through the Veterans Affairs Informatics and Computing Infrastructure. After a 2:1 propensity score matching for SSRI or SNRI users, we identified nonusers with similar covariates. We then applied a multivariate logistic regression (MLR), to calculate the odds ratio (OR) for cardiovascular event (CVE) outcomes within 5 years after the index date. Related hazard ratios (HR) were also calculated to validate the discovery of our findings. We identified 2249 patients with GCA and 3906 patients with PMR. Among patients with GCA, 174 (27%) SSRI users had incident cardiovascular disease as compared to 47 (28%) SNRI users and 277 (19%) nonusers; in the PMR cohort, 108 (13%) were SSRI users compared to 71 (15%) SNRI users and 255 (11%) nonusers. The adjusted ORs of the CVE outcome associated with venlafaxine (2.44, p=0.01) and sertraline (1.45, p=0.04) were significantly greater than 1 in GCA, with similar results observed in the PMR cohort (2.01, p=0.02, and 1.45, p=0.04, respectively). Cox-regression analysis was also conducted, and the hazard ratios were qualitatively consistent with the MLR analysis. In conclusion, the adjusted risk of CVE in patients with GCA or PMR using either venlafaxine or sertraline was higher than that in the non-exposed groups.}, }
@article {pmid40341939, year = {2025}, author = {Byun, J and Han, Y and Choi, J and Sun, R and Shaw, VR and Zhu, C and Xiao, X and Lusk, C and Badr, H and Lee, HS and Jang, HJ and Li, Y and Lim, H and Long, E and Liu, Y and Kachuri, L and Walsh, KM and Wiencke, JK and Albanes, D and Lam, S and Tardon, A and Neuhouser, ML and Barnett, MJ and Chen, C and Bojesen, S and Brenner, H and Landi, MT and Johansson, M and Risch, A and Wichmann, HE and Bickeböller, H and Christiani, DC and Rennert, G and Arnold, S and Field, JK and Shete, S and Le Marchand, L and Liu, G and Andrew, AS and Zienolddiny, S and Grankvist, K and Johansson, M and Caporaso, N and Taylor, F and Lazarus, P and Schabath, MB and Aldrich, MC and Patel, A and Lin, X and Zanetti, KA and Harris, CC and Chanock, S and McKay, J and Schwartz, AG and Hung, RJ and Amos, CI and , }, title = {Genome-wide association study for lung cancer in 6531 African Americans reveals new susceptibility loci.}, journal = {Human molecular genetics}, volume = {}, number = {}, pages = {}, doi = {10.1093/hmg/ddaf059}, pmid = {40341939}, issn = {1460-2083}, support = {U19CA203654//the National Institutes of Health (NIH)/ ; RR170048//Cancer Prevention Research Interest of Texas (CPRIT)/ ; }, abstract = {Despite lung cancer affecting all races and ethnicities, disparities are observed in incidence and mortality rates among different ethnic groups in the United States. Non-Hispanic African Americans had a high incidence rate of lung cancer at 55.8 per 100 000 people, as well as the highest death rate at 37.2 per 100 000 people from 2016 to 2020. While previous genome-wide association studies (GWAS) have identified over 45 susceptibility risk loci that influence lung cancer development, few GWAS have investigated the etiology of lung cancer in African Americans. To address this gap in knowledge, we conducted GWAS of lung cancer focused on studying African Americans, comprising 2267 lung cancer cases and 4264 controls. We identified three loci associated with lung cancer, one with lung adenocarcinoma, and four with lung squamous cell carcinoma in this population at the genomic-wide significance level. Among them, three novel loci were identified near VWF at 12p13.31 for overall lung cancer and GACAT3 at 2p24.3 and LMAN1L at 15q24.1 for lung squamous cell carcinoma. In addition, we confirmed previously reported risk loci with known or new lead variants near CHRNA5 at 15q25.1 and CYP2A6 at 19q13.2 associated with lung cancer and TRIP13 at 5p15.33 and ERC1 at 12p13.33 associated with lung squamous cell carcinoma. Further multi-step functional analyses shed light on biological mechanisms underlying these associations of lung cancer in this population. Our study highlights the importance of ancestry-specific studies for the potential alleviation of lung cancer burden in African Americans.}, }
@article {pmid40341199, year = {2025}, author = {Ajani, JA and D'Amico, TA and Bentrem, DJ and Corvera, CU and Das, P and Enzinger, PC and Enzler, T and Gerdes, H and Gibson, MK and Grierson, P and Gupta, G and Hofstetter, WL and Ilson, DH and Jalal, S and Kim, S and Kleinberg, LR and Klempner, S and Lacy, J and Lee, B and Licciardi, F and Lloyd, S and Ly, QP and Matsukuma, K and McNamara, M and Merkow, RP and Miller, AM and Mukherjee, S and Mulcahy, MF and Perry, KA and Pimiento, JM and Reddi, DM and Reznik, S and Roses, RE and Strong, VE and Su, S and Uboha, N and Wainberg, ZA and Willett, CG and Woo, Y and Yoon, HH and McMillian, NR and Stein, M}, title = {Gastric Cancer, Version 2.2025, NCCN Clinical Practice Guidelines In Oncology.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {23}, number = {5}, pages = {169-191}, doi = {10.6004/jnccn.2025.0022}, pmid = {40341199}, issn = {1540-1413}, mesh = {Humans ; *Stomach Neoplasms/therapy/diagnosis/pathology/mortality ; *Medical Oncology/standards/methods ; Biomarkers, Tumor/analysis ; Prognosis ; Neoplasm Staging ; }, abstract = {Gastric cancer is the fifth leading cause of cancer-related deaths worldwide. Over 95% of gastric cancers are adenocarcinomas, which are typically classified based on anatomic location and histologic type. Gastric cancer generally carries a poor prognosis because it is often diagnosed at an advanced stage. Systemic therapy can provide palliation, improve survival, and enhance the quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing has had a significant impact on clinical practice and patient care. Targeted therapies have demonstrated encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. This selection from the NCCN Clinical Practice Guidelines in Oncology for Gastric Cancer highlights recommendations for biomarker testing and discusses updates for the treatment of advanced disease, including peritoneal carcinoma as only disease and unresectable locally advanced, recurrent, or metastatic disease.}, }
@article {pmid40341193, year = {2025}, author = {Tsang, TK and Rojas, DP and Xu, F and Xu, Y and Zhu, X and Halloran, ME and Longini, IM and Yang, Y}, title = {Estimating transmissibility of Zika virus in Colombia in the presence of surveillance bias.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {4299}, pmid = {40341193}, issn = {2041-1723}, mesh = {Humans ; *Zika Virus Infection/transmission/epidemiology/virology ; Colombia/epidemiology ; Female ; Adolescent ; Male ; Adult ; *Zika Virus/physiology ; Young Adult ; Bayes Theorem ; Disease Outbreaks ; Middle Aged ; Child ; Population Surveillance ; Bias ; Microcephaly/epidemiology/virology ; }, abstract = {The 2015-2016 Zika virus outbreak in the Americas presented significant challenges in understanding the transmission dynamics due to substantial reporting biases, as women of reproductive age (15-39 years) were disproportionately represented in the surveillance data when public awareness of relationship between Zika and microcephaly increased. Using national surveillance data from Colombia during July 27, 2015-November 21, 2016, we developed a Bayesian hierarchical modeling framework to reconstruct the true numbers of symptomatic cases and estimate transmission parameters while accounting for differential reporting across age-sex groups. Our model revealed that the detection rate of symptomatic cases among women of reproductive age was 99% (95% CI: 98.7-100), compared to 85.4% (95% CI: 84.7-86.1) in other demographic groups. After correcting for these biases, our results showed that females aged 15-39 years remained 82.8% (95% CI: 80.2-85.2%) more susceptible to Zika symptomatic infection than males of the same age, independent of differential reporting areas. Departments with medium-high altitude, medium-high population density, low coverage of forest, or high dengue incidence from 2011-2015 exhibited greater Zika risk. This study underscores the importance of accounting for surveillance biases in epidemiological studies to better understand factors influencing Zika transmission and to inform disease control and prevention.}, }
@article {pmid40340857, year = {2025}, author = {Kumar, SK and Callander, NS and Adekola, K and Anderson, LD and Baljevic, M and Baz, R and Campagnaro, E and Costello, C and D'Angelo, C and Derman, B and Devarakonda, S and Elsedawy, N and Godara, A and Godby, K and Hillengass, J and Holmberg, L and Htut, M and Huff, CA and Hultcrantz, M and Kang, Y and Larson, S and Lee, HC and Liedtke, M and Martin, T and Omel, J and Robinson, T and Rosenberg, A and Schroeder, MA and Sherbenou, D and Suvannasankha, A and Valent, J and Varshavsky-Yanovsky, AN and Vogl, D and Kovach, E and Kumar, R}, title = {NCCN Guidelines® Insights: Multiple Myeloma, Version 1.2025.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {23}, number = {5}, pages = {132-140}, doi = {10.6004/jnccn.2025.0023}, pmid = {40340857}, issn = {1540-1413}, mesh = {Humans ; *Multiple Myeloma/diagnosis/therapy ; *Medical Oncology/standards ; }, abstract = {The NCCN Guidelines for Multiple Myeloma (MM) provide recommendations for diagnosis, initial workup, treatment, follow-up, and supportive care for patients with MM. These NCCN Guidelines Insights highlight the important updates and changes specific to systemic therapy for patients with newly diagnosed as well as previously treated MM included in Version 1.2025 of the NCCN Guidelines for MM.}, }
@article {pmid40340130, year = {2025}, author = {Ujjani, C and Wang, H and Broome, C and Gopal, AK and Smith, SD and Lai, C and Shadman, M and Leslie, L and Warren, EH and Lynch, R and Swanson, N and Grossfeld, T and Cheson, BD and Dunleavy, K}, title = {Ibrutinib and Venetoclax in Relapsed and Refractory Follicular Lymphoma.}, journal = {Clinical lymphoma, myeloma &amp; leukemia}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.clml.2025.04.004}, pmid = {40340130}, issn = {2152-2669}, abstract = {BACKGROUND: Bruton tyrosine kinase (BTK) inhibitors are approved in several B-cell malignancies, including the recent authorization of zanubrutinib for relapsed or refractory follicular lymphoma (FL).<br><br>METHODS: Based on preclinical studies demonstrating synergy with ibrutinib and the B-cell lymphoma (BCL)-2 inhibitor, venetoclax, in FL cell lines, we conducted a multicenter phase Ib/II study evaluating this combination in relapsed or refractory FL.<br><br>RESULTS: The recommended phase 2 dose was ibrutinib 560 mg and venetoclax 600 mg. There was no evidence of clinical tumor lysis syndrome, despite the omission of a venetoclax ramp up. At a median duration of therapy of 6 months, the most common adverse events were low grade diarrhea (83%), infection (75%), and rash (58%). Amongst the 24 patients enrolled, the overall and complete response (CR) rates were 63% and 21%. At a median follow up of 6.9 months, the median progression-free survival was 8.2 months, and the median duration of CR (n = 5) was 38 months.<br><br>CONCLUSION: The combination of a BTK and BCL2 inhibitor is efficacious in relapsed/refractory FL and represents a unique dual-targeted approach warranting further investigation.}, }
@article {pmid40339592, year = {2025}, author = {Escrivá-de-Romani, S and Cejalvo, JM and Alba, E and Friedmann, J and Rodríguez-Lescure, &#xc1; and Savard, MF and Pezo, RC and Gion, M and Ruiz-Borrego, M and Hamilton, E and Pluard, T and Webster, M and Beeram, M and Linden, H and Saura, C and Shpektor, D and Salim, B and Harvey, P and Hurvitz, SA}, title = {Zanidatamab plus palbociclib and fulvestrant in previously treated patients with hormone receptor-positive, HER2-positive metastatic breast cancer: primary results from a two-part, multicentre, single-arm, phase 2a study.}, journal = {The Lancet. Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/S1470-2045(25)00140-8}, pmid = {40339592}, issn = {1474-5488}, abstract = {BACKGROUND: New HER2-targeted regimens, including chemotherapy-free options, are needed for metastatic breast cancer. In an ongoing, two-part, phase 2a study, we assessed the safety and antitumour activity of zanidatamab, a HER2-targeted bispecific antibody, plus palbociclib and fulvestrant, in heavily pretreated patients with hormone receptor-positive, HER2-positive advanced or metastatic breast cancer.<br><br>METHODS: This multicentre, single-arm, two-part, phase 2a study is being conducted at 13 university hospitals, cancer centres, or research institutes in Spain, Canada, and the USA. Eligible patients were adults (aged &#x2265;18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1, and with pathologically confirmed unresectable or metastatic breast cancer, assessed locally to be hormone receptor-positive and HER2-positive, with disease progression during or after previous HER2-targeted therapies. Patients were enrolled in part 1, part 2, or part 1 followed by part 2. In part 1, patients received starting doses of zanidatamab (20 mg/kg intravenously once every 2 weeks on days 1 and 15 of a 28-day cycle) with palbociclib (125 mg orally once a day on days 1-21 of each cycle) and fulvestrant (500 mg intramuscular injection once every 2 weeks for the first three doses [cycle 1: days 1 and 15, cycle 2: day 1], then once every 4 weeks [all subsequent cycles: day 1]). In part 1, primary endpoints were safety of the triplet combination and confirmation of recommended doses for part 2. In part 2, patients received the recommended doses confirmed in part 1, and the primary endpoint was progression-free survival at 6 months. Safety and progression-free survival were assessed in all enrolled patients who received any dose of zanidatamab, palbociclib, or fulvestrant. Patients in part 1 who were treated at the recommended doses were analysed together with the patients in part 2. This study is registered with ClinicalTrials.gov, NCT04224272, and is active with recruitment completed.<br><br>FINDINGS: Overall, 51 patients (49 [96%] female and two [4%] male; median age 54&#xb7;0 [46&#xb7;0-62&#xb7;0] years; 42 [82%] White) were enrolled: eight in part 1 (June 10, 2020-Feb 7, 2021) and 43 in part 2 (Feb 8, 2021-Oct 31, 2022). All 51 patients had received study treatment at the data cutoff (Aug 3, 2023); median follow-up was 16&#xb7;1 months (IQR 9&#xb7;9-23&#xb7;4) and the median duration of triplet regimen treatment was 7&#xb7;4 months (3&#xb7;4-14&#xb7;8). The median number of previous HER2-targeted therapies was 4 (IQR 3-4). 12 (24%) of 51 patients had previously received trastuzumab deruxtecan. The planned starting drug doses administered in part 1 of the study were confirmed as the recommended doses for part 2. All 51 patients were treated at the recommended doses. All 51 patients had at least one treatment-related adverse event of any grade, with diarrhoea being the most common (41 [80%] patients, with 34 [67%] having grade 1-2 events). Grade 3 or 4 treatment-related adverse events occurred in 34 (67%) patients, with neutropenia being the most common (26 [51%] patients). One (2%) patient had a serious grade 3 treatment-related adverse event of increased transaminases. No treatment-related deaths occurred. In the overall sample (N=51), progression-free survival at 6 months was 66&#xb7;7% (95% CI 52&#xb7;1-79&#xb7;2).<br><br>INTERPRETATION: Zanidatamab plus palbociclib and fulvestrant was generally safe and showed promising antitumour activity, supporting further evaluation of this chemotherapy-free triplet regimen.<br><br>FUNDING: Zymeworks, Jazz Pharmaceuticals, and Pfizer.}, }
@article {pmid40339051, year = {2025}, author = {Burger, R and Bell-Mandla, N and Harper, A and Richardson, S and Kanema, S and Thomas, R and Mwenge, L and Wilson, E and Floyd, S and Bock, P and Ayles, H and Fidler, S and Hayes, R and Hauck, K and , }, title = {Does enhanced HIV prevention, diagnosis, and linkage to care reduce hospitalisation in high HIV-burden communities in Zambia and South Africa? findings from the HPTN 071 (PopART) randomised trial.}, journal = {PLOS global public health}, volume = {5}, number = {5}, pages = {e0004373}, pmid = {40339051}, issn = {2767-3375}, abstract = {ClinicalTrials.gov NCT01900977.}, }
@article {pmid40339010, year = {2025}, author = {Ely, ZA and Kulstad, ZJ and Gunaydin, G and Addepalli, S and Verzani, EK and Casarrubios, M and Clauser, KR and Wang, X and Lippincott, IE and Louvet, C and Schmitt, T and Kapner, KS and Agus, MP and Hennessey, CJ and Cleary, JM and Hadrup, SR and Klaeger, S and Su, J and Jaeger, AM and Wolpin, BM and Raghavan, S and Smith, EL and Greenberg, PD and Aguirre, AJ and Abelin, JG and Carr, SA and Jacks, T and Freed-Pastor, WA}, title = {Pancreatic cancer-restricted cryptic antigens are targets for T cell recognition.}, journal = {Science (New York, N.Y.)}, volume = {388}, number = {6747}, pages = {eadk3487}, doi = {10.1126/science.adk3487}, pmid = {40339010}, issn = {1095-9203}, mesh = {*Pancreatic Neoplasms/immunology/therapy/genetics ; Humans ; *Antigens, Neoplasm/immunology/genetics ; *Histocompatibility Antigens Class I/immunology ; *T-Lymphocytes, Cytotoxic/immunology ; *Peptides/immunology ; Organoids/immunology ; Receptors, Antigen, T-Cell/immunology ; Antigen Presentation ; Cell Line, Tumor ; }, abstract = {Translation of the noncoding genome in cancer can generate cryptic (noncanonical) peptides capable of presentation by human leukocyte antigen class I (HLA-I); however, the cancer specificity and immunogenicity of noncanonical HLA-I-bound peptides (ncHLAp) are incompletely understood. Using high-resolution immunopeptidomics, we discovered that cryptic peptides are abundant in the pancreatic cancer immunopeptidome. Approximately 30% of ncHLAp exhibited cancer-restricted translation, and a substantial subset were shared among patients. Cancer-restricted ncHLAp displayed robust immunogenic potential in a sensitive ex vivo T cell priming platform. ncHLAp-reactive, T cell receptor-redirected T cells exhibited tumoricidal activity against patient-derived pancreatic cancer organoids. These findings demonstrate that pancreatic cancer harbors cancer-restricted ncHLAp that can be recognized by cytotoxic T cells. Future therapeutic strategies for pancreatic cancer, and potentially other solid tumors, may include targeting cryptic antigens.}, }
@article {pmid40338545, year = {2025}, author = {Schoen, MW and Doherty, J and Eaton, D and Khan, S and Candelieri, D and Fedele, N and Baxi, P and Wynveen, M and Pickett, C and Wilson, RJ and Stackable, K and Ingram, K and Karunanandaa, K and Agarwal, R and Rajasekhar, A and Riekhof, F and Govindan, S and Cheranda, N and Knoche, EM and Etzioni, RD and Montgomery, RB}, title = {Treatment Patterns and Survival Among Veterans With De Novo Metastatic Hormone-Sensitive Prostate Cancer.}, journal = {JAMA network open}, volume = {8}, number = {5}, pages = {e259433}, pmid = {40338545}, issn = {2574-3805}, mesh = {Humans ; Male ; Aged ; Retrospective Studies ; Cross-Sectional Studies ; *Veterans/statistics &amp; numerical data ; *Prostatic Neoplasms/mortality/drug therapy/pathology ; Docetaxel/therapeutic use ; *Androgen Antagonists/therapeutic use ; Middle Aged ; United States/epidemiology ; Aged, 80 and over ; *Androgen Receptor Antagonists/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; }, abstract = {IMPORTANCE: Combination therapy for metastatic hormone-sensitive prostate cancer (mHSPC) has been widely adopted, yet clinical use and outcomes are unknown. Furthermore, optimal therapy is uncertain due to lack of direct comparison of androgen receptor pathway inhibitors (ARPIs) and docetaxel in high-volume disease.<br><br>OBJECTIVE: To evaluate the use of combination therapy and its association with overall survival among patients with mHSPC and to compare ARPIs vs docetaxel doublet therapy by volume of disease.<br><br>This retrospective cross-sectional study was conducted in the US Veterans Health Administration among 6216 US veterans with de novo mHSPC from January 1, 2013, to December 31, 2022, treated with androgen deprivation therapy (ADT) within 3 months of diagnosis. Treatments for mHSPC were collected within 4 months of ADT. Volume of disease was assessed from radiology report review. Data were analyzed from July 2023 to October 2024.<br><br>MAIN OUTCOMES AND MEASURES: Overall survival (OS) and clinical progression-free survival (PFS), indicated by time to castration resistance or death.<br><br>RESULTS: Among 6216 male veterans with mHSPC (mean [SD] age, 73.9 [9.7] years), use of combination therapy increased from 344 of 637 veterans (54.0%) in 2020 to 465 of 737 veterans (63.1%) in 2022. Among 4106 veterans treated from 2017 to 2022, combination therapy was associated with longer OS (40.3 [95% CI, 38.0-42.1] months vs 33.0 [95% CI, 31.2-35.1] months; hazard ratio [HR], 0.80 [95% CI, 0.74-0.87]) and was used more frequently among younger veterans with fewer comorbidities. Among 1174 veterans with high-volume mHSPC, there was no difference in OS between ARPIs and docetaxel (32.3 [95% CI, 29.5-35.3] months vs 34.7 [95% CI, 31.7-37.1] months; HR, 1.06 [95% CI, 0.91-1.23]); however, ARPIs were associated with longer PFS (18.7 [95% CI, 17.1-20.9] months vs 16.0 [95% CI, 14.0-17.7] months; HR, 0.80 [95% CI, 0.70-0.91]; P&#x2009;=&#x2009;.001). In a multivariable model of high-volume mHSPC, there was no difference in OS between ARPIs and docetaxel (adjusted HR, 0.89 [95% CI, 0.76-1.05]). Among 366 veterans with low-volume mHSPC, there was no difference in OS between ARPIs and docetaxel (68.4 [95% CI, 52.6 months to not reached] months vs 55.3 [95% CI, 41.7-78.9] months; HR, 0.81 [95% CI, 0.58-1.13]), but ARPIs were associated with longer PFS (39.7 [95% CI, 34.3-52.9] months vs 24.0 [95% CI, 20.3-32.9] months; HR, 0.57 [95% CI, 0.43-0.76]).<br><br>CONCLUSIONS AND RELEVANCE: In this cross-sectional study of veterans with de novo mHSPC, use of combination therapies increased over time and were associated with longer survival compared with ADT monotherapy. In both high- and low-volume mHSPC, no differences in OS were observed between ARPI and docetaxel combinations; however, ARPIs had longer PFS. Future research into the role of docetaxel is needed to elucidate the benefit of chemotherapy in mHSPC.}, }
@article {pmid40337764, year = {2025}, author = {Damle, SR and Pillarisetty, VG and Safyan, RA and Chiorean, EG}, title = {A new dawn in cancer immunotherapy: the promise of mutant KRAS-specific vaccines.}, journal = {Translational gastroenterology and hepatology}, volume = {10}, number = {}, pages = {20}, pmid = {40337764}, issn = {2415-1289}, }
@article {pmid40337301, year = {2025}, author = {Eckardt, JN and Hahn, W and Ries, RE and Chrost, SD and Winter, S and Stasik, S and Röllig, C and Platzbecker, U and Müller-Tidow, C and Serve, H and Baldus, CD and Schliemann, C and Schäfer-Eckart, K and Hanoun, M and Kaufmann, M and Burchert, A and Schetelig, J and Bornhäuser, M and Wolfien, M and Meshinchi, S and Thiede, C and Middeke, JM}, title = {Age-stratified machine learning identifies divergent prognostic significance of molecular alterations in AML.}, journal = {HemaSphere}, volume = {9}, number = {5}, pages = {e70132}, pmid = {40337301}, issn = {2572-9241}, abstract = {Risk stratification in acute myeloid leukemia (AML) is driven by genetics, yet patient age substantially influences therapeutic decisions. To evaluate how age alters the prognostic impact of genetic mutations, we pooled data from 3062 pediatric and adult AML patients from multiple cohorts. Signaling pathway mutations dominated in younger patients, while mutations in epigenetic regulators, spliceosome genes, and TP53 alterations became more frequent with increasing age. Machine learning models were trained to identify prognostic variables and predict complete remission and 2-year overall survival, achieving area-under-the-curve scores of 0.801 and 0.791, respectively. Using Shapley (SHAP) values, we quantified the contribution of each variable to model decisions and traced their impact across six age groups: infants, children, adolescents/young adults, adults, seniors, and elderly. The highest contributions to model decisions among genetic variables were found for alterations of NPM1, CEBPA, inv(16), and t(8;21) conferring favorable risk and alterations of TP53, RUNX1, ASXL1, del(5q), -7, and -17 conferring adverse risk, while FLT3-ITD had an ambiguous role conferring favorable treatment responses yet poor overall survival. Age significantly modified the prognostic value of genetic alterations, with no single alteration consistently predicting outcomes across all age groups. Specific alterations associated with aging such as TP53, ASXL1, or del(5q) posed a disproportionately higher risk in younger patients. These results challenge uniform risk stratification models and highlight the need for context-sensitive AML treatment strategies.}, }
@article {pmid40335656, year = {2025}, author = {Harris, K}, title = {An uneasy truce between population health and the gene pools within our bodies.}, journal = {Nature reviews. Genetics}, volume = {}, number = {}, pages = {}, pmid = {40335656}, issn = {1471-0064}, }
@article {pmid40334068, year = {2025}, author = {Muhsen, IN and Roloff, GW and Faramand, RG and Othman, T and Valtis, YK and Kopmar, NE and Dekker, SE and Connor, M and Mercadal, S and O'Connor, TE and Dykes, KC and Ahmed, M and Jeyakumar, N and Zhang, A and Miller, K and Sutherland, KC and Guzowski, C and Gupta, VK and Majhail, NS and Battiwalla, M and Solh, MM and Malik, SA and Mathews, J and Oliai, C and Shaughnessy, PJ and Mountjoy, L and Lee, CJ and Logan, AC and Tsai, SB and Leonard, JT and Schwartz, MS and Sasine, JP and Kumaran, M and Frey, NV and Park, JH and Koura, D and Cassaday, RD and Shah, BD and Aldoss, I and Muffly, LS and Hill, LC}, title = {Outcomes of Brexucabtagene Autoleucel in Relapsed/Refractory Acute Lymphoblastic Leukemia Patients with CNS Involvement.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024015779}, pmid = {40334068}, issn = {2473-9537}, abstract = {Relapsed/Refractory (r/r) B-cell acute lymphoblastic leukemia patients with central nervous system involvement (CNS B-ALL) have poor outcomes and were frequently excluded from CD19-targeting chimeric antigen receptor T-cell (CAR T-cell) clinical trials. The efficacy and safety of brexucabtagene autoleucel (brexu-cel) in adults with r/r B-ALL was established by the ZUMA-3 trial, which excluded patients with advanced or symptomatic CNS involvement. In this retrospective multicenter analysis, we investigated the safety and efficacy of brexu-cel in CNS B-ALL patients utilizing data from the Real-World Outcomes Collaborative for CAR T in ALL (ROCCA) consortium. Of 189 patients infused, 31 had CNS-2 (presence of blasts in CSF with < 5 WBC/uL) or CNS-3 (presence of blasts with >5 WBC/uL and/or clinical signs/symptoms) disease pre-apheresis and are the focus of this report. The median age was 46.5 years (range, 24-76), and 58.1% were males. Most (87.1%) received bridging therapy. Following brexu-cel, 21 of 24 with CNS restaging (87.5%) achieved CNS-1. Additionally, 28 of 30 evaluable patients achieved marrow complete remission (CR); 25 were MRD-negative. No statistically significant differences were seen in progression-free survival (PFS) or overall survival (OS) following brexu-cel among patients with or without CNS involvement. Similarly, grade 3-4 immune effector cell associated neurotoxicity syndrome (ICANS) occurred similarly in patients with (35.5%) and without CNS disease (30%). In conclusion, our data suggest that brexu-cel results in high response rates in CNS B-ALL patients with toxicity comparable to patients without CNS involvement.}, }
@article {pmid40334067, year = {2025}, author = {Shadman, M and Burke, JM and Cultrera, J and Yimer, HA and Zafar, SF and Misleh, J and Rao, SS and Farber, CM and Cohen, AC and Yao, H and Idoine, A and An, Q and Flinn, IW and Sharman, JP}, title = {Zanubrutinib is well tolerated and effective in CLL/SLL patients intolerant of ibrutinib/acalabrutinib: Updated results.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024015493}, pmid = {40334067}, issn = {2473-9537}, abstract = {Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib revolutionized chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) treatment, although treatment-related toxicities limit the use of some BTK inhibitors. Zanubrutinib, a potent next-generation BTK inhibitor, has higher selectivity than ibrutinib or acalabrutinib. The ongoing phase 2, single-arm BGB-3111-215 study investigates the safety and efficacy of zanubrutinib in patients with B-cell malignancies who are intolerant of ibrutinib and/or acalabrutinib. Here, results in patients with CLL/SLL are presented. Patients received zanubrutinib 160 mg BID or 320 mg QD. With a 34.5-month median follow-up, 71 patients (ibrutinib intolerant only, n=44; acalabrutinib intolerant only, n=17; ibrutinib and acalabrutinib intolerant, n=10) received ≥1 zanubrutinib dose. On zanubrutinib, 54% (28/52) of ibrutinib-intolerant patients and 70% (19/27) of acalabrutinib-intolerant patients experienced no recurrence of intolerance AEs; 60% and 72% of intolerance AEs did not recur, respectively. Of recurrent ibrutinib-intolerance AEs, 64% were lower grade; 44% of acalabrutinib-intolerance AEs were lower grade. No intolerance AEs recurred at a higher grade with zanubrutinib. The most common recurrent ibrutinib-intolerance and acalabrutinib-intolerance AEs were fatigue and diarrhea, respectively. The most common TEAEs with zanubrutinib were fatigue (32%), COVID-19 (28%), and diarrhea and contusion (each 24%). Grade ≥3 TEAEs occurred in 61%, serious TEAEs in 32%, and TEAEs leading to discontinuation in 11%. Of 67 efficacy-evaluable patients, 94% experienced disease control: 30% had a best response of stable disease and 64% had a partial or complete response. These data demonstrate that patients intolerant of ibrutinib/acalabrutinib may benefit from switching to zanubrutinib therapy. ClinicalTrials.gov: NCT04116437.}, }
@article {pmid40333962, year = {2025}, author = {Zheng, D and van den Heuvel, A and Balog, J and Willemsen, IM and Kloet, S and Tapscott, SJ and Mahfouz, A and van der Maarel, SM}, title = {DUX4 activates common and context-specific intergenic transcripts and isoforms.}, journal = {Science advances}, volume = {11}, number = {19}, pages = {eadt5356}, pmid = {40333962}, issn = {2375-2548}, mesh = {*Homeodomain Proteins/genetics/metabolism ; Muscular Dystrophy, Facioscapulohumeral/genetics/metabolism/pathology ; Animals ; Protein Isoforms/genetics/metabolism ; Mice ; *DNA, Intergenic/genetics ; Transcriptome ; Humans ; Myoblasts/metabolism ; Gene Expression Regulation, Developmental ; Muscle, Skeletal/metabolism ; }, abstract = {DUX4 regulates the expression of genic and nongenic elements and modulates chromatin accessibility during zygotic genome activation in cleavage stage embryos. Its misexpression in skeletal muscle causes facioscapulohumeral dystrophy (FSHD). By leveraging full-length RNA isoform sequencing with short-read RNA sequencing of DUX4-inducible myoblasts, we elucidate an isoform-resolved transcriptome featuring numerous unannotated isoforms from known loci and novel intergenic loci. While DUX4 activates similar programs in early embryos and FSHD muscle, the isoform usage of known DUX4 targets is notably distinct between the two contexts. DUX4 also activates hundreds of previously unannotated intergenic loci dominated by repetitive elements. The transcriptional and epigenetic profiles of these loci in myogenic and embryonic contexts indicate that the usage of DUX4-binding sites at these intergenic loci is influenced by the cellular environment. These findings demonstrate that DUX4 induces context-specific transcriptomic programs, enriching our understanding of DUX4-induced muscle pathology.}, }
@article {pmid40333666, year = {2025}, author = {Olivieri, DJ and Eastment, MC and Mugisha, N and Menon, MP}, title = {Correlates of cervical cancer awareness among women aged 30-49 in five sub-Saharan African nations: Evidence from the Demographic and Health Survey (DHS)-2017-2023.}, journal = {PLOS global public health}, volume = {5}, number = {5}, pages = {e0003344}, pmid = {40333666}, issn = {2767-3375}, abstract = {Cervical cancer is the leading cause of cancer-related mortality in low- and middle-income countries (LMICs). Prior studies associate high cervical cancer awareness with reductions in cervical cancer incidence. In this study, we utilize nationally representative Demographic and Health Surveys Program (DHS) to analyze correlates of cervical cancer awareness to inform global strategies. All DHS surveys between 2017-2023 were queried for questions on cervical cancer awareness. Socio-demographic variables (e.g., age, marital status), socioeconomic variables (e.g., education, wealth, literacy) and variables pertaining to healthcare decision making, distance traveled, intimate partner violence (IPV), and female genital mutilation/circumcision (FGC/M)) were extracted. Sample weights were applied, and logistic regressions were performed. Variables with p < 0.20 were included in multivariate analysis. Data was obtained from 30,214 women aged 30-49 years old living in Benin, Cameroon, Madagascar, Mauritania, and Mozambique, 19,403 of whom were asked questions on cervical cancer awareness. Cervical cancer awareness varied from 53% in Cameroon to 12% in Benin. Literacy, frequency of watching television, mobile telephone ownership, visiting a local healthcare facility and hormonal contraceptive use were associated with increased cervical cancer awareness, while lack of healthcare decision making independence was associated with decreased awareness after multivariate adjustment. Women who experienced emotional IPV were associated with increased awareness in Cameroon. Less than 4% of all women were screened for cervical cancer. Given the known association between awareness and screening, targeted efforts to increase awareness among women without communication modalities has the potential to reduce global cervical cancer disparities. Potential strategies include co-locating cervical cancer awareness programs with public health programs and implementing large-scale telecommunication outreach programs to improve awareness.}, }
@article {pmid40329475, year = {2025}, author = {Sullivan, SD and Grueger, J and Sullivan, AP and Ramsey, SD}, title = {The consequences of pharmaceutical tariffs in the United States.}, journal = {Journal of managed care &amp; specialty pharmacy}, volume = {}, number = {}, pages = {1-4}, doi = {10.18553/jmcp.2025.25090}, pmid = {40329475}, issn = {2376-1032}, abstract = {The Trump Administration has threatened to impose tariffs on imported branded, generic, and biosimilar pharmaceutical products. Although specific details regarding the exact rates and implementation timeline remain unclear, the administration has indicated that these tariffs will be substantial. Tariffs can create supply chain disruptions, increase costs, limit patient access to essential medications, and negatively impact research and innovation. Rather than punitive tariffs, industrial policy options and collaborative international treaties may better serve US economic and public health interests and lead to a more secure and consistent domestic supply of critical medicines.}, }
@article {pmid40329098, year = {2025}, author = {Bulteel, AJB and Barnum, K and Datta, S and Dodge, LE and Lake, L and Elavalakanar, P and Lam, BD and Patell, R}, title = {Clinician characteristics associated with use of risk assessment models for venous thromboembolism and bleeding in hospitalized patients.}, journal = {Annals of hematology}, volume = {}, number = {}, pages = {}, pmid = {40329098}, issn = {1432-0584}, support = {DD20-2002/CC/CDC HHS/United States ; }, }
@article {pmid40328984, year = {2025}, author = {Abernethy, NF and McCloskey, K and Trahey, M and Rinn, L and Broder, G and Andrasik, M and Laborde, R and McGhan, D and Spendolini, S and Marimuthu, S and Kanzmeier, A and Hanes, J and Kublin, JG}, title = {Rapid development of a registry to accelerate COVID-19 vaccine clinical trials.}, journal = {NPJ digital medicine}, volume = {8}, number = {1}, pages = {251}, pmid = {40328984}, issn = {2398-6352}, support = {UM1AI068614//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; UM1AI068635//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; }, abstract = {Response to the SARS-Cov-2 pandemic required the unprecedented, rapid activation of the COVID-19 Prevention Network (CoVPN) representing hundreds of sites conducting vaccine clinical trials. The CoVPN Volunteer Screening Registry (VSR) collected participant information, distributed qualified candidates across sites, and monitored enrollment progress. The system consisted of three web-based interfaces. The Volunteer Questionnaire flowed into a secure database. The Site Portal supported volunteer selection, analytics, and enrollment. The Administrative Portal enabled dynamic analytic reports by geography, clinical trial, and site, including volunteering rates over time. The VSR collected over 650,000 volunteers, serving a key role in the recruitment of diverse participants for multiple Phase 3 clinical trials. Over 47% of the 166,729 volunteers selected for screening represented prioritized groups. The success of the VSR demonstrates how digital tools can be rapidly yet safely integrated into an accelerated clinical trial setting. We summarize the development of the system and lessons learned for pandemic preparedness.}, }
@article {pmid40328898, year = {2025}, author = {Zamora, D and Xie, H and Wong, E and Santiano, C and Vivas-Jimenez, A and Sadowska-Klasa, A and Kampouri, E and Stevens-Ayers, T and Ueda Oshima, M and Leisenring, WM and Hill, JA and Boeckh, M}, title = {ELISPOT as a predictor of clinically significant cytomegalovirus infection after hematopoietic cell transplantation in letermovir recipients.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, pmid = {40328898}, issn = {1476-5365}, support = {T32 AI118690/AI/NIAID NIH HHS/United States ; K23AI163343//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; K23AI163343//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; K23AI163343//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; }, abstract = {We examined cytomegalovirus-specific cell-mediated immunity (CMV-CMI) to pp65 and IE-1 at 100 days after hematopoietic cell transplantation (HCT) following discontinuation of letermovir prophylaxis using ELISPOT (T-SPOT®.CMV, Oxford-Immunotec, Abingdon, UK). We compared ELISPOT results to a laboratory-developed intracellular cytokine staining (ICS) assay and characterized thresholds for the prediction of late clinically significant (cs)CMV infection using receiver operating characteristic analysis. We identified factors associated with high (i.e., at or above threshold) CMV-CMI to both antigens. ELISPOT correlated well with polyfunctional CMV-specific T-cell immunity by ICS. We defined thresholds of 67 and 4 spots per 250,000 cells for pp65 and IE-1, respectively, for predicting late csCMV infection. PBSC graft source, CMV seropositive donor, and/or CMV reactivation in the first 100 days post-HCT were associated with high CMV-CMI to pp65 and/or IE-1. Patients with high CMV-CMI to both antigens at day 100 had a lower incidence of late csCMV infection, however, late changes in immunosuppression affected risk prediction. Clinical risk factors (e.g., early CMV infection, acute graft-versus-host disease) predicted late csCMV and improved the predictive value of CMV-CMI testing. Thus, standardized CMV-CMI, after HCT, combined with clinical factors can be used to accurately stratify the risk of late csCMV infection after letermovir prophylaxis.}, }
@article {pmid40328734, year = {2025}, author = {Chehayeb, RJ and Odzer, N and Albany, RA and Ferrucci, L and Sarpong, D and Perez-Escamilla, R and Lewis, JB and Phipps, AI and Meisner, A and Pusztai, L}, title = {Breastfeeding attributable fraction of triple negative breast cancer in the US.}, journal = {NPJ breast cancer}, volume = {11}, number = {1}, pages = {40}, pmid = {40328734}, issn = {2374-4677}, abstract = {Rates of triple negative breast cancer (TNBC) are higher in Black women than in non-Hispanic White women. Breastfeeding duration and younger age at first birth are known risk factors for TNBC and vary by race. To quantify the contribution of these risk factors to disparities in TNBC, we calculated the population-attributable fraction (PAF). A PubMed search was performed to identify relevant studies and pooled odds ratios for breastfeeding for < 6 months and age at first birth < 25 years were calculated. PAF was calculated using the Levin formula. PAF of breastfeeding for < 6 months was 12% (95% confidence interval (CI) 5-20%) among White women and 15% (95%CI 3-26%) among Black women. We estimate that up to 15% of annual new TNBC in Black women and 12% in White women might be avoided by supporting breastfeeding. Policies supporting breastfeeding could hence reduce TNBC incidence and lessen racial disparities.}, }
@article {pmid40328293, year = {2025}, author = {Davis, CP and Fest, S and Cushing-Haugen, K and Kensler, TW and Chavarro, JE and Harris, HR}, title = {Dietary patterns and age at menarche in a prospective study of girls in the USA.}, journal = {Human reproduction (Oxford, England)}, volume = {}, number = {}, pages = {}, doi = {10.1093/humrep/deaf072}, pmid = {40328293}, issn = {1460-2350}, support = {//Breast Cancer Research Foundation/ ; U01 HL145386/NH/NIH HHS/United States ; T32 CA094880/NH/NIH HHS/United States ; //Breast Cancer Research Foundation/ ; U01 HL145386/NH/NIH HHS/United States ; T32 CA094880/NH/NIH HHS/United States ; }, abstract = {STUDY QUESTION: Are dietary patterns associated with age at menarche after accounting for BMI-for-age (BMIz) and height?<br><br>SUMMARY ANSWER: We observed associations between both the Alternative Healthy Eating Index (AHEI) and the Empirical Dietary Inflammatory Pattern (EDIP) and age at menarche.<br><br>WHAT IS KNOWN ALREADY: Dietary patterns have been sparsely examined in relation to age at menarche and no studies have examined the association between the AHEI, a healthier diet, and EDIP, a pro-inflammatory diet, and menarche.<br><br>STUDY DESIGN, SIZE, DURATION: The Growing Up Today Study (GUTS) is a prospective cohort of children ages 9-14&#xa0;years at study enrollment. GUTS enrolled in two waves with enrollment beginning in 1996 (GUTS1) and 2004 (GUTS2). For this analysis, GUTS1 and GUTS2 participants were followed through 2001 and 2008, respectively.<br><br>We included 7530 participants who completed food frequency questionnaire(s) (FFQ) prior to menarche who then self-reported age at menarche during study follow-up. Cox proportional hazard models were used to calculate multivariable hazard ratios (HRs) and 95% CIs for the associations between two dietary patterns, the AHEI and EDIP, and age at menarche, with and without adjustment for time-varying BMIz and height.<br><br>Six thousand nine hundred ninety-two participants (93%) reported menarche during the study period. On average, participants completed the baseline FFQ 1.75&#x2009;years prior to menarche. Participants in the highest quintile of AHEI diet score (indicating a healthier diet) were 8% less likely to attain menarche within the next month compared to those in the lowest quintile (95% CI&#x2009;=&#x2009;0.85-0.99; Ptrend&#x2009;=&#x2009;0.03). This association remained after adjustment for BMIz and height (corresponding HR&#x2009;=&#x2009;0.93; 95% CI&#x2009;=&#x2009;0.86-1.00; Ptrend&#x2009;=&#x2009;0.04). Participants in the highest quintile of the EDIP score (i.e. most inflammatory diet), were 15% more likely to attain menarche in the next month relative to those in the lowest quintile (95% CI&#x2009;=&#x2009;1.06-1.25; Ptrend&#x2009;=&#x2009;0.0004), and the association remained following adjustment for BMIz and height (corresponding HR&#x2009;=&#x2009;1.15; 95% CI&#x2009;=&#x2009;1.06-1.25; Ptrend&#x2009;=&#x2009;0.0004).<br><br>Self-reported questionnaires are subject to some error; however, given our prospective study design it is likely this error is non-differential with respect to the outcome.<br><br>Our findings of an association between both the AHEI and EDIP and age at menarche indicate that diet quality may play a role in age at menarche independent of BMI or height.<br><br>This work was supported by the Breast Cancer Research Foundation. The GUTS is supported by the National Institutes of Health U01 HL145386. C.P.D. was supported by National Institutes of Health T32 CA094880. The authors have no conflicts of interest to disclose.<br><br>TRIAL REGISTRATION NUMBER: N/A.}, }
@article {pmid40327712, year = {2025}, author = {Jia, C and Peters, BA and Usyk, M and Wang, Z and Hanna, DB and Sharma, A and Anastos, K and Kaplan, R and Burk, R and Qi, Q}, title = {Associations of fecal and blood microbiota-related metabolites with gut microbiota and type 2 diabetes in HIV infection.}, journal = {AIDS (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.1097/QAD.0000000000004231}, pmid = {40327712}, issn = {1473-5571}, abstract = {OBJECTIVES: Assess the relationships of gut microbiota (GMB)-related metabolites in feces and blood with GMB and type 2 diabetes (T2D) in the context of HIV infection, the presence of which could disrupt host metabolism.<br><br>DESIGN: We conducted a cross-sectional study among 111 women with HIV (WWH) and 56 women without HIV (WWOH) in the MACS/WIHS Combined Cohort Study.<br><br>METHODS: We measured 62 targeted metabolites in both feces and plasma and examined their associations with GMB composition (243 species) and prevalent T2D.<br><br>RESULTS: We observed 44 metabolites with detection rates &#x2265;25% in both feces and plasma. Correlations between fecal and plasma metabolites were stronger in WWOH than in WWH (median r: 0.13 vs. 0.04). Fecal metabolites showed stronger correlations with GMB than plasma metabolites among all participants (median r [IQR] of measured vs. GMB-predicted metabolites: 0.24 [0.11, 0.33] vs. 0.08 [-0.03, 0.24]; P&#x200a;=&#x200a;0.002), and the difference in this comparison was more pronounced in WWOH compared to WWH. We found a moderate consistency for the associations of fecal and plasma metabolites with T2D in WWH (r for effect sizes of fecal and plasma metabolites on T2D&#x200a;=&#x200a;0.36; P&#x200a;=&#x200a;0.03), but not in WWOH (r&#x200a;=&#x200a;0.13; P&#x200a;=&#x200a;0.45). Fecal and plasma kynurenate, a tryptophan catabolism metabolite, showed opposite associations with T2D, with a positive association for plasma (OR: 2.54, 95% CI: [1.28-5.76]; P&#x200a;=&#x200a;0.01) and an inverse association for feces (0.59 [0.27-1.23]; P&#x200a;=&#x200a;0.18) in WWH.<br><br>CONCLUSIONS: Fecal metabolites are more strongly associated with GMB than plasma metabolites, especially among WWOH. HIV infection might also influence associations of fecal and plasma metabolites with T2D.}, }
@article {pmid40327300, year = {2025}, author = {Hamilton, EP and Jeselsohn, RM and Vahdat, LT and Hurvitz, SA}, title = {PROteolysis TArgeting Chimera (PROTAC) Estrogen Receptor Degraders for Treatment of Estrogen Receptor-Positive Advanced Breast Cancer.}, journal = {Targeted oncology}, volume = {}, number = {}, pages = {}, pmid = {40327300}, issn = {1776-260X}, abstract = {The estrogen receptor (ER) signaling pathway is a key driver of breast cancer, primarily through the activation of genes that promote tumor cell survival and growth. The recommended first-line treatment for ER-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer is endocrine therapy plus a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. However, most patients experience disease progression, and there is no clear standard of care in the second-line setting. Thus, novel treatments in the advanced setting are needed. In this narrative review, we describe the unique mechanisms of action of a new class of drugs called PROteolysis TArgeting Chimera (PROTAC) ER degraders. Unlike other ER-targeted therapies, these small molecules harness the body's primary intracellular natural protein disposal machinery, the ubiquitin-proteasome system, to directly induce ER degradation. Vepdegestrant (ARV-471) is the furthest advanced PROTAC ER degrader currently in clinical development. Preclinical data demonstrate increased tumor growth inhibition with vepdegestrant alone or in combination with CDK4/6 inhibitors compared with the selective ER degrader fulvestrant. In a first-in-human phase 1/2 clinical study, vepdegestrant administered orally as monotherapy or in combination with palbociclib showed promising clinical activity and a favorable safety profile in patients with heavily pretreated ER+/HER2- advanced breast cancer. Several other PROTAC ER degraders (AC699, ERD-3111, ERD-4001, and HP568) are in early development and have demonstrated activity in preclinical breast cancer models, with some recently entering clinical trials. The data highlight the potential for PROTAC ER degraders to be a new backbone therapy in breast cancer.}, }
@article {pmid40325041, year = {2025}, author = {Langowski, MD and Francica, JR and Roederer, AL and Hurlburt, NK and Rodarte, JV and Da Silva Pereira, L and Flynn, BJ and Bonilla, B and Dillon, M and Kiyuka, P and Ravichandran, R and Weidle, C and Carter, L and Rao, M and Matyas, GR and Pepper, M and Idris, AH and Seder, RA and Pancera, M and King, NP}, title = {Elicitation of liver-stage immunity by nanoparticle immunogens displaying P. falciparum CSP-derived antigens.}, journal = {NPJ vaccines}, volume = {10}, number = {1}, pages = {87}, pmid = {40325041}, issn = {2059-0105}, support = {INV-010680/GATES/Gates Foundation/United States ; INV-010680/GATES/Gates Foundation/United States ; INV-010680/GATES/Gates Foundation/United States ; INV-010680/GATES/Gates Foundation/United States ; INV-010680/GATES/Gates Foundation/United States ; INV-010680/GATES/Gates Foundation/United States ; INV-010680/GATES/Gates Foundation/United States ; INV-010680/GATES/Gates Foundation/United States ; INV-010680/GATES/Gates Foundation/United States ; INV-010680/GATES/Gates Foundation/United States ; DGE-1762114//National Science Foundation/ ; }, abstract = {A vaccine that provides robust, durable protection against malaria remains a global health priority. Although a breakthrough in the fight against malaria has recently been achieved by the licensure of two vaccines based on the circumsporozoite protein (CSP), the effectiveness and durability of protection can still be improved. Both vaccines contain a portion of CSP that does not include epitopes targeted by recently identified, potently protective monoclonal antibodies, suggesting that newer immunogens can expand the breadth of immunity and potentially increase protection. Here we explored >100 alternative CSP-based immunogens and evaluated the immunogenicity and protection of a large number of candidates, comparing several to the licensed R21 vaccine. The data highlight several general features that improve the stability and immunogenicity of CSP-based vaccines, such as inclusion of the C-terminal domain and high-density display on protein nanoparticle scaffolds. We also identify antigen design strategies that do not warrant further exploration, such as synthetic repeat regions that include non-native repeat cadences. The benchmark R21 vaccine outperformed our best immunogen for immunogenicity and protection. Overall, our data provide valuable insights on the inclusion of junctional region epitopes that will guide the development of potent and durable vaccines against malaria.}, }
@article {pmid40323670, year = {2025}, author = {Rodríguez-Díaz, CE and Zangeneh, SZ and Chen, YO and Guo, X and Tsuyuki, K and Ransome, Y and Friedman, RK and Srithanaviboonchai, K and Roberts, ST and Mimiaga, MJ and Mayer, KH and Safren, SA}, title = {The Longitudinal Impact of Psychosocial Syndemic Variables on Adherence to Antiretroviral Therapy Among People With HIV in Brazil, Thailand, and Zambia: An Analysis by HIV Transmission Groups in HPTN 063.}, journal = {AIDS education and prevention : official publication of the International Society for AIDS Education}, volume = {37}, number = {2}, pages = {89-106}, doi = {10.1521/aeap.2025.37.2.89}, pmid = {40323670}, issn = {1943-2755}, mesh = {Humans ; Male ; *HIV Infections/drug therapy/psychology/epidemiology/transmission ; Thailand/epidemiology ; Zambia/epidemiology ; Female ; Adult ; Longitudinal Studies ; Brazil/epidemiology ; *Medication Adherence/psychology ; *Syndemic ; *Anti-HIV Agents/therapeutic use ; Homosexuality, Male/psychology/statistics &amp; numerical data ; Middle Aged ; Substance-Related Disorders/psychology/epidemiology ; Heterosexuality/psychology/statistics &amp; numerical data ; Cross-Sectional Studies ; Young Adult ; }, abstract = {In the field of HIV prevention and care, most studies of HIV syndemic problems are cross-sectional, few differentiate by HIV transmission groups, and few focus on people living with HIV (PWH). We analyzed one-year longitudinal data of 692 sexually active PWH (heterosexual men [HM], heterosexual women [HW], and men who have sex with men [MSM]) in care from Brazil, Thailand, and Zambia. Syndemic scores (0-3+) included stimulant use, polydrug use, depression, alcohol use, and fear of discrimination. Overall, syndemic scores were associated with lower ART adherence over time, but this differed across sexual transmission categories. For HM and HW, those with 2 or 3+ syndemic problems had lower odds of ART adherence than those with none. However, for MSM, the association between syndemic scores and ART adherence was not significant. While syndemic problems generally predicted suboptimal ART adherence among PWH, the association appears nuanced across subgroups.}, }
@article {pmid40323243, year = {2025}, author = {Yu, JB and Grew, D and Sculley, E and Siva, S and Hardcastle, N and Tang, C and Yang, J and Kim, M and Lo, SS}, title = {Practical Considerations for the Treatment of Primary Renal Cell Carcinoma With SABR.}, journal = {Practical radiation oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.prro.2025.03.007}, pmid = {40323243}, issn = {1879-8519}, }
@article {pmid40321251, year = {2025}, author = {Deslandes, B and Wu, X and Lee, MA and Goudswaard, LJ and Jones, GW and Gsur, A and Lindblom, A and Ogino, S and Vymetalkova, V and Wolk, A and Wu, AH and Huyghe, JR and Peters, U and Phipps, AI and Thomas, CE and Pai, RK and Grant, RC and Buchanan, DD and Yarmolinsky, J and Gunter, MJ and Zheng, J and Hazelwood, E and Vincent, EE}, title = {Transcriptome-wide Mendelian randomisation exploring dynamic CD4+ T cell gene expression in colorectal cancer development.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40321251}, support = {HHSN268201200008C/HL/NHLBI NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; R01 CA081488/CA/NCI NIH HHS/United States ; U01 CA122839/CA/NCI NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; HHSN268201200008I/HL/NHLBI NIH HHS/United States ; U19 CA148107/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Recent research has identified a potential protective effect of higher numbers of circulating lymphocytes on colorectal cancer (CRC) development. However, the importance of different lymphocyte subtypes and activation states in CRC development and the biological pathways driving this relationship remain poorly understood and warrant further investigation. Specifically, CD4+ T cells - a highly dynamic lymphocyte subtype - undergo remodelling upon activation to induce the expression of genes critical for their effector function. Previous studies investigating their role in CRC risk have used bulk tissue, limiting our current understanding of the role of these cells to static, non-dynamic relationships only.<br><br>METHODS: Here, we combined two genetic epidemiological methods - Mendelian randomisation (MR) and genetic colocalisation - to evaluate evidence for causal relationships of gene expression on CRC risk across multiple CD4+ T cell subtypes and activation stage. Genetic proxies were obtained from single-cell transcriptomic data, allowing us to investigate the causal effect of expression of 1,805 genes across five CD4+ T cell activation states on CRC risk (78,473 cases; 107,143 controls). We repeated analyses stratified by CRC anatomical subsites and sex, and performed a sensitivity analysis to evaluate whether the observed effect estimates were likely to be CD4+ T cell-specific.<br><br>RESULTS: We identified six genes with evidence (FDR-P<0.05 in MR analyses and H4>0.8 in genetic colocalisation analyses) for a causal role of CD4+ T cell expression in CRC development - FADS2, FHL3, HLA-DRB1, HLA-DRB5, RPL28, and TMEM258. We observed differences in causal estimates of gene expression on CRC risk across different CD4+ T cell subtypes and activation timepoints, as well as CRC anatomical subsites and sex. However, our sensitivity analysis revealed that the genetic proxies used to instrument gene expression in CD4+ T cells also act as eQTLs in other tissues, highlighting the challenges of using genetic proxies to instrument tissue-specific expression changes.<br><br>CONCLUSIONS: Our study demonstrates the importance of capturing the dynamic nature of CD4+ T cells in understanding disease risk, and prioritises genes for further investigation in cancer prevention research.}, }
@article {pmid40313741, year = {2025}, author = {Barrero, DJ and Hedouin, S and Mao, Y and Asbury, CL and Stergachis, A and O'Toole, E and Biggins, S}, title = {Centromeres in the thermotolerant yeast K. marxianus mediate attachment to a single microtubule.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40313741}, issn = {2693-5015}, support = {DP5 OD029630/OD/NIH HHS/United States ; R35 GM134842/GM/NIGMS NIH HHS/United States ; R35 GM149357/GM/NIGMS NIH HHS/United States ; }, abstract = {Eukaryotic chromosome segregation requires spindle microtubules to attach to chromosomes through kinetochores. The chromosomal locus that mediates kinetochore assembly is the centromere and is epigenetically specified in most organisms by a centromeric histone H3 variant called CENP-A. An exception to this is budding yeast which have short, sequenced-defined point centromeres. In S. cerevisiae, a single CENP-A nucleosome is formed at the centromere and is sufficient for kinetochore assembly. The thermophilic budding yeast Kluyveromyces marxianus also has a point centromere but its length is nearly double the S. cerevisiae centromere and the number of centromeric nucleosomes and kinetochore attachment sites is unknown. Purification of native kinetochores from K. marxianus yielded a mixed population, with one subpopulation that appeared to consist of doublets, making it unclear whether K. marxianus shares the same attachment architecture as S. cerevisiae. Here, we demonstrate that though the doublet kinetochores have a functional impact on kinetochore strength, kinetochore localization throughout the cell cycle appears conserved between these two yeasts. In addition, whole spindle electron tomography demonstrates that a single microtubule binds to each chromosome. Single-molecule nucleosome mapping analysis suggests the presence of a single centromeric nucleosome. Taken together, we propose that the K. marxianus point centromere assembles a single centromeric nucleosome that mediates attachment to one microtubule.}, }
@article {pmid40323013, year = {2025}, author = {Garcia, NMG and Becerra, JN and Srinivasan, S and McKinney, BJ and DiMarco, AV and Wu, F and Fitzgibbon, M and Alvarez, JV}, title = {APOBEC3 activity promotes the survival and evolution of drug-tolerant persister cells during EGFR inhibitor resistance in lung cancer.}, journal = {Cancer research communications}, volume = {}, number = {}, pages = {}, doi = {10.1158/2767-9764.CRC-24-0442}, pmid = {40323013}, issn = {2767-9764}, abstract = {APOBEC mutagenesis is one of the most common endogenous sources of mutations in human cancer and is a major source of genetic intratumor heterogeneity. High levels of APOBEC mutagenesis are associated with poor prognosis and aggressive disease across diverse cancers, but the mechanistic and functional impacts of APOBEC mutagenesis on tumor evolution and therapy resistance remain relatively unexplored. To address this, we investigated the contribution of APOBEC mutagenesis to acquired therapy resistance in a model of EGFR-mutant non-small cell lung cancer. We find that inhibition of EGFR in lung cancer cells leads to a rapid and pronounced induction of APOBEC3 expression and activity. Functionally, APOBEC expression promotes the survival of drug-tolerant persister cells (DTPs) following EGFR inhibition. Constitutive expression of APOBEC3B alters the evolutionary trajectory of acquired resistance to the EGFR inhibitor gefitinib, making it more likely that resistance arises through de novo acquisition of the T790M gatekeeper mutation and squamous transdifferentiation during the DTP state. APOBEC3B expression is associated with increased expression of the squamous cell transcription factor deltaNp63 and squamous cell transdifferentiation in gefitinib-resistant cells. Knockout of p63 in gefitinib-resistant cells reduces the expression of the deltaNp63 target genes IL1alpha/beta and sensitizes these cells to the third-generation EGFR inhibitor osimertinib. These results suggest that APOBEC activity promotes acquired resistance by facilitating evolution and transdifferentiation in DTPs, and suggest that approaches to target deltaNp63 in gefitinib-resistant lung cancers may have therapeutic benefit.}, }
@article {pmid40321654, year = {2025}, author = {Alvarez, CS and Kaplan, RC and Camargo, MC and Avilés-Santa, ML and Daviglus, M and Garcia-Bedoya, O and Isasi, CR and Pattany, MS and Thyagarajan, B and Talavera, GA and Graubard, BI and McGlynn, KA}, title = {Associations of Helicobacter pylori with metabolic dysfunction-associated steatotic liver disease and related conditions: cross-sectional results from the Hispanic Community Health Study/Study of Latinos.}, journal = {Lancet regional health. Americas}, volume = {41}, number = {}, pages = {100953}, pmid = {40321654}, issn = {2667-193X}, abstract = {BACKGROUND: Hispanic/Latino populations have been reported to have high rates of both metabolic dysfunction-associated steatotic liver disease (MASLD) and Helicobacter pylori infection. Several observational studies, predominantly from Asian populations, have suggested a link between these conditions. Thus, the primary objective of the current study was to examine the association between H. pylori and MASLD and secondarily, to assess its association with related conditions in the Hispanic Community Health Study/Study of Latinos.<br><br>METHODS: In this cross-sectional study, a total of 16,144 participants with baseline data on H.&#xa0;pylori serology were included. Based on weighted statistics, the median age was 40 years [interquartile range (IQR): 28, 52]; 52.2% women (n&#xa0;=&#xa0;9661) and 47.8% men (n&#xa0;=&#xa0;6483). Participants' Hispanic/Latino heritage included 37.6% Mexicans (n&#xa0;=&#xa0;6397), 20.1% Cubans (n&#xa0;=&#xa0;2307), 15.8% Puerto Ricans (n&#xa0;=&#xa0;2663), 10.0% Dominicans (n&#xa0;=&#xa0;1447), 7.4% Central Americans (n&#xa0;=&#xa0;1710), 4.9% South Americans (1052). MASLD was estimated using the Fatty Liver Index (FLI) and the Hepatic Steatosis Index (HSI). Other conditions examined were obesity, central obesity, diabetes and metabolic syndrome. Multivariable logistic regression models were used to calculate the ratios of (adjusted) prevalences (RP) and 95% confidence intervals (CI) for the overall association of H.&#xa0;pylori seropositivity with MASLD and related conditions. Analyses were also stratified by Hispanic/Latino heritage.<br><br>FINDINGS: The overall prevalence of MASLD ranged from 47% (FLI) to 65% (HSI). After accounting for age, sex, education, and other key variables, the analysis found a modest association between H.&#xa0;pylori seropositivity and MASLD as determined by HSI (RP: 1.06, 95% CI: 1.02-1.10) overall, and among individuals of Puerto Rican and Mexican heritages. Furthermore, an overall association between H.&#xa0;pylori seropositivity and obesity was observed (RP:&#xa0;1.09, 95% CI: 1.02-1.16).<br><br>INTERPRETATION: This study provides support for a positive association of H.&#xa0;pylori seropositivity with MASLD and obesity among Hispanic/Latino populations. However, given the exploratory nature of these findings, caution is warranted in their interpretation. Further research is necessary to establish causality and examine potential mechanisms&#xa0;of these associations.<br><br>FUNDING: The Hispanic Community Health Study/Study of Latinos was carried out as a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina (N01-HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236), San Diego State University (N01-HC65237), and University of Illinois at Chicago (HHSN268201300003I). The following Institutes/Centers/Offices contribute to the HCHS/SOL through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities, United States, the National Institute of Deafness and Other Communications Disorders, the National Institute of Dental and Craniofacial Research, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and the Office of Dietary Supplements. This study was also funded in part by the Intramural Research Program of the National Cancer Institute.}, }
@article {pmid40321290, year = {2025}, author = {Samandari, T and Achola, M and Hutter, JN and Mboya, G and Otieno, W and Kee, JJ and Huang, Y and Aponte, JJ and Ockenhouse, CF and Lee, CK and Polakowski, L and Yacovone, M and Tapley, A and Dadabhai, S and Mkhize, NN and Kaldine, H and Bhebhe, S and Moore, PL and Hural, J and Garrett, N and Kublin, JG}, title = {Neutralizing Antibody Responses After mRNA COVID-19 Booster Vaccination are Unaffected by Parasitemia in a Malaria-Endemic Setting.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40321290}, support = {T32 AI007044/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; }, abstract = {Subclinical malaria may reduce the immunogenicity of mRNA vaccines. We evaluated neutralizing antibody responses in adults with (n=87) and without (n=221) PCR-confirmed Plasmodium falciparum who received a COVID-19 booster. Similar boosted ID50 geometric mean titers >22,000 in parasitemic and non-parasitemic participants suggests that COVID-19 mRNA vaccine responses are not impaired.}, }
@article {pmid40321081, year = {2025}, author = {Lottermoser, JA and Liu, H and Bai, J and Hu, Z and Dittman, JS}, title = {Complexin gains effective access to the assembling SNAREs via its membrane-binding C-terminal domain.}, journal = {The Journal of physiology}, volume = {}, number = {}, pages = {}, doi = {10.1113/JP286500}, pmid = {40321081}, issn = {1469-7793}, support = {NS116747/NS/NINDS NIH HHS/United States ; NS127534/NS/NINDS NIH HHS/United States ; R56NS128048//National Science Foundation/ ; }, abstract = {The conserved presynaptic SNARE-binding protein complexin (Cpx) promotes Ca[2+]-triggered synaptic vesicle (SV) fusion and inhibits spontaneous fusion at some synapses. A membrane-binding motif in the C-terminal domain (CTD) of Cpx plays a critical role in Cpx function, but it remains unclear whether the CTD participates in Cpx regulation of synaptic transmission beyond targeting Cpx to membranes. We examined the impact of the Caenorhabditis elegans CPX-1 CTD in vivo and found that this domain profoundly boosted the efficiency of CPX-1-mediated inhibition of spontaneous SV fusion as a function of protein abundance at the synapse. Removing the C-terminal half of CPX-1 and substituting it with the SV protein RAB-3 was able to fully restore both the fusogenic and inhibitory functions of CPX-1 whereas other SV proteins failed to restore CPX-1 function with the same efficiency regardless of abundance. These results indicate that regulation of spontaneous SV fusion requires a specific interaction of CPX-1 with the SV membrane. We propose that Cpx cannot efficiently access assembling SNAREs from the cytoplasm and that interactions of its CTD with the SV membrane guide Cpx to these sites of SNARE assembly. KEY POINTS: Complexin (Cpx) regulates presynaptic SNARE assembly to control synaptic transmission. A membrane curvature-sensing motif within the Cpx C-terminal domain (CTD) recruits Cpx to vesicles. Replacement of the CTD with the synaptic vesicle protein Rab3 can restore full Cpx function whereas other vesicle proteins fail to substitute regardless of abundance. The efficiency of Cpx-mediated inhibition of synaptic vesicle fusion is profoundly enhanced by the specific localization supplied by its CTD. These results suggest that Cpx reaches the assembling SNARE complexes via its specific CTD-membrane interactions and these SNAREs are inaccessible from the cytoplasmic compartment.}, }
@article {pmid40320146, year = {2025}, author = {Su, CT and Saber, W and Bansal, A and Li, L and Nakamura, R and Cutler, C and Roth, JA and Wright, W and Steuten, L and Ramsey, SD}, title = {Out-of-Pocket Expenditures and Financial Hardship Among Patients with Myelodysplastic Syndrome Undergoing Allogeneic Transplant or Hypomethylating Agent / Supportive Care (BMT CTN 1102).}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.04.015}, pmid = {40320146}, issn = {2666-6367}, abstract = {INTRODUCTION: The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1102 trial demonstrated that allogeneic hematopoietic cell transplantation (HCT) was associated with superior overall survival compared to non-HCT approaches among elderly patients with higher-risk myelodysplastic syndrome (MDS). The trial included an ancillary cost diary component to assess the out-of-pocket (OOP) expenditures and financial hardship in the post-HCT period through three phased surveys for up to 19 months after enrollment.<br><br>OBJECTIVE: The purpose of the study is to assess the OOP costs and financial hardship experienced by participants of BMT CTN 1102.<br><br>STUDY DESIGN: BMT CTN 1102 assigned participants to Donor and No-Donor arms based on donor availability. Participants could additionally enroll in the ancillary cost diary component, with a total of 138 participants returning 267 surveys across three survey waves at 1-, 7-, and 19-months after enrollment. As participants who underwent HCT returned 78% (207/267) of the total surveys, we report on the collected data descriptively.<br><br>RESULTS: Participants who underwent HCT had high levels of monthly OOP expenditure ($1126, $812, $442) and financial hardship (47%, 53%, 57%) across the three survey waves. For reference, participants who did not undergo HCT generally reported lower levels of OOP expenditure ($478, $845, $256) and financial hardship (37%, 55%, 46%).<br><br>CONCLUSION: Among BMT CTN 1102 participants, those who underwent HCT reported high levels of OOP expenditures and financial hardship for up to 19 months after enrollment. Ongoing routine assessment of patient-level OOP expenditures and financial burden may be helpful in the post-HCT survivorship period.}, }
@article {pmid40319195, year = {2025}, author = {Merkel, EC and Meyer, CL and Yusuf, RA and Morrison, CF and Kelly, DL and Levine, DR and LeBlanc, TW and Ullrich, CK and El-Jawahri, A}, title = {What do pediatric transplant physicians think about palliative care? Results from a national survey study.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, pmid = {40319195}, issn = {1476-5365}, abstract = {The benefits of palliative care (PC) for hematopoietic cell transplant (HCT) patients are well established, however, uptake in pediatric HCT remains limited. To understand pediatric transplant physicians' attitudes towards PC, we conducted a cross-sectional study with a 28-question survey. A composite score and regression model identified factors associated with positive attitudes towards subspecialty PC. Ninety-eight participants reported caring for pediatric patients. Most (81%) trust PC clinicians to care for their patients, yet 33% feel PC clinicians lack enough HCT knowledge to counsel patients. Nearly half (46%) see the name "PC" as a barrier to referral. Multivariable analysis showed that spiritual practice (β = 1.53, p = 0.029), <10 years of clinical practice (β = 2.23, p = 0.007), and perceived PC quality (β = 0.73, p < 0.001) were associated with a more positive attitude towards PC. More training in PC (β = -2.70, p = 0.003) and a higher sense of ownership over PC issues (β = -0.51, p = 0.001) were associated with a more negative attitude towards subspecialty PC. These findings highlight barriers to pediatric HCT and PC collaboration, including concerns about PC team knowledge of HCT and patient perceptions. While most pediatric transplant physicians trust PC to enhance patient care, interventions are needed to improve collaboration.}, }
@article {pmid40319052, year = {2025}, author = {Olivieri, DJ and Berridge-Green, A and Othus, M and Radich, JP and Advani, AS and Erba, HP and Walter, RB}, title = {Biobanking and consent to future biospecimen use among adults enrolled in SWOG trials from 2000 to 2024.}, journal = {Blood cancer journal}, volume = {15}, number = {1}, pages = {85}, pmid = {40319052}, issn = {2044-5385}, support = {U10 CA180819/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; ASH HONORS Award (DJO)//American Society of Hematology (ASH)/ ; U10-CA180888, U10-CA180819//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; }, }
@article {pmid40318950, year = {2025}, author = {Grivas, P and Aragon-Ching, JB and Bellmunt, J and Loriot, Y and Climent Duran, MA and Sridhar, SS and Su, PJ and Park, SH and Kopyltsov, E and Yamamoto, Y and Jacob, N and Hoffman, J and Tyroller, K and Manitz, J and Kearney, M and Schlichting, M and Powles, T}, title = {Avelumab First-line Maintenance for Advanced Urothelial Carcinoma: Long-term Analyses of Patient-reported Outcomes and Quality-adjusted Time Without Symptoms or Toxicity from the JAVELIN Bladder 100 Trial.}, journal = {European urology oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.euo.2025.04.004}, pmid = {40318950}, issn = {2588-9311}, abstract = {BACKGROUND AND OBJECTIVE: In JAVELIN Bladder 100, avelumab first-line maintenance plus best supportive care (BSC) significantly prolonged overall survival versus BSC alone, with no detrimental impact on quality of life (QOL), in patients with advanced urothelial carcinoma without progression following first-line platinum-based chemotherapy. We report long-term analyses of patient-reported outcomes (PROs) in patients treated with avelumab (any duration or ≥12 mo) and a post hoc analysis comparing quality-adjusted time without symptoms or toxicity (Q-TWiST) between arms.<br><br>METHODS: PROs were assessed using National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Bladder Symptom Index-18 (FBlSI-18) and EuroQol 5-level EQ-5D (EQ-5D-5L). Q-TWiST was calculated as the utility-weighted sum of mean time in three health states: time with all-cause grade 3/4 toxicity prior to progression, time without grade 3/4 toxicity or symptoms of progression, and time after progression.<br><br>KEY FINDINGS AND LIMITATIONS: In the overall avelumab plus BSC arm (n&#xa0;=&#xa0;350) and the subgroup treated for &#x2265;12&#xa0;mo (n&#xa0;=&#xa0;118), completion rates for PRO assessments during treatment were >80%. FBlSI-18 total and EQ-5D-5L index scores remained stable throughout 24&#xa0;mo of treatment, with no clinically important changes from baseline. The mean Q-TWiST was 18.46&#xa0;mo with avelumab plus BSC versus 15.13&#xa0;mo with BSC alone (22% relative improvement). Limitations include open-label trial design and small patient numbers at later cycles.<br><br>Patients receiving avelumab had preserved health-related QOL and control of cancer-related symptoms with manageable toxicity, further supporting avelumab first-line maintenance as the recommended treatment for advanced urothelial carcinoma not progressed after platinum-based chemotherapy.}, }
@article {pmid40318860, year = {2025}, author = {Tembhare, P and Chen, X and Chan, JKC and Wood, B and Naresh, KN}, title = {Fifth edition WHO classification: precursor lymphoid neoplasms, acute leukaemias of mixed or ambiguous lineage, myeloid/lymphoid neoplasms, and histiocytic and dendritic cell neoplasms, including strategies for application in resource-limited settings.}, journal = {Journal of clinical pathology}, volume = {}, number = {}, pages = {}, doi = {10.1136/jcp-2025-210135}, pmid = {40318860}, issn = {1472-4146}, abstract = {The fifth edition of the WHO classification of haematolymphoid tumours (WHO-HEM5) introduces significant updates to the classification of acute lymphoblastic leukaemia, ALAL (including mixed phenotype acute leukaemia (MPAL)), myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK), and histiocytic and dendritic cell neoplasms, reflecting the advances in the understanding of the genetic basis of these diseases. This review provides an overview of these changes, highlighting a shift to a more refined molecular-genetic approach. The incorporation of newly recognised genetic subtypes into the classification scheme underscores the evolving landscape of these entities. Challenges in diagnosing ALAL/MPAL and MLN-TK are discussed, along with recent insights into histiocytic and dendritic cell neoplasms, including newly defined entities such as ALK-positive histiocytosis.The review also explores the practical implications of WHO-HEM5, particularly in resource-limited settings, where comprehensive molecular testing may be unavailable. While morphology and immunohistochemistry remain essential diagnostic tools, strategic use of flow cytometry and targeted fluorescence in situ hybridisation can facilitate risk-adapted classification and improve survival in regions with limited resources and therapeutic options. Future large-scale studies are necessary to establish the diagnostic and prognostic value of these newly genetically defined entities for diverse healthcare environments, and to standardise guidelines in refining disease classification and optimising patient outcomes.}, }
@article {pmid40318736, year = {2025}, author = {Lee, SJ and Pavletic, S and Blazar, BR and Yao, Y and Ji, R and Marshall, K and Cutler, C and , }, title = {Belumosudil for Chronic Graft-Versus-Host Disease: Analysis of Long-Term Results From the KD025-208 and ROCKstar Studies.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.04.020}, pmid = {40318736}, issn = {2666-6367}, abstract = {BACKGROUND: Belumosudil is an oral selective rho-associated coiled-coil-containing protein kinase-2 (ROCK2) inhibitor approved for the treatment of chronic graft-versus-host disease (cGVHD) following an allogeneic hematopoietic cell transplant (alloHCT) in patients aged ≥12 years after failure of ≥2 prior systemic lines of therapy (LOTs). The KD025-208 (NCT02841995) and KD025-213 (ROCKstar; NCT03640481) studies demonstrated that belumosudil was well tolerated, with clinically meaningful responses in patients with cGVHD. KD025-217 (NCT05305989) is a follow-up study that evaluated extended treatment with belumosudil in patients enrolled in the parent studies, KD025-208 and ROCKstar.<br><br>OBJECTIVE: This pooled analysis reports the long-term follow-up (overall median follow-up duration of 31.4 months) results from these studies in patients with cGVHD.<br><br>STUDY DESIGN: The study included a total of 208 patients across 3 cohorts. Cohort 1 (n=95) received belumosudil 200 mg once daily, cohort 2 (n=92) received belumosudil 200 mg twice daily and cohort 3 (n=21) received belumosudil 400 mg once daily. The primary end point was best overall response rate (ORR). Duration of response (DOR), failure-free survival (FFS) and time to next treatment (TTNT) were also evaluated in this analysis.<br><br>RESULTS: The best ORR in the modified intent-to-treat (mITT) population was 72%. The median DOR for the responder population was 62.3 weeks (range, 36.1-82.6 weeks). The median FFS in the mITT population was 15.1 months (range, 11.3-20.6 months). The 1- and 2-year FFS rates were 56% and 40%, respectively. The median TTNT was 22.1 months (range, 15.2-40.3 months), where 47% of patients received a new systemic therapy for cGVHD by 36 months.<br><br>CONCLUSION: When compared with the published data, the long-term results from this pooled analysis of these two phase 2 studies demonstrated belumosudil was associated with durable responses, and it remained well tolerated with no new safety concerns.}, }
@article {pmid40313749, year = {2025}, author = {Chanda, A and Song, Y and Nazir, J and Lin, C and Cheng, A and Sargent, J and Sikora, AE}, title = {Bridging Gaps in Antibody Responses and Animal Welfare: Assessing Blood Collection Methods and Vaginal Immunity in Mice Immunized with Intranasal Gonococcal Vaccines.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40313749}, issn = {2693-5015}, support = {R01 AI117235/AI/NIAID NIH HHS/United States ; }, abstract = {Assessing antibody titers and functional responses is essential for evaluating vaccine efficacy, yet the impact of blood collection methods on these immunological assessments remains unclear. Retro-orbital (RO) blood collection is commonly used but significant complications can occur. Increasingly, investigators have adopted alternative blood collection approaches, such as saphenous vein (SV) sampling to improve laboratory animal welfare. This study compared RO and SV sampling in the development of a Neisseria gonorrhoeae (Ng) vaccine, evaluating Adhesin Complex Protein (ACP) and multiple transferable resistance (Mtr) E protein (MtrE) as antigen candidates. Epitope mapping revealed that ACP and MtrE possess multiple, highly accessible B-cell and T-cell epitope clusters, reinforcing their immunological potential. Following intranasal immunization with rACP, rACP+CpG, and rMtrE+CpG, we assessed the specificity, magnitude, kinetics, and functional quality of immune responses elicited by the immunization regimens. Out of 45 comparisons, only eight significant differences were detected in antibody titers, while the human serum bactericidal assays revealed no differences between RO and SV in antigen-immunized groups. However, antibodies elicited by rACP alone or ACP+CpG in SV samples restored 30.05% and 75.2% of human lysozyme hydrolytic activity compared to 19.3 and 59.9 % in RO, respectively suggesting that SV sampling may be more reliable for assessing functional antibody responses. Beyond its immunological advantages, SV sampling reduces stress, minimizes ocular trauma, and improves animal welfare, making it a viable alternative to RO collection. Given its widespread use in vaccine research, standardizing SV sampling could improve data reliability, ethical compliance, and translational relevance in preclinical studies.}, }
@article {pmid40317503, year = {2025}, author = {Christie, JR and Romine, P and Eddy, K and Chen, DL and Daher, O and Abdelrazek, M and Malthaner, RA and Qiabi, M and Nayak, R and Kinahan, P and Nair, VS and Mattonen, SA}, title = {Thorax-encompassing multi-modality PET/CT deep learning model for resected lung cancer prognostication: A retrospective, multicenter study.}, journal = {Medical physics}, volume = {}, number = {}, pages = {}, doi = {10.1002/mp.17862}, pmid = {40317503}, issn = {2473-4209}, support = {//Gerald C. Baines Foundation/ ; //London Health Sciences Foundation/ ; 152218//Cancer Research Society/ ; //Natural Sciences and Engineering Research Council of Canada/ ; 2020-06498//Discovery Grants program/ ; //Lawson Health Research Institute's Internal Research Fund (IRF)/ ; T32CA009515/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Patients with early-stage non-small cell lung cancer (NSCLC) typically receive surgery as their primary form of treatment. However, studies have shown that a high proportion of these patients will experience a recurrence after their resection, leading to an increased risk of death. Cancer staging is currently the gold standard for establishing a patient's prognosis and can help clinicians determine patients who may benefit from additional therapy. However, medical images which are used to help determine the cancer stage, have been shown to hold unutilized prognostic information that can augment clinical data and better identify high-risk NSCLC patients. There remains an unmet need for models to incorporate clinical, pathological, surgical, and imaging information, and extend beyond the current staging system to assist clinicians in identifying patients who could benefit from additional therapy immediately after surgery.<br><br>PURPOSE: We aimed to determine whether a deep learning model (DLM) integrating FDG PET and CT imaging from the thoracic cavity along with clinical, surgical, and pathological information can predict NSCLC recurrence-free survival (RFS) and stratify patients into risk groups better than conventional staging.<br><br>MATERIALS AND METHODS: Surgically resected NSCLC patients enrolled between 2009 and 2018 were retrospectively analyzed from two academic institutions (local institution: 305 patients; external validation: 195 patients). The thoracic cavity (including the lungs, mediastinum, pleural interfaces, and thoracic vertebrae) was delineated on the preoperative FDG PET and CT images and combined with each patient's clinical, surgical, and pathological information. Using the local cohort of patients, a multi-modal DLM using these features was built in a training cohort (n&#xa0;=&#xa0;225), tuned on a validation cohort (n&#xa0;=&#xa0;45), and evaluated on testing (n&#xa0;=&#xa0;35) and external validation (n&#xa0;=&#xa0;195) cohorts to predict RFS and stratify patients into risk groups. The area under the curve (AUC), Kaplan-Meier curves, and log-rank test were used to assess the prognostic value of the model. The DLM's stratification performance was compared to the conventional staging stratification.<br><br>RESULTS: The multi-modal DLM incorporating imaging, pathological, surgical, and clinical data predicted RFS in the testing cohort (AUC&#xa0;=&#xa0;0.78 [95% CI:0.63-0.94]) and external validation cohort (AUC&#xa0;=&#xa0;0.66 [95% CI:0.58-0.73]). The DLM significantly stratified patients into high, medium, and low-risk groups of RFS in both the testing and external validation cohorts (multivariable log-rank p&#xa0;<&#xa0;0.001) and outperformed conventional staging. Conventional staging was unable to stratify patients into three distinct risk groups of RFS (testing: p&#xa0;=&#xa0;0.94; external validation: p&#xa0;=&#xa0;0.38). Lastly, the DLM displayed the ability to further stratify patients significantly into sub-risk groups within each stage in the testing (stage I: p&#xa0;=&#xa0;0.02, stage II: p&#xa0;=&#xa0;0.03) and external validation (stage I: p&#xa0;=&#xa0;0.05, stage II: p&#xa0;=&#xa0;0.03) cohorts.<br><br>CONCLUSION: This is the first study to use multi-modality imaging along with clinical, surgical, and pathological data to predict RFS of NSCLC patients after surgery. The multi-modal DLM better stratified patients into risk groups of poor outcomes when compared to conventional staging and further stratified patients within each staging classification. This model has the potential to assist clinicians in better identifying patients that may benefit from additional therapy.}, }
@article {pmid40316478, year = {2025}, author = {Cavanaugh, D and Holt, SK and Dwyer, E and Petersen, E and Gore, JL and Schade, GR and Grivas, P and Hsieh, AC and Lee, JK and Montgomery, B and Schweizer, MT and Yezefski, T and Yu, EY and Chen, JJ and Liao, JJ and Weg, E and Zeng, J and Jannat, S and Berry, DL and Master, VA and Garcia, JM and Reed, MJ and Bentov, I and Wright, JL and Psutka, SP}, title = {Prospective evaluation of comprehensive geriatric assessments in multidisciplinary bladder cancer care and implications for personalized vulnerability phenotyping.}, journal = {Urologic oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.urolonc.2025.03.025}, pmid = {40316478}, issn = {1873-2496}, abstract = {PURPOSE: Frailty predicts adverse outcomes in bladder cancer (BC). Current guidelines endorse completion of Comprehensive Geriatric Assessments (CGAs) in older adults prior to treatment election to objectively measure frailty, however, these are rarely performed in urologic practice due to inadequate resources. We hypothesized CGA implementation would be feasible and identify multifaceted vulnerabilities beyond standard risk assessments in a multidisciplinary BC clinic and developed a novel method to visualize "vulnerability phenotypes" to guide supportive interventions.<br><br>METHODS: Adults with BC were prospectively enrolled (June, 2020-July, 2021). Initially, patients underwent standard of care (SOC) risk assessment (N&#x202f;=&#x202f;27). Subsequently, patients completed CGAs augmented with body composition assessments (N&#x202f;=&#x202f;67). CGA completion time, rates, and patient-reported burden were assessed. Interdependence of CGA domains were quantified using Spearman correlation coefficients and compared decisional conflict and regret between arms. Vulnerability phenotypes were visualized using Spider Plots, generated in R. Clinical and survival associations with CGAs were evaluated using Cox proportional hazards models.<br><br>RESULTS: 94 patients were enrolled with a median age of 72 years. Instrument completion in the CGA cohort was 79% to 100%. 91% of patients reported CGA completion was at most minimally burdensome. CGAs identified vulnerabilities including 31% vulnerable-to-moderately frail, 21% with mild-to-severe depression, 3% with mild-moderate dementia, and 40% at risk for malnutrition-malnourished. Frailty measures across instruments were weakly correlated (rho <0.4). In this heterogeneous cohort, vulnerability domains were not significantly associated with decisional conflict/regret, survival, nor complication rates after treatment. A novel Spider Plot tool is proposed to facilitate communication of the dominant vulnerability-driving individual risks.<br><br>CONCLUSIONS: CGAs can be successfully incorporated into uro-oncology practice with low perceived burden, identifying key vulnerabilities with implications for clinical care. Weak correlations across instruments support the value of gathering information across discrete domains. We present a novel approach to visually characterize personalized vulnerability phenotypes.}, }
@article {pmid40315850, year = {2025}, author = {Wu, W and Ahmad, K and Henikoff, S}, title = {Chromatin-bound U2AF2 splicing factor ensures exon inclusion.}, journal = {Molecular cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.molcel.2025.04.013}, pmid = {40315850}, issn = {1097-4164}, abstract = {Most mRNA splicing occurs co-transcriptionally, but it is unclear how splicing factors accurately select exons for inclusion. Using CUT&amp;RUN profiling in K562 cells, we demonstrate that three splicing factors-SF3B1, U2AF1, and U2AF2-bind near active promoters of intron-containing and intronless genes, implying their association with the general transcriptional machinery. RNase A treatment reduces factor binding at promoters, indicating that these proteins interact with nascent transcripts. Strikingly, the U2AF2 protein also accumulates throughout intron-containing gene bodies and requires histone H3-lysine36 trimethylation but not nascent transcripts or persistent RNA polymerase II. Chromatin-bound U2AF2 preferentially binds to exons of highly expressed, exon-dense genes, with greater occupancy at exons skipped after U2AF2 knockdown, suggesting that U2AF2 enhances exon selection accuracy. U2AF2-targeted genes include those encoding splicing factors, where it improves splicing accuracy and efficiency. Our findings provide a mechanistic basis for the homeostatic regulation of efficient co-transcriptional splicing by chromatin-bound U2AF2.}, }
@article {pmid40315406, year = {2025}, author = {Chen, W and Chang, TC and Rabin, KR and Raetz, EA and Devidas, M and Hunger, SP and Ramirez, NC and Mullighan, CG and Loh, ML and Wu, G}, title = {Performance of Two-Phase Designs for the Time-to-Event Outcome and a Case Study Assessing the Relapse Risk Associated With B-ALL Subtypes.}, journal = {JCO clinical cancer informatics}, volume = {9}, number = {}, pages = {e2400223}, pmid = {40315406}, issn = {2473-4276}, mesh = {Humans ; Case-Control Studies ; *Research Design ; Computer Simulation ; *Neoplasm Recurrence, Local ; }, abstract = {PURPOSE: To reduce costs in genomic studies of time-to-event phenotypes like survival, researchers often sequence a subset of samples from a larger cohort. This process usually involves two phases: first, collecting inexpensive variables from all samples, and second, selecting a subset for expensive measurements, for example, sequencing-based biomarkers. Common two-phase designs include nested case-control and case-cohort designs. Additional designs include sampling subjects based on follow-up time, like extreme case-control designs. Recently an optimal two-phase design using a maximum likelihood-based method was proposed, which could accommodate arbitrary sample selection in the second phase. However, direct comparisons of this optimal design with others in terms of power and computational cost is lacking.<br><br>METHODS: This study performs a direct evaluation of typical two-phase designs, including Tao's optimal design, on type I error, power, effect size estimation, and computational time, using both simulated and real data sets.<br><br>RESULTS: Results show that the optimal design had the highest power and accurate effect size estimation under the Cox regression model. Surprisingly, logistic regression achieved similar power with much lower computational cost than a more sophisticated method. The study further applied these methods to the MP2PRT study, reporting hazard ratios of cancer subtypes on relapse risk.<br><br>CONCLUSION: Recommendations for selecting two-phase designs and analysis methods are regarding power, bias of estimated effect size, and computational time.}, }
@article {pmid40315399, year = {2025}, author = {Carlsson, SV and Barata, PC and Bryce, AH and George, DJ and Gillessen, S and Loeb, S and Montgomery, B and Morris, D and Riaz, IB and Palapattu, G and Schoen, MW and Washington Iii, SL and Cornell, B and Levine, R and Aggarwal, P and McGowan, T and Cotter, M and Thompson, B and Devgan, G and Russell, D and Kuperman, G and Lenero, E and Iwata, K and Miyahira, AK and Soule, HR and Carithers, G and Oh, WK and Agarwal, N}, title = {Prostate Cancer Foundation White Paper on Combination Therapy for Metastatic Hormone-Sensitive Prostate Cancer.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2500050}, doi = {10.1200/OP-25-00050}, pmid = {40315399}, issn = {2688-1535}, abstract = {Despite several randomized controlled trials demonstrating the benefits of combination therapies for metastatic hormone-sensitive prostate cancer (mHSPC), a significant treatment gap persists. This initiative by the Prostate Cancer Foundation (PCF) convened stakeholders from academia, community practices, industry, and patient advocacy groups to address critical challenges in mHSPC care. Expert discussions and a review of real-world evidence and meta-analyses informed the development of strategies to improve care delivery. Evaluation of the data from global registries, such as IRONMAN, and large community databases was used to assess treatment utilization patterns and disparities. Combination therapies with two agents-androgen deprivation therapy (ADT) plus an androgen receptor pathway inhibitor (ARPI)-or three agents-ADT + ARPI + docetaxel-demonstrate significant survival improvements while preserving quality of life for patients with mHSPC, yet adoption remains inconsistent. Of the eligible patients, 20%-60% remain undertreated, with geographic, financial, and systemic barriers contributing to inconsistencies in care. Younger, White, urban-dwelling patients with fewer comorbidities are more likely to receive combination treatment, highlighting disparities across populations. Meta-analyses identified a lack of standardization due to varying inclusion criteria and comparators across trials. Real-world evidence underscored disparities influenced by geographic location, practice type, and access to specialty care. Initiatives such as the PANTHER study highlight improved outcomes in Black patients treated with combination therapies, emphasizing the importance of including diverse populations in clinical trials. To bridge gaps in care, this initiative prioritizes awareness, standardization, and equitable access to evidence-based therapies. Proposed solutions include targeted knowledge dissemination strategies, development of educational resources, and advocacy for policy changes to promote guideline-concordant care. By leveraging collaborative efforts, organizations, including PCF, can contribute to enhancing survival outcomes and quality of life for all patients with mHSPC.}, }
@article {pmid40315333, year = {2025}, author = {Geiger, RA and Khera, D and Tenthorey, JL and Kochs, G and Graf, L and Emerman, M and Malik, HS}, title = {Heterozygous and generalist MxA super-restrictors overcome breadth-specificity trade-offs in antiviral restriction.}, journal = {Science advances}, volume = {11}, number = {18}, pages = {eadu0062}, pmid = {40315333}, issn = {2375-2548}, mesh = {*Myxovirus Resistance Proteins/genetics/metabolism/chemistry ; Humans ; Influenza A Virus, H5N1 Subtype ; *Antiviral Agents/pharmacology ; Thogotovirus ; }, abstract = {Antiviral restriction factors such as MxA (myxovirus resistance protein A) inhibit many viruses. Viral escape drives restriction factors to evolve rapidly at virus-binding interfaces to regain defense. Here, we explore how antiviral proteins balance restricting many viruses with evolving specificity against individual viruses. Human MxA uses its rapidly evolving loop L4 as the specificity determinant for orthomyxoviruses such as thogotovirus (THOV) and influenza (IAV). Previous combinatorial mutagenesis of rapidly evolving residues in human MxA loop L4 identified THOV "super-restrictors" and suggested an antiviral breadth-specificity trade-off. Using a modified combinatorial mutagenesis strategy, we find super-restrictor MxA variants specific to H5N1 IAV. A single L4 residue underlies the MxA breadth-specificity trade-off. However, rare "generalist" super-restrictors or a heterozygous combination of more common "specialist" super-restrictors can overcome the breadth-specificity trade-off. Our findings suggest that at least two strategies enable restriction factors such as MxA to increase their restriction of diverse viruses to overcome breadth-specificity trade-offs, which might be pervasive in host-virus conflicts.}, }
@article {pmid40314975, year = {2025}, author = {Zheng, Y and Ahmad, K and Henikoff, S}, title = {Total whole-arm chromosome losses predict malignancy in human cancer.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {18}, pages = {e2505385122}, doi = {10.1073/pnas.2505385122}, pmid = {40314975}, issn = {1091-6490}, support = {Henikoff//Howard Hughes Medical Institute (HHMI)/ ; HG012797//HHS | National Institutes of Health (NIH)/ ; }, mesh = {Humans ; *Neoplasms/genetics/pathology ; *Aneuploidy ; Centromere/genetics/metabolism ; Histones/genetics/metabolism ; }, abstract = {Aneuploidy is observed as gains or losses of whole chromosomes or chromosome arms and is a common hallmark of cancer. Whereas models for the generation of aneuploidy in cancer invoke mitotic chromosome segregation errors, whole-arm losses might occur simply as a result of centromere breakage. We recently showed that elevated RNA Polymerase II level over the S-phase-dependent histone genes predicts rapid recurrence of human meningioma and is correlated with total whole-arm losses relative to gains. To explain this imbalance in arm losses over gains, we have proposed that histone overexpression at S-phase competes with the histone H3 variant CENP-A, resulting in centromere breaks and whole-arm losses. To test whether centromere breaks alone can drive aneuploidy, we ask whether total whole-arm aneuploids can predict outcomes across different cancer types in large RNA and whole-genome sequencing databanks. We find that total whole-arm losses generally predict outcome, suggesting that centromere breakage is a major initiating factor leading to aneuploidy and the resulting changes in the selective landscape that drive most cancers. We also present evidence that centromere breakage alone is sufficient to account for whole-arm losses and gains, contrary to mitotic spindle error models for the generation of aneuploidy. Our results suggest that therapeutic intervention targeting histone overexpression has the potential to reduce aneuploidy and slow cancer progression.}, }
@article {pmid40311704, year = {2025}, author = {Alfaifi, SA and Louie, AV and Siva, S and Guckenberger, M and Videtic, GMM and Higgins, KA and Alshafa, F and AlGhamdi, H and Gillespie, EF and Stephans, K and Mula-Hussain, L and Harrow, S and Palma, DA}, title = {International Patterns of Practice for Stereotactic Ablative Radiotherapy for Early-Stage Non-Small Cell Lung Cancer: Are We All in Sync?: Global patterns of practice for SABR for early-stage NSCLC.}, journal = {International journal of radiation oncology, biology, physics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ijrobp.2025.04.022}, pmid = {40311704}, issn = {1879-355X}, abstract = {PURPOSE: To generate an understanding of the similarities and variations in international practice patterns for stereotactic ablative radiotherapy (SABR) in early-stage non-small cell lung cancer (NSCLC).<br><br>METHODS: An online survey was conducted from October to December 2023, addressing general clinical and technical considerations for lung SABR, and for 5 specific anatomical NSCLC locations (peripheral, abutting chest wall, near brachial plexus, central, and ultra-central). Invitations to participate were extended through email and were distributed on social media.<br><br>RESULTS: The survey was completed by 255 radiation oncologists, each representing a single institution across 51 countries. Respondents reported treating a median of 20 cases annually. A total of 38% of participants reported using single-fraction SABR, and 54% applied an upper limit on the maximum dose (Dmax). Among those who applied a Dmax limit, 58% reported a Dmax threshold at &#x2265;130% of the prescription, though this limit varied by region and national economy status. Respondents from low- and middle-income countries were less likely to set a Dmax limit at &#x2265;130% (30% vs. 66%, p < 0.01) and less likely to use single-fraction SABR (14% vs. 44%, p < 0.01). Higher annual SABR patient volumes were associated with higher Dmax adoption (&#x433;&#x202f;=&#x202f;0.23, p < 0.01). Across the 5 clinical scenarios presented; 57 distinct dose regimens were recommended. The most common regimen in each scenario was: 54 Gy in 3 fractions for peripheral tumors, 50 Gy in 5 fractions for apical, central, and abutment of chest wall, and 60 Gy in 8 fractions for ultra-central tumors. Approximately two-thirds of practices recommend a biologically effective dose (BED10) <100 Gy for one or more anatomical sites.<br><br>CONCLUSION: The findings reveal considerable variation in global SABR practice. These differences highlight the need for further data to guide prescription practices, and an international experts' consensus may be beneficial to standardize practice.}, }
@article {pmid40311075, year = {2025}, author = {Sharma, R and Holtzman, NG and Pusic, I and Cutler, CS and Treister, N and Mehta, RS and Alousi, AS and Vigneswaran, N and Javaid, A and Boksa, FA and Mody, DP and Costa-da-Silva, AC and Schueller, O and Macé, S and Yao, Y and Ji, R and Hu, B and Marshall, K and Blazar, BR and Lee, SJ and Pavletic, SZ and Mays, JW}, title = {Belumosudil reduces oral chronic graft-versus-host disease tissue inflammation and fibrosis: a ROCKstar companion study.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025016170}, pmid = {40311075}, issn = {2473-9537}, abstract = {Belumosudil (KD025), an oral, selective, Rho-associated, coiled-coil containing protein kinase 2 (ROCK2) inhibitor, is approved for third-line treatment of chronic graft-versus-host disease (cGVHD). Previous studies demonstrated that ROCK2 inhibition reduces blood interleukin (IL)-17 activity and promotes regulatory T-cell (Treg) recovery. However, these studies did not evaluate immune responses within cGVHD-affected tissues. This study assessed tissue-level immune dynamics in 20 subjects with oral cGVHD from the phase 2 ROCKstar trial, before and after 6 months of belumosudil treatment, focusing on key effector sites (oral mucosa [OM], minor salivary glands [MSG], and skin) and peripheral blood. Following belumosudil treatment, reduction in collagen was observed in OM in parallel with decreased IL-17+ cell frequency in both OM (n = 14 pairs) and MSG (n = 11 pairs). IL-17 was primarily produced by non-T cells in the oral tissues. Immune cell frequencies in the OM decreased following treatment, while CD4 Tregs increased in both MSG and blood. Per overall or mouth-specific clinical response criteria, responders to belumosudil exhibited a reduction in collagen type I and IL-17 in OM. Additionally, salivary transforming growth factor β1 (TGF)-β1, a critical driver of fibrosis, decreased significantly, with a strong correlation observed between TGF-β1 and IL-17 levels. These findings illustrate the tissue-level response to belumosudil therapy and suggest that there is a reduction in tissue fibrosis and inflammation, thereby highlighting the therapeutic impact of ROCK2 inhibition in mitigating cGVHD. The ROCKstar study was registered at www.clinicaltrials.gov as NCT03640481.}, }
@article {pmid40309186, year = {2025}, author = {Andrews, SS and Brent, R}, title = {Individual yeast cells signal at different levels but each with good precision.}, journal = {Royal Society open science}, volume = {12}, number = {4}, pages = {241025}, pmid = {40309186}, issn = {2054-5703}, abstract = {Different isogenic cells exhibit different responses to the same extracellular signals. Several authors assumed that this variation arose from stochastic signalling noise with the implication that single eukaryotic cells could not detect their surroundings accurately, but work by us and others has shown that the variation is dominated instead by persistent cell-to-cell differences. Here, we analysed previously published data to quantify the sources of variation in pheromone-induced gene expression in Saccharomyces cerevisiae. We found that 91% of response variation was due to stable cell-to-cell differences, 8% from experimental measurement error, and 1% from signalling noise and expression noise. Low noise enabled precise signalling; individual cells could transmit over 3 bits of information through the pheromone response system and so respond differently to eight different pheromone concentrations. Additionally, if individual cells could reference their responses against constitutively expressed proteins, then cells could determine absolute pheromone concentrations with 2 bits of accuracy. These results help explain how individual yeast cells can accurately sense and respond to different extracellular pheromone concentrations.}, }
@article {pmid40308027, year = {2025}, author = {Gomez, RA and Hou, J and Gersuk, VH and Chow, IT and Farrington, ML and Robinson, D and Kwok, WW}, title = {Ara h 2105-124-Specific TH2A Cells Drive Peanut Allergy in DRB1*15:01 Individuals: A Detailed Epitope Analysis.}, journal = {Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology}, volume = {}, number = {}, pages = {}, doi = {10.1111/cea.70072}, pmid = {40308027}, issn = {1365-2222}, support = {U19 AI135817/NH/NIH HHS/United States ; }, abstract = {BACKGROUND: The IgE-mediated CD4 T-cell response to peanut (Arachis hypogaea) is heterogeneous, yet TH2 cells remain central drivers of pathology. This study aimed to dissect this complexity at the epitope level by focusing on the HLA-DRB1*15:01-DRB5*01:01 haplotype. Specifically, we examined how distinct epitope-specific T-cell subsets shape the immunological landscape of peanut allergy in peanut-allergic (PA) versus non-peanut-allergic (NPA) individuals.<br><br>METHODS: Using in&#xa0;vitro and ex&#xa0;vivo MHC-II tetramer approaches, the phenotype, frequency, function, and transcriptome of CD4 T-cell responses to novel Ara h epitopes were assessed. Bulk RNA sequencing further characterised these T cells, allowing identification of subsets associated with TH2 polarisation in PA individuals.<br><br>RESULTS: Eleven HLA-DRB1*15:01 and DRB5*01:01-restricted epitopes were identified in Ara h 1, 2, 3, 6, 7, and 8 using tetramer-guided epitope mapping on cell lines, followed by ex&#xa0;vivo validation in peripheral blood. T-cell phenotype was epitope-dependent, with a distinct TH2A population specific to the epitope Ara h 2105-124 (Ara h 2 p14) detected only in PA donors. These TH2A cells were phenotypically and transcriptionally distinct, marked by high CRTH2/CD161, low CD27, IL-5 production, and gene enrichment in cytokine signalling and lipid metabolism. Other epitope-specific T-cell subsets displayed more heterogeneous gene profiles related to immune activation, differentiation, and antigen presentation, underscoring the complexity of peanut-specific responses even within a single HLA haplotype.<br><br>CONCLUSION: These findings reveal that the strong TH2 bias in DRB1*15:01-DRB5*01:01 PA individuals arises from a distinct subset of Ara h 2 p14-specific TH2A cells characterised by a specialised metabolic and cytokine signalling program. At the same time, the functional diversity observed in non-Ara h 2 p14 subsets highlights the potential for leveraging these populations in tolerance-promoting therapies. Understanding the epitope-level heterogeneity of peanut-specific T-cells provides insight into the epitope-specific mechanisms driving peanut allergy and has potential implications for therapeutic interventions.}, }
@article {pmid40307656, year = {2025}, author = {Keiser, E and Corbett, AM and Chido-Amajuoyi, O and Antoine, A and Stehman, C and Dorn, I and Goines, D and LoConte, NK}, title = {Acceptability of Stool-Based DNA Colorectal Cancer Screening among Black/African-American Patients Served by Federally Qualified Health Centers.}, journal = {Journal of cancer education : the official journal of the American Association for Cancer Education}, volume = {}, number = {}, pages = {}, pmid = {40307656}, issn = {1543-0154}, support = {UWCCC: University of Wisconsin Carbone Cancer Center Support Grant P30 CA014520/CA/NCI NIH HHS/United States ; }, abstract = {Colorectal cancer (CRC) has an increased burden among Black/African-American populations. Following the COVID-19 pandemic, home-based CRC screening options are being used more frequently. We conducted focus groups to understand the acceptability of stool-based DNA testing for CRC screening in this population. Ten focus groups about the acceptability of various CRC screening modalities were held with Black/African-American participants at two federally qualified health centers (FQHCs) in Milwaukee, Wisconsin. Participants were separated into focus groups based on age and gender. Thematic analysis was carried out using NVivo. Across the groups, there were a total of 79 participants, of which 40.5% were aged 40-50 years ("younger participants"), 59.5% aged > 50 years ("older participants"), 53.2% male, and 46.8% female. Overall, knowledge was low regarding perceived risk of CRC. There was limited awareness of CRC screening options among younger patients and widespread lack of knowledge about stool-based DNA testing. Most respondents preferred colonoscopy as their first-choice screening test but were open to other screening tests. Stool-based DNA tests were more preferred among younger participants but was felt to be acceptable across all groups. Given the low awareness/knowledge of screening modalities identified in our study, educational interventions and shared decision making by primary care providers are needed.}, }
@article {pmid40307080, year = {2025}, author = {Melão, BVLA and Assel, M and Pere, M and Nalavenkata, S and Touijer, KA and Laudone, VP and Lin, DW and Rivas, JG and Bjartell, A and Carlsson, SV}, title = {Assessment of postoperative practices and discharge recommendations after radical prostatectomy.}, journal = {Urologic oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.urolonc.2025.03.027}, pmid = {40307080}, issn = {1873-2496}, abstract = {PURPOSE: Consistent, accurate postoperative guidance is crucial for early recovery and patient satisfaction in urology, especially for radical prostatectomy (RP) patients. However, patients often receive inconsistent information, highlighting the need for standardized, evidence-based postoperative care guidelines.<br><br>MATERIALS AND METHODS: We conducted a comprehensive review and evaluation of current postoperative practices for RP. This involved (1) reviewing existing discharge information at Josie Robertson Surgery Center, Memorial Sloan Kettering Cancer Center to identify areas of improvement; (2) systematically evaluating inconsistencies in discharge instructions and their impact on patient care; (3) distributing an anonymous survey to urologists in the US and Europe via REDCap to gather insights into global postoperative care practices. The survey included questions on various aspects of postoperative care, such as catheter use, medication regimens, dietary restrictions, and physical activity guidelines.<br><br>RESULTS: We received 247 survey responses. Despite some consensus on certain postoperative practices and recommendations, significant variability existed, underscoring the lack of standardized guidelines. Notable differences were observed between US and European cohorts, particularly in postoperative length of stay and discharge practices. Only 1.4% of US responders discharged patients 3 or more days postsurgery compared to 46% in Europe. Variability was also noted in recommendations for erectile function medications and postoperative activity restrictions.<br><br>CONCLUSION: This study underscores the significant variability in postoperative care recommendations for RP and the urgent need for standardized, evidence-based guidelines. Implementing such guidelines will enhance patient recovery, satisfaction, and overall outcomes, improving postoperative care across various surgical procedures.}, }
@article {pmid40306967, year = {2025}, author = {Parihar, AS and Pant, N and Heidari, P and Fong, L and Iravani, A}, title = {Approaches to Imaging Immune Activation Using PET.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {}, number = {}, pages = {}, doi = {10.2967/jnumed.124.268289}, pmid = {40306967}, issn = {1535-5667}, abstract = {This review explores the role of PET in imaging immune activation, particularly in oncology. [18]F-FDG is widely used for assessing treatment response to immunotherapies and can demonstrate unique response patterns as well as immune-related adverse events. However, because of the limited specificity of [18]F-FDG, newer PET radiopharmaceuticals targeting specific cellular or subcellular components of the immune system have been developed that can provide more precise information. The development of immune-specific PET radiopharmaceuticals offers significant potential for improving immune monitoring in both clinical practice and research.}, }
@article {pmid40305682, year = {2025}, author = {Chappidi, MR and Newcomb, LF and Zheng, Y and Liu, M and Schenk, JM and Zhu, K and de la Calle, CM and Brooks, JD and Carroll, PR and Dash, A and Filson, CP and Gleave, ME and Liss, MA and Martin, F and McKenney, JK and Morgan, TM and Wagner, AA and Nelson, PS and Lin, DW}, title = {Magnetic Resonance Imaging at second surveillance biopsy after diagnosis in patients with Grade Group 1 prostate cancer in the Canary Prostate Active Surveillance Study.}, journal = {The Journal of urology}, volume = {}, number = {}, pages = {101097JU0000000000004592}, doi = {10.1097/JU.0000000000004592}, pmid = {40305682}, issn = {1527-3792}, abstract = {PURPOSE: No clear guidelines exist regarding MRI use after confirmatory biopsy during active surveillance (AS). Our objective was to evaluate MRI performance after confirmatory biopsy in patients with vs. without prior MRI-informed biopsy.<br><br>METHODS: Patients in Canary PASS with Gleason grade group (GG) 1 disease undergoing MRI-informed Biopsy 2, defined as second surveillance biopsy after diagnosis, were separated into prior vs. no prior MRI-informed biopsy groups. Primary outcome was reclassification (&#x2265;GG2) at MRI-informed Biopsy 2. Reclassification rates and location (systematic cores, targeted cores, both) were compared between groups. Univariable and multivariable logistic regression identified predictors of reclassification.<br><br>RESULTS: Patients with (n=101) vs. without (n=103) prior MRI-informed biopsy had lower reclassification rates at Biopsy 2 (21% vs. 36%, p=0.017) and lower GG at reclassification (95% vs. 73% of reclassifications to GG2, p=0.039). In multivariable modeling, PI-RADS 4-5 at MRI-informed Biopsy 2 was associated with increased odds of reclassification (OR=2.04 95%CI [1.04-4.05]). The negative predictive value of MRI at Biopsy 2 was 87% (95%CI[78-96]) and 73% (95%CI[61-85]) in with vs. without prior MRI groups, respectively. Reclassification location was identified by targeted cores only in 36% vs. 19% of patients with vs. without prior MRI, respectively (p=0.4). Reclassification location was identified by systematic cores only in 36% vs. 58% of patients with vs. without prior MRI, respectively (p=0.4).<br><br>CONCLUSIONS: These results support MRI use at Biopsy 2 and suggest negative surveillance MRI should not replace Biopsy 2. Both targeted and systematic cores should be taken at Biopsy 2 in patients with and without prior MRI on AS.}, }
@article {pmid40305509, year = {2025}, author = {Gabel, AM and Crosse, EI and Belleville, AE and Hogg, SJ and McKellar, SA and Abdel-Wahab, O and Thomas, JD and Bradley, RK}, title = {Muscleblind-like proteins are novel modulators of the tumor-immune microenvironment.}, journal = {PloS one}, volume = {20}, number = {4}, pages = {e0321148}, pmid = {40305509}, issn = {1932-6203}, mesh = {*Tumor Microenvironment/immunology/genetics ; Animals ; Humans ; Mice ; *RNA-Binding Proteins/genetics/metabolism/immunology ; Cell Line, Tumor ; CD8-Positive T-Lymphocytes/immunology ; Female ; Interferon-gamma/pharmacology ; *Neoplasms/immunology/genetics/pathology ; Gene Expression Regulation, Neoplastic ; Mice, Inbred C57BL ; Antigen Presentation ; }, abstract = {Exploiting the immune system to eradicate cancer cells is an area of intense clinical study. However, the mechanisms that shape the tumor-immune microenvironment are incompletely understood. Here, we identify Muscleblind-like (MBNL) proteins as novel modulators of the tumor-immune microenvironment across diverse cancers. We demonstrate that loss of tumor MBNL expression results in an attenuated response to interferon gamma and reduced tumor antigen presentation in melanoma, breast cancer, and colorectal cancer cells. Parallel experiments in a syngeneic mouse melanoma model revealed that MBNL loss reduces tumor cell killing by CD8 + T cells in vitro and facilitates tumor escape from cytotoxic CD8 + T cell infiltration in vivo. Finally, we extended these studies to 29 human cancer types to find that MBNL expression levels are strongly associated with gene expression signatures of T cell tumor infiltration. These insights suggest that MBNL proteins play important roles in shaping the immune landscape across diverse malignancies.}, }
@article {pmid40305026, year = {2025}, author = {Montano-Campos, JF and Hahn, EE and Haupt, EC and Radich, J and Bansal, A}, title = {Oncologist-Patient Concordance and Treatment Adherence in Chronic Myeloid Leukemia.}, journal = {JAMA network open}, volume = {8}, number = {4}, pages = {e258039}, pmid = {40305026}, issn = {2574-3805}, }
@article {pmid40304602, year = {2025}, author = {Kopyeva, I and Bretherton, RC and Ayers, JL and Yu, M and Grady, WM and DeForest, CA}, title = {Matrix Stiffness and Biochemistry Govern Colorectal Cancer Cell Growth and Signaling in User-Programmable Synthetic Hydrogels.}, journal = {ACS biomaterials science &amp; engineering}, volume = {}, number = {}, pages = {}, doi = {10.1021/acsbiomaterials.4c01632}, pmid = {40304602}, issn = {2373-9878}, abstract = {Colorectal cancer (CRC) studies in vitro have been conducted almost exclusively on 2D cell monolayers or suspension spheroid cultures. Though these platforms have shed light on many important aspects of CRC biology, they fail to recapitulate essential cell-matrix interactions that often define in vivo function. Toward filling this knowledge gap, synthetic hydrogel biomaterials with user-programmable matrix mechanics and biochemistry have gained popularity for culturing cells in a more physiologically relevant 3D context. Here, using a poly(ethylene glycol)-based hydrogel model, we systematically assess the role of matrix stiffness and fibronectin-derived RGDS adhesive peptide presentation on CRC colony morphology and proliferation. Highlighting platform generalizability, we demonstrate that these hydrogels can support the viability and promote spontaneous spheroid or multicellular aggregate formation of six CRC cell lines that are commonly utilized in biomedical research. These gels are engineered to be fully degradable via a "biologically invisible" sortase-mediated reaction, enabling the triggered recovery of single cells and spheroids for downstream analysis. Using these platforms, we establish that substrate mechanics play a significant role in colony growth: soft conditions (∼300 Pa) encourage robust colony formation, whereas stiffer (∼2 kPa) gels severely restrict growth. Tuning the RGDS concentration did not affect the colony morphology. Additionally, we observe that epidermal growth factor receptor (EGFR) signaling in Caco-2 cells is influenced by adhesion ligand identity─whether the adhesion peptide was derived from collagen type I (DGEA) or fibronectin (RGDS)─with DGEA yielding a marked decrease in the level of downstream protein kinase phosphorylation. Taken together, this study introduces a versatile method to culture and probe CRC cell-matrix interactions within engineered 3D biomaterials.}, }
@article {pmid40304595, year = {2025}, author = {Abrams, HR and Saifee, NH and Miller, WS and Cortez, A and Hasan, RA and Panch, SR and Fertrin, KY}, title = {Alloimmunization as a barrier to gene therapy in sickle cell disease.}, journal = {Transfusion}, volume = {}, number = {}, pages = {}, doi = {10.1111/trf.18266}, pmid = {40304595}, issn = {1537-2995}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {Alloimmunization is prevalent in patients with sickle cell disease (SCD) and can be a barrier to gene therapy (GT) due to the necessary transfusion support for successful stem cell collection and infusion. We estimate that standard-of-care GT for an adult with SCD will require an average of 35-45 units of red blood cells over a 6-month period. Institutions should actively plan for these transfusion needs and share information to inform national consensus policies on the management of alloimmunization during GT.}, }
@article {pmid40304490, year = {2025}, author = {Owen, MC and Zhou, Y and Dudley, H and Feehley, T and Hahn, A and Yokoyama, CC and Axelrod, ML and Lin, C-Y and Wang, D and Janowski, AB}, title = {Novel murine model of human astrovirus infection reveals cardiovascular tropism .}, journal = {Journal of virology}, volume = {}, number = {}, pages = {e0024025}, doi = {10.1128/jvi.00240-25}, pmid = {40304490}, issn = {1098-5514}, abstract = {UNLABELLED: Astroviruses are a common cause of gastrointestinal disease in humans and have been linked to fatal cases of encephalitis. A major barrier to the study of human-infecting astroviruses is the lack of an in vivo model as previous attempts failed to identify a host that supports viral replication. We describe a novel murine model of infection using astrovirus VA1/HMO-C (VA1), an astrovirus with high seroprevalence in humans. VA1 is cardiotropic, and viral RNA levels peak in the heart tissue 7 days post-inoculation in multiple different murine genetic backgrounds. Infectious VA1 particles could be recovered from heart tissue 3 and 5 days post-inoculation. Viral capsid was detected intracellularly in the heart tissue by immunostaining, and viral RNA was detected in cardiac myocytes, endocardium, and endothelial cells based on fluorescent in situ hybridization and confocal microscopy. Histologically, we identified inflammatory infiltrates consistent with myocarditis in some mice, with viral RNA colocalizing with the infiltrates. These foci contained CD3 +T cells and CD68 +macrophages. Viral RNA levels increased by >10 fold in the heart tissue or serum samples from Rag1 or Stat1 knockout mice, demonstrating the role of both adaptive and innate immunity in the response to VA1 infection. Based on the in vivo tropisms, we tested cardiac-derived primary cells and determined that VA1 can replicate in primary human cardiac endothelial cells, suggesting a novel cardiovascular tropism in human cells. This novel in vivo model of a human-infecting astrovirus enables further characterization of the host immune response and reveals a new cardiovascular tropism of astroviruses.<br><br>IMPORTANCE: Astroviruses routinely cause infections in humans; however, few methods were available to study these viruses. Here, we describe the first animal system to study human-infecting astroviruses by using mice. We demonstrate that mice are susceptible to astrovirus VA1, a strain that commonly infects humans and has been linked to fatal brain infections. The virus infects the heart tissue and is associated with inflammation. When mice with impaired immune systems were infected with VA1, they were found to have higher amounts of the virus in their hearts and blood. We found that VA1 can infect cells from human blood vessels of the heart, which is associated with human health. This model will enable us to better understand how astroviruses cause disease and how the immune system responds to infection. Our findings also suggest that astroviruses could be linked to cardiovascular diseases, including in humans.}, }
@article {pmid40303999, year = {2025}, author = {Seber, A and Arcuri, LJ and Colturato, VR and Souza, MP and Zogbi, YAN and Funke, V and Lerner, D and Macedo, MC and Daudt, L and Kerbauy, MN and Zecchin, VG and Duarte, FB and Rabello Chiattone, R and Soares, RDA and Bettarello, G and Vaz de Macedo, A and Paton, E and Monteiro, TDM and Schmidt Filho, J and Astigarraga, CC and Scheinberg, P and Vigorito, AC and Vergueiro, CSV and Simione, A and Hashmi, S and Saber, W and Patel, J and Bonfim, CMS and Pasquini, M and Flowers, ME and Hamerschlak, N}, title = {Haploidentical, matched-related, and matched-unrelated hematopoietic cell transplant for acute leukemias in the early years of haploidentical transplant implementation in a developing country with a large unrelated donor registry.}, journal = {Frontiers in oncology}, volume = {15}, number = {}, pages = {1584631}, pmid = {40303999}, issn = {2234-943X}, abstract = {INTRODUCTION: Over the last decades, the donor network for hematopoietic cell transplantation (HCT) has grown exponentially, including unrelated and haploidentical (Haplo) donors. This study aimed to describe HCT outcomes with MSD, Haplo, and matched unrelated donors (MUD) in an early period of Haplo with posttransplant cyclophosphamide in a developing country with a large unrelated donor registry.<br><br>METHODS: This study was conducted in collaboration with the CIBMTR. We included patients with acute leukemias undergoing HCT between 2014-2018.<br><br>RESULTS: With 595 patients, 2-year overall survival (OS) was 69% for the MSD, 65% for the Haplo, and 71% for MUD (p=0.24) in CR1, confirmed in multivariable analysis. Relapse rate was lower for MUD (HR=0.35, p=0.0005) than MSD in patients with CR2+, leading to higher OS. Relapse was also higher with Haplo compared with MUD (HR=2.06, p=0.03).<br><br>DISCUSSION: Only survival bias can explain these findings in CR2+, suggesting some high-risk MUD patients, in which HCT timing is crucial, may not achieve HCT. Alternative donors were associated with higher non-relapse mortality, while PTCy-based Haplo offered the best protection against chronic graft-versus-host disease. Our study suggests Haplo and MUD are acceptable options for patients lacking MSD in developing countries like ours.}, }
@article {pmid40302927, year = {2025}, author = {Dharamshi, A and Neufeld, A and Motwani, K and Gao, LL and Witten, D and Bien, J}, title = {Generalized data thinning using sufficient statistics.}, journal = {Journal of the American Statistical Association}, volume = {120}, number = {549}, pages = {511-523}, pmid = {40302927}, issn = {0162-1459}, support = {P30 DA048736/DA/NIDA NIH HHS/United States ; R01 DA047869/DA/NIDA NIH HHS/United States ; R01 EB026908/EB/NIBIB NIH HHS/United States ; R01 GM123993/GM/NIGMS NIH HHS/United States ; }, abstract = {Our goal is to develop a general strategy to decompose a random variable X into multiple independent random variables, without sacrificing any information about unknown parameters. A recent paper showed that for some well-known natural exponential families, X can be thinned into independent random variables X (1) , … , X (K) , such that X = ∑ k = 1 K X (k) . These independent random variables can then be used for various model validation and inference tasks, including in contexts where traditional sample splitting fails. In this paper, we generalize their procedure by relaxing this summation requirement and simply asking that some known function of the independent random variables exactly reconstruct X . This generalization of the procedure serves two purposes. First, it greatly expands the families of distributions for which thinning can be performed. Second, it unifies sample splitting and data thinning, which on the surface seem to be very different, as applications of the same principle. This shared principle is sufficiency. We use this insight to perform generalized thinning operations for a diverse set of families.}, }
@article {pmid40302197, year = {2025}, author = {Nascimento de Lima, P and Maerzluft, C and Ozik, J and Collier, N and Rutter, CM}, title = {Stress-testing US colorectal cancer screening guidelines: Decennial colonoscopy from age 45 is robust to natural history uncertainty and colonoscopy sensitivity assumptions.}, journal = {Medical decision making : an international journal of the Society for Medical Decision Making}, volume = {}, number = {}, pages = {272989X251334373}, doi = {10.1177/0272989X251334373}, pmid = {40302197}, issn = {1552-681X}, abstract = {PurposeThe 2023 American College of Physicians (ACP) guidelines for colorectal cancer (CRC) screening are at odds with the United States Preventive Task Force (USPSTF) guidelines, with the former recommending screening starting at age 50 y and the latter at age 45 y. This article "stress tests" CRC colonoscopy screening strategies to investigate their robustness to uncertainties stemming from the natural history of disease and sensitivity of colonoscopy.MethodsThis study uses the CRC-SPIN microsimulation model to project the life-years gained (LYG) under several colonoscopy CRC screening strategies. The model was extended to include birth cohort effects on adenoma risk. We estimated natural history parameters under 2 different assumptions about the youngest age of adenoma initiation. For each, we generated 500 parameter sets to reflect uncertainty in the natural history parameters. We simulated 26 colonoscopy screening strategies and examined 4 different colonoscopy sensitivity assumptions, encompassing the range of sensitivities consistent with prior tandem colonoscopy studies. Across this set of scenarios, we identify efficient screening strategies and report posterior credible intervals for benefits of screening (LYG), burden (number of colonoscopies), and incremental burden-effectiveness ratios.ResultsProjected absolute screening benefits varied widely based on assumptions, but strategies starting at age 45 y were consistently in the efficiency frontier. Strategies in which screening starts at age 50 y with 10-y intervals were never efficient, saving fewer life-years than starting screening at age 45 y and performing colonoscopies every 15 y while requiring more colonoscopies per person.ConclusionsDecennial colonoscopy screening initiation at age 45 y remained a robust recommendation. Colonoscopy screening with a 10-y interval starting at age 50 y did not result in an efficient use of colonoscopies in any of the scenarios evaluated.HighlightsColorectal cancer colonoscopy screening strategies initiated at age 45 y were projected to yield more life-years gained while requiring the least number of colonoscopies across different model assumptions about disease natural history and colonoscopy sensitivity.Colonoscopy screening starting at age 50 y with a 10-y interval consistently underperformed strategies that started at age 45 y.}, }
@article {pmid40301663, year = {2025}, author = {Goel, U and Dima, D and Davis, JA and Rashid, A and Wesson, W and Williams, L and Mazzoni, S and Bhurtel, E and Ullah, F and Rudoni, J and Rice, M and Tiger, YKR and Sauter, CS and Anwer, F and Raza, S and Shune, L and Khouri, J}, title = {Development of an Endothelial Activation and Stress Index (EASIX)-based predictive model for cytokine release syndrome and neurotoxicity after B-cell maturation antigen directed chimeric antigen receptor T-cell therapy for relapsed/refractory multiple myeloma.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, pmid = {40301663}, issn = {1476-5365}, }
@article {pmid40299982, year = {2025}, author = {Kubinski, HC and Despres, HW and Johnson, BA and Schmidt, MM and Jaffrani, SA and Turner, AH and Fanuele, CD and Mills, MG and Lokugamage, KG and Dumas, CM and Shirley, DJ and Estes, LK and Pekosz, A and Crothers, JW and Roychoudhury, P and Greninger, AL and Jerome, KR and Di Genova, BM and Walker, DH and Ballif, BA and Ladinsky, MS and Bjorkman, PJ and Menachery, VD and Bruce, EA}, title = {Variant mutation G215C in SARS-CoV-2 nucleocapsid enhances viral infection via altered genomic encapsidation.}, journal = {PLoS biology}, volume = {23}, number = {4}, pages = {e3003115}, pmid = {40299982}, issn = {1545-7885}, mesh = {*SARS-CoV-2/genetics/physiology ; Humans ; Animals ; Mutation ; *COVID-19/virology ; *Coronavirus Nucleocapsid Proteins/genetics/metabolism ; Genome, Viral ; *Nucleocapsid/genetics/metabolism ; Chlorocebus aethiops ; Vero Cells ; *Viral Genome Packaging/genetics ; Virus Assembly/genetics ; Virion/genetics ; Phosphoproteins ; }, abstract = {The evolution of SARS-CoV-2 variants and their respective phenotypes represents an important set of tools to understand basic coronavirus biology as well as the public health implications of individual mutations in variants of concern. While mutations outside of spike are not well studied, the entire viral genome is undergoing evolutionary selection, with several variants containing mutations in the central disordered linker region of the nucleocapsid (N) protein. Here, we identify a mutation (G215C), characteristic of the Delta variant, that introduces a novel cysteine into this linker domain, which results in the formation of a more stable N-N dimer. Using reverse genetics, we determined that this cysteine residue is necessary and sufficient for stable dimer formation in a WA1 SARS-CoV-2 background, where it results in significantly increased viral growth both in vitro and in vivo. Mechanistically, we show that the N:G215C mutant has more encapsidation as measured by increased RNA binding to N, N incorporation into virions, and electron microscopy showing that individual virions are larger, with elongated morphologies.}, }
@article {pmid40298902, year = {2025}, author = {Haack, AJ and Brown, LG and Goldstein, AJ and Mulimani, P and Berthier, J and Viswanathan, AR and Kopyeva, I and Whitten, JM and Lin, A and Nguyen, SH and Leahy, TP and Bouker, EE and Padgett, RM and Mazzawi, NA and Tokihiro, JC and Bretherton, RC and Wu, A and Tapscott, SJ and DeForest, CA and Popowics, TE and Berthier, E and Sniadecki, NJ and Theberge, AB}, title = {Suspended Tissue Open Microfluidic Patterning (STOMP).}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e2501148}, doi = {10.1002/advs.202501148}, pmid = {40298902}, issn = {2198-3844}, support = {R35GM128648/NH/NIH HHS/United States ; R35GM138036/NH/NIH HHS/United States ; R01HL149734/NH/NIH HHS/United States ; R03DE029827/NH/NIH HHS/United States ; T32CA080416/NH/NIH HHS/United States ; F30HL158030/NH/NIH HHS/United States ; R90DE023059/NH/NIH HHS/United States ; 5TL1TR002318-08/NH/NIH HHS/United States ; P50AR065139//Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center - Seattle/ ; }, abstract = {Free-standing tissue structures tethered between pillars are powerful mechanobiology tools for studying cell contraction. To model interfaces ubiquitous in natural tissues and upgrade existing single-region suspended constructs, we developed Suspended Tissue Open Microfluidic Patterning (STOMP), a method to create multi-regional suspended tissues. STOMP uses open microfluidics and capillary pinning to pattern subregions within free-standing tissues, facilitating the study of complex tissue interfaces, such as diseased-healthy boundaries (e.g., fibrotic-healthy) and tissue-type interfaces (e.g., bone-ligament). We observed altered contractile dynamics in fibrotic-healthy engineered heart tissues compared to single-region tissues and differing contractility in bone-ligament enthesis constructs compared to single-tissue periodontal ligament models. STOMP is a versatile platform - surface tension-driven patterning removes material requirements common with other patterning methods (e.g., shear-thinning, photopolymerizable) allowing tissue generation in multiple geometries with native extracellular matrices and advanced four-dimensional (4D)- materials. STOMP combines the contractile functionality of suspended tissues with precise patterning, enabling dynamic and spatially controlled studies.}, }
@article {pmid40298430, year = {2025}, author = {Cai, L and Wu, F and Zhou, Q and Gao, Y and Yao, B and DeBerardinis, RJ and Acquaah-Mensah, GK and Aidinis, V and Beane, JE and Biswal, S and Chen, T and Concepcion-Crisol, CP and Grüner, BM and Jia, D and Jones, RA and Kurie, JM and Lee, MG and Lindahl, P and Lissanu, Y and Lorz, C and MacPherson, D and Martinelli, R and Mazur, PK and Mazzilli, SA and Mii, S and Moll, HP and Moorehead, RA and Morrisey, EE and Ng, SR and Oser, MG and Pandiri, AR and Powell, CA and Ramadori, G and Santos, M and Snyder, EL and Sotillo, R and Su, KY and Taki, T and Taparra, K and Tran, PT and Xia, Y and van Veen, JE and Winslow, MM and Xiao, G and Rudin, CM and Oliver, TG and Xie, Y and Minna, JD}, title = {The Lung Cancer Autochthonous Model Gene Expression Database Enables Cross-Study Comparisons of the Transcriptomic Landscapes Across Mouse Models.}, journal = {Cancer research}, volume = {}, number = {}, pages = {OF1-OF15}, doi = {10.1158/0008-5472.CAN-24-1607}, pmid = {40298430}, issn = {1538-7445}, support = {R01CA285336//National Cancer Institute (NCI)/ ; IRG-21-142-16//American Cancer Society (ACS)/ ; U24CA213274//National Cancer Institute (NCI)/ ; P50CA070907//National Cancer Institute (NCI)/ ; R01GM140012//National Institute of General Medical Sciences (NIGMS)/ ; R01DE030656//National Institute of Dental and Craniofacial Research (NIDR)/ ; //Howard Hughes Medical Institute (HHMI)/ ; R35CA220449//National Cancer Institute (NCI)/ ; R35CA263816//National Cancer Institute (NCI)/ ; R01CA271540//National Cancer Institute (NCI)/ ; R01CA244841//National Cancer Institute (NCI)/ ; U01CA249245//National Cancer Institute (NCI)/ ; U01AI156189//National Institute of Allergy and Infectious Diseases (NIAID)/ ; U01CA213338//National Cancer Institute (NCI)/ ; R35GM136375//National Institute of General Medical Sciences (NIGMS)/ ; R01CA212415//National Cancer Institute (NCI)/ ; R01CA272945//National Cancer Institute (NCI)/ ; P50CA228944//National Cancer Institute (NCI)/ ; GR4575/1-2//Deutsche Forschungsgemeinschaft (DFG)/ ; PI21/00764//Instituto de Salud Carlos III (ISCIII)/ ; }, abstract = {Lung cancer, the leading cause of cancer mortality, exhibits diverse histologic subtypes and genetic complexities. Numerous preclinical mouse models have been developed to study lung cancer, but data from these models are disparate, siloed, and difficult to compare in a centralized fashion. In this study, we established the Lung Cancer Autochthonous Model Gene Expression Database (LCAMGDB), an extensive repository of 1,354 samples from 77 transcriptomic datasets covering 974 samples from genetically engineered mouse models (GEMM), 368 samples from carcinogen-induced models, and 12 samples from a spontaneous model. Meticulous curation and collaboration with data depositors produced a robust and comprehensive database, enhancing the fidelity of the genetic landscape it depicts. The LCAMGDB aligned 859 tumors from GEMMs with human lung cancer mutations, enabling comparative analysis and revealing a pressing need to broaden the diversity of genetic aberrations modeled in the GEMMs. To accompany this resource, a web application was developed that offers researchers intuitive tools for in-depth gene expression analysis. With standardized reprocessing of gene expression data, the LCAMGDB serves as a powerful platform for cross-study comparison and lays the groundwork for future research, aiming to bridge the gap between mouse models and human lung cancer for improved translational relevance. Significance: The Lung Cancer Autochthonous Model Gene Expression Database (LCAMGDB) provides a comprehensive and accessible resource for the research community to investigate lung cancer biology in mouse models.}, }
@article {pmid40298376, year = {2025}, author = {Atmar, RL and Lyke, KE and Posavad, CM and Deming, ME and Brady, RC and Dobrzynski, D and Edupuganti, S and Mulligan, MJ and Rupp, RE and Rostad, CA and Jackson, LA and Martin, JM and Shriver, MC and Rajakumar, K and Coler, RN and El Sahly, HM and Kottkamp, AC and Branche, AR and Frenck, RW and Johnston, C and Babu, TM and Bäcker, M and Archer, JI and Crandon, S and Nakamura, A and Nayak, SU and Szydlo, D and Dominguez Islas, CP and Brown, ER and O'Connell, SE and Montefiori, DC and Eaton, A and Neuzil, KM and Stephens, DS and Beigel, JH and Pasetti, M and Roberts, PC}, title = {Mucosal and Systemic Antibody Responses After Boosting With a Bivalent Messenger RNA Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiaf176}, pmid = {40298376}, issn = {1537-6613}, support = {//Infectious Diseases Clinical Research Consortium/ ; //National Institute of Allergy and Infectious Diseases/ ; UM1AI48372/NH/NIH HHS/United States ; 75N93019C00050)//NIAID Collaborative Influenza Vaccine Innovation Centers/ ; //Vaccine Research Center/ ; }, abstract = {BACKGROUND: Mucosal immunity plays a critical role in preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and replication. Understanding the capacity of coronavirus disease 2019 (COVID-19) vaccines to elicit both mucosal and systemic antibodies could help optimize vaccination strategies.<br><br>METHODS: We conducted an open-label, phase 1/2 adaptive-design clinical trial to evaluate the safety and immunogenicity of COVID-19 immunizations. Healthy adults received 2 priming doses of mRNA-1273, a booster dose of mRNA-1273, and a second booster of bivalent (WA-1 and BA.4/BA.5) mRNA-1273.222. Adverse event data were collected. Serum and mucosal immunity were evaluated.<br><br>RESULTS: One hundred six persons were enrolled. Thirty received all 4 study-related vaccine doses. All vaccines were well tolerated, with injection site pain, malaise, myalgias, and headache being the most frequently reported symptoms. Among those who received a second booster, 24 of 30 (80%) had serological evidence of SARS-CoV-2 infection. Following the second booster, increases in geometric mean binding and pseudovirus neutralization antibody titers to the ancestral strain and BA.1 and BA.5 variants were observed. Increases in mucosal immunoglobulin G and immunoglobulin A (IgA) antibodies in nasal and salivary samples were observed in both previously infected and infection-naive participants, although prior infection markedly boosted virus-specific mucosal IgA responses.<br><br>CONCLUSIONS: The mRNA-1273.222 booster vaccine was safe and immunogenic and induced mucosal antibody responses in previously infected and infection-naive persons.<br><br>CLINICAL TRIALS REGISTRATION: NCT04889209.}, }
@article {pmid40297938, year = {2025}, author = {Richardson, BD and Blette, BS and Gilbert, PB and Hudgens, MG}, title = {Addressing confounding and continuous exposure measurement error using corrected score functions.}, journal = {Biometrics}, volume = {81}, number = {2}, pages = {}, pmid = {40297938}, issn = {1541-0420}, support = {AI068635//U.S. Public Health Service/ ; R37 AI054165/AI/NIAID NIH HHS/United States ; T32 ES007018/ES/NIEHS NIH HHS/United States ; R37AI029168/GF/NIH HHS/United States ; }, mesh = {Humans ; HIV Infections/prevention &amp; control/epidemiology/immunology ; Bias ; Computer Simulation ; Confounding Factors, Epidemiologic ; *Models, Statistical ; Biomarkers ; Data Interpretation, Statistical ; *Biometry/methods ; }, abstract = {Confounding and exposure measurement error can introduce bias when drawing inference about the marginal effect of an exposure on an outcome of interest. While there are broad methodologies for addressing each source of bias individually, confounding and exposure measurement error frequently co-occur, and there is a need for methods that address them simultaneously. In this paper, corrected score methods are derived under classical additive measurement error to draw inference about marginal exposure effects using only measured variables. Three estimators are proposed based on g-formula, inverse probability weighting, and doubly-robust estimation techniques. The estimators are shown to be consistent and asymptotically normal, and the doubly-robust estimator is shown to exhibit its namesake property. The methods, which are implemented in the R package mismex, perform well in finite samples under both confounding and measurement error as demonstrated by simulation studies. The proposed doubly-robust estimator is applied to study the effects of two biomarkers on HIV-1 infection using data from the HVTN 505 preventative vaccine trial.}, }
@article {pmid40296864, year = {2025}, author = {Long, KJ and Silvestri, GA and Kammer, MN and Gibbs, S and Wu, W and Johal, M and Pipavath, S and Pitcher, T and Jett, J and Nair, VS}, title = {Validation of a High-Specificity Blood Autoantibody Test to Detect Lung Cancer in Pulmonary Nodules.}, journal = {CHEST pulmonary}, volume = {3}, number = {1}, pages = {}, pmid = {40296864}, issn = {2949-7892}, support = {T32 HL144470/HL/NHLBI NIH HHS/United States ; }, abstract = {BACKGROUND: Pulmonary nodules (PNs) are frequently detected by chest CT scan, which is increasingly used in clinical practice. Accurately identifying malignant nodules can pose a diagnostic challenge; therefore, a high-specificity biomarker could help clinicians identify malignant nodules and ideally lead to the earlier diagnosis of lung cancer.<br><br>RESEARCH QUESTION: What are the performance characteristics of a blood-based biomarker for identifying malignancy in patients with a CT-detected PN?<br><br>STUDY DESIGN AND METHODS: Banked plasma samples from 2 independent prospective observational cohorts of patients presenting with benign or malignant PNs 8 to 30 mm in size were tested using a 7-autoantibody panel. Sensitivity, specificity, and positive predictive value of the autoantibody test (AAT) to identify cancer were calculated for the individual and combined cohorts.<br><br>RESULTS: Overall, 447 patients (263 and 184 from each cohort) were included in the analysis with a prevalence of malignancy of 55%. The performance of the AAT between the 2 cohorts was similar. The AAT demonstrated a specificity of 90% (95% CI, 85%-93%), a positive predictive value of 66% (95% CI, 52%-77%), sensitivity of 16% (95% CI, 12%-22%), and false-positive rate of 10% in the combined cohort. Using a pretest probability of cancer cutoff of 20% improved the positive predictive value to 76% (95% CI, 61%-88%) and resulted in a 52% decrease in the number of false-positive test results. In the subset of patients who had 18F-fluorodeoxyglucose PET imaging performed for clinical purposes (n = 222), specificity of the AAT was higher (93% vs 58%, P < .001), but the sensitivity was lower than 18F-fluorodeoxyglucose PET scan (17% vs 75%, P < .001).<br><br>INTERPRETATION: This study validates the specificity of a blood-based autoantibody biomarker for identifying malignancy in patients with indeterminate PNs. This rule-in biomarker may help to expedite workup of malignant nodules.<br><br>CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT01752114; URL: www.clinicaltrials.gov CHEST Pulmonary 2025; 3(1):100130.}, }
@article {pmid40295790, year = {2024}, author = {Jelley, L and Aminisani, N and O'Neill, M and Jennings, T and Douglas, J and Utekar, S and Johnston, H and Welch, D and Hadfield, J and ,  and de Ligt, J and Winter, D and French, N and Thomas, PG and Webby, RJ and Huang, S and Geoghegan, JL}, title = {Tracing household transmission of SARS-CoV-2 in New Zealand using genomics.}, journal = {Npj viruses}, volume = {2}, number = {1}, pages = {21}, pmid = {40295790}, issn = {2948-1767}, support = {22/138//New Zealand Health Research Council Grant/ ; 22/138//New Zealand Health Research Council Grant/ ; 22/138//New Zealand Health Research Council Grant/ ; 22/138//New Zealand Health Research Council Grant/ ; 22/138//New Zealand Health Research Council Grant/ ; 22/138//New Zealand Health Research Council Grant/ ; U01 AI 144616//US-NIAID/ ; 75N93021C00016/AI/NIAID NIH HHS/United States ; U01 AI 144616//US-NIAID/ ; }, abstract = {By early 2022, the highly transmissible Omicron variant of SARS-CoV-2 had spread across most of the world. For the first time since the pandemic began, New Zealand was experiencing high levels of community transmission of SARS-CoV-2. We enroled a cohort of households to better understand differences in transmission dynamics among subvariants of Omicron. We enroled 71 households, comprising 289 participants, and aimed to use viral genomes to gain a clearer understanding of variant-specific differences in epidemiological parameters affecting transmission dynamics. Approximately 80% of the households enroled experienced transmission of BA.2, while most of the remaining households had infections with BA.1 or BA.5. Using a logistic regression generalised linear mixed model, we found no difference in household secondary infection rate between Omicron subvariants BA.1, BA.2 and BA.5. Of the households recruited, the vast majority (92%) experienced a single chain of transmission with one inferred introduction. Further, we found that in 48% of the households studied, all household participants became infected following an index case. Most household participants tested positive within a week following an introduction, supporting the seven-day isolation requirement for household contacts that was in place in New Zealand at the time. By integrating genomic and epidemiological data, we show that viral transmission dynamics can be investigated with a higher level of granularity than with epidemiological data alone. Overall, households are a high risk setting for viral transmission in New Zealand.}, }
@article {pmid40294415, year = {2025}, author = {Riddler, SA and Moodie, Z and Clark, J and Yen, C and Allen, M and Furch, BD and Lu, H and Grant, S and Mondal, K and Anderson, M and Maenza, J and Lemos, MP and Woodward Davis, AS and Walsh, SR and Sobieszczyk, ME and Frank, I and Goepfert, P and Stephenson, KE and Baden, LR and Tieu, HV and Keefer, MC and McElrath, MJ and Kublin, JG and Corey, L}, title = {High Frequency of Chronic Urticaria Following an Investigational HIV-1 BG505 MD39.3 Trimer mRNA Vaccine in a Phase 1, Randomized, Open-Label Clinical Trial (HVTN 302).}, journal = {Annals of internal medicine}, volume = {}, number = {}, pages = {}, doi = {10.7326/ANNALS-24-02701}, pmid = {40294415}, issn = {1539-3704}, abstract = {BACKGROUND: The mRNA platform is under investigation for many vaccines, including HIV-1 vaccines.<br><br>OBJECTIVE: To evaluate the safety and tolerability of 3 investigational HIV-1 trimer mRNA vaccines.<br><br>DESIGN: Safety analysis of mRNA vaccination in a phase 1, randomized, open-label trial. (ClinicalTrials.gov: NCT05217641).<br><br>SETTING: Ten research sites in the United States.<br><br>PARTICIPANTS: 108 volunteers aged 18 to 55 years without HIV-1.<br><br>INTERVENTION: Investigational HIV-1 BG505 MD39.3 trimer mRNA vaccines (gp140 soluble trimer, gp151 membrane-bound trimer, and gp151 CD4KO membrane-bound trimer) at doses of 100 and 250 mcg at 0, 2, and 6 months.<br><br>MEASUREMENTS: Solicited and unsolicited adverse reactions and events reported during the 12 months after the first vaccination.<br><br>RESULTS: Participants (n = 108) were randomly assigned to 6 vaccine groups. Mild to moderate local and systemic solicited events were common. Eighty participants reported 190 unsolicited adverse events (AEs); 30 were considered to be related to a study product. Most (73%) related AEs were mild, and the rest were moderate. Among related AEs, urticaria was reported by 7 of 108 participants (7% [95% CI, 3% to 13%]), 4 of whom had unresolved, intermittent urticaria at 12 months. In post hoc analyses, demographic characteristics, history of allergy or medication use, and COVID-19 were not associated with urticaria. In a comparison of participants with versus without urticaria, 100% (7 of 7; CI, 65% to 100%) versus 37% (37 of 101; CI, 28% to 46%) reported previous Moderna COVID-19 vaccination, 29% (2 of 7; CI, 8% to 64%) versus 76% (77 of 101; CI, 67% to 84%) reported previous Pfizer-BioNTech COVID-19 vaccination, and 0% (0 of 7; CI, 0% to 35%) versus 5% (5 of 101; CI, 2% to 11%) reported no previous mRNA COVID-19 vaccination.<br><br>LIMITATIONS: Lack of a placebo group, open-label study, and post hoc evaluation of urticarial risk.<br><br>CONCLUSION: Urticarial reactions associated with experimental HIV-1 mRNA vaccines were observed in this trial. Studies to investigate the mechanism and approaches to mitigate these reactions are underway to further advance HIV-1 vaccine research.<br><br>PRIMARY FUNDING SOURCE: National Institutes of Health, National Institute of Allergy and Infectious Diseases.}, }
@article {pmid40294366, year = {2025}, author = {Huang, BJ and Meyer, LK and Alonzo, TA and Wang, YC and Lamble, AJ and Ries, RE and Wang, W and Hirsch, B and Raca, G and Ma, X and Gamis, AS and Aplenc, R and Kolb, EA and Cooper, TM and Tarlock, K and Loken, MR and Meshinchi, S and Chewning, JH and Woods, WG and Horan, JT}, title = {Hematopoietic Stem Cell Transplantation Outcomes for High-Risk AML: A Report From the Children's Oncology Group.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2401841}, doi = {10.1200/JCO-24-01841}, pmid = {40294366}, issn = {1527-7755}, abstract = {PURPOSE: Hematopoietic stem cell transplantation (HSCT) is used as consolidation for pediatric patients with high-risk AML in first complete remission (CR1). The definition of high-risk AML has evolved considerably over the past two decades with the successive identification of new unfavorable risk factors. We conducted a cross-study analysis to determine whether HSCT improves the outcomes of patients with contemporarily defined high-risk AML.<br><br>METHODS: We combined data from AAML0531 and AAML1031, the last two phase III clinical trials completed by the Children's Oncology Group (COG). These two trials established the prognostic importance of measurable residual disease (MRD) and several high-risk cryptic cytogenetic/molecular (CM) alterations, which were applied to reclassify patients in the current COG phase III clinical trial, AAML1831. We compared the outcomes after HSCT in CR1 with those after chemotherapy alone in CR1 in the redefined high-risk group.<br><br>RESULTS: Our study cohort comprised 463 patients with high-risk CM alterations and 72 patients with standard-risk (SR) CM results with positive MRD at end of induction I. In all, 33.9% and 45.8% of these groups underwent HSCT in CR1, respectively. HSCT was associated with decreased relapse and improved disease-free survival (DFS) in both groups. In the high-risk CM group, 5-year DFS was 26.0% (95% CI, 20.6 to 31.6) and 49.8% (95% CI, 41.7 to 57.4; P < .001) in patients receiving chemotherapy alone and HSCT, respectively. In the SR CM and MRD+ groups, DFS was 16.9% (95% CI, 4.3 to 36.7) compared with 50.9% (95% CI, 32.7 to 66.5; P = .032). HSCT was also associated with improvement in outcomes based on multivariable analysis and across subgroups defined by clinical trial and by high-risk CM subtype, with the exception of chromosome 7 or 5 loss.<br><br>CONCLUSION: HSCT was associated with improved outcomes in pediatric patients with contemporarily defined high-risk AML.}, }
@article {pmid40294356, year = {2025}, author = {Rosenberg, AR and Fladeboe, KM and Zhou, C and Bradford, MC and Kang, T and Maurer, S and Freyer, DR and Baker, KS and Comiskey, L and Junkins, CC and Taylor, MR and Yi-Frazier, JP}, title = {Promoting Resilience in Stress Management: A Randomized Controlled Trial of a Novel Psychosocial Intervention for Adolescents and Young Adults With Advanced Cancer.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2500161}, doi = {10.1200/OP-25-00161}, pmid = {40294356}, issn = {2688-1535}, abstract = {PURPOSE: Adolescents and young adults (AYAs) with advanced cancer (AC) report poor quality of life (QOL), high psychological distress, and minimal engagement in health care discussions. We assessed the effect of a novel resilience coaching program (Promoting Resilience in Stress Management [PRISM]-AC) on AYA outcomes.<br><br>METHODS: We conducted a multisite randomized trial of PRISM-AC versus usual care (UC) among AYAs age 12-24 years, diagnosed with AC within 2 weeks before enrollment. PRISM-AC consists of four sessions targeting AYA-endorsed resilience resources (stress management, goal-setting, cognitive reframing, and meaning-making) plus a session integrating elements of advance care planning. Participants completed surveys at baseline, and 3, 6, 9, and 12 months. The primary outcome was Pediatric QOL at 3 months; secondary/exploratory outcomes included 3-month changes in resilience (10-item Connor-Davidson Resilience Scale) and hope (Snyder Hope Scale), and trajectories of QOL, anxiety, and depression (Hospital Anxiety and Depression Scale) over 12 months. We examined associations with linear mixed effects regression models. We also explored PRISM-AC's impact on AYA participation in critical health care discussions, as documented in the electronic health record.<br><br>RESULTS: Between April 2019 and January 2024, we enrolled 239 AYAs (56% of 426 approached) and randomly assigned 195 (82% of enrolled; 96 UC, 99 PRISM). They were of mean age 16.5 years (standard deviation, 3.9), mostly White (63%), non-Hispanic (59%), and publicly insured (53%). At 3 months, we detected no significant differences between groups with respect to QOL, anxiety, or depression; PRISM-AYAs demonstrated greater improvements in resilience (+1.3 [5.9] v -1.4 (7.5); P = .038) and hope (+2.4 [10.4] v -2.8 [11.2]; P = .001) than UC-AYAs. Over the 12-month study period, PRISM-AYAs reported more improvements in QOL and anxiety, with significant differences at later time points (PRISM-QOL improvements, 6 months: +3.4 [95% CI, 0.1 to 6.6]; P = .043; 12 months: +6.8 [95% CI, 3.3 to 10.3]; P < .001). Although participation in key health care discussions was similar between groups from baseline to 6 months, 67% (95% CI, 35 to 88) and 50% (95% CI, 22 to 78) of PRISM-AYAs participated at 9 and 12 months, respectively, compared with 39% (95% CI, 20 to 61) and 38% (95% CI, 21 to 59) of UC-AYAs.<br><br>CONCLUSION: Among AYAs with AC, PRISM-AC did not immediately improve QOL. Rather, it improved resilience and hope, potentially enabling longer-term improvements in QOL.}, }
@article {pmid40293383, year = {2025}, author = {Colbert, CM and Melancon, D and Kang, J and Ford, EC and Smith, WP}, title = {A Comparative Risk Analysis of Cone Beam Computed Tomography-based Daily Adaptive Radiation Therapy and Cone Beam Computed Tomography-based Radiation Therapy Alone.}, journal = {International journal of radiation oncology, biology, physics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ijrobp.2025.04.009}, pmid = {40293383}, issn = {1879-355X}, abstract = {PURPOSE: When adopting a new therapeutic technology, a comparison to a standard of care is needed. We aim to directly compare the specific safety implications of adaptive radiation therapy (ART) to those of traditional image guided radiation therapy (IGRT), as implemented on a ring gantry linear accelerator with kilovoltage cone beam computed tomography-based online ART capability.<br><br>METHODS AND MATERIALS: An interdisciplinary committee performed a failure modes and effects analysis based on the American Association of Physicists in Medicine (AAPM) Task Group 100 method addressing initial treatment planning, quality assurance, and treatment delivery for both IGRT-alone and IGRT with ART on the Varian Ethos. Failure modes were categorized by process step and associated clinical roles, scored by severity, occurrence, and detectability, and ranked by risk priority number (RPN). Failure modes shared by IGRT and ART were scored and analyzed comparatively.<br><br>RESULTS: We identified 33 unique system failure modes as part of the IGRT-alone workflow, and 9 additional failure modes specific to ART. Most high-risk IGRT-alone system failure modes were associated with initial treatment planning errors. High-risk ART failure modes also included errors related to adaptive replanning. Reanalysis of 33 IGRT-alone failure modes in the ART setting found an overall decrease in median RPN from 96 (IQR, 56-144) to 72 (IQR, 32-120; P = .035). RPN decreased for 12 failure modes, with the greatest change observed among the highest-ranked failure modes for IGRT-alone.<br><br>CONCLUSIONS: Although online ART introduces new avenues for error in the adaptive replanning process, the enhanced staffing and iterative plan review reduce the risk associated with systematic errors originating in initial treatment planning. The finding that the RPN decreased in the adaptive setting provides a unique motivation for the adoption of ART from a patient safety perspective, beyond the well-documented dosimetric benefit of ART.}, }
@article {pmid40293363, year = {2025}, author = {Minalga, B and Siskind, R and Campbell, R and Adamson, T and Cermak, MA and Davis, A and Givens, ED and Dyer, M and McCarthy, K and Montañez, NA and White, R and , }, title = {The Representative Studies Rubric: A Tool for Diversity in Clinical Trials.}, journal = {AJOB empirical bioethics}, volume = {}, number = {}, pages = {1-15}, doi = {10.1080/23294515.2025.2497753}, pmid = {40293363}, issn = {2329-4523}, abstract = {When clinical trials fail to enroll diverse study populations, a multitude of consequences can occur, including compromised validity and generalizability, safety and efficacy uncertainties, regulatory limitations, widened disparities, distrust in science and medicine, and undermined efforts to address urgent health needs. We developed the Representative Studies Rubric (RSR), a questionnaire that evaluates the extent to which clinical trials are designed to enroll representative study populations with a focus on age, ethnicity, drug use, gender, pregnancy, race, and sex assigned at birth. We used the RSR to conduct an analysis of all active studies in the NIH-funded HIV/AIDS Clinical Trials Networks (Networks) and identified patterns of research practices that may limit the participation of underrepresented populations, with ethical implications. The Networks subsequently formalized the RSR as a required protocol development tool for all future studies to correct exclusionary research practices with the goal to achieve more representative study populations.}, }
@article {pmid40288610, year = {2025}, author = {Shouval, R and Strouse, C and Kim, S and Oloyede, T and Ahmed, S and Awan, FT and Luan, D and Bachanova, V and Badar, T and Bar, M and Barba, P and Beitinjaneh, AM and Cashen, A and Dholaria, B and Elsawy, M and Ganguly, S and Geethakumari, PR and Greenbaum, U and Hashmi, H and Hill, LC and Jain, MD and Jain, T and Kebriaei, P and Kittai, AS and Locke, FL and Lulla, PD and Mead, E and McGuirk, JP and Mussetti, A and Nishihori, T and Olson, AL and Pennisi, M and Perales, MA and Riedell, PA and Saber, W and Mirza, AS and Magalhaes-Silverman, M and Shpall, EJ and Sorror, M and Wudhikarn, K and Turtle, CJ and Moskop, A and Pasquini, MC}, title = {Cytokine release syndrome and neurotoxicity following CD19 CAR-T in B-cell lymphoma.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.03.011}, pmid = {40288610}, issn = {2666-6367}, abstract = {BACKGROUND: Chimeric antigen receptor T cell (CAR-T) therapy is an effective treatment for relapsed-refractory large B-cell lymphoma (LBCL). However, toxicities, particularly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), remain significant concerns.<br><br>OBJECTIVE: Analyze temporal trends, risk factors and associations between these toxicities and their severity.<br><br>STUDY DESIGN: In this registry study by the Center for International Blood and Marrow Transplant Research (CIBMTR), we studied CRS and ICANS in 1,916 LBCL patients treated with commercial CAR-T therapies (axicabtagene ciloleucel 74.9%, tisagenlecleucel 25.1%) between 2018 and 2020. Outcomes include development of CRS/ICANS, timing and severity according to ASTC grading, overall survival. Risk factors were assessed using Cox proportional hazards model.<br><br>RESULTS: Among patients developing CRS (75.2%), 11.3% had grade &#x2265;&#x2009;3 CRS. Among patients developing ICANS (43.5%) 47.7% had grade &#x2265; 3 ICANS. Among patients developing CRS, severe CRS rates decreased from 14.0% in 2018 to 9.2% in 2020 (P<&#x2009;.01). However, the proportion of severe ICANS in patients who developed ICANS remained statistically unchanged (41.5% in 2018 to 53.7% in 2020, P=&#x2009;.10). CRS and ICANS were correlated: 57.1% of patients with CRS also experienced ICANS, and CRS was reported in 97.5% of ICANS cases, suggesting a potential continuum between toxicities. Axicabtagene ciloleucel was associated with higher risk of any grade CRS (OR, 4.6; 95%&#x2009;CI, 3.65-5.81) and ICANS (OR, 5.85; 95%&#x2009;CI, 4.48-7.64) as well as early and severe forms of both complications. Older age, lower performance status, and elevated lactate dehydrogenase (LDH) levels prior to infusion also variably predicted these toxicities. In a landmark analysis starting 30 days post-infusion, patients with severe CRS or severe ICANS had shorter overall survival compared to those without these toxicities.<br><br>CONCLUSION: High grades of CRS improved over time likely related to earlier intervention, development of ICANS is intrinsically related with CRS. These findings underscore the need for effective strategies to mitigate these toxicities and improve CAR-T safety.}, }
@article {pmid40287589, year = {2025}, author = {Vo, P and Ng, K and Schoch, G and Cooper, J and Vupalanchi, A and Flowers, M and Sandmaier, BM and Gooley, T and Storb, R}, title = {Subsequent cancers following non-myeloablative conditioning for allogeneic hematopoietic cell transplantation.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, pmid = {40287589}, issn = {1476-5365}, support = {CA 078902//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; CA 078902//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P30 CA 015704//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; }, abstract = {We examined the risk of subsequent malignant neoplasms (SMNs) in 1720 patients with hematologic cancers given allogeneic hematopoietic grafts from 03/1998 to 08/2023 after nonmyeloablative conditioning regimens. With a median follow-up of 12 years, the cumulative incidence of SMNs was 17% (95% CI, [15%, 19%]). Most SMNs (n = 543) were non-melanoma skin cancers seen in 208 patients; unfortunately, information on these cancers was not available in the Surveillance, Epidemiology, and End Results (SEER) database for comparison with such tumors in the general population. However, developing non-melanoma skin cancers was statistically significantly associated with chronic GVHD and, thus, unlikely to be conditioning regimen related. Eighty-six patients (5%) developed 93 other SMNs. This number (93 SNMs) significantly exceeded the expected 73.4 cases in the comparison group (p = 0.03). This increase was driven exclusively by increases in uterine adenocarcinoma (n = 2), squamous lip cancer (n = 5), and squamous penile cancer (n = 2); the latter two cancers were, again, associated with chronic GVHD. Apart from these three tumor types, there were no observed increases in the risk of other tumors compared to those in the general population.}, }
@article {pmid40281324, year = {2025}, author = {Posluszny, DM and Nezu, AM and Bovbjerg, DH and Syrjala, KL and Dew, MA}, title = {Intervention Development to Promote Medical Adherence After Stem Cell Transplant.}, journal = {Journal of clinical psychology in medical settings}, volume = {}, number = {}, pages = {}, pmid = {40281324}, issn = {1573-3572}, support = {K23CA149082 and P30CA047904/CA/NCI NIH HHS/United States ; }, abstract = {Allogeneic hematopoietic cell transplantation (HCT) can be a lifesaving treatment for patients with hematologic disease. However, adherence to the post-HCT clinical regimen has many challenges that patients and their family caregivers must manage after hospital discharge. To address their needs, we developed a Dyadic Problem-Solving Therapy (DPST) intervention, then examined its feasibility and acceptability to patients and their family caregivers. Twelve patient-family caregiver dyads participated. Four dyads received DPST in person, four received it via online video conferencing. Another four received an enhanced usual care (EUC) intervention of the same length. Feasibility was assessed using completion rates, while acceptability was assessed using satisfaction ratings on the Client Satisfaction Questionnaire. DPST and EUC were both feasible (100% of dyads who started the intervention completed it) and acceptable with satisfaction ratings ranging from 3.6 to 4 for patients and 3.6-3.9 for family caregivers on a 1-4 scale for both DPST groups and ranging from 3.3 to 3.8 for EUC patients and 3.5-4 for EUC family caregivers. There were no evident differences by mode of intervention delivery. DPST, both in person and via video, appears feasible and acceptable for training patient-family caregiver dyads to manage challenges to adherence to the post-HCT regimen.}, }
@article {pmid40280707, year = {2025}, author = {Wang, M and Guo, Y and Hippe, DS and Zhao, X and Yuan, C and Saba, L and Zhang, B and Mossa-Basha, M}, title = {Plaque RADS Related to Cerebrovascular Event Risk with Mild/moderate Stenosis: a CARE II study.}, journal = {AJNR. American journal of neuroradiology}, volume = {}, number = {}, pages = {}, doi = {10.3174/ajnr.A8819}, pmid = {40280707}, issn = {1936-959X}, abstract = {BACKGROUND AND PURPOSE: Carotid Plaque-Reporting And Data System (Plaque-RADS) provides a standardized approach for evaluating carotid plaque morphology and composition. The aim of this study was to evaluate carotid Plaque-RADS, and its relationship with clinical risk factors and ipsilateral cerebrovascular symptoms, in a prospectively-acquired multi-center, vessel-wall MRI dataset.<br><br>MATERIALS AND METHODS: Symptomatic patients were recruited from the CARE-II (Chinese Atherosclerosis Risk Evaluation, NCT02017756) study. This cross-sectional study included patients with recent stroke or transient ischemia attack and atherosclerotic plaques in at least one carotid artery. Lipid-rich necrotic core, ulceration, intraplaque hemorrhage, thick or thin fibrous cap, fibrous cap rupture and intraluminal thrombi were identified from multiple contrast vessel wall imaging and used to determine carotid Plaque-RADS. In addition, ancillary features including calcification and plaque burden via maximum normalized wall index (max_NWI) were collected. Degree of stenosis was classified as mild (<30%), moderate (30-69%), and severe (70-99%). Generalized Estimating Equation-based logistic regression was performed to assess the relationship between the Plaque-RADS score and cerebrovascular events.<br><br>RESULTS: A total of 433 patients (62 years &#xb1; 9.97, 302 males (69.7%)) with 866 carotid arteries were included in this study. Symptomatic carotid arteries had higher stenosis degree (11.8%&#xb1;24.7 vs 8.6%&#xb1;18.8, p=0.01), plaque-RADS score (&#x2265;3: 33.9% vs 28.4%, p=0.02) and max_NWI (0.53&#xb1;0.14 vs 0.51&#xb1;0.13, p=0.002) compared to the asymptomatic side. Plaque RADS was significantly associated with cerebrovascular events (OR=1.11 per 1-level increase, 95%CI=1.01-1.24; p=0.04). In patients with mild/moderate bilateral carotid artery stenosis, plaque RADS&#x2265;3 was significantly associated with symptomatic events (OR=1.30, 95%CI=1.01-1.68; p=0.04). Higher plaque-RADS on the symptomatic side was related to advanced age (OR=1.27 per 10-year increase, 95%CI=1.03-1.56; p=0.03), male sex (OR=1.90, 95%CI=1.05-3.43; p=0.03), and smoking history (OR=1.99, 95%CI=1.20-3.31; p=0.007).<br><br>CONCLUSIONS: Male patients of advanced age and with a smoking history were associated with an increased risk of higher plaque-RADS scores. Plaque-RADS demonstrated the ability to stratify patients experiencing cerebrovascular events, even in cases with mildto-moderate stenosis. However, this association did not retain statistical significance after adjusting for stenosis or max_NWI.<br><br>ABBREVIATIONS: IPH = intraplaque hemorrhage; Max-NWI = maximum normalized wall index; MWT = maximum wall thickness; RADS = Reporting And Data System; VWI = vessel wall imaging.}, }
@article {pmid40280142, year = {2025}, author = {Luetkemeyer, AF and Donnell, D and Celum, C}, title = {Doxy-PEP could select for ceftriaxone resistance in Neisseria gonorrhoeae - Authors' reply.}, journal = {The Lancet. Infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1016/S1473-3099(25)00235-X}, pmid = {40280142}, issn = {1474-4457}, }
@article {pmid40279415, year = {2025}, author = {Freie, B and Ibrahim, AH and Carroll, PA and Bronson, RT and Augert, A and MacPherson, D and Eisenman, RN}, title = {MAX inactivation deregulates the MYC network and induces neuroendocrine neoplasia in multiple tissues.}, journal = {Science advances}, volume = {11}, number = {17}, pages = {eadt3177}, pmid = {40279415}, issn = {2375-2548}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA248762/CA/NCI NIH HHS/United States ; R35 CA231989/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, mesh = {Animals ; *Proto-Oncogene Proteins c-myc/genetics/metabolism ; Mice ; *Neuroendocrine Tumors/genetics/pathology/metabolism ; *Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics/metabolism ; Gene Expression Regulation, Neoplastic ; Cell Line, Tumor ; Humans ; *Gene Regulatory Networks ; Carcinoma, Neuroendocrine/genetics/pathology ; Tumor Suppressor Protein p53/genetics ; Cell Proliferation ; }, abstract = {The MYC transcription factor requires MAX for DNA binding and widespread activation of gene expression in both normal and neoplastic cells. Inactivating mutations in MAX are associated with a subset of neuroendocrine cancers including pheochromocytoma, pituitary adenoma, and small cell lung cancer. Neither the extent nor the mechanisms of MAX tumor suppression are well understood. Deleting Max across multiple mouse neuroendocrine tissues, we find that Max inactivation alone produces pituitary adenomas, while Max inactivation cooperates with Rb1/Trp53 loss to accelerate medullary thyroid C cell and pituitary adenoma development. In the thyroid tumor cell lines, MAX loss triggers a marked shift in genomic occupancy by other members of the MYC network (MNT, MLX, MondoA) supporting metabolism, survival, and proliferation of neoplastic neuroendocrine cells. Our work reveals MAX as a broad suppressor of neuroendocrine tumorigenesis through its ability to maintain a balance of genomic occupancies among the diverse transcription factors in the MYC network.}, }
@article {pmid40277348, year = {2025}, author = {Chung, Y and Cai, T and Newcomb, L and Lin, DW and Zheng, Y}, title = {Improving Efficiency and Robustness of the Prognostic Accuracy of Biomarkers With Partial Incomplete Failure-Time Data and Auxiliary Outcome: Application to Prostate Cancer Active Surveillance Study.}, journal = {Statistics in medicine}, volume = {44}, number = {8-9}, pages = {e70072}, doi = {10.1002/sim.70072}, pmid = {40277348}, issn = {1097-0258}, support = {R01 CA236558/NH/NIH HHS/United States ; U01 CA86368/NH/NIH HHS/United States ; UH3CA234196/NH/NIH HHS/United States ; R01 HL089778/NH/NIH HHS/United States ; }, mesh = {Humans ; *Prostatic Neoplasms/diagnosis/therapy ; Male ; Prognosis ; Computer Simulation ; *Biomarkers, Tumor ; Disease Progression ; Models, Statistical ; *Watchful Waiting ; Prostate-Specific Antigen/blood ; }, abstract = {When novel biomarkers are developed for the clinical management of patients diagnosed with cancer, it is critical to quantify the accuracy of a biomarker-based decision tool. The evaluation can be challenging when the definite outcome T $$ T $$ , such as time to disease progression, is only partially ascertained on a limited set of study patients. Under settings where T $$ T $$ is only observed on a subset but an auxiliary outcome correlated with T $$ T $$ is available on all subjects, we propose an augmented estimation procedure for commonly used time-dependent accuracy measures. The augmented estimators are easy to implement without imposing modeling assumptions between the two types of time-to-event outcomes and are more efficient than the complete-case estimator. When the ascertainment of the outcome is non-random and subject to informative censoring, we further augment our proposed method with inverse probability weighting to improve robustness. Results from simulation studies confirm the robustness and efficiency properties of the proposed estimators. The method is illustrated with data from the Canary Prostate Active Surveillance Study.}, }
@article {pmid40276374, year = {2025}, author = {Raskin, S and de Blank, P and Billups, CA and Li, Y and Olson, JM and Leary, SES}, title = {Isotretinoin has no effect on event-free survival across high-risk medulloblastoma molecular groups when added to maintenance: A secondary analysis of the Children's Oncology Group ACNS0332 data.}, journal = {Neuro-oncology advances}, volume = {7}, number = {1}, pages = {vdaf054}, pmid = {40276374}, issn = {2632-2498}, abstract = {BACKGROUND: The Children's Oncology Group (COG) study ACNS0332 examined the effect of adding carboplatin and isotretinoin to high-risk medulloblastoma therapy. Isotretinoin arms were closed early due to futility, but the effect of carboplatin was shown to vary by individual medulloblastoma subgroups. Because isotretinoin arms were closed before subgroup classification was available, a differential effect of isotretinoin among various subgroups was not examined. Here, we conduct a secondary analysis of ACNS0332 data examining the effect of isotretinoin on event-free survival (EFS) among individual medulloblastoma subgroups.<br><br>METHODS: Among 261 patients enrolled in ACNS0332, a subgroup was evaluable in 231 patients. Fisher's exact tests and chi-square tests were used to compare distributions of categorical variables among patients with and without exposure to isotretinoin. EFS for subgroups was estimated, and the log-rank test was used to examine differences in outcome distributions among patient groups.<br><br>RESULTS: Among 231 evaluable patients, 85 were randomized to isotretinoin, 85 were randomized to no isotretinoin, and 61 received no isotretinoin without randomization. All 4 medulloblastoma groups were identified: Randomization to isotretinoin was not associated with any difference in EFS in patients with group 3 (n&#x2005;=&#x2005;79, P&#x2005;=&#x2005;.87), group 4 (n&#x2005;=&#x2005;101, P&#x2005;=&#x2005;.53), SHH (n&#x2005;=&#x2005;37, P&#x2005;=&#x2005;.69) or WNT (n&#x2005;=&#x2005;14, P&#x2005;=&#x2005;1) medulloblastoma.<br><br>CONCLUSIONS: This study confirms that isotretinoin in addition to radiation and chemotherapy did not improve EFS in pediatric high-risk medulloblastoma regardless of molecular subgroup.}, }
@article {pmid40275643, year = {2025}, author = {Rodriguez, CP and Wu, QV and Ng, K and Voutsinas, J and Fromm, JR and Dumenigo-Jimenez, A and Martins, RG and Eaton, KD and Santana-Davila, R and Baik, C and Lee, SM and Tseng, D and Futran, N and Barber, B and Marchiano, E and Laramore, G and Lo, SS and Liao, JJ and Parvathaneni, U}, title = {Dual PD-1 and CTLA4 Immune Checkpoint Blockade and Hypofractionated Radiation in Patients With Advanced Salivary Gland Cancers.}, journal = {Head &amp; neck}, volume = {}, number = {}, pages = {}, doi = {10.1002/hed.28169}, pmid = {40275643}, issn = {1097-0347}, support = {//Bristol-Myers Squibb/ ; }, abstract = {BACKGROUND: No standard systemic therapy exists for recurrent/metastatic salivary gland cancer (R/M SGC). We explored the safety and activity of nivolumab and ipilimumab with palliative hypofractionated radiation (XRT) in this population.<br><br>METHODS: This Phase I/II Trial enrolled R/M SGCs with evidence of progression, ECOG 0-1, no prior anti-PD-1 or CTLA4 therapy, measurable disease excluding the XRT site. Nivolumab 3&#x2009;mg/kg iv Q2&#x2009;weeks&#x2009;&#xd7;&#x2009;12 doses followed by 480&#x2009;mg iv Q4&#x2009;weeks&#x2009;&#xd7;&#x2009;8 doses and ipilimumab 1&#x2009;mg/kg iv Q6&#x2009;weeks&#x2009;&#xd7;&#x2009;4 doses was given. Twenty four gray XRT was given over three fractions, 2&#x2009;weeks after the first dose of nivolumab. The primary endpoint was safety; secondary endpoints included RECIST 1.1 response (non-radiated lesions), progression free, and overall survival.<br><br>RESULTS: Between April 2019 and May 2022, 20 pts. were enrolled, the median age was 58 (range 27-77&#x2009;years), 10 (50%) were male, and 12 (60%) had ECOG 0. Five (20%) Grade 3 AEs were observed in three pts.; no Grade 4 or 5 toxicities were observed. Among 19 response-evaluable patients, RECIST 1.1 PRs were observed in 4 (21%), in 2 pts. with salivary duct, 1 acinic cell, and 1 adenoid cystic, SD in 6 (31.5%) and PD in 9 (47.5%). With a median follow-up of 16&#x2009;months, median OS was 25&#x2009;months (95% CI: [18.7, 31]) and median PFS was 7.3&#x2009;months (95% CI [2.5, 18.7]).<br><br>CONCLUSION: Nivolumab/ipilimumab and palliative XRT result in low rates of severe toxicities and modest response rates for SGC; further work is necessary to explore predictors for response.}, }
@article {pmid40274741, year = {2025}, author = {Juels, M and Larson, JC and Ensrud, KE and Stefanick, ML and Shadyab, AH and Garcia, L and Nassir, R and Schnatz, PF and Nelson, R and Crandall, CJ}, title = {Race, Ethnicity, and Mortality Following Major Osteoporotic Fracture: Results from the Women's Health Initiative Study.}, journal = {Journal of general internal medicine}, volume = {}, number = {}, pages = {}, pmid = {40274741}, issn = {1525-1497}, abstract = {BACKGROUND: Major osteoporotic fracture (MOF) is associated with increased mortality; however, few studies in postmenopausal women have examined racial and ethnic differences in 1-year and 5-year mortality following MOF.<br><br>OBJECTIVE: To assess 1-year and 5-year mortality following MOF by race and ethnicity.<br><br>DESIGN: This prospective cohort study included postmenopausal women enrolled in the Women's Health Initiative (WHI), a population-based, multisite US study. Participants were followed from September 1994 to February 2023. Data were analyzed between August 2023 and November 2023.<br><br>PARTICIPANTS: Postmenopausal women aged 50 to 79&#xa0;years old who experienced a MOF (N&#x2009;=&#x2009;32,675 in 1&#xa0;year and 29,506 in 5&#xa0;years following MOF).<br><br>MAIN MEASURES: Self-reported race and ethnicity. All-cause mortality was determined by death certificates, reports of surrogates, and the National Death Index Search.<br><br>KEY RESULTS: The baseline mean age of participants was 77.0 [SD&#x2009;=&#x2009;8.5] years with 31,223 [95.6%] White participants in the 1-year mortality analysis, and 76.3 [SD&#x2009;=&#x2009;8.5] years with 28,212 [95.6%] White participants in the 5-year mortality analysis. In fully adjusted models, compared to White women, Black women had a higher risk of mortality (adjusted odds ratio (aOR)&#x2009;=&#x2009;1.42, 95% CI [1.06, 1.90], while Asian women had a lower risk of mortality (aOR&#x2009;=&#x2009;0.48 95% CI [0.27, 0.88]), within 1&#xa0;year following MOF. Compared to White women, the mortality risk within 5&#xa0;years after MOF was significantly higher among American Indian/Alaska Native (aOR&#x2009;=&#x2009;3.30, 95% CI [1.65, 6.60]) and lower among Asian (aOR&#x2009;=&#x2009;0.58, 95% CI [0.42,0.80]) women. While there were no mortality differences by ethnicity 1&#xa0;year following MOF, Hispanic/Latina women were less likely to die 5&#xa0;years following MOF (aOR&#x2009;=&#x2009;0.74, [95% CI 0.57-0.96]) compared to Non-Hispanic/Latina women.<br><br>CONCLUSIONS: In this large prospective study, mortality following MOF differed by race. Future research is needed to delineate the mechanism behind these associations.}, }
@article {pmid40274389, year = {2025}, author = {Chan, M and Zhu, S and Nukaya, M and Ferreira, LT and Ronnekleiv-Kelly, SM and Riehle, KJ and Scott, JD and Yeung, RS and Gujral, TS}, title = {DNAJ-PKAc fusion heightens PLK1 inhibitor sensitivity in fibrolamellar carcinoma.}, journal = {Gut}, volume = {}, number = {}, pages = {}, doi = {10.1136/gutjnl-2024-334274}, pmid = {40274389}, issn = {1468-3288}, abstract = {BACKGROUND: Fibrolamellar carcinoma (FLC), a rare and fatal liver cancer lacking effective drug therapy, is driven by the DNAJ-PKAc fusion oncoprotein. However, the underlying mechanism of DNAJ-PKAc's role in FLC tumour growth remains enigmatic.<br><br>OBJECTIVE: We sought to determine the protein kinase-mediated signalling networks that drive growth and proliferation in FLC.<br><br>DESIGN: We integrated a combination of newly established preclinical models of FLC and an unbiased polypharmacology-based approach to identify downstream kinases involved in DNAJ-PKAc-mediated FLC cell growth. We validated our findings in multiple patient-derived mouse models and patient tumours.<br><br>RESULTS: Functional screening, coupled with computational analysis, highlighted Polo-like kinase 1 (PLK1) as vital for FLC cell viability. Genetic and pharmacological PLK1 inhibition significantly reduced FLC cell growth, inducing apoptosis. Further studies showed DNAJ-PKAc's centrosomal presence and direct interaction with PLK1, revealing a novel mechanism that promotes PLK1 activation and mitotic progression. Clinical-grade PLK1 inhibitors effectively suppressed FLC tumour growth across multiple preclinical models, including patient-derived xenograft and an orthotopic model of FLC, suggesting promising therapeutic avenues.<br><br>CONCLUSION: Our findings underscore the role of DNAJ-PKAc in rewiring signalling networks and highlight valuable clinical implications for PLK1-targeted therapies for FLC.}, }
@article {pmid40274340, year = {2025}, author = {Patel, D and Reese Koç, J and Otegbeye, F}, title = {Creating a GMP cell processing program: A focus on quality and regulation.}, journal = {Best practice &amp; research. Clinical haematology}, volume = {38}, number = {1}, pages = {101614}, doi = {10.1016/j.beha.2025.101614}, pmid = {40274340}, issn = {1532-1924}, mesh = {Humans ; United States ; *Cell- and Tissue-Based Therapy/standards ; Quality Control ; United States Food and Drug Administration ; }, abstract = {Implementing current Good Manufacturing Practice (GMP) regulations and principles even in early phases of cell-based therapy studies is crucial for ensuring safety and reproducible quality of these products. This paper outlines the comprehensive steps necessary to establish a robust GMP-compliant cell processing program in academic programs with emphases on adherence to regulatory and quality standards. While there are different regulatory agencies governing practice across the globe, the prevailing quality principles described here incorporate common requirements and guidelines from agencies such as the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA). The goal of this review is to provide guidance for developing a quality management program (QMP) that addresses all critical factors impacting each step in the cell therapy product lifecycle: from procurement and receipt of starter material, through manufacturing, testing, storage, distribution, and administration. The QMP should be designed to assure quality outcomes by maintaining qualified and trained staff at all levels as applicable to their job functions; establishing clear policies and procedures; ensuring the qualification of facilities and equipment; using qualified materials for human use; and providing a framework for detection of trends and implementing process improvement.}, }
@article {pmid40273911, year = {2025}, author = {Kim, WJ and Crosse, EI and De Neef, E and Etxeberria, I and Sabio, EY and Wang, E and Bewersdorf, JP and Lin, KT and Lu, SX and Belleville, A and Fox, N and Castro, C and Zhang, P and Fujino, T and Lewis, J and Rahman, J and Zhang, B and Winick, JH and Lewis, AM and Stanley, RF and DeWolf, S and Urben, BM and Takizawa, M and Krause, T and Molina, H and Chaligne, R and Koppikar, P and Molldrem, J and Gigoux, M and Merghoub, T and Daniyan, A and Chandran, SS and Greenbaum, BD and Klebanoff, CA and Bradley, RK and Abdel-Wahab, O}, title = {Mis-splicing-derived neoantigens and cognate TCRs in splicing factor mutant leukemias.}, journal = {Cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cell.2025.03.047}, pmid = {40273911}, issn = {1097-4172}, abstract = {Mutations in RNA splicing factors are prevalent across cancers and generate recurrently mis-spliced mRNA isoforms. Here, we identified a series of bona fide neoantigens translated from highly stereotyped splicing alterations promoted by neomorphic, leukemia-associated somatic splicing machinery mutations. We utilized feature-barcoded peptide-major histocompatibility complex (MHC) dextramers to isolate neoantigen-reactive T cell receptors (TCRs) from healthy donors, patients with active myeloid malignancy, and following curative allogeneic stem cell transplant. Neoantigen-reactive CD8[+] T cells were present in the blood of patients with active cancer and had a distinct phenotype from virus-reactive T cells with evidence of impaired cytotoxic function. T cells engineered with TCRs recognizing SRSF2 mutant-induced neoantigens arising from mis-splicing events in CLK3 and RHOT2 resulted in specific recognition and cytotoxicity of SRSF2-mutant leukemia. These data identify recurrent RNA mis-splicing events as sources of actionable public neoantigens in myeloid leukemias and provide proof of concept for genetically redirecting T cells to recognize these targets.}, }
@article {pmid40272942, year = {2025}, author = {Karvonen, KA and Vu, A and Lin, K and Gibbons, J and Mendoza, JA and Chow, EJ and Winestone, LE and Gomez, SL}, title = {Historical redlining and mortality in children, adolescents, and young adults with cancer in California, 2000-2019.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djaf105}, pmid = {40272942}, issn = {1460-2105}, abstract = {BACKGROUND: Historical redlining, or the Home Owners Loan Corporation (HOLC) program's racially biased mortgage risk monitoring maps in the 1930s, is implicated in shaping modern neighborhoods and health outcomes. This retrospective cohort study evaluates the association between redlining and mortality in young cancer patients.<br><br>METHODS: Using the California Cancer Registry, we identified patients <25&#x2009;years old diagnosed with malignant cancer between 2000-2019. HOLC maps were spatially joined with patient address at diagnosis to determine redlining status (A "Best", B "Still Desirable", C "Declining", D "Hazardous"). Census tract-level U.S. Census and American Community Survey data were appended to determine modern neighborhood characteristics. The Kaplan-Meier method was used to evaluate overall survival and multivariable Cox proportional hazards models to estimate the associations between HOLC grade and mortality, adjusting for clinical and multilevel social drivers of health.<br><br>RESULTS: In total 8,108 patients resided in HOLC-graded neighborhoods among 51,084 patients statewide. Overall survival at 5&#x2009;years was inferior for patients who resided in D graded neighborhoods at diagnosis vs A graded neighborhoods (80.3%, 95% CI: 78.6-81.8 vs 88.5%, 95% CI: 84.3-91.6). Adjusting for clinical characteristics, patients in D graded neighborhoods experienced greater mortality (HR 1.32, 95% CI: 1.12-1.56) compared with those in A and B graded neighborhoods. Additional adjustment for insurance attenuated the effect (HR 1.17, 95%CI: 1.00-1.36) and for neighborhood socioeconomic status marginally attenuated the effect (HR 0.96, 95% CI: 0.81-1.13).<br><br>CONCLUSION: Findings suggest enduring legacy effects of historical redlining on young individuals with cancer, potentially mediated social factors including health insurance.}, }
@article {pmid40272674, year = {2025}, author = {Fest, SN and Farland, LV and Doody, DR and Eliassen, AH and Rosner, BA and Fung, TT and Hankinson, SE and Kensler, TW and Willett, WC and Harris, HR}, title = {Correction: Hormone-associated dietary patterns and premenopausal breast cancer risk.}, journal = {Breast cancer research and treatment}, volume = {}, number = {}, pages = {}, doi = {10.1007/s10549-025-07706-6}, pmid = {40272674}, issn = {1573-7217}, }
@article {pmid40272393, year = {2025}, author = {Prada, D and Kalia, V and Gao, F and Rexrode, K and Kooperberg, C and Reiner, A and Balasubramanian, R and Wu, HC and Crandall, CJ and Horowitz, C and Cantu-de-Leon, D and Garcia-Cuellar, C and Ramirez, A and González-Ruiz, J and Liao, D and Yanosky, J and Stewart, JD and Whitsel, EA and Baccarelli, AA}, title = {Metabolomic Evaluation of Air Pollution-related Bone Damage and Potential Mediation in Women's Health Initiative Participants.}, journal = {Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research}, volume = {}, number = {}, pages = {}, doi = {10.1093/jbmr/zjaf059}, pmid = {40272393}, issn = {1523-4681}, abstract = {Ambient air pollution has been associated with bone damage. However, no studies have evaluated the metabolomic response to air pollutants and its potential influence on bone health in postmenopausal women. We analyzed data from WHI participants with plasma samples. Whole-body, total hip, femoral neck, and spine BMD were determined using dual-energy X-ray absorptiometry (DXA) at enrollment and follow-up visits (Years 1, 3, 6, and 9 visits; Y1, Y3, Y6, Y9, respectively). Geocoded, participant address-specific, daily particulate matter nitrogen oxide (NO), nitrogen dioxide (NO2), particulate matter ≤10 μm (PM10), and sulfur dioxide (SO2) concentrations were averaged over 1-, 3-, and 5-yr periods before plasma sampling for metabolomic assessments. (at baseline and Y1 visit). The averages were then integrated using masked WHI participant identifiers. Statistical analyses included multivariable-adjusted linear mixed models, pathways analyses, and mediation modeling. At all averaging periods, NO, NO2, and SO2, but not PM10, were associated with taurine, inosine, and C38:4 phosphatidylethanolamine (PE). We found a partial potential mediation of C38:4 PE in the association between 1-yr average NO and lumbar spine BMD (p-value: 0.032). This is the first study suggesting phospholipids may partially mediate air pollution-related bone damage in postmenopausal women.}, }
@article {pmid40269324, year = {2025}, author = {Bajunaid, R and Niu, C and Hambly, C and Liu, Z and Yamada, Y and Aleman-Mateo, H and Anderson, LJ and Arab, L and Baddou, I and Bandini, L and Bedu-Addo, K and Blaak, EE and Bouten, CVC and Brage, S and Buchowski, MS and Butte, NF and Camps, SGJA and Casper, R and Close, GL and Cooper, JA and Cooper, R and Das, SK and Davies, PSW and Dabare, P and Dugas, LR and Eaton, S and Ekelund, U and Entringer, S and Forrester, T and Fudge, BW and Gillingham, M and Goris, AH and Gurven, M and El Hamdouchi, A and Haisma, HH and Hoffman, D and Hoos, MB and Hu, S and Joonas, N and Joosen, AM and Katzmarzyk, P and Kimura, M and Kraus, WE and Kriengsinyos, W and Kuriyan, R and Kushner, RF and Lambert, EV and Lanerolle, P and Larsson, CL and Leonard, WR and Lessan, N and Löf, M and Martin, CK and Matsiko, E and Medin, AC and Morehen, JC and Morton, JP and Must, A and Neuhouser, ML and Nicklas, TA and Nyström, CD and Ojiambo, RM and Pietiläinen, KH and Pitsiladis, YP and Plange-Rhule, J and Plasqui, G and Prentice, RL and Racette, SB and Raichlen, DA and Ravussin, E and Redman, LM and Reilly, JJ and Reynolds, R and Roberts, SB and Samaranayakem, D and Sardinha, LB and Silva, AM and Sjödin, AM and Stamatiou, M and Stice, E and Urlacher, SS and Van Etten, LM and van Mil, EGAH and Wilson, G and Yanovski, JA and Yoshida, T and Zhang, X and Murphy-Alford, AJ and Sinha, S and Loechl, CU and Luke, AH and Pontzer, H and Rood, J and Sagayama, H and Schoeller, DA and Westerterp, KR and Wong, WW and Speakman, JR}, title = {Author Correction: Predictive equation derived from 6,497 doubly labelled water measurements enables the detection of erroneous self-reported energy intake.}, journal = {Nature food}, volume = {}, number = {}, pages = {}, doi = {10.1038/s43016-025-01175-2}, pmid = {40269324}, issn = {2662-1355}, }
@article {pmid40161702, year = {2025}, author = {Kikawa, C and Loes, AN and Huddleston, J and Figgins, MD and Steinberg, P and Griffiths, T and Drapeau, EM and Peck, H and Barr, IG and Englund, JA and Hensley, SE and Bedford, T and Bloom, JD}, title = {High-throughput neutralization measurements correlate strongly with evolutionary success of human influenza strains.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40161702}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R01 GM129325/GM/NIGMS NIH HHS/United States ; T32 AI083203/AI/NIAID NIH HHS/United States ; 75N93021C00015/AI/NIAID NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; R01 AI165821/AI/NIAID NIH HHS/United States ; }, abstract = {Human influenza viruses rapidly acquire mutations in their hemagglutinin (HA) protein that erode neutralization by antibodies from prior exposures. Here, we use a sequencing-based assay to measure neutralization titers for 78 recent H3N2 HA strains against a large set of children and adult sera, measuring ~10,000 total titers. There is substantial person-to-person heterogeneity in the titers against different viral strains, both within and across age cohorts. The growth rates of H3N2 strains in the human population in 2023 are highly correlated with the fraction of sera with low titers against each strain. Notably, strain growth rates are less correlated with neutralization titers against pools of human sera, demonstrating the importance of population heterogeneity in shaping viral evolution. Overall, these results suggest that high-throughput neutralization measurements of human sera against many different viral strains can help explain the evolution of human influenza.}, }
@article {pmid40269243, year = {2025}, author = {Mielke, D and Li, SS and Schuster, DJ and Li, X and Hu, J and Karuna, S and Seaton, KE and Brackett, C and Dunn, B and Keyes, T and Zalaquett, A and Stanfield-Oakley, S and Zhang, L and Wesley, MS and Eisel, N and Yates, NL and Shen, X and Premkumar, L and Germain, RS and Sholukh, AM and Cohen, K and de Rosa, S and Randhawa, AK and Hural, JA and Corey, L and McElrath, MJ and Tomaras, GD and Hyrien, O and Ferrari, G}, title = {Distinct immune responses in people living with HIV following SARS-CoV-2 recovery.}, journal = {Communications medicine}, volume = {5}, number = {1}, pages = {132}, pmid = {40269243}, issn = {2730-664X}, support = {T32 AI141342/AI/NIAID NIH HHS/United States ; INV008612//Bill and Melinda Gates Foundation (Bill &amp; Melinda Gates Foundation)/ ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; U01 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; P30 AI064518/AI/NIAID NIH HHS/United States ; U01 AI068618/AI/NIAID NIH HHS/United States ; U01 AI068614/AI/NIAID NIH HHS/United States ; P30 AI045008/AI/NIAID NIH HHS/United States ; UM1 AI148452/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: SARS-CoV-2 infection results in greater disease severity among immunocompromised individuals compared to healthy individuals. However, there is conflicting information about the impact of chronic HIV infection on immune responses to SARS-CoV-2 infection and vaccination.<br><br>METHOD: We used a combination of machine learning approaches and network analysis to explore 56 immune markers and comprehensively profile humoral and cellular immunity in a cross-sectional observational cohort of people without HIV (PWOH; n&#x2009;=&#x2009;216) and people living with HIV (PLWH; n&#x2009;=&#x2009;43) who recovered from SARS-CoV-2 infection (13-131 days since SARS-COV-2 diagnosis) early in the pandemic.<br><br>RESULTS: PLWH recovered from symptomatic outpatient COVID-19 exhibit lower humoral and B cell responses to SARS-CoV-2 vs. PWOH but, surprisingly, both symptomatic outpatient and hospitalized PLWH have higher anti-endemic coronavirus antibody responses compared to PWOH counterparts and asymptomatic PLWH. The latter observation suggests that this was not strictly due to broadly elevated levels of anti-endemic coronavirus antibodies in PLWH. Moreover, correlation-based analysis reveals that while different compartments of the immune response to SARS-CoV-2 infection are positively correlated in PWOH recovered from symptomatic outpatient COVID-19, these correlations are weaker in PLWH.<br><br>CONCLUSION: Our analyses reveal significant differences in the coordinated immune responses elicited by infection in PLWH compared to PWOH.}, }
@article {pmid40269155, year = {2025}, author = {Kang, Y and Lehmann, KS and Long, H and Jefferson, A and Purice, M and Freeman, M and Clark, S}, title = {Structural basis of lipid transfer by a bridge-like lipid-transfer protein.}, journal = {Nature}, volume = {}, number = {}, pages = {}, pmid = {40269155}, issn = {1476-4687}, abstract = {Bridge-like lipid-transport proteins (BLTPs) are an evolutionarily conserved family of proteins that localize to membrane-contact sites and are thought to mediate the bulk transfer of lipids from a donor membrane, typically the endoplasmic reticulum, to an acceptor membrane, such as that of the cell or an organelle[1]. Although BLTPs are fundamentally important for a wide array of cellular functions, their architecture, composition and lipid-transfer mechanisms remain poorly characterized. Here we present the subunit composition and the cryogenic electron microscopy structure of the native LPD-3 BLTP complex isolated from transgenic Caenorhabditis elegans. LPD-3 folds into an elongated, rod-shaped tunnel of which the interior is filled with ordered lipid molecules that are coordinated by a track of ionizable residues that line one side of the tunnel. LPD-3 forms a complex with two previously uncharacterized proteins, one of which we have named Spigot and the other of which remains unnamed. Spigot interacts with the N-terminal end of LPD-3 where lipids are expected to enter the tunnel, and experiments in multiple model systems indicate that Spigot has a conserved role in BLTP function. Our LPD-3 complex structural data reveal protein-lipid interactions that suggest a model for how the native LPD-3 complex mediates bulk lipid transport and provides a foundation for mechanistic studies of BLTPs.}, }
@article {pmid40269088, year = {2025}, author = {Touré, H and Durand, N and Orgeur, M and Galindo, LA and Girard-Misguich, F and Guénal, I and Herrmann, JL and Szuplewski, S}, title = {ENaC is a host susceptibility factor to bacterial infections in cystic fibrosis context.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {653}, pmid = {40269088}, issn = {2399-3642}, mesh = {Animals ; *Epithelial Sodium Channels/genetics/metabolism ; *Cystic Fibrosis/microbiology/genetics/metabolism/complications ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics/metabolism ; *Mycobacterium abscessus ; Drosophila melanogaster/microbiology/genetics ; *Drosophila Proteins/genetics/metabolism ; *Mycobacterium Infections, Nontuberculous/microbiology/genetics ; Disease Susceptibility ; Humans ; Host-Pathogen Interactions ; }, abstract = {Cystic fibrosis (CF) is a genetic disease caused by dysfunction in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) chloride channel. Patients with CF are hypersusceptible to Mycobacterium abscessus infection, a fast-growing mycobacterium and harmful opportunistic pathogen. Although CFTR dysfunction is known as a host susceptibility factor for M. abscessus infection, the functional impact of the trimeric Epithelial sodium Channel (ENaC), whose activity is negatively regulated by CFTR, towards M. abscessus infection has not been explored yet. To address this issue, we took advantage of miR-263a deficient Drosophila presenting a CF-like phenotype due to ENaC hyperactivity (ENaC+). We observed that the ENaC+ flies were as hypersusceptible to M. abscessus infection as the Cftr-deficient flies. The hypersensitivity of ENaC+ flies to M. abscessus infection was fully rescued by blocking ENaC hyperactivity, both chemically and genetically. Furthermore, we observed that ENaC hyperactivity per se was detrimental to ENaC+ Drosophila, as they were unable to mount an efficient humoral immune response. Upon infection, ENaC+ flies failed to upregulate 20-hydroxyecdysone production, which subsequently altered the production of protective antimicrobial peptides against M. abscessus. Overall, our results show that ENaC plays a key role in host susceptibility to M. abscessus infection and, correlatively to other CF pathogens.}, }
@article {pmid40268927, year = {2025}, author = {Werner, J and Lee, AG and Zhang, C and Abelson, S and Xirenayi, S and Rivera, J and Yousuf, K and Shin, H and Patiño-Escobar, B and Bachl, S and Mandal, K and Barpanda, A and Ramos, E and Izgutdina, A and Chaudhuri, S and Temple, WC and Bhatnagar, S and Dardis, JK and Meyer, J and Morales, C and Meshinchi, S and Loh, ML and Braun, B and Tasian, SK and Wiita, AP and Stieglitz, E}, title = {Cellular immunotherapy targeting CLL-1 for juvenile myelomonocytic leukemia.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {3804}, pmid = {40268927}, issn = {2041-1723}, support = {P30 CA082103/CA/NCI NIH HHS/United States ; R37 CA266550/CA/NCI NIH HHS/United States ; R50 CA274213/CA/NCI NIH HHS/United States ; U54 CA196519/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Leukemia, Myelomonocytic, Juvenile/therapy/immunology/genetics/pathology ; Animals ; Mice ; *Immunotherapy, Adoptive/methods ; *Lectins, C-Type/genetics/immunology/metabolism ; *Receptors, Mitogen/genetics/immunology/metabolism ; Female ; Receptors, Chimeric Antigen/immunology/genetics ; Male ; Xenograft Model Antitumor Assays ; Child ; Mice, SCID ; Neoplastic Stem Cells/immunology ; Infant ; T-Lymphocytes/immunology/transplantation ; }, abstract = {Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative disorder that predominantly affects infants and young children. Hematopoietic stem cell transplantation (HSCT) is standard of care, but post-HSCT relapse is common, highlighting the need for innovative therapies. While adoptive immunotherapy with chimeric antigen receptor (CAR) T cells has improved outcomes for patients with advanced lymphoid malignancies, it has not been comprehensively evaluated in JMML. In the present study, we use bulk and single-cell RNA sequencing, mass spectrometry, and flow cytometry to identify overexpression of CLL-1 (encoded by CLEC12A) on the cell surface of cells from patients with JMML. We develop immunotherapy with CLL-1 CAR T cells (CLL1CART) for preclinical testing and report in vitro and in vivo anti-leukemia activity. Notably, CLL1CART reduce the number of leukemic stem cells and serial transplantability in vivo. These preclinical data support the development and clinical investigation of CLL-1-targeting immunotherapy in children with relapsed/refractory JMML.}, }
@article {pmid40268594, year = {2025}, author = {Gupta, S and Hensley, PJ and Li, R and Choudhury, A and Daneshmand, S and Faltas, BM and Flaig, TW and Grass, GD and Grivas, P and Hansel, DE and Hassanzadeh, C and Kassouf, W and Kukreja, J and Mendoza-Valdés, A and Moschini, M and Mouw, KW and Navai, N and Necchi, A and Rosenberg, JE and Ross, JS and Siefker-Radtke, AO and Taylor, J and Willliams, SB and Zlotta, AR and Buckley, R and Kamat, AM}, title = {Bladder Preservation Strategies in Muscle-invasive Bladder Cancer: Recommendations from the International Bladder Cancer Group.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2025.03.017}, pmid = {40268594}, issn = {1873-7560}, abstract = {BACKGROUND AND OBJECTIVE: Patient-centric management necessitates providing care aligned with patients' values, preferences, and expressed needs. Therefore, critical assessment of bladder preservation therapies (BPTs) as alternatives to radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC) and practical recommendations on the optimal selection of patients for BPTs are needed urgently.<br><br>METHODS: A global committee of bladder cancer experts was assembled to develop BPT recommendations for MIBC. Working groups reviewed the literature and drafted recommendations, which were voted on by International Bladder Cancer Group (IBCG) members using a modified Delphi process. During a live meeting in August 2023, voting results and supporting evidence were presented, and recommendations were refined based on discussions. Final recommendations achieved &#x2265;75% agreement during the meeting, with further refinements through web conferences and e-mail discussions.<br><br>KEY FINDINGS AND LIMITATIONS: Patients with newly diagnosed MIBC should be offered evaluation in a multidisciplinary setting for consideration of BPTs. The main alternative to RC is trimodal therapy (TMT), and favorable prognostic factors for TMT include unifocal cT2 stage, lack of hydronephrosis, and no multifocal carcinoma in situ (CIS). Other options should be reserved for very select patients who are ineligible for or who decline TMT or RC after thorough consideration of benefits versus risks. These include partial cystectomy (PC) for urachal adenocarcinoma and PC or radical transurethral resection alone for solitary tumors amenable to resection with adequate margins and without concomitant CIS or histologic subtypes.<br><br>The IBCG consensus recommendations provide practical guidance on BPTs for MIBC.}, }
@article {pmid40268054, year = {2025}, author = {Bhatt, NS and Lehmann, L and Dandoy, CE and Auletta, JJ and Badia, P and Ballard, SA and Blacken, R and Daraiseh, NM and Desmond, C and Dunseath, C and Epling, P and Fitch, TJ and Flesch, L and Hartley, D and Huber, J and Jenssen, K and Kent, G and Klunk, A and Kapadia, M and Kusnier, K and Liberio, N and Maier, S and Myers, KC and O'Connor, G and Tarquini, S and Phelan, R and Pai, A and Rotz, S}, title = {Multicenter Study on Caregiver Experiences in Pediatric Hematopoietic Stem Cell Transplantation Part I: Integrative Analysis of Mental Health, Psychosocial Stressors, and Support Mechanisms.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.04.013}, pmid = {40268054}, issn = {2666-6367}, abstract = {Caregivers of children undergoing allogeneic hematopoietic stem cell transplantation (HSCT) face substantial psychological, social, and logistical challenges throughout the transplant journey. This multicenter, longitudinal qualitative study explored the evolving mental health experiences, stressors, and coping strategies of 49 caregivers interviewed across four key time points: transplant (Day 0), Day +30, Day +100, and Day +180. Participants reported acute distress early in the process, exacerbated by restrictive hospital environments, the demands of hypervigilant caregiving, financial strain, and the emotional toll of family separation. As care transitioned to the outpatient setting, challenges shifted toward navigating complex home care, managing lingering uncertainty, and balancing the needs of other family members. Throughout the process, caregivers expressed heightened anxiety related to fear of relapse, infection, and long-term complications. Despite these burdens, many caregivers described powerful sources of resilience. Children's emotional strength, honest communication, and a desire to return to normal life helped sustain caregiver optimism. Support from the healthcare team, financial assistance, and access to professional mental health services further alleviated stress. Caregivers emphasized the need for enhanced inpatient environments, clearer outpatient guidance, structured mental health resources, and practical tools like caregiver handbooks. These findings underscore the need for holistic, family-centered care that addresses caregiving's psychological and practical dimensions during pediatric HSCT. Tailored, time-sensitive support strategies are essential to improving caregiver well-being and, in turn, optimizing patient outcomes across the transplant continuum.}, }
@article {pmid40267200, year = {2025}, author = {Brumage, L and Best, S and Hippe, DS and Grunblatt, E and Chanana, P and Wu, F and Lee, MC and Ying, Z and Ibrahim, A and Chung, JH and Vigil, A and Fatherree, J and Beronja, S and Paddison, P and Sullivan, L and Nabet, B and MacPherson, D}, title = {In vivo functional screens reveal KEAP1 loss as a driver of chemoresistance in small cell lung cancer.}, journal = {Science advances}, volume = {11}, number = {17}, pages = {eadq7084}, pmid = {40267200}, issn = {2375-2548}, mesh = {*Small Cell Lung Carcinoma/drug therapy/genetics ; Humans ; *Drug Resistance, Neoplasm ; *Kelch-Like ECH-Associated Protein 1/genetics ; DNA, Complementary/analysis ; Proto-Oncogene Proteins c-myc/metabolism ; Animals ; Mice ; CRISPR-Cas Systems ; Signal Transduction ; *Lung Neoplasms/drug therapy/genetics ; Male ; Female ; Immunologic Deficiency Syndromes ; HEK293 Cells ; }, abstract = {Exquisitely chemosensitive initially, small cell lung cancer (SCLC) exhibits dismal outcomes owing to rapid transition to chemoresistance. Elucidating the genetic underpinnings has been challenging owing to limitations with cellular models. As SCLC patient-derived xenograft (PDX) models mimic therapeutic responses, we perform genetic screens in chemosensitive PDX models to identify drivers of chemoresistance. cDNA overexpression screens identify MYC, MYCN, and MYCL, while CRISPR deletion screens identify KEAP1 loss as driving chemoresistance. Deletion of KEAP1 switched a chemosensitive SCLC PDX model to become chemoresistant and resulted in sensitivity to inhibition of glutamine metabolism. Data from the IMpower133 clinical trial revealed ~6% of patients with extensive-stage SCLC exhibit KEAP1 genetic alterations, with activation of a KEAP1/NRF2 transcriptional signature associated with reduced survival upon chemotherapy treatment. While roles for KEAP1/NRF2 have been unappreciated in SCLC, our genetic screens revealed KEAP1 loss as a driver of chemoresistance, while patient genomic analyses demonstrate clinical importance.}, }
@article {pmid40266065, year = {2025}, author = {Mielke, D and Tuyishime, M and Kelkar, NS and Wang, Y and Parks, R and Santra, S and Rountree, W and Williams, LD and Peters, T and Eisel, N and Sawant, S and Zhang, L and Goodman, D and Jha, S and Zalaquett, A and Ramasubramanian, P and Stanfield-Oakley, S and Matyas, G and Beck, Z and Rao, M and Ake, J and Denny, TN and Montefiori, DC and Ackerman, ME and Corey, L and Tomaras, GD and Korber, BT and Haynes, BF and Shen, X and Ferrari, G}, title = {Computationally Selected Multivalent HIV-1 Subtype C Vaccine Protects Against Heterologous SHIV Challenge.}, journal = {Vaccines}, volume = {13}, number = {3}, pages = {}, pmid = {40266065}, issn = {2076-393X}, abstract = {Background: The RV144 trial in Thailand is the only HIV-1 vaccine efficacy trial to date to demonstrate any efficacy. Genetic signatures suggested that antibodies targeting the variable loop 2 (V2) of the HIV-1 envelope played an important protective role. The ALVAC prime and protein boost follow-up trial in southern Africa (HVTN702) failed to show any efficacy. One hypothesis for this is the greater diversity of subtype C viruses in southern Africa relative to CRF01_AE in Thailand. Methods: Here, we determined whether an ALVAC prime with computationally selected gp120 boost immunogens maximizing coverage of diversity of subtype C viruses in the variable V1 and V2 regions (V1V2) improved the protection of non-human primates (NHPs) from a heterologous subtype C SHIV challenge compared to more traditional regimens. Results: An ALVAC prime with Trivalent subtype C gp120 boosts resulted in statistically significant protection from repeated intrarectal SHIV challenges compared to the control. Evaluation of the immunogenicity of each vaccine regimen at the time of challenge demonstrated that different gp120 combination boosts elicited similar high magnitudes of gp120 and breadth of V1V2-binding antibodies, as well as strong Fc-mediated immune responses. Low-to-no neutralization of the challenge virus was detected. A Cox proportional hazard analysis of five pre-selected immune parameters at the time of challenge identified ADCC against the challenge envelope as a correlate of protection. Systems serology analysis revealed that immune responses elicited by the different vaccine regimens were distinct and identified further correlates of resistance to infection. Conclusions: Computationally designed vaccines with maximized subtype C V1V2 coverage mediated protection of NHPs from a heterologous Tier-2 subtype C SHIV challenge.}, }
@article {pmid40265297, year = {2025}, author = {Mahla, RS}, title = {Epitope Spreading and Systemic Sclerosis.}, journal = {Arthritis &amp; rheumatology (Hoboken, N.J.)}, volume = {}, number = {}, pages = {}, doi = {10.1002/art.43196}, pmid = {40265297}, issn = {2326-5205}, }
@article {pmid40264918, year = {2025}, author = {Ghosh, N and Bellasea, S and Li, H and Olszewski, AJ and Bryan, L and Danilov, A and Smith, S and LeBlanc, M and Friedberg, JW}, title = {SWOG 2308: Randomized Phase III Study of Mosunetuzumab Versus Rituximab for Low-Tumor Burden Follicular Lymphoma.}, journal = {JCO oncology advances}, volume = {2}, number = {1}, pages = {e2500037}, pmid = {40264918}, issn = {2994-9750}, }
@article {pmid40264148, year = {2025}, author = {Montaño, MA and Chen, Y and Saldarriaga, EM and Thuo, N and Kiptinness, C and Stergachis, A and Mugambi, ML and Ngure, K and Ortblad, KF and Sharma, M}, title = {Willingness to pay for HIV pre- and post-exposure prophylaxis services delivered via an online pharmacy in Kenya.}, journal = {BMC health services research}, volume = {25}, number = {1}, pages = {576}, pmid = {40264148}, issn = {1472-6963}, support = {INV-037646/GATES/Gates Foundation/United States ; INV-037646/GATES/Gates Foundation/United States ; INV-037646/GATES/Gates Foundation/United States ; INV-037646/GATES/Gates Foundation/United States ; INV-037646/GATES/Gates Foundation/United States ; INV-037646/GATES/Gates Foundation/United States ; INV-037646/GATES/Gates Foundation/United States ; INV-037646/GATES/Gates Foundation/United States ; INV-037646/GATES/Gates Foundation/United States ; INV-037646/GATES/Gates Foundation/United States ; K99/R00 MH121166/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; Kenya ; *HIV Infections/prevention &amp; control ; Male ; *Pre-Exposure Prophylaxis/economics ; Female ; Adult ; Surveys and Questionnaires ; *Post-Exposure Prophylaxis/economics ; *Pharmaceutical Services, Online/economics ; Young Adult ; Middle Aged ; Adolescent ; *Financing, Personal ; }, abstract = {BACKGROUND: HIV pre- and post-exposure prophylaxis (PrEP/PEP) provision via online pharmacies could expand reach of HIV prevention in Eastern and Southern Africa, but designing sustainable delivery models will require assessing the amount potential users are willing to pay for online PrEP/PEP provision.<br><br>METHODS: We administered willingness to pay (WTP) questionnaires to both potential online PrEP users and current online PrEP/PEP users in Nairobi, Kenya using a stated preference approach to measure the amount participants were willing to pay for PrEP/PEP service delivery components. Participants&#x2009;&#x2265;&#x2009;18 years were recruited via banner ads on an online pharmacy website on pages displaying sexual health products. We used multivariable gamma regression models to assess characteristics associated with differences in mean WTP for a 30-day PrEP or 28-day PEP course (including HIV self-testing, remote clinical consultation, drugs, and delivery fees).<br><br>RESULTS: From May 2022 and December 2023, 1,512 participants completed WTP questionnaires: 772 potential online PrEP users and 740 current online PrEP/PEP users. Most participants (98.3%, 1486/1,512) were willing to pay some amount for online PrEP services. For a one-month PrEP supply, potential online PrEP users were willing to pay 1388 KSH ($11.77 USD) and current online PrEP/PEP users were willing to pay 1271.2 KSH ($10.77 USD) on average. Most current online PrEP/PEP users (81.4%, 602/740) were also willing to pay for online PEP services; for a 28-day PEP supply, they were willing to pay 812.9 KSH ($6.89 USD) on average. Among potential online PrEP users, male sex, current enrollment in school, high income, and a history of online pharmacy purchases were associated with higher WTP for PrEP. Among current online PrEP/PEP users, higher income and prior online pharmacy purchases were associated with higher WTP for PrEP, and older age (>&#x2009;24) and prior online pharmacy purchases were associated with higher WTP for PEP.<br><br>CONCLUSION: Most potential and current online PrEP/PEP users in Nairobi were willing to pay for online pharmacy-based PrEP/PEP and demonstrated similar WTP. Providing PrEP/PEP through online pharmacies may sustainably expand coverage of these HIV prevention services.}, }
@article {pmid40262193, year = {2025}, author = {Shigesi, N and Harris, HR and Fang, H and Ndungu, A and Lincoln, MR and ,  and ,  and Cotsapas, C and Knight, J and Missmer, SA and Morris, AP and Becker, CM and Rahmioglu, N and Zondervan, KT}, title = {The phenotypic and genetic association between endometriosis and immunological diseases.}, journal = {Human reproduction (Oxford, England)}, volume = {}, number = {}, pages = {}, doi = {10.1093/humrep/deaf062}, pmid = {40262193}, issn = {1460-2350}, support = {RG2031//Wellbeing of Women UK/ ; 101017562//EU Horizon 2020 funded project FEMaLe/ ; 32170663//National Natural Science Foundation of China/ ; }, abstract = {STUDY QUESTION: Is there an increased risk of immunological diseases among endometriosis patients, and does a shared genetic basis contribute to this risk?<br><br>SUMMARY ANSWER: Endometriosis patients show a significantly increased risk of autoimmune, autoinflammatory, and mixed-pattern diseases, including rheumatoid arthritis, multiple sclerosis, coeliac disease, osteoarthritis, and psoriasis, with genetic correlations between endometriosis and osteoarthritis, rheumatoid arthritis, and multiple sclerosis, and a potential causal link to rheumatoid arthritis.<br><br>WHAT IS KNOWN ALREADY: The epidemiological evidence for an increased risk of immunological diseases among women with endometriosis is limited in scope and has varied in robustness due to the opportunity for biases. The presence of a biological basis for increased comorbidity across immunological conditions has not been investigated. Here we investigate the phenotypic and genetic association between endometriosis and 31 immune conditions in the UK Biobank.<br><br>STUDY DESIGN, SIZE, DURATION: Phenotypic analyses between endometriosis and immune conditions (17 classical autoimmune, 10 autoinflammatory, and 4 mixed-pattern diseases) were conducted using two approaches (8223 endometriosis, 64&#xa0;620 immunological disease cases): (i) retrospective cohort study design to incorporate temporality between diagnoses and (ii) cross-sectional analysis for simple association. Genome-wide association studies (GWAS) and meta-analyses for those immune conditions that showed phenotypic association with endometriosis (1493-77&#xa0;052 cases) were conducted.<br><br>Comprehensive phenotypic association analyses were conducted in females in the UK Biobank. GWAS for immunological conditions were conducted in females-only and sex-combined study populations in UK Biobank and meta-analysed with existing largest available GWAS results. Genetic correlation and Mendelian randomization (MR) analyses were conducted to investigate potential causal relationships. Those immune conditions with significant genetic correlation with endometriosis were included in multi-trait analysis of GWAS to boost discovery of novel and shared genetic variants. These shared variants were functionally annotated to identify affected genes utilizing expression quantitative trait loci (eQTL) data from GTEx and eQTLGen databases. Biological pathway enrichment analysis was conducted to identify shared underlying biological pathways.<br><br>In both retrospective cohort and cross-sectional analyses, endometriosis patients were at significantly increased (30-80%) risk of classical autoimmune (rheumatoid arthritis, multiple sclerosis, coeliac disease), autoinflammatory (osteoarthritis), and mixed-pattern (psoriasis) diseases. Osteoarthritis (genetic correlation (rg) = 0.28, P&#x2009;=&#x2009;3.25 &#xd7; 10-15), rheumatoid arthritis (rg&#x2009;=&#x2009;0.27, P&#x2009;=&#x2009;1.5 &#xd7; 10-5) and multiple sclerosis (rg&#x2009;=&#x2009;0.09, P&#x2009;=&#x2009;4.00 &#xd7; 10-3) were significantly genetically correlated with endometriosis. MR analysis suggested a causal association between endometriosis and rheumatoid arthritis (OR&#x2009;=&#x2009;1.16, 95% CI&#x2009;=&#x2009;1.02-1.33). eQTL analyses highlighted genes affected by shared risk variants, enriched for seven pathways across all four conditions, with three genetic loci shared between endometriosis and osteoarthritis (BMPR2/2q33.1, BSN/3p21.31, MLLT10/10p12.31) and one with rheumatoid arthritis (XKR6/8p23.1).<br><br>We conducted the first female-specific GWAS analyses for immune conditions. Given the novelty of these analyses, the sample sizes from which results were derived were limited compared to sex-combined GWAS meta-analyses, which limited the power to use female-specific summary statistics to uncover the shared genetic basis with endometriosis in follow-up analyses. Secondly, the 39 genome-wide significant endometriosis-associated variants used as instrumental variables in the MR analysis explained approximately 5% of disease variation, which may account for the nominal or non-significant MR results.<br><br>Endometriosis patients have a moderately increased risk for osteoarthritis, rheumatoid arthritis, and to a lesser extent, multiple sclerosis, due to underlying shared biological mechanisms. Clinical implications primarily involve the need for increased awareness and vigilance. The shared genetic basis opens up opportunities for developing new treatments or repurposing therapies across these conditions.<br><br>We thank all the UK Biobank and 23andMe participants. Part of this research was conducted using the UK Biobank Resource under Application Number 9637. N.R. was supported by a grant from the Wellbeing of Women UK (RG2031) and the EU Horizon 2020 funded project FEMaLe (101017562). A.P.M. was supported in part by Versus Arthritis (grant 21754). H.F. was supported by the National Natural Science Foundation of China (grant 32170663). N.R., S.A.M., and K.T.Z. were supported in part by a grant from CDMRP DoD PRMRP (W81XWH-20-PRMRP-IIRA). K.T.Z. and C.M.B. reported grants in 3 years prior, outside the submitted work, from Bayer AG, AbbVie Inc., Volition Rx, MDNA Life Sciences, PrecisionLife Ltd., and Roche Diagnostics Inc. S.A.M. reports grants in the 3 years prior, outside this submitted work, from AbbVie Inc. N.R. is a consultant for Endogene.bio, outside this submitted work. The other authors have no conflicts of interest to declare.<br><br>TRIAL REGISTRATION NUMBER: N/A.}, }
@article {pmid40261872, year = {2025}, author = {Unsworth, M and Fabens, I and Setswe, G and Moyo, K and Pienaar, J and Makhele, C and Phohole, M and Igaba, N and Hlongwane, S and Sardini, M and Dong, T and Sharma, M and Tweya, H and Ndebele, F and Holec, M and Feldacker, C}, title = {Expanding two-way texting for post-operative follow-up: A cost analysis of the implementation and scale-up in routine voluntary medical male circumcision settings in South Africa.}, journal = {PLOS global public health}, volume = {5}, number = {4}, pages = {e0004049}, pmid = {40261872}, issn = {2767-3375}, support = {P30 AI027757/AI/NIAID NIH HHS/United States ; R01 NR019229/NR/NINR NIH HHS/United States ; }, abstract = {Up to 98% of adult voluntary medical male circumcision (VMMC) clients heal without adverse events (AEs) in South Africa and in the sub-Saharan Africa region. Yet, all clients in South Africa are required to attend in-person reviews, creating added effort for providers and clients. A randomized controlled trial (RCT) using our fee-free, open-source, two-way texting (2wT) approach showed that males could independently monitor their healing with nurse-led telehealth support. 2wT was more cost-effective than routine visits for quality post-operative monitoring. The objectives of this study were:1) assess the additive cost of 2wT vs. standard of care (SoC) during a stepped wedge design (SWD) expansion trial; 2) determine the cost of augmenting 2wT implementation with dedicated personnel during peak VMMC periods; and 3) estimate the cost savings of 2wT from the payer perspective if scaled in routine settings. Data were collected from routine financial reports and complemented by previous RCT time-motion estimates. We conducted activity-based costing of SWD and peak season periods. Sensitivity analysis to estimates 2wT costs at scale. Data included 6,842 males; 2,586 (38%) opted for 2wT. 2wT participants attended an average of zero in-person visits; SoC males had an average of 2 in-person visits. Under 2wT, quality care improved: AE ascertainment increased while loss to follow-up decreased. Given a VMMC population of 10,000 adults, scenario analysis suggests that: 1) 2wT becomes cost neutral with 45% 2wT enrollment; 2) 2wT saves $0.29/client with 60% 2wT enrollment; and 3) 2wT saves $0.46/client with 80% 2wT enrollment. When scaled, 2wT appears to significantly reduce healthcare system costs while improving the quality of post-operative care without additional client costs. Further scale-up of 2wT for eligible males across VMMC and other post-operative contexts in South Africa would likely increase cost savings while dramatically reducing the burden of in-person visits on patients and clinics.}, }
@article {pmid40261064, year = {2025}, author = {Žuštra, A and Leonard, VR and Holland, LA and Hu, JC and Mu, T and Holland, SC and Wu, LI and Begnel, ER and Ojee, E and Chohan, BH and Richardson, BA and Kinuthia, J and Wamalwa, D and Slyker, J and Lehman, DA and Gantt, S and Lim, ES}, title = {Longitudinal dynamics of the nasopharyngeal microbiome in response to SARS-CoV-2 Omicron variant and HIV infection in Kenyan women and their children.}, journal = {mSystems}, volume = {}, number = {}, pages = {e0156824}, doi = {10.1128/msystems.01568-24}, pmid = {40261064}, issn = {2379-5077}, abstract = {UNLABELLED: The nasopharynx and its microbiota are implicated in respiratory health and disease. The interplay between viral infection and the nasopharyngeal microbiome is an area of increased interest. The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of the coronavirus disease 2019 pandemic, on the nasopharyngeal microbiome among individuals living with HIV is not fully characterized. Here, we describe the nasopharyngeal microbiome before, during, and after SARS-CoV-2 infection in a longitudinal cohort of Kenyan women (21 living with HIV and 14 HIV-uninfected) and their children (18 HIV-exposed, uninfected and 7 HIV-unexposed, uninfected) between September 2021 and March 2022. We show using genomic epidemiology that mother and child dyads were infected with the same strain of the SARS-CoV-2 Omicron variant that spread rapidly across Kenya. We used metagenomic sequencing to characterize the nasopharyngeal microbiome of 20 women and children infected with SARS-CoV-2, six children negative for SARS-CoV-2 but experiencing respiratory symptoms, and 34 timepoint-matched SARS-CoV-2-negative mothers and children. Since individuals were sampled longitudinally before and after SARS-CoV-2 infection, we could characterize the short- (within a week of infection) and longer- (average of 38 days post-infection) term impact of SARS-CoV-2 infection on the nasopharyngeal microbiome. We found that mothers and children had significantly different microbiome composition and bacterial load (P-values < 0.0001). In both mothers and children, the nasopharyngeal microbiome did not differ before and after SARS-CoV-2 infection, regardless of HIV exposure status. Our results indicate that the nasopharyngeal microbiome is resilient to SARS-CoV-2 infection and was not significantly modified by HIV.<br><br>IMPORTANCE: The nasopharyngeal microbiome plays an important role in human health. The degree of impact that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has on the nasopharyngeal microbiome varies among studies and may be influenced by diverse SARS-CoV-2 variants and variations in the microbiome between individuals. Our results show that the nasopharyngeal microbiome was not altered substantially by SARS-CoV-2 infection nor by HIV infection in mothers or HIV exposure in children. Our findings highlight the resilience of the nasopharyngeal microbiome after SARS-CoV-2 infection. These findings advance our understanding of the nasopharyngeal microbiome and its interactions with viral infections.}, }
@article {pmid40261015, year = {2025}, author = {Radford, CE and Bloom, JD}, title = {Comprehensive maps of escape mutations from antibodies 10-1074 and 3BNC117 for Envs from two divergent HIV strains.}, journal = {Journal of virology}, volume = {}, number = {}, pages = {e0019525}, doi = {10.1128/jvi.00195-25}, pmid = {40261015}, issn = {1098-5514}, abstract = {Antibodies capable of neutralizing many strains of HIV are being explored as prophylactic and therapeutic agents, but viral escape mutations pose a major challenge. Efforts have been made to experimentally define the escape mutations from specific antibodies in specific viral strains, but it remains unclear how much the effects of mutations on neutralization differ among HIV strains. Here, we use pseudovirus deep mutational scanning to comprehensively map escape mutations from the V3 loop targeting antibody 10-1074 and the CD4-binding site targeting antibody 3BNC117 for both a clade A (BF520) and a clade B (TRO.11) HIV Envelope (Env). Mutations that escape neutralization by antibody 10-1074 are largely similar for the two Envs, but mutations that escape 3BNC117 differ greatly between Envs. Some differences in the effects of mutations on escape between Envs can be explained by strain-to-strain variation in mutational tolerance or potential N-linked glycosylation motifs, but other mutations have different effects on escape for unclear reasons. Overall, the extent to which measurements of mutational effects on antibody neutralization can be generalized across HIV strains differs among antibodies 10-1074 and 3BNC117.IMPORTANCEBroadly neutralizing antibodies are promising candidates as prophylactics and therapeutics for HIV. This study uses pseudoviruses to map all escape mutations for antibodies 10-1074 and 3BNC117 for the Envelope proteins from two different HIV strains. These maps can inform analyses of viral mutations observed in clinical trials and help understand how the escape mutations from these antibodies differ across HIV strains.}, }
@article {pmid40260855, year = {2025}, author = {Jatt, LP and Mgodi, NM and Buchbinder, SP and Gray, GE and Kublin, JG}, title = {An HIV Vaccine in the Era of Twice-Yearly Lenacapavir for PrEP - Essential or Irrelevant?.}, journal = {The New England journal of medicine}, volume = {392}, number = {16}, pages = {1561-1563}, doi = {10.1056/NEJMp2415893}, pmid = {40260855}, issn = {1533-4406}, }
@article {pmid40259184, year = {2025}, author = {Zelaya, DG and Janssen, T and Windes, B and Wheeler, DP and Fields, SD and Beauchamp, G and Kahler, CW and Wilton, L and Mayer, KH}, title = {The Association of Positive Intersectionality Latent Classes with Psychosocial Factors and PrEP Outcomes in Black Men Who Have Sex with Men (HPTN 073).}, journal = {Journal of racial and ethnic health disparities}, volume = {}, number = {}, pages = {}, pmid = {40259184}, issn = {2196-8837}, support = {K23AA030339/AA/NIAAA NIH HHS/United States ; K01AA026335/AA/NIAAA NIH HHS/United States ; AA019072/AA/NIAAA NIH HHS/United States ; P30AI042853//Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ ; UM1AI068619//Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ ; UM1AI069412//Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ ; }, abstract = {Experiences of discrimination and HIV risk in Black men who have sex with men (MSM) need to be examined from the perspective of strength and resilience and not just risk. Scholars have theorized that a strong connection with one's sociocultural identities may increase individuals' ability to cope with discrimination which has been related to positive health outcomes. Scholars have coined the term positive intersectionality to refer to how one's stigmatized identity(ies) can be used to draw strength and create a positive sense of self. The current study is a secondary data analysis of a study of 225 Black MSM. We utilized Latent Class Analysis to determine profiles of positive intersectionality measured by indicators of racial/ethnic identity, having an integrated sexual orientation and racial/ethnic identity, and levels of internalized homophobia. Fit indices suggested a five-latent class solution: low positive intersectionality (n = 3), ambivalent positive intersectionality (n = 19), moderate positive intersectionality (n = 66), salient/high positive intersectionality (n = 124), and conflict(ed) positive intersectionality (n = 13). Differences were found across classes on key outcomes, broadly individuals in classes with more positive intersectionality tended to report more positive psychosocial outcomes (i.e., more social support and less depression) than those in classes with lower positive intersectionality. Regarding PrEP outcomes, adherence (examined via a biomarker) was highest among those reporting ambivalent or conflict positive intersectionality compared to those with low positive intersectionality. Our findings underscore the need for the development of strengths-based and culturally tailored interventions may help to improve well-being for Black MSM.}, }
@article {pmid40255392, year = {2025}, author = {Manghisi, B and Cotilli, G and Fedele, M and Perfetti, P and Terruzzi, E and Verga, L and Borin, LM and Carrer, A and Fumagalli, M and Ferrari, MB and Moretti, A and Rona, R and Benini, A and Vergnano, B and Palumbo, G and Zincone, A and Maglia, O and Scollo, C and Steidl, C and Iovino, L and Balduzzi, A and Piazza, R and Gambacorti-Passerini, C and Parma, M and Aroldi, A}, title = {Case Report: Successful use of emapalumab in adult B-cell acute lymphoblastic leukemia experiencing severe neurotoxicity and hemophagocytic lymphohistiocytosis-like features after CAR-T cell therapy.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1563736}, pmid = {40255392}, issn = {1664-3224}, mesh = {Adult ; Humans ; *Antibodies, Monoclonal/therapeutic use ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Cytokine Release Syndrome ; *Immunotherapy, Adoptive/adverse effects ; *Lymphohistiocytosis, Hemophagocytic/etiology/drug therapy/diagnosis ; *Neurotoxicity Syndromes/etiology/drug therapy/diagnosis ; *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/therapy/immunology ; Receptors, Chimeric Antigen ; Treatment Outcome ; }, abstract = {Chimeric antigen receptor (CAR)-T cell therapy is a powerful adoptive immunotherapy associated with significant toxicity, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). As CAR-T usage expands, hyperinflammatory toxicities resembling hemophagocytic lymphohistiocytosis (HLH) syndrome are increasingly recognized. Immune effector cell-associated HLH-like syndrome (IEC-HS) describes HLH-like symptoms attributable to CAR-T cell therapy, often presenting as CRS resolves. Treatments for IEC-HS are adapted from primary HLH, including corticosteroids, the recombinant human interleukin (IL)-1 receptor antagonist anakinra and the Janus Kinase inhibitor ruxolitinib. Emapalumab, an anti-IFN-γ antibody, is promising but underexplored in adult IEC-HS cases. We report an adult B-cell acute lymphoblastic leukemia (B-ALL) patient treated with brexucabtagene autoleucel (brexu-cel). The patient developed CRS, refractory neurotoxicity, and IEC-HS with worsening multiorgan failure and hyperinflammatory markers. Treatment included tocilizumab, high-dose corticosteroids, anakinra, siltuximab, and ruxolitinib. Despite aggressive management, hyperinflammation and neurotoxicity persisted. Emapalumab was initiated on day +11, resulting in normalization of the biochemical parameters and full neurological recovery by day +21. The patient recovered from IEC-HS and underwent allogeneic stem cell transplantation. This case highlights the role of emapalumab in managing refractory IEC-HS and persistent neurotoxicity in adults, underscoring the need for targeted interventions in severe CAR-T complications.}, }
@article {pmid40253488, year = {2025}, author = {Li, X and Mamouni, K and Zhao, R and Bai, L and Chen, Y and Wu, Y and Xie, ZR and Sautto, GA and Liu, D and Bowen, NJ and Danaher, A and Li, D and Cook, N and Grayson, S and Zhu, J and Coleman, IM and Nelson, PS and Bao, Q and Zhou, J and Osunkoya, AO and Kucuk, O and Gera, L and Wu, D}, title = {Novel Skp1 inhibitor has potent preclinical efficacy against castration-resistant prostate cancer.}, journal = {British journal of cancer}, volume = {}, number = {}, pages = {}, pmid = {40253488}, issn = {1532-1827}, support = {R01CA256058//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R42CA217491//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R01 CA266452/CA/NCI NIH HHS/United States ; R21CA277368//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P50CA097186//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R50CA274336//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R01 CA266452/CA/NCI NIH HHS/United States ; R21CA277368//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P50CA097186//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; }, abstract = {BACKGROUND: Metastatic, castration-resistant prostate cancer (mCRPC) directly contributes to the mortality and morbidity of prostate cancer. It is imperative to identify new molecular targets and discover effective therapeutic agents against lethal mCRPC.<br><br>METHODS: The anticancer activities and mechanism of action of the small-molecule lead compound were investigated in preclinical models of human prostate cancer. Immunohistochemistry was employed to determine the expression of S-phase kinase-associated protein 1 (Skp1) in human prostate tissues.<br><br>RESULTS: GH501 demonstrates nanomolar potency in the NCI-60 human cancer cell panel and multiple mCRPC cell lines with diverse genetic backgrounds, including those resistant to androgen deprivation therapy drugs. Mechanistically, GH501 may bind Skp1 and disrupt the physical interaction between Skp1 and S-phase kinase-associated protein 2 (Skp2) within the Skp1-Cullin1-F-box protein ubiquitin ligase complexes (SCF), thereby affecting multiple oncogenic signals implicated in mCRPC progression, including p21, p27, &#x3b2;-catenin, cyclin D1, enhancer of zeste homolog 2 (EZH2), c-Myc, and survivin. GH501 exhibits excellent in vitro and in vivo safety pharmacology, and GH501 monotherapy effectively inhibits the in vivo growth of cell- and patient-derived xenografts in intraosseous and subcutaneous models. Skp1 expression is significantly increased in human prostate cancer specimens.<br><br>CONCLUSION: These results indicate that interrupting Skp1-Skp2 interaction is an effective approach to target mCRPC and warrant further preclinical development of GH501 as a promising therapeutic candidate.}, }
@article {pmid40251235, year = {2025}, author = {Dimopoulou, O and Fuller, H and Richmond, RC and Bouras, E and Hayes, B and Dimou, N and Murphy, N and Brenner, H and Gsur, A and Le Marchand, L and Moreno, V and Pai, RK and Phipps, AI and Um, CY and van Duijnhoven, FJB and Vodicka, P and Martin, RM and Platz, EA and Gunter, MJ and Peters, U and Lewis, SJ and Cao, Y and Tsilidis, KK}, title = {Mendelian randomization study of sleep traits and risk of colorectal cancer.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {13478}, pmid = {40251235}, issn = {2045-2322}, support = {C18281/A29019/CRUK_/Cancer Research UK/United Kingdom ; }, mesh = {Humans ; *Mendelian Randomization Analysis ; *Colorectal Neoplasms/genetics/epidemiology ; Male ; Female ; *Sleep/genetics ; Genome-Wide Association Study ; Risk Factors ; Polymorphism, Single Nucleotide ; Genetic Predisposition to Disease ; Circadian Rhythm/genetics ; Sleep Initiation and Maintenance Disorders/genetics ; }, abstract = {A potential association of endogenous circadian rhythm disruption with risk of cancer development has been suggested, however, epidemiological evidence for the association of sleep traits with colorectal cancer (CRC) is limited and often contradictory. Here we investigated whether genetically predicted chronotype, insomnia and sleep duration are associated with CRC risk in males, females and overall and according to CRC anatomical subsites using Mendelian randomization (MR). The two-sample inverse variance weighted (IVW) method was applied using summary-level data in up to 58,221 CRC cases and 67,694 controls and genome-wide association data of genetic variants for self-reported sleep traits. Secondary analyses using alternative instruments and sensitivity analyses assessing potential violations of MR assumptions were conducted. Genetically predicted morning preference was associated with 13% lower risk of CRC in men (ORIVW = 0.87, 95% CI = 0.78, 0.97, P = 0.01), but not in women or in both sexes combined. Τhis association remained consistent in some, but not all, sensitivity analyses and was very similar for colon and rectal cancer. There was no evidence of an association for any other sleep trait. Overall, this study provides little to no evidence of an association between genetically predicted sleep traits and CRC risk.}, }
@article {pmid40250799, year = {2025}, author = {Karvonen, KL and Anunwah, E and Gilmore, S and Griffiths-Randolph, U and Karvonen, KA and Moore, D and Miller, K and Overall, J and Wooten, L and Afulani, PA}, title = {Gaps, Successes, and Opportunities Related to Social Drivers of Health from the Perspectives of Black Preterm Infant Caregivers: A Qualitative Study.}, journal = {The Journal of pediatrics}, volume = {}, number = {}, pages = {114598}, doi = {10.1016/j.jpeds.2025.114598}, pmid = {40250799}, issn = {1097-6833}, abstract = {OBJECTIVE: To identify Black preterm infant caregiver experiences and institutional priorities regarding screening and addressing social drivers of health (SDH).<br><br>STUDY DESIGN: In the Centering Black Preterm Infant Caregiver Priorities (CENTER &amp; CARE) study, Black female researchers conducted semi-structured interviews in 2024 with Black caregivers of preterm infants born in the San Francisco Bay Area of California. Transcripts were coded using a book generated from an interview guide and the resulting data were analyzed using thematic analysis. Themes were generated and refined through discussion.<br><br>RESULTS: Twenty socio-demographically diverse caregivers participated. Five themes were identified: (1) financial insecurity and inadequate access to resources for everyday social needs contribute negatively to caregiver and child health and well-being; (2) a trusted provider who takes a personal approach to screening and addressing SDH is needed in medical settings; (3) inequitably distributed, fragmented, and disorganized medical and social support systems in the transition to home period are burdensome and a source of stress; (4) community-based organizations centering Black families holistically address SDH and promote social well-being and connectedness; and (5) state and federal legislation, policies, and programs are critical opportunities to address SDH.<br><br>CONCLUSION: SDH are a significant source of stress for caregivers after preterm birth, and there are opportunities across state and federal legislative policies, community-based organizations, medical systems, and connections across the systems to address them.}, }
@article {pmid40249911, year = {2025}, author = {Perales, MA and Riches, M and He, N and Martens, MJ and Chemaly, RF and Dandoy, CE and Hill, JA and Díaz, MA and Hashmi, S and Prockop, SE and Lazarus, HM and Beitinjaneh, AM and Hildebrandt, GC and Auletta, JJ and Szabolcs, P}, title = {Delayed T cell recovery after hematopoietic cell transplantation is associated with decreased overall survival in adults.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024015288}, pmid = {40249911}, issn = {2473-9537}, abstract = {Allogeneic hematopoietic cell transplantation (alloHCT) can provide curative treatment for hematologic malignancies but is associated with prolonged lymphopenia that may contribute to an increased risk of infection and relapse, resulting in decreased survival. We hypothesized that patients with rapid and robust CD4 T and B cell recovery have improved survival and decreased treatment-related mortality (TRM). 2089 patients were included who underwent first alloHCT for AML/ALL/MDS from 2008 to 2019 reported to CIBMTR with available CD4 counts at days 100 (D100) and 180 (D180). Patients (median age 51, range 2-75) were categorized into four groups based on GVHD prophylaxis: ex-vivo T cell depletion (TCD/CD34), post-transplant cyclophosphamide (PTCy), calcineurin-inhibitor alone (CNI) or with anti-thymocyte globulin (CNI+ATG). Based upon survival we could identify optimal cut-points for CD4+ T cells in pediatric (age <20y) patients: 248 x 106/L and 420 x 106/L at D100 and D180, respectively; and in adult (age >20y) patients: 104 x 106/L and 115 x 106/L at D100 and D180, respectively. In adults, D100 CD4 count was associated with overall survival, progression-free survival (PFS) and TRM, but not relapse, incidence of infections, or chronic GVHD. Similarly, CD4 counts above the cut-point at D180 in adults were associated with improved OS, PFS, and TRM but no other outcomes. No clinical associations for CD4 counts were identifiable in pediatric patients. These findings underscore the importance of tailoring transplant strategies for adults to optimize immune recovery and improve patient outcomes.}, }
@article {pmid40196517, year = {2025}, author = {Readshaw, JJ and Doyle, LA and Puiu, M and Kelly, A and Nelson, A and Kaiser, AJ and McGuire, S and Peralta-Acosta, J and Smith, DL and Stoddard, BL and Kaiser, BK and Blower, TR}, title = {PglZ from Type I BREX phage defence systems is a metal-dependent nuclease that forms a sub-complex with BrxB.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40196517}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 GM105691/GM/NIGMS NIH HHS/United States ; R01 GM129325/GM/NIGMS NIH HHS/United States ; R15 GM140375/GM/NIGMS NIH HHS/United States ; }, abstract = {BREX (Bacteriophage Exclusion) systems, identified through shared identity with Pgl (Phage Growth Limitation) systems, are a widespread, highly diverse group of phage defence systems found throughout bacteria and archaea. The varied BREX Types harbour multiple protein subunits (between four and eight) and all encode a conserved putative phosphatase (PglZ aka BrxZ) and an equally conserved, putative ATPase (BrxC). Almost all BREX systems also contain a site-specific methyltransferase (PglX aka BrxX). Despite having determined the structure and fundamental biophysical and biochemical behaviours for the PglX methyltransferase, the BrxL effector, the BrxA DNA-binding protein and the BrxR transcriptional regulator, the mechanism by which BREX impedes phage replication remains largely undetermined. In this study, we identify a stable BREX sub-complex of PglZ:BrxB, validate the structure and dynamic behaviour of that sub-complex, and assess the biochemical activity of PglZ, revealing it to be a metal-dependent nuclease. PglZ can cleave cyclic oligonucleotides, linear oligonucleotides, plasmid DNA and both non-modified and modified linear phage genomes. PglZ nuclease activity has no obvious role in BREX-dependent methylation, but does contribute to BREX phage defence. BrxB binding does not impact PglZ nuclease activity. These data contribute to our growing understanding of the BREX phage defence mechanism.}, }
@article {pmid40195998, year = {2025}, author = {Kareithi, T and D Roche, S and Omollo, V and Ong'wen, PA and Kiptinness, C and Otieno, P and Juma, L and Malen, RC and Harkey, K and Anyona, MO and Curran, K and Banerjee, P and Gichuru, E and Asewe, M and Yu, K and Pintye, J and Mugambi, M and Shah, PD and Sharma, M and Meisner, A and Were, D and Ngure, K and Bukusi, EA and Ortblad, KF}, title = {Testing different models of pharmacy-based HIV pre- and post-exposure prophylaxis initiation and management in Kenya: protocol for a cluster-randomized controlled trial.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40195998}, issn = {2693-5015}, support = {R00 MH121166/MH/NIMH NIH HHS/United States ; }, abstract = {BACKGROUND: In Kenya, as in many African countries, private pharmacies are ubiquitous, frequently accessed, and underutilized for the delivery of HIV prevention services. Whether enabling private pharmacies to initiate and manage clients on HIV pre- and post-exposure prophylaxis (PrEP and PEP) leads to greater uptake and continuation than the current standard-pharmacy referral to clinic-based PrEP/PEP-is unknown. To address this gap and inform how private pharmacies might partner with the public sector, we are testing several models of pharmacy-delivered PrEP/PEP in comparison to the current standard.<br><br>METHODS: The Pharm PrEP cRCT is a 60-pharmacy, four-arm cluster-randomized controlled trial ongoing in Central and Western Kenya (first enrollment: 26 June 2023). Eligible pharmacies were licensed by the government, had a private room, and were willing to complete research activities (including a three-day provider training). Study pharmacies were randomized 1:1:1:1 to: 1) client-sustained delivery, in which clients pay pharmacies 250 KES (~$2 USD) per PrEP/PEP visit, 2) implementor-sustained delivery, in which clients pay nothing and implementors pay pharmacies 250 KES per PrEP/PEP visit, 3) implementor-sustained + counselor-supported delivery, in which clients pay nothing, delivery is supported by an HIV testing services (HTS) counselor, and implementors pay pharmacies 100 KES (~$1 USD) per PrEP/PEP visit, or 4) referral (control), in which clients pay nothing and implementors pay pharmacies 100 KES per referral to clinic-based PrEP/PEP. Pharmacies delivering PrEP/PEP receive supporting commodities free from government stock. Primary outcomes are PrEP initiation and continuation (any refilling) reported by clients 60 days post-enrollment; secondary outcomes include PEP initiation, PEP-to-PrEP transition, repeat PEP use, PrEP/PEP initiation, and PrEP/PEP continuation at 60 and 270 days post-enrollment. Primary analyses will compare each intervention arm to the control; secondary analyses will compare intervention arms to one another. We will additionally assess implementation outcomes (e.g., acceptability, feasibility, cost) from client and provider perspectives.<br><br>DISCUSSION: This trial will generate evidence on the potential benefits of leveraging private pharmacies for delivery of PrEP and PEP and the relative effectiveness of pharmacy delivery when subsidized by clients, implementors, and/or supported by HTS counselors. The findings may inform enabling policy and approaches for scale-up.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov: NCT05842122.}, }
@article {pmid40195984, year = {2025}, author = {Fredericks, MN and Kolodner, Z and Waalkes, A and Sawatzki, K and Hao, L and Long, DR and Penewit, K and Midkiff, CC and McCormick, CJ and Beraki, S and Edlefsen, PT and Barrow, J and Greninger, AL and Gale, M and Blair, RV and Salipante, SJ and Fuller, DH and O'Connor, MA}, title = {SIV/SARS-CoV-2 co-infection in rhesus macaques impacts viral shedding, host immunity, the microbiome, and viral evolution.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40195984}, issn = {2693-5015}, support = {K01 MH123258/MH/NIMH NIH HHS/United States ; P51 OD011104/OD/NIH HHS/United States ; S10 OD030347/OD/NIH HHS/United States ; }, abstract = {People living with HIV (PLWH) have an increased risk of severe COVID-19, including prolonged viral shedding and emergence of mutations. To investigate the simian immunodeficiency virus (SIV) macaque model for HIV/SARS-CoV-2 co-infection, seven SIV+ rhesus macaques were co-infected with SARS-CoV-2. COVID-19 in all macaques was mild. SARS-CoV-2 replication persisted in the upper, but not the lower respiratory tract for 14 days post-infection. Animals showed impaired generation of anti-SARS-CoV-2 antibodies and T-cells. Animals also displayed transient changes in microbial communities in the upper airway and gastrointestinal tract. Evidence of SARS-CoV-2 evolution was observed in the upper respiratory tract. This study demonstrates that SIV/SARS-CoV-2 co-infection in rhesus macaques recapitulates aspects of COVID-19 in PLWH. We show that SIV impairs anti-SARS-CoV-2 immunity, potentially leading to prolonged viral shedding, altered pathogenesis, and viral evolution. This highlights the importance of HIV status in COVID-19 and supports the use of this model for HIV/SARS-CoV-2 co-infection.}, }
@article {pmid40166161, year = {2025}, author = {Wang, K and Saniei, S and Poddar, N and Autar, S and Carcamo, S and Sreenath, M and Peplinski, JH and Ries, RE and Martinez, IG and Chao, C and Mei, AH and Rahman, N and Mekerishvili, L and Quijada-Álamo, M and Freed, G and Zhang, M and Lachman, K and Diaz, Z and Gonzalez, MM and Zhang, J and Pham, G and Filipescu, D and Berisa, M and Balestra, T and Reisz, JA and D'Alessandro, A and Puleston, DJ and Bernstein, E and Chipuk, JE and Wunderlich, M and Tasian, SK and Marcellino, BK and Glass, IA and ,  and Sturgeon, CM and Landau, DA and Chen, Z and Papapetrou, EP and Izzo, F and Meshinchi, S and Hasson, D and Wagenblast, E}, title = {Ontogeny Dictates Oncogenic Potential, Lineage Hierarchy, and Therapy Response in Pediatric Leukemia.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40166161}, issn = {2692-8205}, support = {S10 OD026880/OD/NIH HHS/United States ; R01 CA290681/CA/NCI NIH HHS/United States ; R01 CA292503/CA/NCI NIH HHS/United States ; UL1 TR004419/TR/NCATS NIH HHS/United States ; R24 HD000836/HD/NICHD NIH HHS/United States ; S10 OD030463/OD/NIH HHS/United States ; P30 CA196521/CA/NCI NIH HHS/United States ; }, abstract = {Accumulating evidence links pediatric cancers to prenatal transformation events, yet the influence of the developmental stage on oncogenesis remains elusive. We investigated how hematopoietic stem cell developmental stages affect leukemic transformation, disease progression, and therapy response using a novel, humanized model of NUP98∷NSD1-driven pediatric acute myeloid leukemia, that is particularly aggressive with WT1 co-mutations. Fetal-derived hematopoietic stem cells readily transform into leukemia, and WT1 mutations further enhance stemness and alter lineage hierarchy. In contrast, stem cells from later developmental stages become progressively resistant to transformation. Single-cell analyses revealed that fetal-origin leukemia stem cells exhibit greater quiescence and reliance on oxidative phosphorylation than their postnatal counterparts. These differences drive distinct therapeutic responses, despite identical oncogenic mutations. In patients, onco-fetal transcriptional programs correlate with worse outcomes. By targeting key vulnerabilities of fetal-origin leukemia cells, we identified combination therapies that significantly reduce aggressiveness, highlighting the critical role of ontogeny in pediatric cancer treatment.}, }
@article {pmid40166020, year = {2025}, author = {Peluso, MJ and Sandel, DA and Deitchman, AN and Kim, SJ and Dalhuisen, T and Tummala, HP and Tibúrcio, R and Zemelko, L and Borgo, GM and Singh, SS and Schwartz, K and Deswal, M and Williams, MC and Hoh, R and Shimoda, M and Narpala, S and Serebryannyy, L and Khalili, M and Vendrame, E and SenGupta, D and Whitmore, LS and Tisoncik-Go, J and Gale, M and Koup, RA and Mullins, JI and Felber, BK and Pavlakis, GN and Reeves, JD and Petropoulos, CJ and Glidden, DV and Spitzer, MH and Gama, L and Caskey, M and Nussenzweig, MC and Chew, KW and Henrich, TJ and Yukl, SA and Cohn, LB and Deeks, SG and Rutishauser, RL}, title = {Combination immunotherapy induces post-intervention control of HIV.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40166020}, issn = {2693-5015}, support = {R01 DE032033/DE/NIDCR NIH HHS/United States ; K23 AI162249/AI/NIAID NIH HHS/United States ; UM1 AI164560/AI/NIAID NIH HHS/United States ; P30 AI027763/AI/NIAID NIH HHS/United States ; R01 AI170239/AI/NIAID NIH HHS/United States ; P30 AI152501/AI/NIAID NIH HHS/United States ; P01 AI169606/AI/NIAID NIH HHS/United States ; T32 GM136547/GM/NIGMS NIH HHS/United States ; K23 AI157875/AI/NIAID NIH HHS/United States ; K24 AA022523/AA/NIAAA NIH HHS/United States ; UL1 TR001872/TR/NCATS NIH HHS/United States ; T32 AI060530/AI/NIAID NIH HHS/United States ; P01 AI178375/AI/NIAID NIH HHS/United States ; }, abstract = {The identification of therapeutic strategies to induce sustained antiretroviral therapy (ART)-free control of HIV infection is a major priority.[1] Combination immunotherapy including HIV vaccination, immune stimulation/latency reversal, and passive transfer of broadly neutralizing antibodies (bNAbs) has shown promise in non-human primate models,[2-7] but few studies have translated such approaches into people. Here, we performed a single-arm, proof-of-concept combination study of these three approaches in ten people with HIV on ART that included (1) therapeutic vaccination with an HIV/Gag conserved element (CE)-targeted DNA+IL-12 prime/MVA boost regimen followed by (2) administration of two bNAbs (10-1074 and VRC07-523LS) and a toll-like receptor 9 (TLR9) agonist (lefitolimod) during ART suppression, followed by (3) repeat bNAb administration at the time of ART interruption. Seven of the ten participants exhibited partial (low viral load set point) or complete (aviremic) post-intervention control after stopping ART, independent of residual bNAb plasma levels. Robust expansion of activated CD8+ T cells early in response to rebounding virus correlated with lower viral load set points. These data suggest that combination immunotherapy approaches might prove effective to induce sustained control of HIV by slowing rebound and improving CD8+ T cell responses, and that these approaches should continue to be optimized.}, }
@article {pmid40161829, year = {2025}, author = {Agrawal, P and Khechaduri, A and Salladay, KR and MacCamy, A and Ralph, DK and Riker, A and Stuart, AB and Siddaramaiah, LK and Shen, X and Matsen, FA and Montefiori, D and Stamatatos, L}, title = {Increased immunogen valency improves the maturation of vaccine-elicited HIV-1 VRC01-class antibodies.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40161829}, issn = {2692-8205}, support = {P01 AI138212/AI/NIAID NIH HHS/United States ; R01 AI143370/AI/NIAID NIH HHS/United States ; R01 AI146028/AI/NIAID NIH HHS/United States ; R01 AI177095/AI/NIAID NIH HHS/United States ; }, abstract = {Antibodies belonging to the VRC01-class display broad and potent neutralizing activities and have been isolated from several people living with HIV (PLWH). A member of that class, monoclonal antibody VRC01, was shown to reduce HIV-acquisition in two phase 2b efficacy trials. VRC01-class antibodies are therefore expected to be a key component of an effective HIV-1 vaccine. In contrast to the VRC01-class antibodies that are highly mutated, their unmutated forms do not engage HIV-1 envelope (Env) and do not display neutralizing activities. Hence, specifically modified Env-derived proteins have been designed to engage the unmutated forms of VRC01-class antibodies, and to activate the corresponding naïve B cells. Selected heterologous Env must then be used as boost immunogens to guide the proper maturation of these elicited VRC01-class antibodies. Here we examined whether and how the valency of the prime and boost immunogens influences VRC01-class antibody-maturation. Our findings indicate that, indeed the valency of the immunogen affects the maturation of elicited antibody responses by preferentially selecting VRC01-class antibodies that have accumulated somatic mutations present in broadly neutralizing VRC01-class antibodies isolated from PLWH. As a result, antibodies isolated from animals immunized with the higher valency immunogens display broader Env cross-binding properties and improved neutralizing potentials than those isolated from animals immunized with the lower valency immunogens. Our results are relevant to current and upcoming phase 1 clinical trials that evaluate the ability of novel immunogens aiming to elicit cross-reactive VRC01-class antibody responses.}, }
@article {pmid40161760, year = {2025}, author = {Simonich, CAL and McMahon, TE and Ju, X and Yu, TC and Brunette, N and Stevens-Ayers, T and Boeckh, MJ and King, NP and Greninger, AL and Bloom, JD}, title = {RSV F evolution escapes some monoclonal antibodies but does not strongly erode neutralization by human polyclonal sera.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40161760}, issn = {2692-8205}, support = {K12 HD000850/HD/NICHD NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 AI141707/AI/NIAID NIH HHS/United States ; U19 AI181767/AI/NIAID NIH HHS/United States ; }, abstract = {Vaccines and monoclonal antibodies targeting the respiratory syncytial virus (RSV) fusion protein (F) have recently begun to be widely used to protect infants and high-risk adults. Some other viral proteins evolve to erode polyclonal antibody neutralization and escape individual monoclonal antibodies. However, little is known about how RSV F evolution affects antibodies. Here we develop an experimental system for measuring neutralization titers against RSV F using pseudotyped lentiviral particles. This system is easily adaptable to evaluate neutralization of relevant clinical strains. We apply this system to demonstrate that natural evolution of RSV F leads to escape from some monoclonal antibodies, but at most modestly affects neutralization by polyclonal serum antibodies. Overall, our work sheds light on RSV antigenic evolution and describes a tool to measure the ability of antibodies and sera to neutralize contemporary RSV strains.}, }
@article {pmid40249804, year = {2025}, author = {Bhattacharya, T and Alleman, EM and Freeman, TS and Noyola, AC and Emerman, M and Malik, HS}, title = {A conserved opal termination codon optimizes a temperature-dependent trade-off between protein production and processing in alphaviruses.}, journal = {Science advances}, volume = {11}, number = {16}, pages = {eads7933}, doi = {10.1126/sciadv.ads7933}, pmid = {40249804}, issn = {2375-2548}, mesh = {*Codon, Terminator/genetics ; Animals ; *Temperature ; *Alphavirus/genetics ; *Protein Biosynthesis ; Virus Replication/genetics ; *Sindbis Virus/genetics ; *Viral Proteins/genetics/metabolism ; Humans ; RNA, Viral/genetics ; Mutation ; Cell Line ; }, abstract = {Most mosquito-transmitted alphaviruses encode a premature opal termination codon upstream of their viral polymerase. We show that the Sindbis virus (SINV) opal codon outperforms other stop codons in primate cells at 37°C due to optimal translational readthrough. However, increased readthrough of all stop codons reduces opal preference at 28°C in primate and mosquito cells. Opal also outperforms all sense codons because opal-to-sense substitutions lead to excess polyprotein production at 37°C, disrupting orderly polyprotein processing and production of viral genomic RNAs (gRNAs) required for virus production. Increased readthrough at 28°C dampens the fitness advantages of opal codons. Unexpectedly, we find that a naturally occurring SINV mutation restores sense-codon fitness by further delaying polyprotein processing, allowing adequate time to produce gRNAs. Similar temperature-dependent mechanisms occur in the distantly related dual-host alphavirus, Ross River virus. Our work highlights sophisticated strategies dual-host alphaviruses use to optimize replication in divergent temperatures through a single codon.}, }
@article {pmid40249111, year = {2025}, author = {Sievers, P and Arora, S and Hielscher, T and Savran, D and Schrimpf, D and Banan, R and Vonhören, D and Pusch, S and Sill, M and Appay, R and Wirsching, HG and Hortobagyi, T and Dohmen, H and Acker, T and Kohlhof-Meinecke, P and Schweizer, L and Wefers, AK and Harter, PN and Hartmann, C and Beschorner, R and Schittenhelm, J and Behling, F and Tabatabai, G and Mawrin, C and Snuderl, M and Maas, SLN and Wesseling, P and Brandner, S and Korshunov, A and Ratliff, M and Krieg, SM and Wick, W and Jones, DTW and Pfister, SM and Holland, EC and von Deimling, A and Szulzewsky, F and Sahm, F}, title = {Molecular signatures define BAP1-altered meningioma as a distinct CNS tumor with deregulation of Polycomb repressive complex target genes.}, journal = {Neuro-oncology}, volume = {}, number = {}, pages = {}, doi = {10.1093/neuonc/noaf105}, pmid = {40249111}, issn = {1523-5866}, abstract = {BACKGROUND: Meningiomas are the most common primary intracranial neoplasms, with highly variable patient outcomes. While most meningiomas are benign, a significant subset recurs postoperatively, presenting substantial treatment challenges. BAP1 gene inactivation has been suggested as a marker for aggressive meningiomas, although its precise molecular and clinical roles remain poorly understood.<br><br>METHODS: To comprehensively investigate BAP1-altered meningiomas, we used six meningiomas with known BAP1 alterations as a discovery set. Genome-wide DNA methylation profiling of these samples, along 11,151 reference meningiomas, identified a distinct molecular cluster (n = 42) using unsupervised visualization approaches. These tumors were further characterized by DNA/RNA sequencing, histopathological examination, and a retrospective review of clinical data, compared to reference meningioma cohorts, providing a thorough characterization of this rare tumor subtype.<br><br>RESULTS: Our integrative analysis revealed BAP1-altered meningiomas as a distinct CNS tumor subtype, characterized by recurrent loss of chromosome 3p21 and driven by various BAP1-inactivating alterations. Although rhabdoid morphology is present in some cases, it is not exclusive and should not be used as a grading criterion. Progression-free survival analysis showed a median of 21 months (95% CI: 12-NA), with a 2-year overall survival rate of 79% (95% CI: 60%-100%), highlighting the aggressive nature of these tumors. Gene expression profiling revealed upregulation of PRC target genes, dysregulated Polycomb signaling, and elevated expression in several cellular and growth factor pathways.<br><br>CONCLUSIONS: BAP1-altered meningiomas represent a distinct and aggressive CNS tumor subtype associated with PRC dysregulation and recurrent 3p chromosome loss. These findings support the designation "meningioma, BAP1-altered."}, }
@article {pmid40248714, year = {2025}, author = {Girard, B and Figueroa, AL and De Rosa, SC and McElrath, MJ and Azzi, JR and Stolman, D and Siangphoe, U and de Windt, E and Miller, JM and Das, R and Priddy, F}, title = {mRNA-1273 COVID-19 vaccine induces CD4+ T-cell responses among solid organ transplant recipients.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1505871}, pmid = {40248714}, issn = {1664-3224}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; 2019-nCoV Vaccine mRNA-1273/immunology ; *CD4-Positive T-Lymphocytes/immunology ; *COVID-19/prevention &amp; control/immunology ; *COVID-19 Vaccines/immunology/administration &amp; dosage ; Cytokines ; Immunity, Cellular ; Kidney Transplantation ; *Organ Transplantation ; *SARS-CoV-2/immunology ; Spike Glycoprotein, Coronavirus/immunology ; Transplant Recipients ; }, abstract = {BACKGROUND: Cell-mediated immunity may provide durable protection against severe COVID-19, including among solid organ transplant recipients (SOTRs). This exploratory analysis in the open-label phase 3b trial evaluated cell-mediated immunity of mRNA-1273 in a subset of participants (59 kidney and 33 liver SOTRs; 12 immunocompetent participants).<br><br>METHODS: In Part A, SOTRs received three 100-&#xb5;g doses of mRNA-1273; immunocompetent participants received two doses. In Part B, an additional 100-&#xb5;g dose was offered &#x2265;4 months after the primary series. SARS-CoV-2 spike (S) protein-specific T-cell responses were measured by intracellular cytokine staining and polyfunctionality analyses.<br><br>RESULTS: The primary series and additional dose of mRNA-1273 induced S protein-specific CD4[+] T-cell responses exhibiting a Th-1-biased profile in both SOTRs and immunocompetent participants; however, response rates and magnitudes were lower among SOTRs. S protein-specific Th-2 CD4[+] T-cell responses were below those observed for Th-1; CD8[+] T-cell responses were not as robust among SOTRs compared with immunocompetent participants. Kidney SOTRs received multiple immunosuppressants and had lower cell-mediated immunity responses than liver SOTRs. Polyfunctional responses exhibited Th-1 cytokine signatures with &#x2264;5 functional markers reported in SOTRs and immunocompetent participants.<br><br>CONCLUSION: Overall, a three-dose mRNA-1273 primary series elicited Th-1-biased CD4[+] T-cell responses among SOTRs that were improved with an additional dose.<br><br>CLINICAL TRIAL REGISTRATION: https://beta.clinicaltrials.gov/study/NCT04860297?term=NCT04860297%20&amp;rank=1, identifier NCT04860297.}, }
@article {pmid40246795, year = {2025}, author = {Szabados, BE and Guerrero-Ramos, F and Grande, E and Grivas, P and Grünwald, V and Miguel, MC and Hussain, SA and Kulkarni, GS and Wilson, AL and Shore, ND and Sridhar, SS and Hoyt, M and Strumeier, S and Sutton, J and Brinkmann, J and Teresi, RE and Todenhöfer, T}, title = {On the Horizon: A Global Multidisciplinary Perspective on Delivering Emerging Therapies for Patients with BCG-Naïve High-Risk NMIBC.}, journal = {Oncology and therapy}, volume = {}, number = {}, pages = {}, pmid = {40246795}, issn = {2366-1089}, abstract = {Patients with high-risk non-muscle invasive bladder cancer (NMIBC) are generally treated with transurethral resection of the bladder tumor followed by intravesical bacillus Calmette-Guérin (BCG), the current standard of care. However, recurrence or progression is common and may result in patients requiring radical cystectomy. Additionally, BCG continues to be in short supply worldwide. Therefore, there is an unmet need for new therapies that provide durable disease control and maintain quality of life. In the BCG-naïve high-risk NMIBC setting, potential new treatment options are emerging, with several regimens combining intravesical therapy with systemic PD-1 or PD-L1-directed immune checkpoint inhibitors (ICIs) currently under investigation in several Phase 3 trials. In routine clinical practice, NMIBC has traditionally been managed almost entirely by urologists. However, the introduction of systemic ICIs would likely require medical oncology expertise to help assess patients' fitness for these therapies and potentially for treatment administration and immune-related adverse event management. While multidisciplinary workflows are common practice for advanced bladder cancer, they would represent a paradigm shift in NMIBC. Based on current experience of managing patients with NMIBC across different countries and healthcare systems from our perspective as urologists, medical oncologists, and nurses, we discuss best practices for the potential integration of emerging therapies such as ICIs into the treatment of BCG-naïve high-risk NMIBC. We emphasize the need for multidisciplinary care, either through formalized multidisciplinary teams or cross-discipline collaborative workflows adapted to local needs, to ensure efficient coordination and sharing of responsibilities. Specialized nurses have the potential to play key roles across multiple aspects of patient care. We also highlight the crucial importance of effective communication across teams, increases in resourcing, and education for healthcare professionals, patients, and caregivers to enable eligible patients with high-risk NMIBC to benefit optimally from the introduction of these potential new treatment options.}, }
@article {pmid40245370, year = {2025}, author = {Triplette, M}, title = {Do Differences in Comorbidity Explain Sex-based Differences in Lung Cancer Screening Outcomes?.}, journal = {Annals of the American Thoracic Society}, volume = {}, number = {}, pages = {}, doi = {10.1513/AnnalsATS.202504-391ED}, pmid = {40245370}, issn = {2325-6621}, }
@article {pmid40245079, year = {2025}, author = {Trouth, A and Ravichandran, K and Gafken, PR and Martire, S and Boyle, GE and Veronezi, GMB and La, V and Namciu, SJ and Banaszynski, LA and Sarthy, JF and Ramachandran, S}, title = {The length of G1 phase is an essential determinant of H3K27me3 landscape across diverse cell types.}, journal = {PLoS biology}, volume = {23}, number = {4}, pages = {e3003119}, doi = {10.1371/journal.pbio.3003119}, pmid = {40245079}, issn = {1545-7885}, abstract = {Stem cells have lower facultative heterochromatin as defined by trimethylation of histone H3 lysine 27 (H3K27me3) compared to differentiated cells. However, the mechanisms underlying these differential H3K27me3 levels remain elusive. Because H3K27me3 levels are diluted 2-fold in every round of replication and then restored through the rest of the cell cycle, we reasoned that the cell cycle length could be a key regulator of total H3K27me3 levels. Here, we propose that a short G1 phase restricts H3K27me3 levels in stem cells. To test this model, we determined changes to H3K27me3 levels in mouse embryonic stem cells (mESCs) globally and at specific loci upon G1 phase lengthening - accomplished by thymidine block or growth in the absence of serum (with the "2i medium"). H3K27me3 levels in mESCs increase with G1 arrest when grown in serum and in 2i medium. Additionally, we observed via CUT&amp;RUN and ChIP-seq that regions that gain H3K27me3 in G1 arrest and 2i media overlap, supporting our model of G1 length as a critical regulator of the stem cell epigenome. Furthermore, we demonstrate the inverse effect - that G1 shortening in differentiated human HEK293 cells results in a loss of H3K27me3 levels. Finally, in human tumor cells with extreme H3K27me3 loss, lengthening of the G1 phase leads to H3K27me3 recovery despite the presence of the dominant negative, sub-stoichiometric H3.K27M mutation. Our results indicate that G1 length is an essential determinant of H3K27me3 landscapes across diverse cell types.}, }
@article {pmid40243688, year = {2025}, author = {Yap, TA and Goldman, JW and Vinayak, S and Tomova, A and Hamilton, E and Naito, Y and Giordano, A and Bondarenko, I and Yamashita, T and Zhou, L and Moreau, A and Neumann, H and Tougias, J and Liu, F and Park, J and Delioukina, M and Jhaveri, K}, title = {First-In-Human Phase 1/2a Study of the First-In-Class CDK2/4/6 Inhibitor PF-06873600 Alone or with Endocrine Therapy in Patients with Breast Cancer.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-24-2740}, pmid = {40243688}, issn = {1557-3265}, abstract = {PURPOSE: The discovery that cyclin E overexpression is a key CDK4/6 inhibitor resistance mechanism has reinvigorated interest in targeting CDK2, and simultaneous inhibition of CDK2/4/6 as a novel therapeutic approach. This first-in-human study assessed safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of PF-06873600, the first-in-class inhibitor of CDK2/4/6.<br><br>PATIENTS AND METHODS: Dose escalation included 78 patients with advanced breast cancer, triple negative breast cancer, or ovarian cancer who received oral PF-06873600 1-50 mg twice daily (BID) (Part 1A, n=51), or PF-06873600 with endocrine therapy (Part 1B, n=16; Part 1C n=11) to determine the recommended dose for expansion (RDE). Dose expansion (Part 2A, n=45; Part 2C, n=28) assessed preliminary antitumor activity, safety and tolerability at the RDE in combination with fulvestrant in patients with HR+/HER2- mBC. Pharmacodynamics and translational readouts were assessed by phosphorylated Rb and Ki67 in tumor biopsies and circulating tumor DNA (ctDNA).<br><br>RESULTS: The RDE of PF-06873600 was 25mg BID. During dose escalation, six of 42 (14.3%) evaluable patients had treatment-related dose-limiting toxicities. Most common all-causality adverse events (N=151) were nausea (62.9%), anemia (44.4%) and fatigue (43.7%). Reductions in Ki67-positive cells, pRb H-score, and ctDNA levels were observed. Three RECIST partial responses (PRs) were observed in Part 1. In Part 2A there were three PRs (objective response rate [ORR] 6.7%, 95% CI: 1.4-18.3%) and, in Part 2C, five PRs (ORR 22.7%, 95% CI: 7.8-45.4%).<br><br>CONCLUSIONS: PF-06873600 demonstrated a benefit-risk profile consistent with the CDK4/6 inhibitor class of drugs, with preliminary clinical activity in HR+/HER2- mBC.<br><br>CLINICALTRIALS: gov identifier: NCT03519178.}, }
@article {pmid40243533, year = {2025}, author = {Thomas, CE and Takashima, Y and Buchanan, DD and Wesselink, E and Qu, C and Hsu, L and Dias Costa, A and Gallinger, S and Grant, RC and Huyghe, JR and Thomas, S and Ugai, S and Zhong, Y and Matsuda, K and Ugai, T and Peters, U and Ogino, S and Nowak, JA and Phipps, AI}, title = {Density of T cell subsets in colorectal cancer in relation to disease-specific survival.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-25-0287}, pmid = {40243533}, issn = {1538-7755}, abstract = {BACKGROUND: Prior studies have demonstrated that the overall density of T cells in colorectal tumors is favorably associated with colorectal cancer (CRC) survival; however, few studies have considered the potentially distinct roles of heterogeneous T cell subsets in different tissue regions in relation to CRC outcomes.<br><br>METHODS: Including 1,113 CRC tumors from three observational studies, we conducted in-situ T cell profiling using a customized 9-plex [CD3, CD4, CD8, CD45RA, CD45RO, FOXP3, KRT (keratin), MKI67 (Ki-67), and DAPI] multispectral immunofluorescence assay. Multivariable-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of T cell subset densities in both epithelial and stromal tissue areas in CRC with disease-specific survival.<br><br>RESULTS: Higher CD3+CD4+ and CD3+CD8+ naive, memory, and regulatory T cell densities were significantly associated with better CRC-specific survival in both epithelial and stromal tissue areas (HRs highest quantile versus lowest quantile ranging 0.41-0.68). These associations persisted in models further adjusted for stage at diagnosis and were largely consistent when stratified by microsatellite instability (MSI) status. However, the further stratification into CD4+ or CD8+ T cell subsets beyond CD3+ subsets did not significantly improve how well our model explains CRC prognosis.<br><br>CONCLUSIONS: The density of T cells in CRC tissue, both overall and for several T cell subset populations, is significantly associated with CRC-specific survival independent of MSI status and stage at diagnosis.<br><br>IMPACT: Higher levels of T cell densities in different locations with different functions are associated with better CRC-specific survival.}, }
@article {pmid40241769, year = {2025}, author = {Pang, Y and Li, Q and Sergi, Z and Yu, G and Kim, O and Lu, P and Chan, M and Sang, X and Wang, H and Ranjan, A and Robey, RW and Soheilian, F and Tran, B and Núñez, FJ and Zhang, M and Song, H and Zhang, W and Davis, D and Gilbert, MR and Gottesman, MM and Liu, Z and Thomas, CJ and Castro, MG and Gujral, TS and Wu, J}, title = {Exploiting the therapeutic vulnerability of IDH-mutant gliomas with zotiraciclib.}, journal = {iScience}, volume = {28}, number = {4}, pages = {112283}, pmid = {40241769}, issn = {2589-0042}, abstract = {Isocitrate dehydrogenase (IDH)-mutant gliomas have distinctive metabolic and biological traits that potentially render them susceptible to targeted treatments. Here, by conducting a high-throughput drug screen, we pinpointed a specific vulnerability of IDH-mutant gliomas to zotiraciclib (ZTR). ZTR exhibited selective growth inhibition across multiple IDH-mutant glioma in vitro and in vivo models. Mechanistically, ZTR at low doses suppressed CDK9 and RNA Pol II phosphorylation in IDH-mutant cells, disrupting mitochondrial function and NAD+ production, resulting in oxidative stress. Integrated biochemical profiling of ZTR kinase targets and transcriptomics unveiled that ZTR-induced bioenergetic failure was linked to the suppression of PIM kinase activity. We posit that the combination of mitochondrial dysfunction and an inability to adapt to oxidative stress resulted in significant cell death upon ZTR treatment, ultimately increasing the therapeutic vulnerability of IDH-mutant gliomas. These findings prompted a clinical trial evaluating ZTR in IDH-mutant gliomas (NCT05588141).}, }
@article {pmid40240612, year = {2025}, author = {Nesselbush, MC and Luca, BA and Jeon, YJ and Jabara, I and Meador, CB and Garofalo, A and Binkley, MS and Hui, AB and van 't Erve, I and Xu, N and Shi, WY and Liu, KJ and Sugio, T and Kastelowitz, N and Hamilton, EG and Liu, CL and Olsen, M and Bonilla, RF and Wang, YP and Jiang, A and Lau, B and Eichholz, J and Banwait, M and Schroers-Martin, J and Boegeholz, J and King, DA and Luikart, H and Esfahani, MS and Mehrmohamadi, M and Stehr, H and Raclin, T and Tibshirani, R and Khush, K and Srinivas, S and Yu, H and Rogers, AJ and Nair, VS and Isbell, JM and Li, BT and Piotrowska, Z and Sequist, LV and Hata, AN and Neal, JW and Wakelee, HA and Gentles, AJ and Alizadeh, AA and Diehn, M}, title = {An ultrasensitive method for detection of cell-free RNA.}, journal = {Nature}, volume = {}, number = {}, pages = {}, pmid = {40240612}, issn = {1476-4687}, abstract = {Sensitive methods for detection of cell-free RNA (cfRNA) could facilitate non-invasive gene expression profiling and monitoring of diseases[1-6]. Here we describe RARE-seq (random priming and affinity capture of cfRNA fragments for enrichment analysis by sequencing), a method optimized for cfRNA analysis. We demonstrate that platelet contamination can substantially confound cfRNA analyses and develop an approach to overcome it. In analytical validations, we find RARE-seq to be approximately 50-fold more sensitive for detecting tumour-derived cfRNA than whole-transcriptome RNA sequencing (RNA-seq), with a limit of detection of 0.05%. To explore clinical utility, we profiled 437 plasma samples from 369 individuals with cancer or non-malignant conditions and controls. Detection of non-small-cell lung cancer expression signatures in cfRNA increased with stage (6 out of 20 (30%) in stage I; 5 out of 8 (63%) in stage II; 10 out of 15 (67%) in stage III; 80 out of 96 (83% sensitivity) in stage IV at 95% specificity) and RARE-seq was more sensitive than tumour-naive circulating tumour DNA (ctDNA) analysis. In patients with EGFR-mutant non-small-cell lung cancer who developed resistance to tyrosine kinase inhibitors, we detected both histological transformation and mutation-based resistance mechanisms. Finally, we demonstrate the potential utility of RARE-seq for determination of tissue of origin, assessing benign pulmonary conditions and tracking response to mRNA vaccines. These results highlight the potential value of ultrasensitive cfRNA analysis and provide proof of concept for diverse clinical applications.}, }
@article {pmid40240607, year = {2025}, author = {Mahendrawada, L and Warfield, L and Donczew, R and Hahn, S}, title = {Low overlap of transcription factor DNA binding and regulatory targets.}, journal = {Nature}, volume = {}, number = {}, pages = {}, pmid = {40240607}, issn = {1476-4687}, abstract = {DNA sequence-specific transcription factors (TFs) modulate transcription and chromatin architecture, acting from regulatory sites in enhancers and promoters of eukaryotic genes[1,2]. How multiple TFs cooperate to regulate individual genes is still unclear. In yeast, most TFs are thought to regulate transcription via binding to upstream activating sequences, which are situated within a few hundred base pairs upstream of the regulated gene[3]. Although this model has been validated for individual TFs and specific genes, it has not been tested in a systematic way. Here we integrated information on the binding and expression targets for the near-complete set of yeast TFs and show that, contrary to expectations, there are few TFs with dedicated activator or repressor roles, and that most TFs have a dual function. Although nearly all protein-coding genes are regulated by one or more TFs, our analysis revealed limited overlap between TF binding and gene regulation. Rapid depletion of many TFs also revealed many regulatory targets that were distant from detectable TF binding sites, suggesting unexpected regulatory mechanisms. Our study provides a comprehensive survey of TF functions and offers insights into interactions between the set of TFs expressed in a single cell type and how they contribute to the complex programme of gene regulation.}, }
@article {pmid40240114, year = {2025}, author = {Ebadi, M and Tseng, YD}, title = {Old but Gold Radiation.}, journal = {International journal of radiation oncology, biology, physics}, volume = {122}, number = {1}, pages = {7-8}, doi = {10.1016/j.ijrobp.2024.12.042}, pmid = {40240114}, issn = {1879-355X}, }
@article {pmid40241937, year = {2024}, author = {Wright, C and Meng, Q and Breshock, MR and Atta, L and Taub, MA and Jager, LR and Muschelli, J and Hicks, SC}, title = {Open Case Studies: Statistics and Data Science Education through Real-World Applications.}, journal = {Journal of statistics and data science education : an official journal of the of the American Statistical Association}, volume = {32}, number = {4}, pages = {331-344}, pmid = {40241937}, issn = {2693-9169}, support = {U24 HG010263/HG/NHGRI NIH HHS/United States ; UE5 CA254170/CA/NCI NIH HHS/United States ; UL1 TR003098/TR/NCATS NIH HHS/United States ; }, abstract = {With unprecedented and growing interest in data science education, there are limited educator materials that provide meaningful opportunities for learners to practice statistical thinking, as defined by Wild and Pfannkuch, with messy data addressing real-world challenges. As a solution, Nolan and Speed advocated for bringing applications to the forefront in undergraduate statistics curriculum with the use of in-depth case studies to encourage and develop statistical thinking in the classroom. Limitations to this approach include the significant time investment required to develop a case study - namely, to select a motivating question and to create an illustrative data analysis - and the domain expertise needed. As a result, case studies based on realistic challenges, not toy examples, are scarce. To address this, we developed the Open Case Studies (opencasestudies.org) project, which offers a new statistical and data science education case study model. This educational resource provides self-contained, multimodal, peer-reviewed, and open-source guides (or case studies) from real-world examples for active experiences of complete data analyses. We developed an educator's guide describing how to most effectively use the case studies, how to modify and adapt components of the case studies in the classroom, and how to contribute new case studies (opencasestudies.org/OCS_Guide).}, }
@article {pmid40239994, year = {2025}, author = {Shen, BW and Heiter, D and Yang, W and Xu, SY and Stoddard, BL}, title = {Cryo-EM structures of DNA-free and DNA-bound BsaXI: architecture of a Type IIB restriction-modification enzyme.}, journal = {Nucleic acids research}, volume = {53}, number = {7}, pages = {}, pmid = {40239994}, issn = {1362-4962}, support = {R01 GM049857/GM/NIGMS NIH HHS/United States ; R35 GM148166/GM/NIGMS NIH HHS/United States ; grid.436923.9//EMSL/ ; U24 GM129547/GM/NIGMS NIH HHS/United States ; U24GM129547/GF/NIH HHS/United States ; }, mesh = {Cryoelectron Microscopy ; *DNA/chemistry/metabolism ; *Deoxyribonucleases, Type II Site-Specific/chemistry/ultrastructure/genetics/metabolism ; Models, Molecular ; DNA Cleavage ; Protein Binding ; Binding Sites ; Protein Conformation ; }, abstract = {We have determined multiple cryogenic electron microscopy (cryo-EM) structures of the Type IIB restriction-modification enzyme BsaXI. Such enzymes cleave DNA on both sides of their recognition sequence and share features of Types I, II, and III restriction systems. BsaXI forms a heterotrimeric (RM)2S assemblage in the presence and absence of bound DNA. Two unique structural motifs-a multi-helical "knob" and a long antiparallel double-helical "paddle"-are involved in DNA binding and cleavage. Binding of the DNA target triggers a large conformational change from an 'open' to 'closed' configuration, resulting in a mixture of two different conformations with respect to the positioning of the S subunit and its target recognition domains on the enzyme's bipartite DNA target site. Structure-guided mutagenesis studies implicated two clusters of residues in the RM subunit as being critical for DNA cleavage, both are located proximal to a DNA cleavage site. One corresponds to a canonical PD-(D/E)xK endonuclease site in the N-terminal endonuclease domain, while the other corresponds to residues clustered within the paddle motif (near to the C-terminal end of the RM subunit). This analysis facilitates a comparison of three potential mechanisms by which such enzymes cleave DNA on each side of the bound target.}, }
@article {pmid40239646, year = {2025}, author = {Zhu, Y and Balaji, A and Han, M and Andronov, L and Roy, AR and Wei, Z and Chen, C and Miles, L and Cai, S and Gu, Z and Tse, A and Yu, BC and Uenaka, T and Lin, X and Spakowitz, AJ and Moerner, WE and Qi, LS}, title = {High-resolution dynamic imaging of chromatin DNA communication using Oligo-LiveFISH.}, journal = {Cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cell.2025.03.032}, pmid = {40239646}, issn = {1097-4172}, abstract = {Three-dimensional (3D) genome dynamics are crucial for cellular functions and disease. However, real-time, live-cell DNA visualization remains challenging, as existing methods are often confined to repetitive regions, suffer from low resolution, or require complex genome engineering. Here, we present Oligo-LiveFISH, a high-resolution, reagent-based platform for dynamically tracking non-repetitive genomic loci in diverse cell types, including primary cells. Oligo-LiveFISH utilizes fluorescent guide RNA (gRNA) oligo pools generated by computational design, in vitro transcription, and chemical labeling, delivered as ribonucleoproteins. Utilizing machine learning, we characterized the impact of gRNA design and chromatin features on imaging efficiency. Multi-color Oligo-LiveFISH achieved 20-nm spatial resolution and 50-ms temporal resolution in 3D, capturing real-time enhancer and promoter dynamics. Our measurements and dynamic modeling revealed two distinct modes of chromatin communication, and active transcription slows enhancer-promoter dynamics at endogenous genes like FOS. Oligo-LiveFISH offers a versatile platform for studying 3D genome dynamics and their links to cellular processes and disease.}, }
@article {pmid40239400, year = {2025}, author = {Shatila, M and Cruz, CC and Lu, L and Abdul-Baki, K and Baerman, E and Takigawa, K and Rivera, AU and Lee, IJ and Ngo, S and Sperling, G and Aleem, AS and Menon, R and Sullivan, A and Vemulapalli, V and Natha, C and Gupta, T and Khan, A and Mittal, N and Coleman, G and Salim, H and Wali, S and Varatharajalu, K and Kim, KC and Reddy, SA and Grivas, P and Thomas, AS and Wang, Y}, title = {The association between metformin use, immune mediated colitis and overall survival in patients treated with checkpoint inhibitor.}, journal = {European journal of cancer (Oxford, England : 1990)}, volume = {221}, number = {}, pages = {115405}, doi = {10.1016/j.ejca.2025.115405}, pmid = {40239400}, issn = {1879-0852}, abstract = {INTRODUCTION: Metformin is frequently prescribed to treat type 2 diabetes. Its primarily regulates hepatic and colonic glucose metabolism, but recent studies have suggested an anti-inflammatory effect, especially in colitis. It has been suggested that metformin may enhance immune checkpoint inhibition (ICI) efficacy for cancer treatment. Our study aims to explore the impact of metformin on ICI efficacy and the risk for colitis.<br><br>METHODS: This was a single center, retrospective analysis of consecutive patients at a tertiary cancer center who received ICI between 01/2010-12/2022 and developed immune-mediated colitis (IMC). Patients were screened for colitis based on stool tests, then divided into two groups depending on metformin use prior to colitis onset. We collected data on demographic and colitis clinical information including treatments, and outcomes.<br><br>RESULTS: A total of 953 patients were included. The incidence of IMC was higher among metformin users (7.6&#x202f;%) than non-metformin users (4.9&#x202f;%; p&#x202f;<&#x202f;0.01). There were no significant differences in colitis features and outcomes, except for longer hospital stay among metformin users (8 days vs 6 for non-metformin users; p&#x202f;=&#x202f;0.03). Metformin use was associated with shorter overall survival vs non-metformin users among patients with IMC (p&#x202f;=&#x202f;0.03).<br><br>DISCUSSION: Our study is among the first to explore the impact of metformin on IMC and overall survival. We found that metformin use may be associated with higher risk of IMC. We also found an association between metformin use and shorter overall survival among patients who developed IMC. Larger studies with risk-stratified analysis are needed to validate our findings.}, }
@article {pmid40239123, year = {2025}, author = {Giri, VN and Rumble, RB and Yu, EY and Lu, K}, title = {Germline and Somatic Genomic Testing for Metastatic Prostate Cancer: ASCO Guideline Clinical Insights.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2500186}, doi = {10.1200/OP-25-00186}, pmid = {40239123}, issn = {2688-1535}, }
@article {pmid40233328, year = {2025}, author = {Annesley, C and Seidel, KD and Wu, Q and Summers, C and Wayne, AS and Pulsipher, MA and Agrawal, AK and Brown, CT and Mgebroff, S and Lindgren, CG and Rawlings-Rhea, SD and Huang, W and Wilson, A and Jensen, MC and Park, JR and Gardner, RA}, title = {Outcomes of PLAT-02 and PLAT-03: Evaluating CD19 CAR T-Cell Therapy and CD19-expressing T-APC Support in Pediatric B-ALL.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2025028359}, pmid = {40233328}, issn = {1528-0020}, abstract = {This study reports outcomes of PLAT-02, a phase 2 trial of SCRI-CAR19, a second-generation CAR T-cell product with FMC63 scFv and 41BB costimulation, in pediatric and young adult patients with B-cell acute lymphoblastic leukemia; and PLAT-03, a companion study evaluating exogenous CD19 antigen stimulation with serial infusions of T cells expressing truncated CD19, T-cell antigen presenting cells (T-APCs). The efficacy cohort of PLAT-02 (n=72 patients, median age 12.5 years) received fludarabine/cyclophosphamide lymphodepletion followed by a dose of 1X106 CAR+ T cells/kg. MRD-negative complete remission rate was 89%. Leukemia free survival (LFS) with 95% CI at 1 and 2 years was 0.71 (0.58, 0.81) and 0.64 (0.51, 0.75). Patients with low disease burden had significantly higher 1-year LFS (0.91 vs. 0.42). Rapid in vivo contraction of CAR T cells after infusion was associated with CAR loss within six months compared to those without rapid contraction (57% vs. 19%, respectively). Most common grade 3/4 adverse events included cytokine release syndrome in 13% and neurotoxicity in 16%. The companion pilot, PLAT-03, enrolled 26 patients, and 19 received T-APCs. Neither cytokine-release syndrome nor neurotoxicity were observed after T-APC infusion. T-APC infusion in patients improved persistence (P=0.03) with rapid CAR T-cell contraction was associated with decreased early CAR loss (20% with T-APC vs. 57% without). Further exploration of serial artificial CD19 antigen exposure is warranted based on these pilot results. PLAT-02 (NCT02028455) and PLAT-03 (NCT03186118).}, }
@article {pmid40228175, year = {2025}, author = {Subbiah, V and Othus, M and Palma, J and Cuglievan, B and Kurzrock, R}, title = {Designing Clinical Trials for Patients With Rare Cancers: Connecting the Zebras.}, journal = {American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting}, volume = {45}, number = {3}, pages = {e100051}, doi = {10.1200/EDBK-25-100051}, pmid = {40228175}, issn = {1548-8756}, mesh = {Humans ; *Neoplasms/therapy/diagnosis/genetics ; *Clinical Trials as Topic/methods ; *Rare Diseases/therapy/diagnosis ; Precision Medicine ; *Research Design ; }, abstract = {The field of rare cancer research is rapidly transforming, marked by significant progress in clinical trials and treatment strategies. Rare cancers, as defined by the National Cancer Institute, occur in fewer than 150 cases per million people each year, yet they collectively represent a significant portion of all cancer diagnoses. Because of their infrequency, these cancers pose distinct challenges for clinical trials, including limited patient populations, geographical dispersion, and a general lack of awareness of treatment options. Economic limitations further complicate drug development, making initiatives such as the Orphan Drug Act essential for incentivizing research. The advent of next-generation sequencing (NGS) and precision medicine has been instrumental in identifying actionable genetic alterations in parallel with an explosion in the development of genomically targeted therapies, immunotherapies, and antibody drug conjugates. Advances in clinical NGS, precision medicine, and tumor-agnostic therapies have become central to the progress in rare cancer research. The development and approval of tumor-agnostic drugs, such as BRAF, NTRK, and RET inhibitors, and immunotherapy for mismatch repair deficient/microsatellite instability-high status cancers highlight the potential of personalized treatments across diverse cancer types and across the age spectrum. Collaborative trials from cooperative groups including SWOG DART, ASCO TAPUR, NCI-MATCH, pediatric COG-match, DRUP, IMPRESS, and innovative registrational basket and platform trials (eg, VE-Basket, ROAR, LIBRETTO-001, ARROW), along with patient advocacy group-run trials like TRACK, are enhancing access to clinical trials. In addition, artificial intelligence has the potential to improve the trial matching process. An integrated approach, combining these innovations in collaboration with multiple stakeholders, is crucial for advancing rare cancer research, offering hope for better patient outcomes and quality of life.}, }
@article {pmid40227208, year = {2025}, author = {Kaaks, R and Cooley, V and Mukama, T and Teras, LR and Patel, AV and Masala, G and Crous-Bou, M and Harris, HR and Langseth, H and Surcel, HM and Wentzensen, N and Terry, K and Sasamoto, N and Tworoger, S and Fortner, RT}, title = {A Prospective Study Consortium for the Discovery and Validation of Early Detection Markers for Ovarian Cancer ("PREDICT") - Baseline findings for CA125.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-24-1845}, pmid = {40227208}, issn = {1557-3265}, abstract = {PURPOSE: Epithelial ovarian cancer (EOC) is a lethal malignancy. CA125, the "best" available marker for detecting EOC, has insufficient sensitivity and specificity for earlier-stage disease and is not a meaningful screening tool, motivating the search for further biomarkers. Cancer biomarker discovery is enhanced by "omics" technologies. Discovery studies for EOC biomarkers should be conducted in pre-diagnosis blood samples from prospective cohorts to maximize likelihood of identifying markers that can detect disease before usual diagnosis and in earlier disease stage, while reducing methodologic biases.<br><br>EXPERIMENTAL DESIGN: Individual cohorts with pre-diagnosis blood samples have insufficient sample size for such studies. thus, we established "PREDICT" ("Prospective Early Detection Consortium for Ovarian Cancer")-a collaboration of nine prospective studies-to assemble a sufficient number of EOC cases with blood samples collected &#x2264;18 months before diagnosis plus controls. The 457 cases and 1,687 controls have circulating CA125 measured using a clinical assay.<br><br>RESULTS: The discrimination capacity for single CA125 measurements in samples collected <6 months prior to diagnosis was high (area under the curve (AUC), PREDICT overall=0.92; range across cohorts of non-pregnant individuals=0.89-0.98), and declined with extended time between blood collection and diagnosis. Between-cohort variability in CA125 levels and predictive performance was observed.<br><br>CONCLUSIONS: Ongoing investigations in PREDICT are evaluating the early detection potential of tumor-associated autoantibodies and microRNAs, using CA125 as a benchmark. PREDICT is a well-characterized resource for identifying and validating detection markers for EOC that may then be used in multi-modal screening, as a complement to CA125 and combined with imaging.}, }
@article {pmid40226958, year = {2025}, author = {Heng, AK and Gooley, T and Lo, SS and Yang, JT and Gillespie, EF and Halasz, LM and Tseng, YD}, title = {The Impact of Race and Ethnicity on Location and Delivery of Palliative Radiotherapy.}, journal = {American journal of clinical oncology}, volume = {}, number = {}, pages = {}, doi = {10.1097/COC.0000000000001202}, pmid = {40226958}, issn = {1537-453X}, abstract = {OBJECTIVES: Among patients that underwent palliative RT (pRT) at a single institution, we evaluated whether differences exist across race and ethnicity in location of pRT consultation and delivery of pRT.<br><br>METHODS: This retrospective study included cancer patients aged 18 years or older who received pRT between 10/2021 and 10/2022. Logistic regression models were used to examine univariable (UVA) and multivariable (MVA) associations between race and pRT consult in the inpatient (vs. outpatient) setting. A subset analysis of quality metrics for pRT delivery was limited to patients who had outpatient consults for pain.<br><br>RESULTS: Four hundred forty patients underwent 548 pRT consults (104 inpatient and 444 outpatient) followed by a course of pRT. Most patients were male (58.2%), White non-Hispanic (WNH) (72.6%), and English-speaking (92.9%). On MVA adjusting for histology, language, and insurance type, consults for Black/African American (BAA) patients had 2.92 higher odds of being performed in the inpatient setting compared with consults for WNH patients (95% CI: 1.28-6.70, P=0.011), although the global P-value was P=0.217. Among 290 outpatient consults for painful lesions, no differences in time to pRT start (global P=0.84), number of prescribed fractions of RT (global P=0.94), or new prescriptions for opioids (global P=0.69) were noted by race and ethnicity.<br><br>CONCLUSIONS: In this study, BAA race was associated with the location of pRT consultation, but no discernible differences were noted regarding the outpatient delivery of pRT for pain. These findings support the importance of inpatient pRT programs to ensure equitable access. More research is needed to understand barriers to outpatient consult.}, }
@article {pmid40231215, year = {2023}, author = {He, B and Phipps, W and Aboulafia, DM}, title = {Engaging Resource-Constrained Countries in Research Trials of HIV and Cancer: Lessons from Sub-Saharan Africa and the AIDS Malignancy Consortium.}, journal = {International journal of cancer care and delivery}, volume = {3}, number = {2}, pages = {}, pmid = {40231215}, issn = {2770-3533}, support = {UM1 CA121947/CA/NCI NIH HHS/United States ; }, abstract = {HIV contributes significantly to the global burden of cancer. In developing countries, AIDS-defining cancers predominate due to inconsistent access to antiretroviral therapy (ART). Even though AIDS-defining cancers are now less common in developed countries, the prevalence of non-AIDS-defining cancers (NADCs) has increased due to longer life expectancy in a milieu of chronic immune activation, exposure to oncogenic viruses, lifestyle factors, and environmental variables. In resource-constrained countries with inconsistent access to ART, Kaposi sarcoma, aggressive B-cell lymphomas, and cervical cancer continue to be a large problem. Not only do people living with HIV (PLWH) face higher cancer incidence and mortality, but they also encounter persistent stigmatization and barriers to equitable access to cancer treatment. To bridge this gap, the United States National Cancer Institute (NCI) established the AIDS Malignancy Consortium (AMC) to evaluate novel treatments, preventive strategies, and clinical guidelines for PLWH by conducting both domestic and international research. The AMC also emphasizes the development of robust research infrastructure in resource-limited countries, training of researchers, and fair management of clinical trial specimens. Despite various challenges, the AMC has contributed significant insights to international cancer trials among PLWH, thereby transforming clinical practice in low-resource areas. The high global burden of HIV-associated cancer underscores the need for comprehensive research, improved healthcare access, and greater inclusion of PLWH in cancer clinical trials.}, }
@article {pmid40224258, year = {2025}, author = {Tereshchenko, LG and Haq, KT and Howell, SJ and Mitchell, EC and Hyde, J and Martínez, J and Ahmed, CA and Briceno, G and Patel, H and Pena, J and Khan, A and Soliman, EZ and Lima, JAC and Kapadia, SR and Misra-Hebert, AD and Kansal, MM and Daviglus, ML and Kaplan, R}, title = {Sex differences in global electrical heterogeneity: The Hispanic Community Health Study/Study of Latinos.}, journal = {Heart rhythm O2}, volume = {6}, number = {1}, pages = {97-102}, pmid = {40224258}, issn = {2666-5018}, }
@article {pmid40222449, year = {2025}, author = {Alver, SK and Peters-Samuelson, BA and Mossavar-Rahmani, Y and Qi, Q and McClain, AC and Van Horn, L and Burk, RD and Kaplan, RC}, title = {Association of meal timing with adiposity measures and gut microbiome characteristics in a cohort study: the Hispanic Community Health Study/Study of Latinos.}, journal = {The American journal of clinical nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajcnut.2025.04.003}, pmid = {40222449}, issn = {1938-3207}, abstract = {BACKGROUND: Time-restricted eating may help control weight through caloric restriction, circadian rhythm, or influence on the gut microbiome (GMB). Physical activity (PA) also plays a role, as people with a longer eating window (EW: time between first and last daily intake) may be more active. The associations between meal timing, adiposity, PA, sedentary behavior (SB) and GMB characteristics are of interest in Hispanic/Latino persons, who experience a high burden of cardiometabolic diseases.<br><br>OBJECTIVE: We explored the relationship of EW with energy intake and accelerometer-measured activity and assessed whether a longer EW and later midpoint of intake (MOI: midpoint time of intake) are associated with adiposity and GMB differences in Hispanic/Latino adults.<br><br>METHODS: Using data from the prospective Hispanic Community Health Study/Study of Latinos (n=11,778 participants with valid 24-hour dietary recall and accelerometer data, no unplanned weight loss, and BMI &#x2265;18.5; n=1925 with GMB data) we explored the relationship between EW, SB and energy intake. We used multivariable linear regression models to study the relationship between EW or MOI and adiposity measures and GMB characteristics, adjusted for clinical, behavioral, and demographic characteristics.<br><br>RESULTS: Those with longer EW tended to have less SB and greater energy intake, suggesting that some individuals may balance greater intake with greater expenditure. After adjustments including energy balance, each hour of EW was associated with 0.29% higher BMI (95% CI 0.07, 0.51), p=0.011. Longer EW and caloric EW (EWC: EW, caloric meals only) were associated with several obesity-associated GMB taxa, such as Streptococcus (enriched, &#x3b2; [95% CI] 0.04 [0.01, 0.07] for EW). MOI was not significantly associated with adiposity or GMB characteristics.<br><br>CONCLUSIONS: Shorter EW may promote healthy weight, but some individuals with longer vs shorter EWs tend to have greater activity that could balance their greater energy intake. EW and EWC may influence GMB characteristics.}, }
@article {pmid40221882, year = {2025}, author = {Dima, D and Goel, U and Ullah, F and Faiman, B and Basali, D and Mazzoni, S and Williams, LS and Samaras, C and Valent, J and Anwer, F and Khouri, J and Raza, S}, title = {Presentation and Outcomes of Localized Immunoglobulin Light Chain Amyloidosis: 14-Year Experience of an Academic Center.}, journal = {Hematological oncology}, volume = {43}, number = {3}, pages = {e70082}, pmid = {40221882}, issn = {1099-1069}, mesh = {Humans ; Male ; Female ; *Immunoglobulin Light-chain Amyloidosis/therapy/mortality/diagnosis/pathology ; Middle Aged ; Aged ; Retrospective Studies ; Adult ; Aged, 80 and over ; Prognosis ; Survival Rate ; Academic Medical Centers ; Follow-Up Studies ; Treatment Outcome ; }, abstract = {Localized light chain amyloidosis (loc-AL) is a rare disorder characterized by localized deposition of misfolded AL fibrils. There are limited data on patterns of disease presentation and long-term outcomes. In this study, we retrospectively reviewed 146 patients with loc-AL at our institution between January 1, 2010, and March 1, 2024. We excluded patients with evidence of systemic AL amyloidosis. We calculated local (PFSL) and systemic (PFSs) progression free survival (PFS) and overall survival (OS) using the Kaplan-Meier method. We found that loc-AL most commonly involved the respiratory (26%), gastrointestinal (17%), head and neck (17%) and genitourinary (10%) systems. Overall, 51% patients were asymptomatic at presentation, and 16% had a co-existent autoimmune disease. First line management included observation (52%), surgical resection (39%), chemotherapy (3%), and radiation (2%). Most patients (59%) had a response with first-line therapy. The median PFSL was ∼15 years (10-year PFSL 68%), and median OS was not reached (10-year OS 83%). None of the patients had progression to systemic amyloidosis. Seventeen patients had local recurrence and required second line therapy. In conclusion, loc-AL has an excellent prognosis and does not progress to systemic AL amyloidosis. Observation and/or surgical removal are usually adequate first-line approaches; however, a small proportion of patients can relapse locally requiring repeated interventions for symptom control.}, }
@article {pmid40221372, year = {2025}, author = {Lawrence, MG and Keerthikumar, S and Townley, SL and Clark, AK and Cuffe, GB and Laven-Law, G and Hanson, AR and Shrestha, RK and Knutson, TP and Richards, MG and Teng, L and Choo, N and Crumbaker, M and Joshua, AM and Corey, E and Nelson, PS and Dehm, SM and Risbridger, GP and Tilley, WD and Hickey, TE and Taylor, RA and Selth, LA}, title = {Reprogramming of Androgen Receptor Activity in Castration-resistant Prostate Cancer is Shaped by Truncated Variants.}, journal = {European urology focus}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.euf.2025.03.017}, pmid = {40221372}, issn = {2405-4569}, abstract = {BACKGROUND AND OBJECTIVE: Under the selective pressure of treatment, prostate cancer cells express constitutively active androgen receptor (AR) variants. Whether AR variants mediate therapy resistance remains contested, because they are often coexpressed with abundant full-length AR. Therefore, we sought to determine how truncated variants shape AR chromatin occupancy and responses to treatments in both the presence and absence of full-length AR.<br><br>METHODS: We used a cohort of patient-derived xenografts of metastatic prostate cancer with diverse AR alterations. Chromatin immunoprecipitation and RNA sequencing were used to compare the landscape of AR binding and transcriptomic features. We assessed responses to castration by castrating host mice and evaluated responses to bipolar androgen therapy by administering testosterone cypionate.<br><br>KEY FINDINGS AND LIMITATIONS: By profiling the AR cistrome, we identified a distinct group of tumours defined by ARv567es expression, a variant arising due to structural rearrangements of the AR gene. ARv567es-positive tumours also had a distinct epigenomic profile and altered transcriptional features, including loss of canonical AR-regulated gene signatures and elevated expression of AR-repressed genes. ARv567es-positive tumours were resistant to castration and bipolar androgen therapy. In tumours that coexpress full-length AR, this involves dampened transcriptional responses and disruption of the autoregulatory loop that modulates AR levels. Study limitations include the need for additional models of AR-driven prostate cancer.<br><br>The emergence of ARv567es via gene rearrangements causes transcriptional reprogramming and therapy resistance. This highlights ARv567es as a potential as a marker to guide treatment decisions.}, }
@article {pmid40216759, year = {2025}, author = {Zhang, X and Brody, JA and Graff, M and Highland, HM and Chami, N and Xu, H and Wang, Z and Ferrier, KR and Chittoor, G and Josyula, NS and Meyer, M and Gupta, S and Li, X and Li, Z and Allison, MA and Becker, DM and Bielak, LF and Bis, JC and Boorgula, MP and Bowden, DW and Broome, JG and Buth, EJ and Carlson, CS and Chang, KM and Chavan, S and Chiu, YF and Chuang, LM and Conomos, MP and DeMeo, DL and Du, M and Duggirala, R and Eng, C and Fohner, AE and Freedman, BI and Garrett, ME and Guo, X and Haiman, C and Heavner, BD and Hidalgo, B and Hixson, JE and Ho, YL and Hobbs, BD and Hu, D and Hui, Q and Hwu, CM and Jackson, RD and Jain, D and Kalyani, RR and Kardia, SLR and Kelly, TN and Lange, EM and LeNoir, M and Li, C and Le Marchand, L and McDonald, MN and McHugh, CP and Morrison, AC and Naseri, T and ,  and O'Connell, J and O'Donnell, CJ and Palmer, ND and Pankow, JS and Perry, JA and Peters, U and Preuss, MH and Rao, DC and Regan, EA and Reupena, SM and Roden, DM and Rodriguez-Santana, J and Sitlani, CM and Smith, JA and Tiwari, HK and Vasan, RS and Wang, Z and Weeks, DE and Wessel, J and Wiggins, KL and Wilkens, LR and Wilson, PWF and Yanek, LR and Yoneda, ZT and Zhao, W and Zöllner, S and Arnett, DK and Ashley-Koch, AE and Barnes, KC and Blangero, J and Boerwinkle, E and Burchard, EG and Carson, AP and Chasman, DI and Ida Chen, YD and Curran, JE and Fornage, M and Gordeuk, VR and He, J and Heckbert, SR and Hou, L and Irvin, MR and Kooperberg, C and Minster, RL and Mitchell, BD and Nouraie, M and Psaty, BM and Raffield, LM and Reiner, AP and Rich, SS and Rotter, JI and Benjamin Shoemaker, M and Smith, NL and Taylor, KD and Telen, MJ and Weiss, ST and Zhang, Y and Heard-Costa, N and Sun, YV and Lin, X and Cupples, LA and Lange, LA and Liu, CT and Loos, RJF and North, KE and Justice, AE}, title = {Whole genome sequencing analysis of body mass index identifies novel African ancestry-specific risk allele.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {3470}, pmid = {40216759}, issn = {2041-1723}, support = {U01 HL054472/HL/NHLBI NIH HHS/United States ; U19 CA203654/CA/NCI NIH HHS/United States ; R01 DK075787/DK/NIDDK NIH HHS/United States ; F32 HL085989/HL/NHLBI NIH HHS/United States ; U01 HL072524/HL/NHLBI NIH HHS/United States ; I01 BX003340/BX/BLRD VA/United States ; P20 GM109036/GM/NIGMS NIH HHS/United States ; P01 CA134294/CA/NCI NIH HHS/United States ; U01 HG009088/HG/NHGRI NIH HHS/United States ; T32 HL007055/HL/NHLBI NIH HHS/United States ; R01 DK122503/DK/NIDDK NIH HHS/United States ; R35 CA197449/CA/NCI NIH HHS/United States ; R01 HL104135/HL/NHLBI NIH HHS/United States ; I01 BX004821/BX/BLRD VA/United States ; R01 HL133040/HL/NHLBI NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; R01 AR048797/AR/NIAMS NIH HHS/United States ; U01 HG007416/HG/NHGRI NIH HHS/United States ; U01 HL054509/HL/NHLBI NIH HHS/United States ; R01 DK 122503//U.S. Department of Health &amp; Human Services | NIH | Office of Extramural Research, National Institutes of Health (OER)/ ; U01 HL120393/HL/NHLBI NIH HHS/United States ; U01 HL089897/HL/NHLBI NIH HHS/United States ; R01 HL113338/HL/NHLBI NIH HHS/United States ; R01 DK135938/DK/NIDDK NIH HHS/United States ; R01 AG058921/AG/NIA NIH HHS/United States ; R01 HL142302/HL/NHLBI NIH HHS/United States ; R01 DK110113/DK/NIDDK NIH HHS/United States ; R01 NS058700/NS/NINDS NIH HHS/United States ; R01 DK107786/DK/NIDDK NIH HHS/United States ; R01 HL119443/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; R01 AI114555/AI/NIAID NIH HHS/United States ; U01 HL089856/HL/NHLBI NIH HHS/United States ; T32 HL129982/HL/NHLBI NIH HHS/United States ; R01 HL067348/HL/NHLBI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; R01 HL104608/HL/NHLBI NIH HHS/United States ; R01 AI132476/AI/NIAID NIH HHS/United States ; K08 HL136928/HL/NHLBI NIH HHS/United States ; M01 RR007122/RR/NCRR NIH HHS/United States ; KL2 TR002490/TR/NCATS NIH HHS/United States ; R01 HL142825/HL/NHLBI NIH HHS/United States ; R01 DK124097/DK/NIDDK NIH HHS/United States ; R01 HL093093/HL/NHLBI NIH HHS/United States ; I01 BX003362/BX/BLRD VA/United States ; R01 HL068959/HL/NHLBI NIH HHS/United States ; U01 HL072507/HL/NHLBI NIH HHS/United States ; R01 DK071891/DK/NIDDK NIH HHS/United States ; P01 HL132825/HL/NHLBI NIH HHS/United States ; R01 HG010297/HG/NHGRI NIH HHS/United States ; U01 HL054495/HL/NHLBI NIH HHS/United States ; R01 HL055673/HL/NHLBI NIH HHS/United States ; R01 HL092301/HL/NHLBI NIH HHS/United States ; U01 HL054473/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Body Mass Index ; Polymorphism, Single Nucleotide ; *Whole Genome Sequencing ; Genome-Wide Association Study ; *Obesity/genetics/ethnology ; Male ; Female ; Alleles ; Genetic Predisposition to Disease ; *Black People/genetics ; Adult ; Middle Aged ; }, abstract = {Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals (P < 5 × 10[-9]), including two secondary signals. Notably, we identified and replicated a novel low-frequency single nucleotide polymorphism (SNP) in MTMR3 that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the POC5 and DMD loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine.}, }
@article {pmid40215224, year = {2025}, author = {Fisher, LH and Lazarus, E and Yu, C and Moodie, Z and Stieh, DJ and Yates, N and Zhang, L and Sawant, S and De Rosa, SC and Cohen, KW and Morris, D and Grant, S and Randhawa, A and Miner, MD and Hendriks, J and Wegmann, F and Gill, KM and Laher, F and Bekker, LG and Gray, GE and Corey, L and McElrath, MJ and Martin, T and Gilbert, PB and Tomaras, G and Walsh, SR and Baden, LR and , }, title = {ALVAC-prime and monomeric gp120 protein boost induces distinct HIV-1 specific humoral and cellular responses compared with adenovirus-prime and trimeric gp140 protein boost.}, journal = {PLOS global public health}, volume = {5}, number = {4}, pages = {e0004250}, pmid = {40215224}, issn = {2767-3375}, abstract = {Although clade-specific and cross-clade mosaic prime-boost HIV-1 vaccine regimens were advanced to the HVTN 702 and HVTN 705 efficacy trials, neither regimen prevented HIV acquisition. The respective Phase 1/2a studies, HVTN 100 (NCT02404311) and HVTN 117/HPX2004 (NCT02788045), provided rich immunological data, including previously identified correlates of risk, for comparing immune responses elicited by these vaccine regimens over time. We analyzed antibody responses measured by binding antibody multiplex assay, and CD4+ and CD8+ T-cell responses measured by intracellular cytokine staining in per-protocol vaccinees in HVTN 100 (n=186) vs. HVTN 117/HPX2004 (n=99) after the months 6 and 12 vaccinations (months 6.5/7 and 12.5/13), and 6 months after the last vaccination (month 18). At month 12.5/13, both regimens induced similarly high IgG breadth against gp120, gp140, and V1V2 antigens, and similar IgG responses to gp70-BCaseA V1V2. IgG V1V2 responses were more durable in HVTN 117/HPX2004, with the largest difference in the gp70-BCaseA V1V2 IgG response rate at month 18 (17.8% in HVTN 100 vs 61.9% in HVTN 117/HPX2004, p<0.001). IgG3 responses to consensus Env antigens were higher and more durable in HVTN117/HPX2004; for example, IgG3 response rate to the consensus gp140 antigen was 65.9% in HVTN 117/HPX2004 vs 6.3% in HVTN 100 at month 18 (TMLE p<0.0001). At month 18, both regimens induced similar IgG3 responses to gp70-BCaseA V1V2 (3.2% in HVTN 100 vs 1.1% in HVTN 117/HPX2004). Polyfunctional CD4+ Env was significantly higher in HVTN 100, and polyfunctional CD4+ Gag was higher in HVTN 117/HPX2004. CD8+ T-cell responses were not seen in HVTN 100, while CD8+ T-cell response rates in HVTN 117/HPX2004 reached up to 42%. Despite the distinct immune responses induced by the two HIV vaccine regimens, the lack of demonstrated efficacy suggests that broader, higher magnitude, and possibly qualitatively different immune responses are needed for protection against HIV acquisition. Trial registration: ClinicalTrials.gov NCT02404311 and NCT02788045; South African National Clinical Trials Registry (DOH-27-0215-4796).}, }
@article {pmid40214435, year = {2025}, author = {Ramani, H and Cleret-Buhot, A and Sylla, M and Bunet, R and Bertrand, F and Peet, MM and Chartrand-Lefebvre, C and Trottier, B and Thomas, R and Routy, JP and Fortin, C and Martel-Laferrière, V and Sadouni, M and Cloutier, G and Allard, L and Kizer, JR and Chomont, N and Ancuta, P and Hanna, DB and Kaplan, RC and Jenabian, MA and Landay, AL and Durand, M and El-Far, M and Tremblay, CL}, title = {Opposite Roles of IL-32α Versus IL-32β/γ Isoforms in Promoting Monocyte-Derived Osteoblast/Osteoclast Differentiation and Vascular Calcification in People with HIV.}, journal = {Cells}, volume = {14}, number = {7}, pages = {}, pmid = {40214435}, issn = {2073-4409}, support = {R01 AG054324/AG/NIA NIH HHS/United States ; 2R01AG054324-08A1/NH/NIH HHS/United States ; }, mesh = {Humans ; *Interleukins/metabolism ; *Monocytes/metabolism/pathology/cytology ; *Osteoblasts/metabolism/pathology ; *Cell Differentiation ; *HIV Infections/complications/pathology/metabolism ; *Vascular Calcification/metabolism/pathology/complications ; Protein Isoforms/metabolism ; *Osteoclasts/metabolism/pathology/cytology ; Male ; Calcium/metabolism ; Transforming Growth Factor beta/metabolism ; Middle Aged ; Female ; }, abstract = {People with HIV (PWH) have an increased risk of developing cardiovascular disease (CVD). Our recent data demonstrated that the multi-isoform proinflammatory cytokine IL-32 is upregulated in PWH and is associated with arterial stiffness and subclinical atherosclerosis. However, the mechanisms by which IL-32 contributes to the pathogenesis of these diseases remain unclear. Here, we show that while the less expressed IL-32α isoform induces the differentiation of human classical monocytes into the calcium-resorbing osteoclast cells, the dominantly expressed isoforms IL-32β and IL-32γ suppress this function through the inhibition of TGF-β and induce the differentiation of monocytes into the calcium-depositing osteocalcin+ osteoblasts. These results aligned with the increase in plasma levels of osteoprotegerin, a biomarker of vascular calcification, and its association with the presence of coronary artery subclinical atherosclerosis and calcium score in PWH. These findings support a novel role for the proinflammatory cytokine IL-32 in the pathophysiology of CVD by increasing vascular calcification in PWH.}, }
@article {pmid40212049, year = {2025}, author = {Onwuka, JU and Zahed, H and Feng, X and Alcala, K and Erhunmwunsee, L and Williams, RM and Aldrich, MC and Ahluwalia, JS and Albanes, D and Arslan, AA and Bassett, JK and Brennan, P and Cai, Q and Chen, C and Dimou, N and Ferrari, P and Freedman, ND and Huang, WY and Jones, ME and Jones, MR and Kaaks, R and Koh, WP and Langhammer, A and Liao, LM and Malekzadeh, R and Milne, RL and Rohan, TE and Sánchez, MJ and Sheikh, M and Sinha, R and Shu, XO and Stevens, VL and Tinker, LF and Visvanathan, K and Wang, Y and Wang, R and Weinstein, SJ and White, E and Yuan, JM and Zheng, W and Johansson, M and Robbins, HA}, title = {Association between socioeconomic position and lung cancer incidence in 16 countries: a prospective cohort consortium study.}, journal = {EClinicalMedicine}, volume = {82}, number = {}, pages = {103152}, pmid = {40212049}, issn = {2589-5370}, abstract = {BACKGROUND: Studies have reported higher lung cancer incidence among groups with lower socioeconomic position (SEP). However, it is not known how this difference in lung cancer incidence between SEP groups varies across different geographical settings. Furthermore, most prior studies that assessed the association between SEP and lung cancer incidence were conducted without detailed adjustment for smoking. Therefore, we aimed to assess this relationship across world regions.<br><br>METHODS: In this international prospective cohort consortium study, we used data from the Lung Cancer Cohort Consortium (LC3), which includes 20 prospective population cohorts from 16 countries in North America, Europe, Asia, and Australia. Participants were enrolled between 1985 and 2010 and followed for cancer outcomes using registry linkages and/or active follow-up. We estimated hazard ratios (HRs) for the association between educational level (our primary measure of SEP, in 4 categories) and incident lung cancer using Cox proportional hazards models separately for participants with and without a smoking history. The models were adjusted for age, sex, cohort (when multiple cohorts were included), smoking duration, cigarettes per day, and time since cessation.<br><br>FINDINGS: Among 2,487,511 participants, 53,830 developed lung cancer during a 13.5-year median follow-up (IQR&#xa0;=&#xa0;6.5-15.0 years). Among participants with a smoking history, higher education was associated with decreased lung cancer incidence in nearly every cohort after detailed smoking adjustment. By world region, this association was observed in North America (HR per one-category increase in education [HRtrend]&#xa0;=&#xa0;0.88, 95% CI&#xa0;=&#xa0;0.87-0.89), Europe (HRtrend&#xa0;=&#xa0;0.89, 95% CI&#xa0;=&#xa0;0.88-0.91), and Asia (HRtrend&#xa0;=&#xa0;0.91, 95% CI&#xa0;=&#xa0;0.86-0.96), but not in the Australian study (HRtrend&#xa0;=&#xa0;1.02, 95% CI&#xa0;=&#xa0;0.95-1.09). By histological subtype, education associated most strongly with squamous cell carcinoma and more weakly with adenocarcinoma (p-heterogeneity < 0.0001). Among participants who never smoked, there was no association between education and lung cancer incidence in any cohort (all p-trend > 0.05), except the USA Southern Community Cohort Study (HRtrend&#xa0;=&#xa0;0.75, 95% CI&#xa0;=&#xa0;0.62-0.90).<br><br>INTERPRETATION: Based on longitudinal data from 2.5 million participants from 16 countries, our findings suggest that higher educational attainment was associated with lower lung cancer risk among participants with a smoking history, but not among participants who never smoked. Limitations of our study include that cohort participants cannot fully represent the general populations of the geographical regions included, and education was the only measure of SEP consistently available across our consortium.<br><br>FUNDING: This study was supported in part by the National Cancer Institute (NCI), the Lung Cancer Research Foundation (LCRF), and the World Cancer Research Fund (WCRF).}, }
@article {pmid40211539, year = {2025}, author = {Jennewein, MF and Schultz, MD and Beaver, S and Battisti, P and Bakken, J and Hanson, D and Akther, J and Zhou, F and Mohamath, R and Singh, J and Cross, N and Kasal, DN and Ykema, MR and Reed, S and Kalange, D and Cheatwood, IR and Tipper, JL and Foote, JB and King, RG and Silva-Sanchez, A and Harrod, KS and Botta, D and Gerhardt, A and Casper, C and Randall, TD and Lund, FE and Voigt, EA}, title = {Intranasal replicon SARS-CoV-2 vaccine produces protective respiratory and systemic immunity and prevents viral transmission.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ymthe.2025.04.007}, pmid = {40211539}, issn = {1525-0024}, abstract = {While mRNA vaccines have been effective in combating SARS-CoV-2, waning of vaccine-induced antibody responses and lack of vaccine-induced respiratory tract immunity contribute to ongoing infection and transmission. In this work, we compare and contrast intranasal (i.n.) and intramuscular (i.m.) administration of a SARS-CoV-2 replicon vaccine delivered by a nanostructured lipid carrier (NLC). Both i.m. and i.n. vaccines induce potent systemic serum neutralizing antibodies, bone marrow-resident IgG-secreting cells, and splenic T cell responses. The i.n. vaccine additionally induces robust respiratory mucosal immune responses, including SARS-CoV-2-reactive lung-resident memory T cell populations. As a booster following previous i.m. vaccination, the i.n. vaccine also elicits the development of mucosal virus-specific T cells. Both the i.m. and i.n. administered vaccines durably protect hamsters from infection-associated morbidity upon viral challenge, significantly reducing viral loads and preventing challenged hamsters from transmitting virus to naïve cagemates. This replicon-NLC vaccine's potent systemic immunogenicity, and additional mucosal immunogenicity when delivered i.n., may be key for combating SARS-CoV-2 and other respiratory pathogens.}, }
@article {pmid40210677, year = {2025}, author = {Petty, LE and Chen, HH and Frankel, EG and Zhu, W and Downie, CG and Graff, M and Lin, P and Sharma, P and Zhang, X and Scartozzi, AC and Roshani, R and Landman, JM and Boehnke, M and Bowden, DW and Chambers, JC and Mahajan, A and McCarthy, MI and Ng, MCY and Sim, X and Spracklen, CN and Zhang, W and Preuss, M and Bottinger, EP and Nadkarni, GN and Loos, RJF and Chen, YI and Tan, J and Ipp, E and Genter, P and Emery, LS and Louie, T and Sofer, T and Stilp, AM and Taylor, KD and Xiang, AH and Buchanan, TA and Roll, K and Gao, C and Palmer, ND and Norris, JM and Wagenknecht, LE and Nousome, D and Varma, R and McKean-Cowdin, R and Guo, X and Hai, Y and Hsueh, W and Sandow, K and Parra, EJ and Cruz, M and Valladares-Salgado, A and Wacher-Rodarte, N and Rotter, JI and Goodarzi, MO and Rich, SS and Bertoni, A and Raffel, LJ and Nadler, JL and Kandeel, FR and Duggirala, R and Blangero, J and Lehman, DM and DeFronzo, RA and Thameem, F and Wang, Y and Gahagan, S and Blanco, E and Burrows, R and Huerta-Chagoya, A and Florez, JC and Tusie-Luna, T and González-Villalpando, C and Orozco, L and Haiman, CA and Hanis, CL and Rohde, R and Whitsel, EA and Reiner, AP and Kooperberg, C and Li, Y and Duan, Q and Lee, M and Correa-Burrows, P and Fried, SK and North, KE and McCormick, JB and Fisher-Hoch, SP and Gamazon, ER and Morris, AP and Mercader, JM and Highland, HM and Below, JE and ,  and , }, title = {Large-scale multi-omics analyses in Hispanic/Latino populations identify genes for cardiometabolic traits.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {3438}, pmid = {40210677}, issn = {2041-1723}, support = {R56 DK062370/DK/NIDDK NIH HHS/United States ; U01 HG007416/HG/NHGRI NIH HHS/United States ; R01 DK107786/DK/NIDDK NIH HHS/United States ; R01 DK062370/DK/NIDDK NIH HHS/United States ; R56 HG010297/HG/NHGRI NIH HHS/United States ; U01 HG011723/HG/NHGRI NIH HHS/United States ; U01 DK062370/DK/NIDDK NIH HHS/United States ; R01 HL142302/HL/NHLBI NIH HHS/United States ; R01 DK110113/DK/NIDDK NIH HHS/United States ; R01 DK101855/DK/NIDDK NIH HHS/United States ; R01HL142302//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; }, mesh = {Humans ; *Diabetes Mellitus, Type 2/genetics/ethnology/blood ; Genome-Wide Association Study ; *Hispanic or Latino/genetics ; Mendelian Randomization Analysis ; Male ; Genetic Predisposition to Disease ; Female ; Proteomics ; Cholesterol, HDL/genetics/blood ; Polymorphism, Single Nucleotide ; Quantitative Trait Loci ; Lipids/blood/genetics ; Membrane Proteins/genetics ; Triglycerides/blood ; Multiomics ; White ; }, abstract = {Here, we present a multi-omics study of type 2 diabetes and quantitative blood lipid and lipoprotein traits conducted to date in Hispanic/Latino populations (nmax = 63,184). We conduct a meta-analysis of 16 type 2 diabetes and 19 lipid trait GWAS, identifying 20 genome-wide significant loci for type 2 diabetes, including one novel locus and novel signals at two known loci, based on fine-mapping. We also identify sixty-one genome-wide significant loci across the lipid/lipoprotein traits, including nine novel loci, and novel signals at 19 known loci through fine-mapping. Next, we analyze genetically regulated expression, perform Mendelian randomization, and analyze association with transcriptomic and proteomic measure using multi-omics data from a Hispanic/Latino population. Using this approach, we identify genes linked to type 2 diabetes and lipid/lipoprotein traits, including TMEM205 and NEDD9 for HDL cholesterol, TREH for triglycerides, and ANXA4 for type 2 diabetes.}, }
@article {pmid40208630, year = {2025}, author = {Zhao, Y and Gulati, R and Lange, J and Olivas-Martinez, A and Raoof, S and Zheng, Y and Feng, Z and Etzioni, R}, title = {Sensitivity Measures in Studies of Cancer Early Detection Biomarkers.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-24-1849}, pmid = {40208630}, issn = {1538-7755}, abstract = {BACKGROUND: The sensitivity of a cancer screening biomarker to detect prevalent preclinical cancer drives screening benefit. Studies estimate sensitivity at different points in the biomarker development process. We examine how closely these estimates reflect the sensitivity to detect preclinical cancer (preclinical sensitivity).<br><br>METHODS: We posit that preclinical sensitivity is inversely proportional to the preclinical sojourn time. We simulate studies and estimates of sensitivity corresponding to the Early Detection Research Network's Phases of Biomarker Development. Sensitivity estimates based on clinically diagnosed cases (Phase 2, clinical sensitivity), archived-sample studies (Phase 3, archived-sample sensitivity), and prospectively screened cohorts (Phases 4 and 5, prospective empirical sensitivity) are defined and compared against the corresponding expected preclinical sensitivity.<br><br>RESULTS: Clinical sensitivity is generally optimistic. Archived-sample sensitivity is optimistic near clinical diagnosis but may be pessimistic at longer look-back intervals, with bias dependent also on test specificity. Prospective empirical sensitivity is optimistic when the sojourn time is long relative to the screening interval. Bias in prospective empirical sensitivity depends also on the frequency and accuracy of confirmation testing following a positive screening test.<br><br>CONCLUSIONS: Sensitivity estimates from different phases of biomarker development should be distinguished and labeled accordingly to facilitate realistic assessment of diagnostic performance and prediction of potential benefit.<br><br>IMPACT: Our study highlights the need for clearer terminology to describe sensitivity of cancer early detection biomarkers. We introduce new labels, explain biases in sensitivity estimates, and advocate for improved communication to enhance understanding of diagnostic test performance.}, }
@article {pmid40207620, year = {2025}, author = {Gray, CN and Ashokkumar, M and Janssens, DH and Kirchherr, JL and Allard, B and Hsieh, E and Hafer, TL and Archin, NM and Browne, EP and Emerman, M}, title = {Integrator complex subunit 12 knockout overcomes a transcriptional block to HIV latency reversal.}, journal = {eLife}, volume = {13}, number = {}, pages = {}, pmid = {40207620}, issn = {2050-084X}, support = {DP1 DA051110/DA/NIDA NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R61 DA047023/DA/NIDA NIH HHS/United States ; R01 AI143381/AI/NIAID NIH HHS/United States ; T32 AI083203/AI/NIAID NIH HHS/United States ; T32 AI 083203//National Institute of Allergy and Infectious Diseases/ ; R56 AI170226/AI/NIAID NIH HHS/United States ; 1UM1-A1-164567//National Institute of Allergy and Infectious Diseases/ ; }, mesh = {*Virus Latency/drug effects/genetics ; Humans ; *HIV-1/physiology/drug effects/genetics ; Virus Activation/drug effects ; *HIV Infections/virology ; *Transcription, Genetic ; Gene Knockout Techniques ; Heterocyclic Compounds, 4 or More Rings/pharmacology ; CD4-Positive T-Lymphocytes/virology ; }, abstract = {The latent HIV reservoir is a major barrier to HIV cure. Combining latency reversal agents (LRAs) with differing mechanisms of action such as AZD5582, a non-canonical NF-kB activator, and I-BET151, a bromodomain inhibitor is appealing toward inducing HIV-1 reactivation. However, even this LRA combination needs improvement as it is inefficient at activating proviruses in cells of people living with HIV (PLWH). We performed a CRISPR screen in conjunction with AZD5582 &amp; I-BET151 and identified a member of the Integrator complex as a target to improve this LRA combination, specifically Integrator complex subunit 12 (INTS12). Integrator functions as a genome-wide attenuator of transcription that acts on elongation through its RNA cleavage and phosphatase modules. Knockout of INTS12 improved latency reactivation at the transcriptional level and is more specific to the HIV-1 provirus than AZD5582 &amp; I-BET151 treatment alone. We found that INTS12 is present on chromatin at the promoter of HIV and therefore its effect on HIV may be direct. Additionally, we observed more RNAPII in the gene body of HIV only with the combination of INTS12 knockout with AZD5582 &amp; I-BET151, indicating that INTS12 induces a transcriptional elongation block to viral reactivation. Moreover, knockout of INTS12 increased HIV-1 reactivation in CD4 T cells from virally suppressed PLWH ex vivo, and we detected viral RNA in the supernatant from CD4 T cells of all three virally suppressed PLWH tested upon INTS12 knockout, suggesting that INTS12 prevents full-length HIV RNA production in primary T cells. Finally, we found that INTS12 more generally limits the efficacy of a variety of LRAs with different mechanisms of action.}, }
@article {pmid40205614, year = {2025}, author = {Villalobos, A and Lipman, PD and Beebe-Dimmer, J and Borrayo, EA and Briant, KJ and Bruegl, A and Dee, C and Chavez, S and Drake, B and Johnson, SS and Kikuchi, K and Leeman, J and Lowery, J and Mendoza, JA and Parker, M and Purvis, L and Wells Sittig, K and Thompson, HS and Wangen, M and Wheeler, SB}, title = {Synergies, partnership outcomes, and lessons learned: A qualitative evaluation of cancer center-coalition engagement.}, journal = {JNCI cancer spectrum}, volume = {}, number = {}, pages = {}, doi = {10.1093/jncics/pkaf038}, pmid = {40205614}, issn = {2515-5091}, abstract = {BACKGROUND: Nine National Cancer Institute (NCI)-Designated Cancer Centers received supplemental funding to expand community outreach and engagement (COE) activities through a partnership with Centers for Disease Control and Prevention (CDC)-funded comprehensive cancer control coalitions. This article reports on an evaluation of these awards focused on organizational relationship synergies and partnership outcomes.<br><br>METHODS: NCI, COE, and coalition representatives co-designed the evaluation, which involved document review and 18 semi-structured interviews with 16 COE and 19 coalition representatives. AI-generated interview transcripts were dual-coded in NVivo 20/R1.<br><br>RESULTS: The funding generated a diverse collection of projects and partnerships. COE-coalition synergies and lessons learned were evident in the following domains: infrastructure, community and partner engagement, data monitoring, and intervention implementation, evaluation, and dissemination. Outcomes of this funding initiative were evident in the following domains: strengthened partnerships, expanded knowledge, improved health or healthcare programs and policies, and thriving communities.<br><br>CONCLUSIONS: Fostering COE-coalition partnerships created opportunities to leverage synergies and build capacity for engagement across multiple domains, contributing to enhanced trust and implementation of interventions across the cancer continuum. The findings provide examples and lessons about synergistic opportunities for cancer centers and coalitions to capitalize on. Successful collaborative relationships were based on identifying shared goals and complimentary expertise and roles, sharing of financial and other resources, and a commitment to authentic and open dialogue. While modest and short-term, supplemental funding can strengthen organizational relationships and promote effective collaboration on community-facing activities; it can also lead to improved research engagement and translation of evidence to practice.}, }
@article {pmid40205312, year = {2025}, author = {Elbur, AI and Donnell, D and Hosek, S and Dye, B and Velloza, J and Delany-Moretlwe, S and Celum, C}, title = {The Association Between Use of Adherence Support Interventions and Adherence to HIV Preexposure Prophylaxis Among Young South African and Zimbabwean Women in HPTN 082.}, journal = {AIDS and behavior}, volume = {}, number = {}, pages = {}, pmid = {40205312}, issn = {1573-3254}, support = {UM1-AI068619//National Institute of Allergy and Infectious Diseases/ ; UM1-AI068617//National Institute of Allergy and Infectious Diseases/ ; UM1-AI068613//National Institute of Allergy and Infectious Diseases/ ; T32AI007433//National Institute of Allergy and Infectious Diseases/ ; }, abstract = {We assessed the association between PrEP adherence support interventions and intracellular tenofovir-diphosphate (TFV-DP) levels, a biomarker for PrEP adherence, using data from 368 South African and Zimbabwean adolescent girls and young women enrolled in the HIV Prevention Trials Network 082 trial from 2016 to 2018. Group-based trajectory modeling identified trajectories of TFV-DP levels and adherence support interventions, including weekly two-way SMS and optional monthly adherence clubs. Two trajectories of TFV-DP levels were identified: a consistently low trajectory (N = 248, 67.4%, with consistent TFV-DP levels of 100 fmol/punch) and a high-decreasing trajectory (N = 120, 32.6%, with TFV-DP levels decreasing from approximately 900 to 500 fmol/punch). Two trajectories were also observed for adherence club attendance: consistently moderate (N = 249, 67.7%, attended approximately two out of three clubs in a three-month period) and low-increasing (N = 119, 32.3%). Similarly, SMS response patterns included a consistently high engagement group (N = 222, 66.1%), who responded to approximately 90% of messages, and a consistently low engagement group (N = 114, 33.9%). Women with consistently high SMS responses had higher odds of being in the high-decreasing TFV-DP levels trajectory group (Adjusted Odds Ratio [AOR]: 6.6; 95% CI 2.8-15.5; p < 0.001), while those with a consistently moderate adherence club attendance trajectory had an AOR of 1.3 (95% CI 0.5-3.3, p = 0.620) for being in the same group. Use of PrEP was aligned with the higher response trajectories of SMS responses but not with attendance to adherence support clubs.}, }
@article {pmid40203876, year = {2025}, author = {Gilligan, T and Lin, DW and Adra, N and Bagrodia, A and Feldman, DR and Yamoah, K and Aggarwal, R and Chandrasekar, T and Costa, D and Drakaki, A and Eggener, S and Emamekhoo, H and Geynisman, DM and Graham, L and Humphrey, P and Leuva, H and Levine, EG and Luckenbaugh, A and Maughan, BL and McGregor, B and Monk, P and Picus, J and Pierorazio, P and Rais-Bahrami, S and Reichert, Z and Rwigema, JC and Saylor, P and Shah, A and Shah, S and Singla, N and Sircar, K and VanderWeele, D and Zhumkhawala, A and Montgomery, S and Sliker, B}, title = {NCCN Guidelines® Insights: Testicular Cancer, Version 2.2025.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {23}, number = {4}, pages = {}, doi = {10.6004/jnccn.2025.0018}, pmid = {40203876}, issn = {1540-1413}, mesh = {Humans ; *Testicular Neoplasms/therapy/diagnosis ; Male ; *Neoplasms, Germ Cell and Embryonal/therapy/diagnosis ; Seminoma/therapy/diagnosis ; *Medical Oncology/standards ; Neoplasm Staging ; }, abstract = {The NCCN Guidelines for Testicular Cancer provide recommendations for the multidisciplinary approach to the diagnostic workup, treatment, and follow-up for testicular germ cell tumors, including both seminoma and nonseminoma. These NCCN Guidelines Insights discuss the current treatment recommendations and supporting clinical data for seminomas as presented in Version 2.2025 of the NCCN Guidelines for Testicular Cancer.}, }
@article {pmid40203873, year = {2025}, author = {Biermann, JS and Hirbe, A and Ahlawat, S and Bernthal, NM and Binitie, O and Boles, S and Brigman, B and Callan, AK and Cipriano, C and Cranmer, LD and Davis, J and Donnelly, E and Ferguson, M and Graham, A and Groundland, J and Hess, M and Hiniker, SM and Hoover-Regan, ML and Hornick, JL and Jonard, B and Kuechle, JB and Lindskog, D and Mayerson, JL and McGarry, SV and Morris, CD and Olson, D and Rose, PS and Santana, VM and Satcher, RL and Schwartz, H and Shulman, RM and Thorpe, SW and Wilky, BA and Wustrack, RL and Yoon, J and Hang, LE and Jones, F and Sansone, N and Lyons, M}, title = {Bone Cancer, Version 2.2025, NCCN Clinical Practice Guidelines In Oncology.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {23}, number = {4}, pages = {}, doi = {10.6004/jnccn.2025.0017}, pmid = {40203873}, issn = {1540-1413}, mesh = {Humans ; *Bone Neoplasms/therapy/diagnosis/mortality/pathology ; *Medical Oncology/standards/methods ; Combined Modality Therapy/methods ; *Sarcoma, Ewing/therapy/diagnosis ; *Osteosarcoma/therapy/diagnosis ; }, abstract = {Ewing sarcoma and osteosarcoma constitute 36% of all primary bone cancers. However, these 2 subtypes represent the most commonly diagnosed bone cancer types in the pediatric and adolescent population. Although still largely unknown, certain genetic mutations, rearrangements, and/or predisposition syndromes likely play a role in the pathogenesis of bone cancer. Osteosarcoma may also develop as a direct result of the long-term side effects of radiation therapy. With the implementation of a multimodality approach to treatment, including multiagent neoadjuvant and adjuvant chemotherapy regimens, targeted therapy options, surgery, and radiation, individuals with Ewing sarcoma and osteosarcoma are showing higher cure rates and improved overall survival. The NCCN Guidelines for Bone Cancer provide a consensus and evidence-based framework for the workup, management, and surveillance of local and recurrent/metastatic disease.}, }
@article {pmid40203872, year = {2025}, author = {Lerner, BA and Gupta, S and Burke, CA and Kupfer, S and Katona, BW and Grady, WM and Samadder, JJ and Yurgelun, MB and Kelly, KJ and Moreno Prats, M and Joseph, N and Idos, GE and Swanson, BJ and Kieber-Emmons, A and Weiss, JM and Llor, X}, title = {Advancing the Evaluation and Management of CDH1-Associated Gastric Cancer.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {23}, number = {4}, pages = {}, doi = {10.6004/jnccn.2025.7006}, pmid = {40203872}, issn = {1540-1413}, mesh = {Humans ; *Stomach Neoplasms/genetics/diagnosis/therapy/surgery/pathology ; Gastrectomy/methods ; *Cdh1 Proteins/genetics ; *Antigens, CD/genetics ; *Carcinoma, Signet Ring Cell/genetics/diagnosis/surgery/pathology ; Genetic Predisposition to Disease ; Germ-Line Mutation ; Cadherins ; }, abstract = {Gastric cancer is a significant global health concern, with CDH1-associated gastric cancer representing a small but important subset of cases. Historically, individuals with CDH1 pathogenic germline variants were advised to undergo prophylactic total gastrectomy due to the high reported risk of gastric cancer and the limited sensitivity of upper endoscopy in detecting signet ring cell carcinoma (SRCC). However, emerging data suggest that the cumulative lifetime risk of advanced gastric cancer among CDH1 germline pathogenic variant carriers is lower than previously thought, and early-stage SRCC detected on endoscopy does not necessarily indicate imminent-or even eventual-progression to advanced cancer. The near-universal presence of T1a SRCC in gastrectomy specimens from asymptomatic CDH1 pathogenic variant carriers calls into question the reflexive recommendation for gastrectomy, including upon detection of SRCC during surveillance. Furthermore, the morbidity and quality-of-life impact associated with total gastrectomy require careful consideration. Active endoscopic surveillance has shown promise as an alternative management strategy for gastrectomy in patients lacking indicators of >T1a SRCC, though current data are limited by short follow-up periods and selection bias. This review synthesizes recent findings on the natural history of CDH1-associated gastric cancer and evaluates the risks and benefits of gastrectomy versus active endoscopic surveillance, with the goal of helping clinicians provide personalized and evidence-based recommendations for patients with CDH1 pathogenic variants.}, }
@article {pmid40203277, year = {2025}, author = {Shadman, M and Brown, JR and Mohseninejad, L and Yang, K and Burnett, H and Neupane, B and Williams, R and Lamanna, N and O'Brien, SM and Tedeschi, A and Tam, CS}, title = {Comparative efficacy of Bruton tyrosine kinase inhibitors in high-risk relapsed/refractory CLL: a network meta-analysis.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024014523}, pmid = {40203277}, issn = {2473-9537}, abstract = {Bruton tyrosine kinase inhibitors (BTKis) have led to changes in the treatment algorithm for patients with high-risk relapsed/refractory chronic lymphocytic leukemia (R/R CLL), defined based on the presence of genetic mutations. Given the lack of head-to-head trials comparing next-generation BTKis used to treat high-risk R/R disease, a network meta-analysis (NMA) was performed to estimate their relative efficacy. High-risk populations were defined based on the pre-specified definitions within each trial, including patients with del(17p) and/or TP53 mutations in ALPINE (n=150), and ASCEND (n=86), and del(17p)/del(11q) in ELEVATE-RR (n=533). Bayesian NMAs found zanubrutinib to be the most efficacious treatment for high-risk patients, with significantly reduced risk of progression or death compared with ibrutinib (hazard ratio [95% credible interval (CrI)]: 0.49 [0.31, 0.78]), acalabrutinib (0.55 [0.32, 0.94]), and bendamustine + rituximab or idelalisib + rituximab (BR/IR) (0.12 [0.05, 0.26]). Differences in overall survival demonstrated a numerical trend favoring zanubrutinib (probability better ≥80%) compared to ibrutinib (hazard ratio [95% credible interval]: 0.59 [0.31, 1.11]), acalabrutinib (0.72 [0.35, 1.50]) and BR/IR (0.65 [0.23, 1.75]). Rates of response also demonstrated trends favoring zanubrutinib compared to acalabrutinib, with significant results compared to ibrutinib. The NMA suggests that the most efficacious BTKi for patients with high-risk R/R CLL is zanubrutinib.}, }
@article {pmid40203192, year = {2025}, author = {Yegya-Raman, N and Plastaras, JP and Wright, CM and Chelius, MR and Zhang, S and Baron, JA and Hubbeling, H and Sim, AJ and Robinson, TJ and Jain, MD and Imber, BS and Fregonese, B and Yahalom, J and Ladbury, C and Dandapani, S and Pinnix, CC and Gunther, JR and Fang, PQ and Wu, SY and Dabaja, BS and Yang, JC and Chew, J and Braunstein, S and Sinha, S and Denlinger, N and Sun, S and Terezakis, SA and Sakthivel, G and Constine, LS and Chowdhry, AK and Reagan, PM and Burke, S and Tseng, YD and LaRiviere, MJ and Maity, A and Schuster, SJ and Chong, EA and Figura, NB}, title = {Bridging Radiotherapy Prior to Chimeric Antigen Receptor T-Cells for B-Cell Lymphomas: An ILROG Multicenter Study.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025015855}, pmid = {40203192}, issn = {2473-9537}, abstract = {Despite the increasing utilization of bridging radiotherapy (Br-RT), its impact on chimeric antigen receptor T-cell therapy (CAR-T) efficacy and toxicity remains poorly characterized. We retrospectively reviewed patients with relapsed/refractory B-cell lymphomas (r/r BCL) who received Br-RT followed by CAR-T from 2018-2020 across 10 institutions. Br-RT toxicities were graded per CTCAE v5.0, and cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) per ASTCT Consensus Guidelines. 172 patients (168 large BCL, 3 mantle cell, 1 Burkitt) received Br-RT prior to axicabtagene ciloleucel (73%), tisagenlecleucel (23%), or brexucabtagene autoleucel (2%). At leukapheresis, most patients (74%) had advanced-stage disease and 39% had bulky disease measuring ≥10cm. Comprehensive Br-RT was administered to 39% (n=67) and bridging systemic therapy to 35% (n=60). Among all patients, grade ≥3 Br-RT toxicity occurred in 2% [one grade 5 toxicity], grade ≥3 CRS in 9%, and grade ≥3 ICANS in 24%. Median follow-up was 31.3 months. Two-year PFS and OS were 38% and 53%, respectively. On multivariable analysis, comprehensive Br-RT was associated with superior PFS (HR 0.38, p<0.001) and OS (HR 0.48, p=0.011). Patients with LDH normalization following Br-RT (high pre-Br-RT LDH, normal post-Br-RT LDH) had superior PFS and OS compared to those with high post-Br-RT LDH, and similar PFS and OS compared to those with normal baseline LDH. In this particularly high-risk cohort, Br-RT prior to CAR-T demonstrates an acceptable toxicity profile with favorable clinical outcomes when compared to historical controls. Comprehensive Br-RT and LDH normalization post-Br-RT may be associated with superior PFS and OS.}, }
@article {pmid40203190, year = {2025}, author = {Kampouri, E and Flaherty, PW and Xie, H and Sekhon, MK and Chalal, C and Stevens-Ayers, TL and Green, DJ and Gauthier, J and Shadman, M and Pérez-Osorio, AC and Jerome, KR and Leisenring, WM and Boeckh, MJ and Hill, JA}, title = {The Impact of CMV Reactivation on Mortality After Chimeric Antigen Receptor T-Cell Therapy.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024015164}, pmid = {40203190}, issn = {2473-9537}, }
@article {pmid39951615, year = {2025}, author = {Pierson, SK and Brandstadter, JD and Torigian, DA and Bagg, A and Lechowicz, MJ and Alapat, D and Casper, C and Chadburn, A and Chandrakasan, S and Dispenzieri, A and Fosså, A and Hoffmann, C and Ide, M and Kurzrock, R and Mukherjee, S and Nasta, S and Navarro, JT and Noy, A and Oksenhendler, E and Bustamante, MS and Shyamsundar, S and Streetly, M and Wong, RSM and Zhang, L and Lim, MS and Srkalovic, G and van Rhee, F and Fajgenbaum, DC}, title = {Characterizing the heterogeneity of Castleman disease and oligocentric subtype: findings from the ACCELERATE registry.}, journal = {Blood advances}, volume = {9}, number = {8}, pages = {1952-1965}, doi = {10.1182/bloodadvances.2024014391}, pmid = {39951615}, issn = {2473-9537}, support = {R01 FD007632/FD/FDA HHS/United States ; R01 HL141408/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Castleman Disease/diagnosis/pathology/etiology/classification/epidemiology ; Registries ; Female ; Male ; Adult ; Middle Aged ; Phenotype ; Aged ; Young Adult ; Adolescent ; }, abstract = {Castleman disease (CD) describes a group of rare lymphoproliferative disorders that exhibit a wide range of symptomatology and degree of lymphadenopathy, particularly across the 2 forms of CD with unknown etiology, unicentric CD (UCD), and human herpesvirus-8-negative/idiopathic multicentric CD (iMCD). Whereas UCD cases typically present with localized lymphadenopathy and mild symptoms, iMCD involves multicentric lymphadenopathy and cytokine storm-driven symptoms with 3 recognized clinical phenotypes. Increasingly, there are anecdotal reports of cases that do not fit into this framework, but these cases have not been systematically described. Herein, we use the ACCELERATE natural history registry to characterize the spectrum of CD based on disease features, symptomatology, and severity. Our results characterize a cohort of 179 CD cases, which were reviewed and confirmed by an expert panel of clinicians and hematopathologists. We show that patients with CD present on a continuous spectrum of clinical phenotypes, and we describe oligocentric CD (OligoCD), an intermediate phenotype that does not fit the criteria for UCD or iMCD. These cases tend to have "oligocentric" lymphadenopathy (median [interquartile range] regions of lymphadenopathy, 3.0 [2.0-4.0]) in a regional pattern and exhibit a mild clinical phenotype that is more similar to UCD than iMCD. We also show that patients with OligoCD are inconsistently categorized as UCD vs iMCD, highlighting the need for this characterization. Future data collected through ACCELERATE may further elucidate the natural history and risk profile of these patients.}, }
@article {pmid40202852, year = {2025}, author = {McQuoid, J and Blackwell, M and Bradley, D and Durazo, A and Frank-Pearce, SG and Heffner, JL and Islam, S and Le, M and Ling, PM and Pan, S and Raye, T and Tan, ASL and Vogel, EA and Wilson, M and Kendzor, DE}, title = {"It took me on a journey other than just to stop smoking": Pilot trial outcomes of an Empowerment Theory-based smoking cessation intervention for sexual and/or gender minoritized people in Oklahoma.}, journal = {Nicotine &amp; tobacco research : official journal of the Society for Research on Nicotine and Tobacco}, volume = {}, number = {}, pages = {}, doi = {10.1093/ntr/ntaf080}, pmid = {40202852}, issn = {1469-994X}, abstract = {INTRODUCTION: Sexual and/or gender minoritized (SGM) people are more likely to smoke if they live where SGM stigma is high, and existing SGM-tailored cessation interventions do not address unique challenges of these environments. This paper reports outcomes from a single-arm pilot trial of an Empowerment Theory-based smoking cessation intervention for SGM people living in high-stigma environments.<br><br>METHODS: SGM adults willing to quit smoking (N=20; Oklahoma) participated in a 12-week intervention comprised of online SGM-serving volunteer activity sessions concurrent with remotely-delivered smoking cessation support (i.e., behavioral support plus combination nicotine replacement therapy [NRT]). Baseline and exit surveys and in-depth exit interviews addressed retention, acceptability, engagement, and adherence.<br><br>RESULTS: Study retention was 80.0% (16/20). Most exit survey respondents attended &#x2265;4 volunteer activity sessions (62.5%; 10/16) and &#x2265;4 cessation counseling sessions (87.5%; 14/16), had moderate/high NRT adherence (patch 84.6%; 11/13 and gum/lozenge 76.9%; 10/13), and would recommend the intervention (81.3%; 13/16). At exit, 7-day point prevalence abstinence was self-reported by 45.0% (9/20; missing=smoking) of all participants and 56.3% (9/16) of exit survey respondents. At least half of participants reported pre-post intervention increases in perceived assertiveness and/or decreases in sexual identity acceptance concerns, concealment concerns, and internalized transphobia. Interviews identified intervention endorsement reasons, including experiencing greater belonging and hope.<br><br>CONCLUSION: A novel approach to SGM-tailored smoking cessation treatment that leveraged Empowerment Theory was feasible and acceptable. Future work should refine and adapt this intervention for other high-stigma places, test its efficacy and treatment mechanisms, and measure organizational and individual-level outcomes.<br><br>IMPLICATIONS: This study adds to the literature on culturally tailored smoking cessation interventions as the first tobacco intervention tailored for SGM people in high-stigma environments. It used a novel application of Empowerment Theory to advance SGM smoking cessation and resilience in the face of minority stress. Findings from this pilot study in Oklahoma indicate promising feasibility and acceptability and will inform future interventions to address tobacco use disparities among SGM people in high-stigma environments.}, }
@article {pmid40201647, year = {2025}, author = {Dickson, E and Kuhlemeier, A and Adsul, P and Sanchez-Youngman, S and Myers, K and Akintobi, TH and Rosas, LG and Mendoza, JA and Oetzel, J and Castro-Reyes, P and Alaniz, C and Jacquez, B and Wallerstein, N}, title = {Developing the engage for equity institutional multi-sector survey: Assessing academic institutional culture and climate for community-based participatory research (CBPR).}, journal = {Journal of clinical and translational science}, volume = {9}, number = {1}, pages = {e44}, pmid = {40201647}, issn = {2059-8661}, abstract = {INTRODUCTION: Community-engaged research/community-based participatory research/patient-engaged research (CEnR/CBPR/PEnR) are increasingly recognized as important approaches for addressing health equity. However, there is limited support for CEnR/CBPR/PEnR within Academic Health Centers (AHCs). It is important for AHCs to measure and monitor the context, process, and policies in support for CEnR/CBPR/PEnR. The Engage for Equity (E2) team developed the first Institutional Multi-Sector Survey (IMSS) instrument to assess and explore CEnR/CBPR/PEnR-related practices at three AHCs.<br><br>METHODS: Working with "champion teams" consisting of academic leaders, researchers, and patient/community partners at each AHC, we developed the IMSS to assess the following domains: institutional mission, vision, and values; CEnR/CBPR/PEnR policies/practices; community processes/structures; function of formal community advisory boards; climate/culture for CEnR/CBPR; perceptions of institutional leadership for CEnR/CBPR/PEnR. The survey was piloted to a convenience sample of CEnR/CBPR/PEnR participants at each AHC site.<br><br>RESULTS: A sample aggregated across all sites consisting of community (n = 49) and academic (n = 50) participants perceived high levels of advocacy for CEnR/CBPR/PEnR among their AHC research teams. Participants indicated that institutional leadership supported CEnR/CBPR/PEnR in principle, but resources to build CEnR/CBPR/PEnR capacity at their respective institutions were lacking. Differences in responses from community and academic partners are summarized.<br><br>CONCLUSIONS: While limited by survey length and question adaptation, the findings contribute to identification of institutional barriers and facilitators to CEnR/CBPR/PEnR in AHCs. These findings are critically important to support and improve CEnR/CBPR/PEnR practice in academic institutions and to elevate community partner voices and needs for advancing community and patient partners' research.}, }
@article {pmid40201643, year = {2025}, author = {Aschbrenner, KA and Walsh-Bailey, C and Brown, MC and Khan, T and Baggett, TP and Jones, SMW and Levy, DE and Pace, LE and Winickoff, JP}, title = {Practical considerations for engaging staff in resource-constrained healthcare settings in implementation research: A qualitative focus group and consensus building study.}, journal = {Journal of clinical and translational science}, volume = {9}, number = {1}, pages = {e65}, pmid = {40201643}, issn = {2059-8661}, abstract = {BACKGROUND: The primary purpose of this study was to assess perceived burdens and benefits of participating in implementation research among staff employed in resource-constrained healthcare settings. Another objective was to use findings to generate considerations for engaging staff in research across different phases of implementation research.<br><br>METHODS: This qualitative focus group and consensus building study involved researchers affiliated with the National Cancer Institute Implementation Science Centers in Cancer Control program and nine Community Health Centers (CHCs) in Massachusetts. Six focus groups (n = 3 with CHC staff; n = 3 with researchers) assessed barriers and facilitators to staff participation in implementation research. During consensus discussions, we used findings to develop considerations for engaging staff as participants and partners throughout phases of implementation research.<br><br>RESULTS: Sixteen researchers and 14 staff participated in separate focus groups; nine researchers and seven staff participated in separate consensus discussions. Themes emerged across participant groups in three domains: (1) influences on research participation; (2) research burdens and benefits; and (3) ways to facilitate staff participation in research. Practical considerations included: (a) aligning research with organizational and staff values and priorities; (b) applying user-centered design to research methods; (c) building organizational and individual research capacity; and (d) offering equitable incentives for staff participation.<br><br>CONCLUSIONS: Engaging staff as participants and partners across different phases of implementation research requires knowledge about what contributes to research burden and benefits and addressing context-specific burdens and benefits.}, }
@article {pmid40201639, year = {2025}, author = {Briant, KJ and Adsul, P and Carosso, EA and Chakoian, M and Mapes, D and Coutee, T and Hempstead, B and Hassell, L and Law, W and Mendoza, JA}, title = {Adoption of E2PLUS tools and resources to promote the development of institutional capacity for patient-centered and community-engaged research at a cancer center.}, journal = {Journal of clinical and translational science}, volume = {9}, number = {1}, pages = {e72}, pmid = {40201639}, issn = {2059-8661}, abstract = {INTRODUCTION: The Fred Hutch/University of Washington/Seattle Children's Cancer Consortium's (Consortium) Office of Community Outreach &amp; Engagement (OCOE) joined Stanford Medicine and Morehouse School of Medicine in implementing Engage for Equity Plus (E2PLUS), a multi-institutional community of practice to learn and share patient-centered and community-engaged research (P/CEnR) practices. University of New Mexico (UNM) facilitated this collaboration.<br><br>METHODS: The Consortium formed a Champion Team of 12 people who participated in two virtual workshops facilitated by UNM. Consortium executive leadership (n = 4) participated in interviews, and investigators (n = 4) and community members/patient advocates (n = 8) participated in focus groups to provide institutional context regarding P/CEnR. This is a paper on the process and findings.<br><br>RESULTS: Through E2PLUS engagement, the Champion Team identified four strategies to address institutional health inequities: 1) increase participation of underrepresented groups at all levels of institutional leadership and advisory boards; 2) create an Office of Patient Engagement to train and support patients who participate in institutional initiatives and advise research teams; 3) expand community engagement training, resources, and institutional commitment to focus on community-identified social and health needs; and 4) establish an umbrella entity for health equity efforts across the Consortium.<br><br>CONCLUSION: While the Consortium had longstanding community advisory boards and faculty and staff with P/CEnR expertise, it did not have centralized and institutionally supported P/CEnR resources, policies, and infrastructure. By participating in E2PLUS, the Champion Team received technical assistance to leverage qualitative data to influence strategies to guide the development of Consortium health equity infrastructure and capacity for P/CEnR in Washington.}, }
@article {pmid40200765, year = {2025}, author = {Macris, PC and McMillen, K}, title = {Nutrition issues in adult hematopoietic cell transplantation: A narrative review of latest advances.}, journal = {Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1002/ncp.11288}, pmid = {40200765}, issn = {1941-2452}, abstract = {Patients undergoing hematopoietic cell transplantation (HCT) are a highly heterogenous population with respect to their unique nutrient requirements and need for nutrition support. Dose-intensive conditioning regimens in addition to the debilitating effects of graft-vs-host disease impact and adversely affect the transplant recipient's nutrition status. Decreased oral intake, increased nutrient requirements, and impaired nutrient absorption and utilization often necessitate specialized nutrition support. The use of parenteral nutrition and enteral nutrition support, as well as dietary intervention strategies for immunocompromised patients, have varied over the past five decades and are highly dependent on the type of transplant used. This review highlights adult nutrition assessment components, nutrition support practices, and management of complex nutrition consequences associated with HCT.}, }
@article {pmid40199861, year = {2025}, author = {Chunara, F and Lugo, C and Osinski, K and Shah, MR and Shah, N and Kent, J and Mohyuddin, GR and Radhakrishnan, SV and Kaur, G and Chakraborty, R and Banerjee, R and Rasche, L and Schinke, C and D'Souza, A and Szabo, A and Mohan, M}, title = {Real-world treatment patterns for teclistamab and talquetamab in multiple myeloma (MM): experience from 609 patients.}, journal = {Blood cancer journal}, volume = {15}, number = {1}, pages = {61}, pmid = {40199861}, issn = {2044-5385}, }
@article {pmid40198924, year = {2025}, author = {Chen, Y and Montaño, MA and Naik, P and Thuo, N and Kiptinness, C and Rafferty, M and Stergachis, A and Mugambi, ML and Ngure, K and Ortblad, KF and Sharma, M}, title = {Incremental cost of pre- and post-exposure prophylaxis service provision via an online pharmacy in Kenya.}, journal = {Journal of acquired immune deficiency syndromes (1999)}, volume = {}, number = {}, pages = {}, doi = {10.1097/QAI.0000000000003680}, pmid = {40198924}, issn = {1944-7884}, abstract = {BACKGROUND: Online pharmacy HIV pre- and post-exposure prophylaxis (PrEP/PEP) provision is a novel strategy to expand HIV prevention coverage. In the ePrEP pilot study, we found online pharmacy PrEP/PEP was feasible and reached populations at HIV risk in Kenya. However, program costs data are lacking.<br><br>METHODS: We conducted a costing within the ePrEP pilot study in Nairobi from 11/01/2022-12/29/2023. We obtained costs from expense reports and conducted time-and-motion observations and staff interviews. We estimated total and unit costs in the first year of implementation, cost per client and per PrEP client-month (2023 US Dollars (USD)).<br><br>RESULTS: Overall, 229 clients initiated PrEP (507 months of PrEP coverage) and 1320 initiated PEP. Based on observed program volume, annual financial cost was $109,945 USD (PrEP: $19,456; PEP: $90,489). Cost per client was higher for PrEP than PEP ($85 vs $68.6), and cost per PrEP client-month was $38 (mean duration: 2.2 months). Main drivers of financial costs were courier-delivery of HIV testing kits and drugs (PrEP: 50.6%; PEP: 40.5%), demand generation (PrEP: 25.9%; PEP: 32.1%), and equipment, system development, and utilities (PrEP: 9.3%; PEP: 9.8%). Assuming a scaled-up client volume of 2500 (PrEP: 370; PEP: 2130) reduced per-client financial costs for PrEP ($65.5) and PEP ($56) and cost per PrEP client-month ($29.6).<br><br>CONCLUSIONS: Costs of online PrEP/PEP provision is likely higher than clinic-based PrEP. Implementing cost sharing models including charging clients for HIV testing and optimizing courier delivery routes can increase program efficiencies. Our cost estimates can inform economic evaluations of online PrEP/PEP delivery.}, }
@article {pmid40198877, year = {2025}, author = {Tuazon, SA and Portuguese, AJ and Pont, MJ and Cowan, AJ and Cole, GO and Sather, BD and Song, X and Thomas, S and Wood, BL and Blake, ML and Works, MG and Shadman, M and Liang, EC and Wu, Q and Voutsinas, JM and Gooley, TA and Turtle, CJ and Till, BG and Coffey, DG and Maloney, DG and Riddell, SR and Green, DJ}, title = {A phase 1 trial of fully human BCMA CAR-T therapy for relapsed/refractory multiple myeloma with 5-year follow-up.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024027681}, pmid = {40198877}, issn = {1528-0020}, abstract = {FCARH143, an autologous BCMA-targeted CAR-T therapy which incorporates a fully human BCMA-specific scFv and 4-1BB costimulatory domain, was evaluated in a phase 1 trial (NCT03338972) for relapsed/refractory multiple myeloma (RRMM). Patients were stratified by bone marrow (BM) plasma cell involvement (10-30% or >30%) and received lymphodepleting chemotherapy followed by escalating CAR-T cell doses (50×106 to 450×106). The primary endpoint was safety; secondary endpoints were overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Among 28 enrolled patients, all underwent leukapheresis and successful CAR-T manufacturing, though three (11%) did not proceed to infusion. The 25 treated patients (median age 64 years) had a median of eight prior therapies, 80% were triple-class refractory, and 44% had extramedullary disease (EMD). Cytokine release syndrome (CRS) occurred in 84% (8% grade 3-4, no grade 5), and neurotoxicity in 24% (12% grade 3, no grade 4-5). No treatment-related deaths occurred. At a median follow-up of 67.3 months, treated patients had an ORR of 100%, including a stringent complete response in 64%. Median PFS and overall survival (OS) were 15.5 and 32.1 months, respectively. In an intention-to-treat analysis (median follow-up 69.6 months), the ORR was 89.3%, and OS was 30.2 months. FCARH143 demonstrated potent anti-myeloma activity with a 100% response rate and manageable toxicity, independent of disease burden or cytogenetic risk. Further evaluation in high-risk RRMM is warranted.}, }
@article {pmid40198850, year = {2025}, author = {Li, YL and Langley, C and Emerman, M and Gross, JD}, title = {APOBEC3G Antagonism by Vif, or When Structure Meets Biological and Evolutionary Studies.}, journal = {Annual review of virology}, volume = {}, number = {}, pages = {}, doi = {10.1146/annurev-virology-092623-091351}, pmid = {40198850}, issn = {2327-0578}, abstract = {Restriction factors serve as innate host defenses against viruses and act as critical barriers to cross-species transmission. In response, viruses have evolved accessory proteins to counteract restriction factors, enabling evasion of innate immune responses. The interplay between primate APOBEC3G (A3G) and lentiviral virion infectivity factor (Vif) exemplifies a molecular arms race between a restriction factor and its viral antagonist. This review integrates evolutionary and functional analyses of this system, showing how genetic signatures of molecular arms races map onto high-resolution cryo-electron microscopy structures. However, A3G's interaction with Vif is not limited to the evolutionary dynamic interface, characterized by rapidly evolving residues under selective pressure, but also involves a conserved interface mediated by RNA binding that positions A3G for antagonism by Vif. These findings propose a model wherein Vif and potentially other viral antagonists target functional complexes using a dual strategy: leveraging both adaptive interfaces subject to evolutionary pressures and conserved interfaces that constrain host escape mechanisms.}, }
@article {pmid40198766, year = {2025}, author = {Dima, D and Afrough, A and Goel, U and Grajales-Cruz, A and Khouri, J and Julian, K and Pasvolsky, O and Banerjee, R and Razzo, B and Ferreri, CJ and Vazquez Martinez, MA and Davis, JA and Sannareddy, A and Castaneda Puglianini, O and Raza, S and Portuguese, AJ and Gaballa, MR and Rana, M and Lieberman-Cribbin, A and DeJarnette, S and Gonzalez, R and Chen, A and Herr, MM and Mikkilineni, L and Hosoya, H and Ouchveridze, E and Kaur, G and Rossi, AC and Shune, L and Anwer, F and Lin, Y and Richard, S and Sborov, DW and Baz, RC and Garfall, A and Lee, HC and Anderson, LD and Cowan, AJ and Patel, KK and Voorhees, PM and Sidana, S and Hansen, DK and Atrash, S and Susanibar-Adaniya, SP}, title = {Teclistamab for Patients with Heavily Pretreated Relapsed/Refractory Multiple Myeloma and Renal Impairment.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025016059}, pmid = {40198766}, issn = {2473-9537}, abstract = {Outcomes of bispecific antibodies in patients with renal impairment (RI) are not well-characterized given the exclusion of these patients from clinical trials. Herein, we evaluated patients with relapsed/refractory multiple myeloma and RI treated with standard-of-care teclistamab. RI was defined as creatinine clearance (CrCl) <40mL/min. CrCl <30mL/min or dialysis dependence were defined as severe RI. Of the 384 included patients, 81 (21%) had RI, including 45 (18%) with severe RI, and 18 (5%) on dialysis. Patients with RI were more likely to be older (median age 71 vs. 67 years, p=0.002), and have a higher median number of prior lines of therapy (7 vs. 6, p=0.04). Rates and severity of cytokine release syndrome (51% vs. 59%, grade ≥3: 1.2% vs. 1%) and immune effector cell-associated neurotoxicity syndrome (16% vs. 13%; grade ≥3: 2.5% vs 2.6%) were similar in patients with and without RI, respectively. Patients with RI had higher baseline and day-30 post-teclistamab grade ≥3 anemia and grade ≥3 thrombocytopenia. Renal function did not worsen after teclistamab initiation in patients with RI outside of the context of disease progression. Overall response rate (52% vs. 56%, p=0.61) and survival outcomes (median progression-free survival: 4.6 vs. 6.5 months; p=0.62) were comparable in patients with and without RI, respectively, after a median follow-up of 9.9 months. No differences in overall survival or non-relapse mortality were noted. Our findings suggest that treatment with teclistamab is feasible in patients with RI including those on dialysis, with a similar safety and efficacy profile to patients without RI.}, }
@article {pmid40198713, year = {2025}, author = {Ashokkumar, M and Hafer, TL and Felton, A and Archin, NM and Margolis, DM and Emerman, M and Browne, EP}, title = {A targeted CRISPR screen identifies ETS1 as a regulator of HIV-1 latency.}, journal = {PLoS pathogens}, volume = {21}, number = {4}, pages = {e1012467}, doi = {10.1371/journal.ppat.1012467}, pmid = {40198713}, issn = {1553-7374}, abstract = {Human Immunodeficiency virus (HIV) infection is regulated by a wide array of host cell factors that combine to influence viral transcription and latency. To understand the complex relationship between the host cell and HIV-1 latency, we performed a lentiviral CRISPR screen that targeted a set of host cell genes whose expression or activity correlates with HIV-1 expression. We further investigated one of the identified factors - the transcription factor ETS1, and found that it is required for maintenance of HIV-1 latency in both latently infected cell lines and in a primary CD4 T cell latency model. Interestingly, ETS1 played divergent roles in actively infected and latently infected CD4 T cells, with knockout of ETS1 leading to reduced HIV-1 expression in actively infected cells, but increased HIV-1 expression in latently infected cells, indicating that ETS1 can play both a positive and negative role in HIV-1 expression. CRISPR/Cas9 knockout of ETS1 in CD4 T cells from ART-suppressed people with HIV-1 (PWH) confirmed that ETS1 maintains transcriptional repression of the clinical HIV-1 reservoir. Transcriptomic profiling of ETS1-depleted cells from PWH identified a set of host cell pathways involved in viral transcription that are controlled by ETS1 in resting CD4 T cells. In particular, we observed that ETS1 knockout increased expression of the long non-coding RNA MALAT1 that has been previously identified as a positive regulator of HIV-1 expression. Furthermore, the impact of ETS1 depletion on HIV-1 expression in latently infected cells was partially dependent on MALAT1. Additionally, we demonstrate that ETS1 knockout resulted in enhanced abundance of activating modifications (H3K9Ac, H3K27Ac, H3K4me3) on histones located at the HIV-1 long terminal repeat (LTR), indicating that ETS1 regulates the activity of chromatin-targeting complexes at the HIV-1 LTR. Overall, these data demonstrate that ETS1 is an important regulator of HIV-1 latency that impacts HIV-1 expression through repressing MALAT1 expression and by regulating modification of proviral histones.}, }
@article {pmid40198382, year = {2025}, author = {Jones, MK and Nicklawsky, A and Shortt, J and Pattee, J and Kennerley, V and Eule, CJ and Candelario, N and ,  and O'Donnell, PH and Flaig, TW}, title = {Pharmacogenomics of chemotherapy induced peripheral neuropathy using an electronic health record-derived definition: a genome-wide association study.}, journal = {Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer}, volume = {33}, number = {5}, pages = {362}, pmid = {40198382}, issn = {1433-7339}, support = {University of Colorado Cancer Center Support Grant P30CA04934//University of Colorado/ ; }, mesh = {Humans ; Genome-Wide Association Study ; *Peripheral Nervous System Diseases/chemically induced/genetics ; Female ; Male ; Electronic Health Records ; Middle Aged ; *Antineoplastic Agents/adverse effects/administration &amp; dosage ; Aged ; Pharmacogenetics ; Genetic Predisposition to Disease ; Bridged-Ring Compounds/adverse effects/administration &amp; dosage ; Taxoids/adverse effects/administration &amp; dosage ; Adult ; *Neoplasms/drug therapy ; Polymorphism, Single Nucleotide ; Vinca Alkaloids/adverse effects/administration &amp; dosage ; }, abstract = {PURPOSE: Prior studies evaluating the genetic predisposition to chemotherapy induced peripheral neuropathy (CIPN) have been limited by small populations due to difficulty with real-world data extraction. This genome-wide association study (GWAS) evaluates the genetic differences between patients who developed CIPN against those unaffected, using an electronic health record (EHR) definition of CIPN.<br><br>METHODS: This study included all patients who received chemotherapy associated with CIPN and had germline genetic data within the biobank at the Colorado Center for Personalized Medicine. CIPN was defined by a new neuropathic pain medication or an ICD-diagnosis of neuropathy after specified chemotherapy initiation. GWAS were stratified by (1) total population, (2) platinum chemotherapy, (3) taxane chemotherapy, and (4) vinca alkaloid chemotherapy. Genes previously associated with CIPN were analyzed within each GWAS.<br><br>RESULTS: Nine hundred fifteen patients received chemotherapy associated with CIPN, with 528 patients (57%) developing CIPN. Median age at chemotherapy initiation was 60.5&#xa0;years; female sex (n&#x2009;=&#x2009;517, 56.5%) and White or Caucasian race (n&#x2009;=&#x2009;822, 89.8%) were most common. Among single nucleotide polymorphisms (SNPs) that reached suggestive levels of genome-wide significance (p&#x2009;<&#x2009;1&#x2009;&#xd7;&#x2009;10[-5]), 60 SNPs occurred within 11 genes that may play a role in the development of or protection against CIPN, including RCOR1, CLDN14, TRIM5, and TMC2. No SNPs previously associated with CIPN achieved genome-wide significance in this population.<br><br>CONCLUSION: This pharmacogenomic study suggests several genomic loci that may modulate the development of CIPN. This EHR-definition may allow for increased sample sizes and improved statistical power in future genetic studies of CIPN.}, }
@article {pmid40197896, year = {2025}, author = {Kantarjian, H and Zhai, Y and Oehler, VG and Jamy, O and Koller, PB and Haddad, FG and Sasaki, K and Jabbour, EJ}, title = {Olverembatinib in chronic myeloid leukemia-Review of historical development, current status, and future research.}, journal = {Cancer}, volume = {131}, number = {8}, pages = {e35832}, doi = {10.1002/cncr.35832}, pmid = {40197896}, issn = {1097-0142}, support = {//Ascentage Pharma Group Corp Ltd. (Hong Kong)/ ; }, mesh = {Humans ; *Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy/genetics ; *Protein Kinase Inhibitors/therapeutic use/pharmacology ; Drug Resistance, Neoplasm/genetics/drug effects ; Fusion Proteins, bcr-abl/genetics/antagonists &amp; inhibitors ; Mutation ; *Antineoplastic Agents/therapeutic use ; Clinical Trials as Topic ; }, abstract = {Once considered an incurable disease with a poor prognosis (median survival, 3-6 years), chronic myeloid leukemia (CML) is now managed with a diverse clinical armamentarium that includes BCR::ABL1 tyrosine kinase inhibitors (TKIs), which have largely normalized life expectancy in most patients in the chronic phase of the disease (CML-CP). Clinical challenges remain, including ABL1 mutation-driven treatment resistance (under the selection pressures exerted by TKIs), as well as treatment intolerance, which can involve potentially serious arterial occlusive events. Olverembatinib is a third-generation TKI approved in China for TKI-resistant CML-CP and accelerated-phase CML with the T135I mutation, as well as for CML-CP resistant to or intolerant of first- and/or second-generation TKIs. Olverembatinib exhibits a broad coverage of ABL1 mutants, including the gatekeeper T315I variant and compound mutations. In preclinical models, olverembatinib inhibited multiple downstream protein kinases, which has potentially opened avenues for future management of other malignancies, including acute myeloid and lymphoid leukemias, gastrointestinal tumors, and others. The pharmacokinetic profile of olverembatinib is compatible with alternate-day dosing. In clinical trials, olverembatinib exerted potent antileukemic effects in heavily pretreated patients with CML, including those with ponatinib or asciminib resistance or intolerance, and was well tolerated. Future studies include the phase 3 registrational POLARIS-1 (NCT06051409; in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia), POLARIS-2 (NCT06423911; in patients with CML with or without the T315I mutation), and POLARIS-3 (NCT06640361; in patients with succinate dehydrogenase-deficient gastrointestinal stromal tumors) clinical trials.}, }
@article {pmid40195948, year = {2025}, author = {Sandfort, TGM and Szydlo, D and Fogel, JM and Chimwaza, Y and Rinnooy Kan, CE and Hamilton, EL and Mudhune, V and Panchia, R and Reynolds, D}, title = {Gaps in HIV Treatment and Care Cascade Among Men and Transfeminine Persons Who Have Sex with Men in Kenya, Malawi, and South Africa: Findings from the HIV Prevention Trials Network 075 Study (2015-2017).}, journal = {AIDS patient care and STDs}, volume = {}, number = {}, pages = {}, doi = {10.1089/apc.2025.0028}, pmid = {40195948}, issn = {1557-7449}, abstract = {Improving HIV outcomes for men who have sex with men (MSM) in sub-Saharan Africa requires addressing gaps in the HIV treatment cascade. This study examined these gaps among 71 treatment-naive MSM with HIV in the HIV Prevention Trials Network 075, a 1-year prospective biobehavioral cohort study (2015-2017) across four sub-Saharan African sites. Following a positive diagnosis, 86% of participants sought HIV care. Reasons for not having sought care or delays included a lack of perceived health issues and practical challenges. Most participants (80%) who engaged in care were prescribed antiretroviral therapy (ART). Although self-reported adherence was high, over one-third of those prescribed ART had no detectable antiretroviral drugs (ARVs) at the study's conclusion. ARV detection was significantly associated with study site, higher income, and experienced homophobia. The highest adherence rates were observed at the site offering direct, integrated treatment, underscoring the potential of "one-stop shop" services to mitigate intra-, interpersonal, and structural barriers. Despite a supportive study environment, gaps remain in linking MSM and transfeminine individuals to sustained HIV care and ART adherence. Given the urgency of addressing HIV among these populations, targeted interventions that promote engagement in care and adherence to treatment are critical.}, }
@article {pmid40193202, year = {2025}, author = {Zhang, X and Scadden, AW and Marthi, A and Buchanan, VL and Qu, Y and Ferrier, KR and Chen, BD and Graff, M and Avila, J and Boerwinkle, E and Buyske, S and Clish, CB and Cruz, D and Fornage, M and Gerzsten, RE and Gignoux, CR and Glover, L and Hou, L and Justice, AE and Kooperberg, C and Kramer, H and Lange, L and Loos, RJF and Matise, T and Mychaleckyj, JC and Olabisi, OA and Peters, U and Raffield, LM and Reiner, AP and Rich, SS and Rotter, JI and Taylor, KD and Yu, B and Zheng, Y and North, KE and Mottl, AK and Highland, HM and Stanislawski, MA}, title = {Alterations in DNA Methylation, Proteomic, and Metabolomic Profiles in African Ancestry Populations with APOL1 Risk Alleles.}, journal = {Journal of the American Society of Nephrology : JASN}, volume = {}, number = {}, pages = {}, doi = {10.1681/ASN.0000000688}, pmid = {40193202}, issn = {1533-3450}, abstract = {BACKGROUND: The APOL1 high-risk haplotype has been associated with chronic kidney disease (CKD) and the deterioration of kidney function, particularly in populations with West African ancestry. However, the mechanisms by which APOL1 risk variants increase the risk for kidney disease and its progression have not been fully elucidated.<br><br>METHODS: We compared methylation (N = 3,191; 715 [22%] carriers), proteomic (N = 1,240; 169 [14%] carriers), and metabolomic (N = 6,309; 674 [11%] carriers) profiles in African and Hispanic/Latino carriers of two APOL1 high-risk alleles (G1/G1, G2/G2, G1/G2) and non-carriers (G0/G0), excluding heterozygotes (G0/G1, G0/G2), from the PAGE Consortium and UK BioBank. In each study, the associations between the APOL1 high-risk haplotype and up to 722,719 CpG sites, 2,923 proteins, or 836 metabolites were estimated using covariate-adjusted linear regression models, followed by fixed-effects sample size weighted meta-analyses.<br><br>RESULTS: Significant associations were observed between APOL1 high-risk haplotype and methylation at 52 CpG sites, with 48 located on chromosome 22 and 18 in the vicinity of APOL1 - 4 and MYH9. All significant CpG sites near APOL2 were hypomethylated, whereas those near APOL3 and APOL4 were hypermethylated. APOL1-associated CpG sites were also identified in genes involved in ion transport and mitochondrial stress pathways. Sensitivity analyses indicated consistent yet attenuated effects among heterozygotes, supporting an additive effect of APOL1 risk alleles. Further analyses of the 52 CpG sites identified two near APOL4 exhibiting G1-specific effects, eight associated with CKD but none with eGFR, and three showing heterogeneity by CKD status. Additionally, carrying two APOL1 risk alleles was associated with higher plasma APOL1 protein (&#x3b2; = 1.12, PFDR = 2.26e-70) and lower C18:1 cholesteryl ester metabolite (Z = -4.50, PFDR = 4.83e-3).<br><br>CONCLUSIONS: Our results demonstrate differential methylation, proteomic, and metabolomic profiles associated with APOL1 high-risk haplotypes.}, }
@article {pmid40191562, year = {2024}, author = {Chintsanya, M and Talham, C and Zhang, B and Taylor, TE and Seydel, KB}, title = {Vital Sign alterations within 24 hours prior to death in children with retinopathy-positive Cerebral Malaria at Queen Elizabeth Central Hospital Malawi.}, journal = {Malawi medical journal : the journal of Medical Association of Malawi}, volume = {36}, number = {2}, pages = {128-133}, pmid = {40191562}, issn = {1995-7270}, mesh = {Humans ; *Malaria, Cerebral/mortality/complications/diagnosis/physiopathology ; Male ; Female ; Malawi/epidemiology ; Retrospective Studies ; Case-Control Studies ; Child, Preschool ; *Vital Signs ; Infant ; Child ; *Malaria, Falciparum/mortality/complications ; *Retinal Diseases/parasitology/mortality ; Coma ; }, abstract = {BACKGROUND: Malaria is a significant obstacle to child health and survival. Plasmodium falciparum infections, especially in children under five, lead to high morbidity and mortality. Cerebral malaria (CM) is a life-threatening complication characterized by coma, and its diagnosis can be improved by observing malarial retinopathy in children. Monitoring vital signs is essential for managing patients with CM.<br><br>OBJECTIVES: To determine if changes in vital signs predict death in children with retinopathy positive cerebral malaria (RPCM).<br><br>METHODS: This was a retrospective case-control study using data collected from children admitted to the Paediatric Research Ward at Queen Elizabeth Central Hospital in Blantyre between 1997 and 2020. Patients who died 24 hours or more after admission were matched with control patients who survived. Linear regression analyses were used to assess the differential time trends of each vital sign in the survivor group and death group. Classification models were used to quantify various vital signs' predictive power of death.<br><br>RESULTS: Among the population that died, the estimated change in average respiratory rate per hour approaching death was 0.02 breaths per minute compared to -0.25 breaths per minute among those who survive (p < 0.001), and the estimated change in average BCS per hour approaching death was -0.01 compared to 0.06 among the survivors (p < 0.001). Changes in temperature and heart rate were not associated with clinical deterioration. Three models were developed, and the best receiver operating characteristic curve was 100% sensitive, the corresponding false positive rate was 75%.<br><br>CONCLUSION: Changes in respiratory rate and BCS have prognostic significance in the final 24 hours before death in children with cerebral malaria. Extra attention should be paid to these two vital signs as they may help to identify children who are at increased risk of deteriorating.}, }
@article {pmid40190112, year = {2025}, author = {Moodie, Z and Li, SS and Giorgi, EE and Williams, LD and Dintwe, O and Carpp, LN and Chen, S and Seaton, KE and Sawant, SS and Zhang, L and Heptinstall, J and Liu, S and Grunenberg, N and Tomaka, F and Rerks-Ngarm, S and Pitisuttithum, P and Nitayaphan, S and Ake, JA and Vasan, S and Pantaleo, G and Frank, I and Baden, LR and Goepfert, PA and Keefer, M and Chirenje, M and Hosseinipour, MC and Mngadi, K and Laher, F and Garrett, N and Bekker, LG and De Rosa, S and Andersen-Nissen, E and Kublin, JG and Lu, S and Gilbert, PB and Gray, GE and Corey, L and McElrath, MJ and Tomaras, GD}, title = {A polyvalent DNA prime with matched polyvalent protein/GLA-SE boost regimen elicited the most robust and broad IgG and IgG3 V1V2 binding antibody and CD4+ T cell responses among 13 HIV vaccine trials.}, journal = {Emerging microbes &amp; infections}, volume = {14}, number = {1}, pages = {2485317}, doi = {10.1080/22221751.2025.2485317}, pmid = {40190112}, issn = {2222-1751}, mesh = {Humans ; *AIDS Vaccines/immunology/administration &amp; dosage ; *CD4-Positive T-Lymphocytes/immunology ; *HIV Infections/prevention &amp; control/immunology/virology ; *HIV Antibodies/immunology/blood ; Female ; *Immunoglobulin G/immunology/blood ; Adult ; Male ; Vaccines, DNA/immunology/administration &amp; dosage ; *HIV-1/immunology ; Young Adult ; Middle Aged ; Immunization, Secondary ; Immunogenicity, Vaccine ; Adolescent ; }, abstract = {Developing an effective HIV vaccine is a momentous challenge. An exceptionally wide range of candidate HIV vaccines have been tested, yet many were poorly immunogenic, and of the select few that advanced into efficacy trials, only one demonstrated any efficacy. Here we report the results of the largest-scale cross-protocol immunogenicity comparison to date: 13 HIV vaccine trials (including 36 vaccine regimens) conducted across nine countries worldwide, strengthened by standardized trial designs, validated assays in centralized laboratories, and harmonized immunogenicity endpoints - providing an objective approach to identify the HIV vaccine candidate(s) with the best immunogenicity. A polyvalent DNA prime + protein boost regimen (HVTN 124) including Env immunogens of four subtypes, matched between prime and boost, achieved the best anti-V1V2 antibody responses by a large margin and also induced high CD4+ T-cell responses - two key immune responses implicated in HIV vaccine protection. Our results provide strong support to test this promising HIV vaccine design in more advanced phase clinical trials and will also guide the future design of additional HIV vaccines.Trial registration: ClinicalTrials.gov identifier: NCT01799954..Trial registration: ClinicalTrials.gov identifier: NCT02109354..Trial registration: ClinicalTrials.gov identifier: NCT02404311..Trial registration: ClinicalTrials.gov identifier: NCT02207920..Trial registration: ClinicalTrials.gov identifier: NCT02296541..Trial registration: ClinicalTrials.gov identifier: NCT03284710..Trial registration: ClinicalTrials.gov identifier: NCT02915016..Trial registration: ClinicalTrials.gov identifier: NCT02997969..Trial registration: ClinicalTrials.gov identifier: NCT03122223..Trial registration: ClinicalTrials.gov identifier: NCT03409276..Trial registration: ClinicalTrials.gov identifier: NCT02968849..Trial registration: ClinicalTrials.gov identifier: NCT03060629..Trial registration: ClinicalTrials.gov identifier: NCT00223080..}, }
@article {pmid40190065, year = {2025}, author = {Osei-Assibey, BA and Lewis, FM}, title = {Helping Her Heal-Ghana: A pilot feasibility study of a culturally adapted educational counseling intervention for spouse caregivers of women with breast cancer.}, journal = {Palliative &amp; supportive care}, volume = {23}, number = {}, pages = {e88}, doi = {10.1017/S1478951524002153}, pmid = {40190065}, issn = {1478-9523}, mesh = {Humans ; Female ; Ghana ; *Breast Neoplasms/psychology/complications/therapy ; Middle Aged ; Feasibility Studies ; Pilot Projects ; *Caregivers/psychology/education ; Adult ; *Counseling/methods/standards ; *Spouses/psychology ; Aged ; Male ; Adaptation, Psychological ; }, abstract = {INTRODUCTION: Breast cancer is the leading cancer in Ghana, Africa, accounting for 31% of all cancers in women. The effects of breast cancer are not limited to the woman but also impact the spouse's anxiety, depressed mood, and coping behavior. Helping Her Heal (HHH)-Ghana is a culturally adapted evidenced-based intervention with potential to improve health outcomes of spouse caregivers.<br><br>OBJECTIVES: The purpose of the study was to ascertain the feasibility, acceptability, and short-term impact of HHH-Ghana, a culturally adapted evidenced-based intervention for spouses of women with breast cancer in Ghana.<br><br>METHODS: The study used a single group pre-post design. Participants (n = 14) were recruited from medical care providers and were eligible if they were spouse caregivers of wives with Stage I, II, or III breast cancer, were 18 years or older, and had been living with their wives for at least 6 months. Data were obtained by spouse self-report on standardized measures of depressed mood, anxiety, self-care skills, self-efficacy to support their wife, self-efficacy to carry out their own self-care, and the quality of marital communication about breast cancer. Exit interviews were additionally obtained to describe the gains spouses attributed to their participation in the study.<br><br>RESULTS: The HHH-Ghana study was feasible and acceptable. Spouses actively engaged in each intervention session and completed the at-home assignments; retention was 87.5%. Spouses significantly improved on standardized measures of anxiety (p = 0.010), depressed mood (p = 0.002), self-care skills (p = 0.006), and their self-efficacy in supporting their wife (p = 0.001) and in carrying out their own self-care (p = 0.011). Although there was no statistically significant change in marital communication, spouses reported in their exit interviews that the intervention enabled them to communicate better and be more attentive listeners to their wives.<br><br>SIGNIFICANCE OF RESULTS: Results warrant a larger clinical trial in Ghana.}, }
@article {pmid40188457, year = {2025}, author = {Sarchi, M and Clough, CA and Gallì, A and Picone, C and Ferrari, B and Crosse, EI and Baquero Galvis, LD and Fiducioso, C and Aydinyan, N and Creamer, JP and Pozzi, S and Molteni, E and Elena, C and Bradley, RK and Malcovati, L and Doulatov, S}, title = {Distinct routes of clonal progression in SF3B1-mutant myelodysplastic syndromes.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024014965}, pmid = {40188457}, issn = {2473-9537}, abstract = {Myelodysplastic syndromes (MDS) are clonal stem cell disorders driven by heterogeneous genetic alterations leading to variable clinical course. MDS with splicing factor SF3B1 mutations is a distinct subtype with a favorable outcome. However, selected co-mutations induce poor prognosis and how these genetic lesions cooperate in human hematopoietic stem and progenitor cells (HSPCs) during disease progression is still unclear. Here, we integrated clinical and molecular profiling of patients with SF3B1 mutations with gene editing of primary and iPSC-derived human HSPCs to show that high-risk co-mutations impart distinct effects on lineage programs of SF3B1-mutant HSPCs. Secondary RUNX1 or STAG2 mutations were clinically associated with advanced disease and reduced survival. However, RUNX1 and STAG2 mutations induced opposing regulation of myeloid transcriptional programs and differentiation in SF3B1-mutant HSPCs. Moreover, high-risk RUNX1 and STAG2, but not low-risk TET2, mutations expanded distinct SF3B1-mutant HSPC subpopulations. These findings provide evidence that progression from low- to high-risk MDS involves distinct molecular and cellular routes depending on co-mutation patterns.}, }
@article {pmid40187495, year = {2025}, author = {Guo, M and Keane, EP and Baliousis, M and Gudenkauf, LM and Mate-Kole, MN and Boardman, AC and Larizza, IS and Song, MT and Wolfe, ED and Schaefer, DA and Cutler, C and Jim, HS and Lee, SJ and El-Jawahri, A and Amonoo, HL}, title = {A Structured Peer Support Intervention for Patients with Hematologic Malignancies Undergoing Hematopoietic Stem Cell Transplantation: Peer Support Interventionists' Perspectives.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.03.017}, pmid = {40187495}, issn = {2666-6367}, abstract = {BACKGROUND: Peer support is emerging as an important component of supportive care for patients with hematologic malignancies, but it has not been robustly implemented in patients undergoing hematopoietic stem cell transplantation (HSCT).<br><br>OBJECTIVES: This qualitative study aimed to explore the experiences of peer support interventionists (participants) delivering a structured, five-session, phone-delivered peer support intervention, the Supporting Transplant Experiences with Peer Program (STEPP) for patients undergoing HSCT.<br><br>METHODS: Adult patients who underwent allogeneic or autologous HSCT for the treatment of a hematologic malignancy within the past three years were eligible to volunteer in this study as trained STEPP participants. Semi-structured qualitative interviews were conducted to explore participants' experiences, including their motivations for volunteering, reflections on intervention delivery and on the impact of peer support, and challenges faced while serving in this role. Interviews were deductively analyzed by two coders using framework-guided rapid analysis.<br><br>RESULTS: Twenty STEPP interventionists participated in this study. Participants were 65% men, with a median age of 63.5 years. 75% had undergone allogeneic HSCT. Emerging themes from the qualitative interviews highlighted that participants were motivated to serve as interventionists by a sense of gratitude for their transplant care and a desire to share their transplant experiences with others. The impact of the STEPP intervention on interventionists included opportunities to process their transplant journey while also providing support to their peers. Interventionists reported a preference for free-flowing conversations, which were still guided by the structured manual. Challenges included terminating the interventionist-patient relationship at the conclusion of STEPP.<br><br>CONCLUSION: Peer support interventions for patients undergoing HSCT have the potential to enhance well-being and provide meaning for both patients preparing to undergo HSCT and HSCT survivors who serve as interventionists. Large-scale randomized clinical trials are needed to test the efficacy of peer support interventions for improving health-related outcomes among patients undergoing HSCT and HSCT survivors serving as interventionists for these interventions.}, }
@article {pmid40187050, year = {2025}, author = {Rajan, A and Karpac, J}, title = {Inter-organ communication in Drosophila: Lipoproteins, adipokines, and immune-metabolic coordination.}, journal = {Current opinion in cell biology}, volume = {94}, number = {}, pages = {102508}, doi = {10.1016/j.ceb.2025.102508}, pmid = {40187050}, issn = {1879-0410}, abstract = {Inter-organ communication networks are essential for maintaining systemic homeostasis in multicellular organisms. In Drosophila melanogaster, studies of adipokines and lipoproteins reveal evolutionarily conserved mechanisms coordinating metabolism, immunity, and behavior. This mini-review focuses on two key pathways: the adipokine Unpaired 2 (Upd2) and lipoprotein-mediated signaling. Upd2, a leptin analog, mediates fat-brain communication to regulate insulin secretion, sleep, and feeding behavior. Recent work has uncovered an LC3/Atg8-dependent secretion mechanism for Upd2, linking nutrient sensing to systemic adaptation. Lipoproteins, particularly ApoLpp and LTP, function beyond lipid transport, orchestrating neural maintenance and immune responses. During infection, macrophage-derived signals trigger lipoprotein-mediated lipid redistribution to support host defense. Additionally, muscle tissue emerges as an unexpected mediator of immune-metabolic coordination through inter-organ signaling. These findings highlight the intricate cross-talk between organs required for organismal survival and suggest therapeutic strategies for metabolic disorders.}, }
@article {pmid40186724, year = {2025}, author = {Hopkins, T and Bell-Brown, A and Martinez-Pinto, P and Henderson, V and Ko, LK and Isler, A and Issaka, RB}, title = {A Video Decision Aid Decreases Fear of Colonoscopy After an Abnormal Fecal Immunochemical Test Result: A Pilot Study.}, journal = {Journal of cancer education : the official journal of the American Association for Cancer Education}, volume = {}, number = {}, pages = {}, pmid = {40186724}, issn = {1543-0154}, support = {2022 Health Equity Research Award//American College of Gastroenterology/ ; K08CA241296/CA/NCI NIH HHS/United States ; UL1 TR002319/TR/NCATS NIH HHS/United States ; }, abstract = {Colonoscopy completion after abnormal fecal immunochemical test (FIT) results is inadequate, and patient fear is a commonly reported barrier. We developed and piloted a video decision aid that addresses fear of colonoscopy among patients with abnormal FIT results. We developed a video decision aid and, in a pilot study, randomized patients in a safety-net healthcare system with abnormal FIT results and no follow-up colonoscopy to the intervention or usual care. Both groups completed a baseline survey that measured fear of colonoscopy, knowledge about colorectal cancer (CRC), self-efficacy, and intent to complete a colonoscopy, and the intervention group repeated the survey after watching the video. Sixty patients were enrolled in the study. Participants that watched the video reported a 17.7% decrease in fear of colonoscopy (p < 0.01) across six domains, including fear of the bowel prep (p < 0.01), the actual colonoscopy procedure (p < 0.01), and possible complications from the procedure (p = 0.04). Participant CRC knowledge also increased across several measures, including a 43.5% decrease in the belief that it is difficult to know which CRC prevention recommendations to follow. Overall, 78.3% of participants found the video to be helpful, and 90.6% would recommend the video to other patients with abnormal FIT results. In a safety-net population with abnormal FIT results, a video decision aid decreased fear of colonoscopy and increased knowledge about CRC. The video decision aid was acceptable to participants and can be considered an additional tool to improve follow-up of abnormal FIT results.}, }
@article {pmid40186355, year = {2025}, author = {Choe, M and Einav, T and Phillips, R and Titov, DV}, title = {Glycolysis model shows that allostery maintains high ATP and limits accumulation of intermediates.}, journal = {Biophysical journal}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.bpj.2025.03.037}, pmid = {40186355}, issn = {1542-0086}, abstract = {Glycolysis is a conserved metabolic pathway that produces ATP and biosynthetic precursors. It is not well understood how the control of mammalian glycolytic enzymes through allosteric feedback and mass action accomplishes various tasks of ATP homeostasis, such as controlling the rate of ATP production, maintaining high and stable ATP levels, ensuring that ATP hydrolysis generates a net excess of energy, and maintaining glycolytic intermediate concentrations within physiological levels. To investigate these questions, we developed a biophysical model of glycolysis based on enzyme rate equations derived from in vitro kinetic data. This is the first biophysical model of human glycolysis that successfully recapitulates the above tasks of ATP homeostasis and predicts absolute concentrations of glycolytic intermediates and isotope tracing kinetics that align with experimental measurements in human cells. We use the model to show that mass action alone is sufficient to control the ATP production rate and maintain the high energy of ATP hydrolysis. Meanwhile, allosteric regulation of hexokinase (HK) and phosphofructokinase (PFK) by ATP, ADP, inorganic phosphate, and glucose-6-phosphate is required to maintain high ATP levels and to prevent uncontrolled accumulation of phosphorylated intermediates of glycolysis. Allosteric feedback achieves the latter by maintaining HK and PFK enzyme activity at one-half of ATP demand and, thus, inhibiting the reaction of Harden and Young, which otherwise converts glucose to supraphysiological levels of phosphorylated glycolytic intermediates at the expense of ATP. Our methodology provides a roadmap for a quantitative understanding of how metabolic homeostasis emerges from the activities of individual enzymes.}, }
@article {pmid40184567, year = {2025}, author = {Menon, MP and Ddungu, H and Mubiru, KR and Adams, SV and Asea, J and Namagembe, R and Namuli, P and Kambugu, J and Towlerton, AMH and Puronen, C and Uldrick, TS and Orem, J and Warren, EH}, title = {Phase I Study of Subcutaneous Rituximab Hyaluronidase Combined With CHOP Chemotherapy for the Treatment of Diffuse Large B-Cell Lymphoma in Uganda.}, journal = {JCO global oncology}, volume = {11}, number = {}, pages = {e2400489}, doi = {10.1200/GO-24-00489}, pmid = {40184567}, issn = {2687-8941}, mesh = {Humans ; *Rituximab/administration &amp; dosage/therapeutic use/pharmacology ; *Lymphoma, Large B-Cell, Diffuse/drug therapy/pathology/mortality ; Male ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/pharmacology/administration &amp; dosage ; Female ; Adult ; Uganda ; Vincristine/therapeutic use/administration &amp; dosage/pharmacology ; Cyclophosphamide/therapeutic use/administration &amp; dosage/pharmacology ; Doxorubicin/therapeutic use/administration &amp; dosage ; Prednisone/therapeutic use/administration &amp; dosage/pharmacology ; Middle Aged ; *Hyaluronoglucosaminidase/administration &amp; dosage/therapeutic use ; Young Adult ; }, abstract = {PURPOSE: Patients with diffuse large B-cell lymphoma (DLBCL) who are treated in low-resource settings have inferior outcomes compared with those in high-resource settings. Rituximab, an anti-CD20 monoclonal antibody, when combined with chemotherapy, improves overall survival (OS) for DLBCL. However, in part due to the limited availability of infusion centers in low-resource countries, rituximab is rarely used. Subcutaneous rituximab (sqR) is a potential solution; however, its safety and efficacy have not been tested in low-income countries.<br><br>METHODS: This open-label phase I study enrolled patients 18 years or older with newly diagnosed DLBCL. The first cohort (n = 6) received intravenous rituximab plus CHOP. This cohort received sqR for subsequent cycles. The second cohort (n = 12) received sqR plus CHOP for all cycles. Safety and tolerability were evaluated; secondary outcomes included response rates and treatment completion.<br><br>RESULTS: Between October 25, 2019, and October 7, 2022, 18 patients, with a median age of 36.5 years, were enrolled; 10 were male, and 10 presented with advanced-stage disease. The most common hematologic toxicity was neutropenia (n = 9, 50%). Fifteen of the 18 participants completed treatment; 14 (93.3%) patients achieved a complete response, and one patient (6.7%) had a partial response. The OS and progression-free survival (PFS) at 12 months were 83% (95% CI, 68 to 100) and 67% (95% CI, 48 to 92), respectively. The OS and PFS at 24 months were 66% (95% CI, 47 to 92) and 67% (95% CI, 48 to 92), respectively.<br><br>CONCLUSION: As demonstrated in other parts of the world, sqR together with CHOP was safe, well-tolerated, and efficacious among Ugandan patients with DLBCL. The very high OS rates are nearly double those of historical controls and comparable with outcomes expected in resource-rich settings. This study demonstrated the feasibility, safety, and efficacy of sqR-CHOP, increased the research infrastructure in Uganda, and will improve care in other resource-limited settings.}, }
@article {pmid40184428, year = {2025}, author = {Reeves, DB and Litchford, M and Fish, CS and Farrell-Sherman, A and Poindexter, M and Ahmed, N and Cassidy, NAJ and Neary, J and Wamalwa, D and Langat, A and Chebet, D and Moraa, H and Antar, AAR and Slyker, J and Benki-Nugent, S and Cohn, LB and Schiffer, JT and Overbaugh, J and John-Stewart, G and Lehman, DA}, title = {Intact HIV DNA decays in children with and without complete viral load suppression.}, journal = {PLoS pathogens}, volume = {21}, number = {4}, pages = {e1013003}, doi = {10.1371/journal.ppat.1013003}, pmid = {40184428}, issn = {1553-7374}, abstract = {To inform cure in children living with HIV (CWH), we elucidated the dynamics and mechanisms underlying HIV persistence during antiretroviral therapy (ART). In 120 Kenyan CWH who initiated ART between 1-12 months of age, 55 had durable viral load suppression, and 65 experienced ART interruptions. We measured plasma HIV RNA levels, CD4+ T cell count, and levels of intact and defective HIV DNA proviruses via the cross-subtype intact proviral DNA assay (CS-IPDA). By modeling data from the durably suppressed subset, we found that during early ART (year 0-1 on ART), plasma RNA levels decayed rapidly and biphasically and intact and defective HIV DNA decayed with mean 3 and 9 month half-lives, respectively. After viral suppression was achieved (years 1-8 on ART), intact HIV DNA decay slowed to a mean 22 month half-life, whilst defective HIV DNA no longer decayed. In five CWH, we found individual CD4+ TCRβ clones wax and wane, but average kinetics resembled those of defective DNA and CD4 count, suggesting that differential decay of intact HIV DNA arises from selective pressures overlaying normal CD4+ T cell kinetics. Finally, by modeling HIV RNA and DNA in CWH with treatment interruptions, we linked temporary viremia to transient rises in HIV DNA, but long-term intact reservoirs were not strongly influenced, suggesting brief treatment interruptions may not significantly increase HIV reservoirs in children.}, }
@article {pmid40184422, year = {2025}, author = {Nelson, CR and Mallett, DR and Biggins, S}, title = {Spindle integrity is regulated by a phospho-dependent interaction between the Ndc80 and Dam1 kinetochore complexes.}, journal = {PLoS genetics}, volume = {21}, number = {4}, pages = {e1011645}, doi = {10.1371/journal.pgen.1011645}, pmid = {40184422}, issn = {1553-7404}, abstract = {Faithful chromosome segregation depends upon kinetochores, large protein complexes that anchor chromosomes to dynamic microtubules, allowing for their movement at anaphase. Critical microtubule-coupling components of the budding yeast kinetochore, the Dam1 (Dam1c) and Ndc80 (Ndc80c) complexes, work cooperatively to ensure that kinetochores track with the plus-ends of microtubules. Additionally, the Dam1 complex plays a distinct role in ensuring the integrity of the mitotic spindle. However, the events required to orchestrate these diverse functions of Dam1c remain unclear. To identify regulatory events on kinetochores, we performed phosphoproteomics on purified kinetochore proteins and identified many previously unknown phosphorylation events. We demonstrate that Ndc80 is phosphorylated at Thr-248 and Thr-252 to promote the interaction between Ndc80 and the Dam1c. The phosphorylation of T248 is cell cycle regulated and depends on Mps1. Ndc80 phosphorylation at T248 and T252 does not appear to regulate kinetochore function and instead contributes to Dam1c localization to the anaphase spindle. A ndc80 phospho-deficient mutant exhibited a genetic interaction and altered spindle morphology when combined with dam1 mutant alleles. Taken together, we propose that Mps1-dependent phosphorylation of Ndc80 at T248 and T252 is removed at anaphase to allow Dam1c to help organize and stabilize the spindle.}, }
@article {pmid40180499, year = {2025}, author = {Porter, J and Ward, LC and Nguo, K and Davidson, Z and Gibson, S and Prentice, R and Neuhouser, ML and Truby, H}, title = {Investigating the impact of body composition on the estimation of resting metabolic rate: new equations for adults aged ≥65 years developed using cross-sectional data.}, journal = {The American journal of clinical nutrition}, volume = {121}, number = {4}, pages = {795-803}, doi = {10.1016/j.ajcnut.2024.12.023}, pmid = {40180499}, issn = {1938-3207}, mesh = {Humans ; *Basal Metabolism ; *Body Composition ; Aged ; Male ; Female ; Cross-Sectional Studies ; Aged, 80 and over ; }, abstract = {BACKGROUND: Due to changes in body composition during aging, the inclusion of body composition measures as a variable within equations to predict resting metabolic rate (RMR) may improve their predictive accuracy.<br><br>OBJECTIVES: This analysis of cross-sectional data aimed to develop and validate new RMR equations for older adults (&#x2265;65 y) incorporating variables for body composition, to predict performance and accuracy, and to explore the relative contribution of body composition variables acting directly or potentially via fat-free mass (FFM) to RMR.<br><br>METHODS: Analyses were conducted utilizing a unique international dataset of gold standard measures developed for this purpose. RMR was predicted from potential predictive variables using stepwise multiple regression. Predictive performance of the final model was assessed using double cross-validation. The new prediction equation was compared with published prediction equations for similar populations and with previously published RMR prediction equations that did not include FFM. Direct associations between the determined predictor variables and RMR with indirect effects mediated via FFM were examined using mediation final (or pathway) analysis.<br><br>RESULTS: The dataset contained 1238 participants. The predictive equations {utilizing either FFM (Equation 1) or lean body weight [LBW](Equation 2)} follow. Equation 1: RMR = 8.645 &#xd7; height + 23.684 &#xd7; weight - 29.717 &#xd7; age + 38.213 &#xd7; FFM + 209.637 &#xd7; sex + 2693.223; Equation 2: RMR = -30.570 &#xd7; age + 80.736 &#xd7; LBW - 186.825 &#xd7; sex + 3956.822 where RMR (kJ/d); height (cm); weight (kg); age (y); FFM (kg); LBW (kg); sex (M = 1, F = 0). The equation performed similarly to some anthropometric-based prediction equations. Predictors using FFM performed marginally better than those using LBW. All variables had significant (P < 0.001) direct effects upon RMR and significant (P < 0.001) indirect effects for sex, weight, and height.<br><br>CONCLUSIONS: New prediction equations predict RMR at the population level with minimal bias; however, the difference in performance with anthropometry-based equations is minimal. This may be explained by the contribution of FFM to weight, whereby equations that include weight are already accounting for FFM.}, }
@article {pmid40180419, year = {2025}, author = {Arias-Badia, M and Pai, CS and Lwin, YM and Chen, P and Srinath, A and Tanaka, M and Musser, E and Goodearl, A and Gorman, JV and Ritacco, W and Fong, L}, title = {Impact of tumor localization on antitumor immunity with conditionally activated CTLA-4 blockade.}, journal = {Journal for immunotherapy of cancer}, volume = {13}, number = {4}, pages = {}, pmid = {40180419}, issn = {2051-1426}, support = {P30 DK063720/DK/NIDDK NIH HHS/United States ; R35 CA253175/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Mice ; *CTLA-4 Antigen/antagonists &amp; inhibitors ; Humans ; *Immune Checkpoint Inhibitors/pharmacology/therapeutic use ; Male ; Cell Line, Tumor ; *Neoplasms/immunology/drug therapy ; *Immunotherapy/methods ; }, abstract = {BACKGROUND: Immune checkpoint blockade (ICB) can induce antitumor efficacy but also induces immune-related adverse events. Systemically administered ICB can activate immune cells throughout the host. Conditionally active ICB with proteolytically cleaved masking domains can potentially reduce the adverse events seen with anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) antibody.<br><br>METHODS: We examined how different formats of a conditionally activated dual variable domain IgG (DVD) that binds CTLA-4 and the tumor-associated antigen prostate stem cell antigen (PSCA) can lead to efficacy in syngeneic subcutaneous and metastatic murine tumor models. We also defined the capacity of these DVDs to modulate immune responses by multiparameter flow cytometry.<br><br>RESULTS: Conditionally active DVDs can uncouple antitumor efficacy from toxicity. A fully cleavable construct (symmetric DVD, sDVD), which can be released from the target tumor cells, showed superior antitumor efficacy compared with asymmetric DVD, which retains its tumor antigen binding. The sDVD elicited the highest tumor-antigen-specific T-cell responses detected in tumors and tumor-draining lymph nodes, as well as presenting the highest rate of intratumoral and splenic "non-exhausted" antigen-specific CD8 T cells. SDVD also induced the highest degrees of T-cell memory and self-renewal potential. These effects were dependent on PSCA expression by the tumors.<br><br>CONCLUSIONS: These findings support the notion that ICB modulation of antitumor immunity away from the tumor cells is critically important for optimal antitumor immunity. The bispecific sDVD antibody design may enable improved systemic antitumor responses than traditional ICB in both primary tumors and metastases.}, }
@article {pmid40180180, year = {2025}, author = {Diacova, T and Cifelli, CJ and Davis, CD and Holscher, HD and Kable, ME and Lampe, JW and Latulippe, ME and Swanson, KS and Karl, JP}, title = {Best Practices and Considerations for Conducting Research on Diet-Gut Microbiome Interactions and their Impact on Health in Adult Populations: An Umbrella Review.}, journal = {Advances in nutrition (Bethesda, Md.)}, volume = {}, number = {}, pages = {100419}, doi = {10.1016/j.advnut.2025.100419}, pmid = {40180180}, issn = {2156-5376}, abstract = {Diet modulates gut microbiome composition and function. However, determining causal links between diet-gut microbiome interactions and human health is complicated by inconsistencies in the evidence, arising partially from variability in research methods and reporting. Widespread adoption of standardized best practices would advance the field but requires those practices be identified, consolidated and discussed. This umbrella review aimed to identify recommended best practices, define existing gaps, and collate considerations for conducting research on diet-gut microbiome interactions and their impact on human health outcomes. Reviews meeting inclusion criteria and published after 2013 were identified using a systematic search. Recommendations, considerations and gaps relating to best practices associated with study design, participant selection, dietary intervention/assessment, biological sample collection, and data analysis and reporting were extracted and consolidated. Eight narrative reviews were included. Several general points of agreement were identified, and a recurring theme was that best practices are dependent upon the research aims, outcomes and feasibility. Multiple gaps were also identified. Some, such as suboptimal diet assessment methods and lack of validated dietary intake biomarkers, are particularly relevant to nutrition science. Others, including defining a "healthy" gut microbiome and the absence of standardized sample and data collection/analysis protocols were relevant specifically to gut microbiome research. Gaps specific to diet-gut microbiome research include the underrepresentation of microbiome-modulating dietary components in food databases, lack of knowledge regarding interventions eliciting changes in the gut microbiome to confer health benefits, lack of in situ measurement methods and the need to further develop and refine statistical approaches for integrating diet and gut microbiome data. Future research and cross-disciplinary exchange will address these gaps and evolve best practices. In the interim, the best practices and considerations discussed herein, and the publications from which that information was extracted, provide a roadmap for conducting diet-gut microbiome research. PROSPERO registration: CRD42023437645.}, }
@article {pmid40179338, year = {2025}, author = {Wu, M and Russell, K and Shaw, CM and Halpern, AB and Ghiuzeli, C and Appelbaum, JS and Hendrie, P and Walter, RB and Percival, MM}, title = {Predictors of Cardiac Recovery in Adults With AML Who Develop Heart Failure During Treatment.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2400734}, doi = {10.1200/OP-24-00734}, pmid = {40179338}, issn = {2688-1535}, abstract = {PURPOSE: Heart failure is a leading cause of death in patients with AML, who face higher risks of cardiac complications than nonleukemic cancer patients treated with anthracyclines. This study examines factors associated with myocardial dysfunction and recovery occurring during treatment of AML.<br><br>METHODS: We retrospectively analyzed patients with AML who sustained reduced left ventricular ejection fraction (LVEF) during induction therapy at the University of Washington/Fred Hutchinson Cancer Center (2008-2022). Multivariable analysis compared characteristics between patients who eventually recovered LVEF and those who did not, with survival analysis performed by landmark censoring.<br><br>RESULTS: Of 86 patients with AML diagnosed with systolic dysfunction, 41 (48%) failed to recover LVEF. These patients were more frequently male, older than 60 years, had preexisting cardiovascular risk factors, and leukemias of higher risk. Ischemia-related systolic failure was associated with nonrecovery (B = -2.89, P = .005), whereas chemotherapy-related dysfunction was associated with eventual recovery (B = 1.15, P = .014). Frequent use and higher doses of guideline-directed medical therapy (GDMT) were found among patients who recovered LVEF. Failure to recover cardiac function was associated with a greater incidence of cardiac-specific mortality (51% v 23%, P = .042), although impact on overall survival was unclear.<br><br>CONCLUSION: Our retrospective single-center analysis suggests that approximately half of the patients with AML who experience LVEF decline during induction will not recover. Ischemic events during treatment were predictive of nonrecovery. The use of GDMT may improve prognosis for some patients. Given the impact of recovery, we propose the prospective verification and establishment of cardiac management algorithms in patients with AML.}, }
@article {pmid40178906, year = {2025}, author = {Violari, A and Otwombe, K and Hahn, W and Chen, S and Josipovic, D and Baba, V and Angelidou, A and Smolen, KK and Levy, O and Mkhize, NN and Woodward Davis, AS and Martin, TM and Haynes, BF and Williams, WB and Sagawa, ZK and Kublin, JG and Polakowski, L and Brewinski Isaacs, M and Yen, C and Tomaras, G and Corey, L and Janes, H and Gray, GE}, title = {Safety and implementation of phase 1 randomized GLA-SE-adjuvanted CH505TF gp120 HIV vaccine trial in newborns.}, journal = {The Journal of clinical investigation}, volume = {}, number = {}, pages = {}, doi = {10.1172/JCI186927}, pmid = {40178906}, issn = {1558-8238}, abstract = {BACKGROUND: The neonatal immune system is uniquely poised to generate broadly neutralizing antibodies (bnAbs) and thus infants are ideal for evaluating HIV vaccine candidates. We present the design and safety of a new-in-infants glucopyranosyl lipid A (GLA)-stable emulsion (SE) adjuvant admixed with a first-in-infant CH505 transmitter-founder (CH505TF) gp120 immunogen designed to induce precursors for bnAbs against HIV.<br><br>METHODS: HVTN 135 is a phase I randomized, placebo-controlled trial of CH505TF+GLA-SE or placebo. Healthy infants aged &#x2264; 5 days, born to mothers living with HIV but HIV nucleic acid negative at birth were randomized to five doses of CH505TF + GLA-SE or placebo at birth and 8, 16, 32, and 54 weeks.<br><br>RESULTS: 38 infants (median age = 4 days; interquartile range 4, 4.75 days) were enrolled November 2020 to January 2022. Among 28 (10) infants assigned to receive CH505TF + GLA-SE (placebo), most (32/38) completed the 5-dose immunization series and follow-up (35/38). Solicited local and systemic reactions were more frequent in vaccine (8, 28.6% local; 16, 57.1% systemic) vs. placebo recipients (1, 10% local, P = 0.25; 4, 40.0% systemic, P = 0.38). All events were Grade 1 except two Grade 2 events (pain, lethargy). Serious vaccine-related adverse events were not recorded.<br><br>CONCLUSIONS: This study illustrates the feasibility of conducting trials of new-in-infants adjuvanted HIV vaccines in HIV-exposed infants receiving standard infant vaccinations. The safety profile of the CH505TF + GLA-SE vaccine was reassuring.<br><br>CLINICALTRIALS: gov NCT04607408.<br><br>FUNDING: The trial was funded through National Institute of Allergy and Infectious Disease of the National Institutes of Health under grants UM1 AI068614 (HVTN Leadership and Operations Center), UM1 AI068635 (HVTN Statistical and Data Management Center), and UM1 AI068618 (HVTN Laboratory Center).}, }
@article {pmid40176173, year = {2025}, author = {Hu, Y and Haessler, J and Lundin, JI and Darst, BF and Whitsel, EA and Grove, M and Guan, W and Xia, R and Szeto, M and Raffield, LM and Ratliff, S and Wang, Y and Wang, X and Fohner, AE and Lynch, MT and Patel, YM and Lani Park, S and Xu, H and Mitchell, BD and Bis, JC and Sotoodehnia, N and Brody, JA and Psaty, BM and Peloso, GM and Tsai, MY and Rich, SS and Rotter, JI and Smith, JA and Kardia, SLR and Reiner, AP and Lange, L and Fornage, M and Pankow, JS and Graff, M and North, KE and Kooperberg, C and Peters, U}, title = {Methylome-wide association analyses of lipids and modifying effects of behavioral factors in diverse race and ethnicity participants.}, journal = {Clinical epigenetics}, volume = {17}, number = {1}, pages = {54}, pmid = {40176173}, issn = {1868-7083}, support = {N01HC95160/HL/NHLBI NIH HHS/United States ; 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, 75N92021D00005, and S10OD028685/NH/NIH HHS/United States ; 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1TR001881, DK063491, HL148610, and R01HL105756/HL/NHLBI NIH HHS/United States ; R01 HL087652/HL/NHLBI NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; HHSN268201800010I/HB/NHLBI NIH HHS/United States ; N01HC85081/HL/NHLBI NIH HHS/United States ; R01 HL103612/HL/NHLBI NIH HHS/United States ; 75N92020D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; HHSN268201500003C/HL/NHLBI NIH HHS/United States ; U01HG007397/HG/NHGRI NIH HHS/United States ; HHSN268201800012C/HL/NHLBI NIH HHS/United States ; 75N92020D00005/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; U01HL054457, RC1HL100185, R01HL087660, R01HL119443, R01HL133221/HL/NHLBI NIH HHS/United States ; 75N92022D00001/NH/NIH HHS/United States ; N01HC95163/HL/NHLBI NIH HHS/United States ; U01 HL080295/HL/NHLBI NIH HHS/United States ; UL1 TR001079/TR/NCATS NIH HHS/United States ; DK063491//National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center/ ; HHSN268201800014I/HB/NHLBI NIH HHS/United States ; U01CA164973/CA/NCI NIH HHS/United States ; U01 HL130114/HL/NHLBI NIH HHS/United States ; R01 HL087660/HL/NHLBI NIH HHS/United States ; HHSN268200800007C/HL/NHLBI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; 75N92020D00001/HL/NHLBI NIH HHS/United States ; N01HC95169/HL/NHLBI NIH HHS/United States ; N01HC95164/HL/NHLBI NIH HHS/United States ; UL1 TR000124/TR/NCATS NIH HHS/United States ; N01HC55222/HL/NHLBI NIH HHS/United States ; HHSN268201800014C/HL/NHLBI NIH HHS/United States ; N01HC95162/HL/NHLBI NIH HHS/United States ; N01HC85086/HL/NHLBI NIH HHS/United States ; 75N92020D00003/HL/NHLBI NIH HHS/United States ; R01 HL119443/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; N01HC95168/HL/NHLBI NIH HHS/United States ; K08 HL116640/HL/NHLBI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; P30 DK063491/DK/NIDDK NIH HHS/United States ; RC1 HL100185/HL/NHLBI NIH HHS/United States ; HHSN268201200036C/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; HHSN268201800013I/MD/NIMHD NIH HHS/United States ; UL1TR000124/TR/NCATS NIH HHS/United States ; U01 HL054457/HL/NHLBI NIH HHS/United States ; N01HC95165/HL/NHLBI NIH HHS/United States ; N01HC95159/HL/NHLBI NIH HHS/United States ; HHSN268201800012I/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; N01HC95161/HL/NHLBI NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; 75N92020D00004/HL/NHLBI NIH HHS/United States ; HHSN268201800011C/HL/NHLBI NIH HHS/United States ; 75N92020D00007/HL/NHLBI NIH HHS/United States ; R01AG023629/AG/NIA NIH HHS/United States ; HHSN268201800013I, HHSN268201800014I, HHSN268201800015I, HHSN268201800010I, HHSN268201800011I, and HHSN268201800012I/MD/NIMHD NIH HHS/United States ; HHSN268201500003I/HL/NHLBI NIH HHS/United States ; R01HL105756, HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, R01AG023629, 75N92021D00006, U01HL080295, U01HL130114, K08HL116640, R01HL087652, R01HL092111, R01HL103612, R01HL111089, R01HL116747 and R01HL120393/HL/NHLBI NIH HHS/United States ; R01 HL133221/HL/NHLBI NIH HHS/United States ; 75N92021D00006/HL/NHLBI NIH HHS/United States ; R01HG010297/HG/NHGRI NIH HHS/United States ; N01HC85082/HL/NHLBI NIH HHS/United States ; N01HC95167/HL/NHLBI NIH HHS/United States ; N01HC85083/HL/NHLBI NIH HHS/United States ; HHSN268201800015I/HB/NHLBI NIH HHS/United States ; 75N92020D00006/HL/NHLBI NIH HHS/United States ; N01HC85079/HL/NHLBI NIH HHS/United States ; N01HC95166/HL/NHLBI NIH HHS/United States ; R01 AG023629/AG/NIA NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; HHSN268201800011I/HB/NHLBI NIH HHS/United States ; N01HC85080/HL/NHLBI NIH HHS/United States ; R01 HG010297/HG/NHGRI NIH HHS/United States ; U01 CA164973/CA/NCI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; R01 HL111089/HL/NHLBI NIH HHS/United States ; R01 HL116747/HL/NHLBI NIH HHS/United States ; R01 HL092111/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Genome-Wide Association Study/methods ; Female ; Male ; *DNA Methylation/genetics ; Middle Aged ; CpG Islands ; Adult ; Alcohol Drinking/genetics ; *Lipids/blood/genetics ; Ethnicity/genetics ; Racial Groups/genetics ; Smoking/genetics ; White People/genetics ; Aged ; }, abstract = {Circulating lipid concentrations are clinically associated with cardiometabolic diseases. The phenotypic variance explained by identified genetic variants remains limited, highlighting the importance of searching for additional factors beyond genetic sequence variants. DNA methylation has been linked to lipid concentrations in previous studies, although most of the studies harbored moderate sample sizes and exhibited underrepresentation of non-European ancestry populations. In addition, knowledge of nongenetic factors on lipid profiles is extremely limited. In the Population Architecture Using Genomics and Epidemiology (PAGE) Study, we performed methylome-wide association analysis on 9,561 participants from diverse race and ethnicity backgrounds for HDL-c, LDL-c, TC, and TG levels, and also tested interactions between smoking or alcohol intake and methylation in their association with lipid levels. We identified novel CpG sites at 16 loci (P < 1.18E-7) with successful replication on 3,215 participants. One additional novel locus was identified in the self-reported White participants (P = 4.66E-8). Although no additional CpG sites were identified in the genome-wide interaction analysis, 13 reported CpG sites showed significant heterogeneous association across smoking or alcohol intake strata. By mapping novel and reported CpG sites to genes, we identified enriched pathways directly linked to lipid metabolism as well as ones spanning various biological functions. These findings provide new insights into the regulation of lipid concentrations.}, }
@article {pmid40014402, year = {2025}, author = {Arias-Badia, M and Chen, P and Lwin, YM and Srinath, A and Lyu, A and Fan, Z and Kwek, SS and Luong, DN and Setayesh, A and Sakamoto, M and Clark, M and Lea, A and Wolters, RM and Goodearl, A and Harding, FA and Gorman, JV and Ritacco, W and Fong, L}, title = {Sequential JAK inhibition enhances antitumor immunity after combined anti-PD-1 and anti-CTLA4.}, journal = {JCI insight}, volume = {10}, number = {7}, pages = {}, doi = {10.1172/jci.insight.187921}, pmid = {40014402}, issn = {2379-3708}, mesh = {Animals ; Interferon-gamma/metabolism/immunology ; Female ; Humans ; Mice, Inbred C57BL ; Imidazoles/pharmacology ; }, abstract = {While immune checkpoint inhibition (CPI) has reshaped cancer treatment, the majority of patients with cancer do not benefit from this approach, which can also cause immune-related adverse events. Induction of IFN-γ responses is thought be necessary for antitumor immunity, but growing evidence also implicates IFN-γ as a tumor-intrinsic mediator of CPI resistance. CPI-induced IFN-γ mediates activation-induced cell death in T cells as an immune-intrinsic mechanism of resistance. In this study, we found that transient block of IFN-γ signaling through administration of the JAK1 inhibitor ABT-317 enhanced antitumor T cell responses with CPI in preclinical models. Importantly, sequential but not concomitant ABT-317 treatment led to significantly reduced toxicity and improved tumor efficacy. Sequential treatment reduced activation-induced T cell death and enhanced expansion of tumor-reactive T cell subsets with increased effector function in vivo and ex vivo. Only CPI in combination with ABT-317 also enhanced memory responses by protecting mice from tumor rechallenge. These results demonstrate that JAK inhibition within a discrete time window following CPI addresses an immune-intrinsic mechanism of therapeutic resistance.}, }
@article {pmid40175263, year = {2025}, author = {Chari, A and Bal, S and Ailawadhi, S and Krishnan, A and Patel, KK and Berdeja, JG and Garfall, A and Callander, N and Banerjee, R and Alsina, M and Nooka, AK and Dhakal, B and Gasparetto, C and Costello, C}, title = {Expert Perspectives on Current Challenges and Emerging Approaches for Multiple Myeloma: Narrative Review of an Inaugural Bridging the Gaps in Leukemia, Lymphoma, and Multiple Myeloma.}, journal = {Clinical lymphoma, myeloma &amp; leukemia}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.clml.2025.03.008}, pmid = {40175263}, issn = {2152-2669}, abstract = {PURPOSE: The management of multiple myeloma (MM) is becoming increasingly more complex. The approval of novel treatment approaches provides much-needed opportunities but also raises questions and controversies about how to optimally sequence therapies and select treatments for individual patients.<br><br>METHODS AND RESULTS: A panel of experts assembled to discuss current controversies in the care of patients with MM across the disease continuum. Workshop topics included: management of smoldering MM; treatment selection for transplant-eligible and transplant-ineligible patients; risk assessment and the possibility of risk-adapted treatment; use of measurable residual disease (MRD) as a clinical trial end point and to guide treatment decisions; management of early relapse; management of triple class-refractory MM; treatment sequencing; and novel therapies.<br><br>CONCLUSION: Many controversies remain regarding the management of patients with MM related to risk assessment, treatment selection and sequencing, and the optimal use of current therapies while balancing efficacy, toxicity, patient considerations, and treatment logistics. Ongoing research efforts are needed to further define the optimal use of current therapies and to develop more efficacious therapies for all patients and for particular subset populations with unmet need.}, }
@article {pmid40173015, year = {2025}, author = {Russell, ML and Trofimov, A and Bradley, P and Matsen Iv, FA}, title = {Statistical analysis of repertoire data demonstrates the influence of microhomology in V(D)J recombination.}, journal = {Nucleic acids research}, volume = {53}, number = {6}, pages = {}, pmid = {40173015}, issn = {1362-4962}, support = {R01 AI146028/GF/NIH HHS/United States ; //Mahan Fellowship/ ; /HHMI/Howard Hughes Medical Institute/United States ; }, mesh = {*V(D)J Recombination/genetics ; Humans ; High-Throughput Nucleotide Sequencing ; Receptors, Antigen, T-Cell, alpha-beta/genetics ; Animals ; }, abstract = {V(D)J recombination generates the diverse B and T cell receptors essential for recognizing a wide array of antigens. This diversity arises from the combinatorial assembly of V(D)J genes and the junctional deletion and insertion of nucleotides. While previous in vitro studies have shown that microhomology-short stretches of sequence homology between gene ends-can bias the recombination process, the extent of microhomology's impact in vivo, particularly in humans, remains unknown. In this paper, we assess how germline-encoded microhomology influences trimming and ligation during V(D)J recombination using statistical inference on previously published high-throughput TCRα repertoire sequencing data. We find that microhomology increases both trimming and ligation probabilities, making it an important predictor of recombination outcomes. These effects are consistent across other receptor loci and sequence types. Further, we demonstrate that accounting for germline microhomology effects significantly alters sequence annotation probabilities and rankings, highlighting its practical importance for accurately inferring the V(D)J recombination events that generated an observed sequence. Together, these results enhance our understanding of how germline-encoded microhomologous nucleotides shape the human V(D)J recombination process.}, }
@article {pmid40172323, year = {2025}, author = {Milch, HS and Lee, CI}, title = {Establishing the Evidence Needed for AI-driven Mammography Screening.}, journal = {Radiology. Artificial intelligence}, volume = {7}, number = {3}, pages = {e250152}, doi = {10.1148/ryai.250152}, pmid = {40172323}, issn = {2638-6100}, }
@article {pmid40171709, year = {2025}, author = {Nakamura, M and Parkhurst, SM}, title = {Septin complexes: Ahead of the curve.}, journal = {Cytoskeleton (Hoboken, N.J.)}, volume = {82}, number = {4}, pages = {229-233}, pmid = {40171709}, issn = {1949-3592}, support = {R01 GM111635/GM/NIGMS NIH HHS/United States ; }, mesh = {*Septins/metabolism ; Animals ; Actomyosin/metabolism ; Actin Cytoskeleton/metabolism ; Drosophila Proteins/metabolism ; Actins/metabolism ; Drosophila/metabolism ; }, abstract = {Individual cells have robust repair systems to survive cell cortex damage caused by mechanical and chemical stresses, allowing them to maintain the integrity of tissues and organs. The contraction of an actomyosin ring at the wound edge is a major mechanism for physically closing the cell wound. In contrast to polymerization and bundling of actin filaments, little is known about how linear actin filaments are bent to be integrated into the actin ring structure encircling the wound edge. We recently found that the five Drosophila Septins function simultaneously in the regulation of actomyosin ring assembly, contraction, and disassembly during cell wound repair. These Septins form two distinct complexes-Sep1-Sep2-Pnut and Sep4-Sep5-Pnut-composed of different subunits from the same groups. Strikingly, these two distinct Septin complexes have different degrees of F-actin bending activities that are consistent with their spatial recruitment: different degrees of curved actin filaments are required for the robust formation of different regions of the actomyosin ring. In addition, we found that the two Septin complexes are regulated by different molecular pathways as a loss of Anillin only affects Sep1-Sep2-Pnut complex recruitment. These findings open new directions for how individual Septin subunits form complexes and function differentially in cellular and developmental processes.}, }
@article {pmid40170549, year = {2025}, author = {Hoffman, RM and Wolf, AMD and Raoof, S and Guerra, CE and Church, TR and Elkin, EB and Etzioni, RD and Shih, YT and Skates, SJ and Manassaram-Baptiste, D and Smith, RA}, title = {Multicancer early detection testing: Guidance for primary care discussions with patients.}, journal = {Cancer}, volume = {131}, number = {7}, pages = {e35823}, pmid = {40170549}, issn = {1097-0142}, mesh = {Humans ; *Early Detection of Cancer/methods ; *Neoplasms/diagnosis ; *Primary Health Care ; Practice Guidelines as Topic ; }, abstract = {Multicancer early detection (MCED) tests are an emerging technology for cancer screening. MCED tests can detect cancer signals from multiple cancers concurrently in biological samples such as blood, urine, saliva, or other bodily fluids. Some tests can suggest the most likely cancer origin, whereas others report cancer detected somewhere in the body. Although some MCED tests are currently commercially available, none are approved by the Food and Drug Administration or endorsed by any clinical practice guideline or recommendation. Most insurance companies do not currently cover MCED testing. MCED tests have not yet been evaluated for safety and effectiveness in randomized controlled trials. Because patients already are asking for MCED test prescriptions or for interpretation of results from tests acquired elsewhere, clinicians should be prepared to discuss what is known about the benefits, risks, and uncertainties of MCED testing, including performance characteristics in screening populations and preferred follow-up strategies for positive test results. At this time, clinicians should not feel obligated to initiate discussions about MCED testing with their patients. However, clinicians should engage patients who inquire about getting tested or previous MCED test results in shared decision-making, and take the opportunity to offer and help patients complete age- and sex-appropriate guideline-recommended cancer screenings. In this article, the current evidence and issues around MCED testing are summarized, and a framework for shared decision-making discussions is provided.}, }
@article {pmid40170460, year = {2025}, author = {Griffin, SP and Signorelli, J and Raheem, F and Adler, K and Benitez, LL and Cheng, RM and Dotson, E and Fares, M and Ganti, BR and Hickey Zacholski, E and Lasko, AR and Lewallen, AB and Lynch, AC and Paulic, N and Quach, D and Vogel, V and Yacobucci, M and Riebandt, G}, title = {Time to complete oncology pharmacist tasks: A joint opinion of the Hematology/Oncology Pharmacy Association and American College of Clinical Pharmacy's Hematology/Oncology Practice and Research Network.}, journal = {Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners}, volume = {}, number = {}, pages = {10781552251330252}, doi = {10.1177/10781552251330252}, pmid = {40170460}, issn = {1477-092X}, abstract = {PurposeThe time to complete oncology pharmacist tasks is needed to determine workload and productivity. The Hematology/Oncology Pharmacy Association (HOPA) and the Hematology/Oncology Practice and Research Network (PRN) of the American College of Clinical Pharmacy (ACCP) partnered with the aim of establishing consensus on the time required to complete oncology pharmacy tasks.MethodsFifteen patient care tasks and 9 non-patient care tasks, commonly completed by oncology pharmacists were each assigned an average amount of time to be completed. This list was then converted into 24 statements and the Delphi survey method was utilized with an expert panel to arrive at consensus between December 2023 and February 2024. Consensus was defined as at least 75% agreement. The complete manuscript was endorsed by HOPA and ACCP Hematology/Oncology PRN.ResultsThirty-three pharmacist-experts agreed to participate in this survey with all participating in round 1, and 29 (87.9%) participating in round 2. In round 1, 9 tasks achieved consensus, with 7 of these being classified as patient care associated. Seven statements reaching 65% but less than 75% agreement were deemed to reach borderline consensus. Eight statements failed to achieve at least 65% agreement and were modified based on respondent feedback. In round 2, 15 statements were included with all achieving consensus. At the completion of round 2, all 24 statements reached consensus, and the survey was deemed complete.ConclusionThis project produced the first comprehensive consensus statements for the average time for a US-based oncology pharmacist to complete common patient and non-patient care-related tasks.}, }
@article {pmid40169355, year = {2025}, author = {Zhang, X and Perrigue, M and Schenk, JM and Drewnowski, A and Wang, CY and Beatty, SJ and Neuhouser, ML}, title = {Objective and subjective appetite measures: high versus low eating frequency in a randomized crossover clinical trial.}, journal = {Obesity (Silver Spring, Md.)}, volume = {}, number = {}, pages = {}, doi = {10.1002/oby.24265}, pmid = {40169355}, issn = {1930-739X}, support = {K00CA253745/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 DK103674/DK/NIDDK NIH HHS/United States ; }, abstract = {OBJECTIVE: The objective of this study was to examine objective (ghrelin and peptide YY [PYY]) and subjective appetite measures following 21-day high and low eating frequency (EF) interventions among healthy adults.<br><br>METHODS: In the randomized crossover trial (Frequency of Eating and Satiety Hormones [FRESH] study), participants completed two eucaloric 21-day study periods of low (3 meals/day) and high (6 meals/day) EF with a 14-day washout period. Self-selected foods and total energy consumed were identical in both arms. On day 21 of each period, participants completed a 7-h clinic visit with meals provided according to assigned EF. Postprandial plasma ghrelin and PYY concentrations were assessed through serial blood draws (hourly), and self-reported appetite ratings were collected every 30&#x2009;min.<br><br>RESULTS: Fifty participants were recruited and completed the trial (mean age, 32&#x2009;years, 78% women, and 60% non-Hispanic White). High EF resulted in smaller changes in postprandial ghrelin and PYY concentrations compared to low EF, with significant area under the curve differences between groups (p value for ghrelin&#x2009;=&#x2009;0.03; p value for PYY&#x2009;<&#x2009;0.001). Similar patterns were found in self-reported hunger, desire to eat, and fullness. Differences in postprandial PYY were greater among participants with overweight/obesity or high body fat percentage.<br><br>CONCLUSIONS: High EF led to smaller changes in objective and subjective appetite measures, suggesting that small frequent meals may lead to blunted satiety and less optimal appetite regulation.}, }
@article {pmid40167599, year = {2025}, author = {Tanaka, M and Lum, L and Hu, KH and Chaudhary, P and Hughes, S and Ledezma-Soto, C and Samad, B and Superville, D and Ng, K and Chumber, A and Benson, C and Adams, ZN and Kersten, K and Aguilar, OA and Fong, L and Combes, AJ and Krummel, MF and Reeves, MQ}, title = {Tumor cell heterogeneity drives spatial organization of the intratumoral immune response.}, journal = {The Journal of experimental medicine}, volume = {222}, number = {6}, pages = {}, pmid = {40167599}, issn = {1540-9538}, support = {//Five For The Fight/ ; //Cancer League/ ; IRG-21-131-01//American Cancer Society/ ; V2024-002//V Foundation/ ; //University of Texas/ ; //University of California, San Francisco/ ; S10 OD021644/OD/NIH HHS/United States ; //Parker Institute for Cancer Immunotherapy/ ; //Sanford Burnham Prebys/ ; R21 CA264599/CA/NCI NIH HHS/United States ; RR230012//Cancer Prevention and Research Institute of Texas/ ; R21CA264599/CA/NCI NIH HHS/United States ; 1S10OD021644-01A1/NH/NIH HHS/United States ; P30CA040214//Huntsman Cancer Institute Cancer Center/ ; }, mesh = {Animals ; *Tumor Microenvironment/immunology ; Mice ; *T-Lymphocytes/immunology ; Macrophages/immunology/metabolism ; Mice, Inbred C57BL ; Immunotherapy/methods ; Chemokine CX3CL1/metabolism ; Cell Line, Tumor ; Neoplasms/immunology/pathology ; Humans ; }, abstract = {Intratumoral heterogeneity (ITH)-defined as genetic and cellular diversity within a tumor-is linked to failure of immunotherapy and an inferior anti-tumor immune response. We modeled heterogeneous tumors comprised of "hot" and "cold" tumor populations (giving rise to T cell-rich and T cell-poor tumors, respectively) and introduced fluorescent labels to enable precise spatial tracking. We found the cold tumor cell population exerted a "dominant cold" effect in mixed tumors. Strikingly, spatial analysis revealed that the tumor cells themselves created distinct local microenvironments within heterogeneous tumors: regions occupied by cold tumor cells showed pronounced immunosuppression, harboring increased CD206Hi macrophages and diminished local T cell function. This inferior T cell activity in cold regions persisted even after immunotherapy and mechanistically was mediated by CX3CL1 produced by the cold tumor cells. An immune cold tumor population within a heterogeneous tumor thus impairs tumor immunity on both a tumor-wide and a highly localized spatial scale.}, }
@article {pmid40167119, year = {2025}, author = {Sharifi, MN and Sperger, JM and Taylor, AK and Tippins, KE and Reese, SR and Carreno, V and Kaufmann, KR and Chang, AH and Nunamaker, LA and Linebarger, C and Mora-Rodriguez, L and Schehr, JL and Krause, HM and Helzer, KT and Bootsma, ML and Blitzer, GC and Floberg, JM and Kyriakopoulos, CE and Emamekhoo, H and Heath, EI and Wells, M and Tagawa, ST and Sjöström, M and Choudhury, AD and Yu, M and Armstrong, AJ and Rathkopf, DE and Beltran, H and Nelson, PS and Feng, FY and Dehm, SM and Kosoff, D and Wei, XX and McKay, RR and Zhao, SG and Lang, JM}, title = {High-Purity CTC RNA Sequencing Identifies Prostate Cancer Lineage Phenotypes Prognostic for Clinical Outcomes.}, journal = {Cancer discovery}, volume = {}, number = {}, pages = {OF1-OF19}, doi = {10.1158/2159-8290.CD-24-1509}, pmid = {40167119}, issn = {2159-8290}, support = {DP2 OD030734/NH/NIH HHS/United States ; PC190039//Department of Defense/ ; 2024 TACTICAL Award//Prostate Cancer Foundation/ ; PICI//University of Wisconsin Office of the Vice Chancellor for Research and Graduate Education/ ; }, abstract = {Treatment resistance remains a universal driver of lethal metastatic prostate cancer, associated with acquired genomic alterations and lineage transitions. Using a novel high-purity CTC isolation approach for CTC transcriptional profiling, we identified four lineage phenotypes differentially associated with prognosis in metastatic prostate cancer.}, }
@article {pmid40164700, year = {2025}, author = {Feng, EM and Vo-Phamhi, J and Subramanian, AN and Dias, M and Foye, A and Vinson, J and Hong, JC and Freedland, SJ and Alumkal, JJ and Beltran, H and Morrissey, C and Nelson, PS and Chinnaiyan, AM and Aggarwal, R and Small, EJ and Quigley, DA and Sjöström, M and Zhao, SG and Chen, WS}, title = {Racial variation in the advanced prostate cancer genome.}, journal = {Prostate cancer and prostatic diseases}, volume = {}, number = {}, pages = {}, pmid = {40164700}, issn = {1476-5608}, abstract = {BACKGROUND: Racial differences in metastatic castration-resistant prostate cancer (mCRPC) genomes have not yet been fully studied. We aimed to investigate transcriptomic, mutational, and clinical differences by race in a large multi-institutional cohort of men with mCRPC.<br><br>METHODS: Genomic and clinicopathologic data from four mCRPC tumor biopsy cohorts were obtained and aggregated. Gene set enrichment analyses were performed to assess pathway-level differences in gene expression by patient race. DNA alteration frequencies of known prostate cancer driver genes and clinical outcomes were compared across racial groups.<br><br>RESULTS: In our cohort of 445 men with mCRPC, tumors from African American patients (N&#x2009;=&#x2009;26) demonstrated higher expression of MYC pathway genes (FDR q&#x2009;=&#x2009;0.03) and lower expression of IFN-&#x3b3;, IL-6/JAK/STAT3, and inflammatory pathway genes (FDR q&#x2009;<&#x2009;0.001) compared to tumors from European American patients. TMPRSS2:ERG gene fusions were observed more frequently in tumors from European American compared to African American patients (41% vs. 11%, P&#x2009;=&#x2009;0.015). Asian patients (N&#x2009;=&#x2009;9) and other racial groups comprised a small minority of our cohort. No differences in overall survival were noted across racial groups.<br><br>CONCLUSIONS: Despite demonstrating similar clinical outcomes, cancers from African Americans display distinct tumor biology. Specifically, we observed racial differences in expression of prostate cancer driver gene pathways (including potential clinically actionable pathways of IFN-&#x3b3; and JAK/STAT) and DNA alterations, including TMPRSS2:ERG gene fusion. Our findings highlight the importance of racial diversity in future genomic profiling and clinical trials efforts.}, }
@article {pmid40163891, year = {2025}, author = {Shasha, C and Glass, DR and Moelhman, E and Islas, L and Tian, Y and Chour, T and Xu, G and Szeto, GL and Peng, T and Song, X and Wurscher, M and Cowan, AJ and Bumol, TF and Torgerson, TR and Greenberg, PD and Green, DJ and Newell, EW}, title = {Hallmarks of terminal T-cell exhaustion are absent in multiple myeloma from diagnosis through maintenance therapy.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024025655}, pmid = {40163891}, issn = {1528-0020}, abstract = {Dysregulation of the bone marrow (BM) niche in multiple myeloma (MM) alters the composition and state of resident immune cells, potentially impeding anti-tumor immunity. One common mechanism of immune inhibition in solid tumors is the induction of exhaustion in tumor-specific T cells. However, the extent of T cell exhaustion is not well-characterized in MM. As the specific mechanisms of immune evasion are critical for devising effective therapeutic strategies, we deeply profiled the CD8+ T cell compartment of newly-diagnosed MM (NDMM) patients for evidence of T cell activation and exhaustion. We applied single-cell multi-omic sequencing and mass cytometry to longitudinal BM and peripheral blood (PB) samples taken from timepoints spanning from diagnosis through induction therapy, autologous stem cell transplant (ASCT), and maintenance therapy. We identified an exhausted-like population that lacked several canonical exhaustion markers, was not significantly enriched in NDMM patients, and consisted of small, nonpersistent clonotypes. We also observed an activated population with increased frequency in the PB of NDMM patients exhibiting phenotypic and clonal features consistent with homeostatic, cytokine-driven activation. As an orthogonal measurement of T cell exhaustion, we performed intracellular cytokine staining and found NDMM patients lacked functionally exhausted T cells. In summary, there was no evidence of "tumor-experienced" T cells displaying hallmarks of terminal exhaustion and/or antigen-driven activation/expansion in NDMM patients at any timepoint.}, }
@article {pmid40163754, year = {2025}, author = {Zähringer, A and Morgado, I and Erny, D and Ingelfinger, F and Gawron, J and Chatterjee, S and Wenger, V and Schmidt, D and Schwöbel, LF and Adams, RC and Langenbach, M and Hartmann, A and Osswald, N and Wolf, J and Schlunck, G and Briquez, PS and Grueter, K and Ruess, DA and Frew, I and Burk, AC and Holzmüller, V and Grimbacher, B and Michonneau, D and Andrieux, G and Socié, G and Kolter, J and Börries, M and Follo, M and Blaeschke, F and Sevenich, L and Prinz, M and Zeiser, R and Vinnakota, JM}, title = {AhR activation mitigates graft-versus-host disease of the central nervous system by reducing microglial NF-κB signaling.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024015000}, pmid = {40163754}, issn = {2473-9537}, abstract = {Acute Graft-versus-Host Disease (GVHD) that occurs after allogeneic hematopoietic cell transplantation (allo-HCT) can affect the central nervous system (CNS). The majority of allo-HCT patients receive antibiotic treatment, which alters the microbiome and essential microbiome-derived metabolites. We investigated the impact of microbiome modifications on CNS-GVHD and therapeutic strategies to overcome the microbiome-derived metabolite depletion. Antibiotic treatment of mice undergoing allo-HCT increased microglia numbers in the brain, indicating increased inflammation. In addition, microglia morphology shifted towards a highly branched phenotype. Consistent with a pro-inflammatory phenotype microglia exhibited increased NF-κB and Src activity. Antibiotic treatment caused the depletion of the bacteria-derived arylhydrocarbon receptor (AhR) ligand indole-3-acetate in the brain. Conversely, treatment of primary microglia with the AhR-ligand- 6-formylindolo (3, 2-b) carbazole (FICZ) reduced NF-κB activity and phagocytic potential. Microglia expansion and morphological changes were reversed by AhR-ligand-FICZ-treatment. Moreover, the AhR-ligand indole-3-acetate was also reduced in the CNS of patients that developed acute GVHD concomitant with increased microglial NF-κB expression. In summary, we demonstrated that antibiotic treatment and a subsequent decrease of AhR-ligands resulted in increased microglia activation during CNS-GVHD. FICZ-treatment hampered CNS inflammation by inhibiting NF-κB activity, thereby providing a metabolic modifier to interfere with pathogenic microglia signaling and CNS-GVHD in vivo.}, }
@article {pmid40163689, year = {2025}, author = {Punie, K and Kurian, AW and Ntalla, I and Sjekloca, N and Estrin, A and Dabrowski, EC and Lai, C and Hurvitz, S}, title = {Unmet need for previously untreated metastatic triple-negative breast cancer: a real-world study of patients diagnosed from 2011 to 2022 in the United States.}, journal = {The oncologist}, volume = {30}, number = {3}, pages = {}, pmid = {40163689}, issn = {1549-490X}, support = {//Gilead Sciences/ ; }, mesh = {Humans ; *Triple Negative Breast Neoplasms/pathology/mortality/drug therapy/therapy ; Female ; Middle Aged ; Retrospective Studies ; United States/epidemiology ; Aged ; Adult ; Neoplasm Metastasis ; Aged, 80 and over ; }, abstract = {BACKGROUND: This real-world study describes the treatment landscape evolution after targeted therapy approval and associated survival outcomes for previously untreated metastatic triple-negative breast cancer (mTNBC) in the United States.<br><br>PATIENTS AND METHODS: This retrospective analysis used de-identified electronic health record-derived data of patients diagnosed with mTNBC (January 2011-July 2022; index date was first-line [1L] treatment start date). Patient characteristics, treatment patterns, real-world overall survival (rwOS), and time to next treatment or death (TTNTD) were determined. Outcomes before (2011-2017, early cohort) and after (2018-2022, late cohort) targeted therapy approval were evaluated.<br><br>RESULTS: Among 2004 eligible patients, 21% were classified as Black, 13% had Eastern Cooperative Oncology Group performance status &#x2265;2, and 63% were diagnosed with recurrent disease; median age was 60 years. First-line chemotherapy-only (single- and multiple-agent chemotherapy) use decreased with the introduction of targeted therapies from 96% before 2018 to 65% between 2019 and 2022. From 2019, 33% of patients received programmed death-(ligand) 1 inhibitor-based regimen; ~2% received poly (ADP-ribose) polymerase inhibitors. Median 1L treatment duration was 2.6 months and this did not change over time. Of all 1L patients, 34% died before second-line (2L) and 51% subsequently received 2L treatment. Median (95% CI) 1L rwOS and TTNTD were 11.3 (10.7-12.0) months and 4.3 (4.1-4.6) months, respectively. Median 1L 5-year survival [95% CI] showed statistically significant but small improvement from the early (10.9 [10.3-11.6] months) to late cohort (11.9 [10.7-13.1] months; HR [95% CI], 0.87 [0.78-0.96]).<br><br>CONCLUSION: This analysis demonstrated that, despite changes in care over time, survival improvements were not clinically meaningful; thus, a substantial unmet need for more efficacious treatments in previously untreated patients with mTNBC remains.}, }
@article {pmid40163550, year = {2025}, author = {Shinde, P and Willemsen, L and Anderson, M and Aoki, M and Basu, S and Burel, JG and Cheng, P and Ghosh Dastidar, S and Dunleavy, A and Einav, T and Forschmiedt, J and Fourati, S and Garcia, J and Gibson, W and Greenbaum, JA and Guan, L and Guan, W and Gygi, JP and Ha, B and Hou, J and Hsiao, J and Huang, Y and Jansen, R and Kakoty, B and Kang, Z and Kobie, JJ and Kojima, M and Konstorum, A and Lee, J and Lewis, SA and Li, A and Lock, EF and Mahita, J and Mendes, M and Meng, H and Neher, A and Nili, S and Olsen, LR and Orfield, S and Overton, JA and Pai, N and Parker, C and Qian, B and Rasmussen, M and Reyna, J and Richardson, E and Safo, S and Sorenson, J and Srinivasan, A and Thrupp, N and Tippalagama, R and Trevizani, R and Ventz, S and Wang, J and Wu, CC and Ay, F and Grant, B and Kleinstein, SH and Peters, B}, title = {Putting computational models of immunity to the test-An invited challenge to predict B.pertussis vaccination responses.}, journal = {PLoS computational biology}, volume = {21}, number = {3}, pages = {e1012927}, doi = {10.1371/journal.pcbi.1012927}, pmid = {40163550}, issn = {1553-7358}, abstract = {Systems vaccinology studies have been used to build computational models that predict individual vaccine responses and identify the factors contributing to differences in outcome. Comparing such models is challenging due to variability in study designs. To address this, we established a community resource to compare models predicting B. pertussis booster responses and generate experimental data for the explicit purpose of model evaluation. We here describe our second computational prediction challenge using this resource, where we benchmarked 49 algorithms from 53 scientists. We found that the most successful models stood out in their handling of nonlinearities, reducing large feature sets to representative subsets, and advanced data preprocessing. In contrast, we found that models adopted from literature that were developed to predict vaccine antibody responses in other settings performed poorly, reinforcing the need for purpose-built models. Overall, this demonstrates the value of purpose-generated datasets for rigorous and open model evaluations to identify features that improve the reliability and applicability of computational models in vaccine response prediction.}, }
@article {pmid40162984, year = {2025}, author = {Lin, LY and Ferte, T and Chachage, M and Casteano, C and Laumond, G and Schmidt, S and Tahar, O and Carapito, R and Bekker, LG and Churchyard, G and Keefer, M and Moodie, Z and Viegas, E and Geldmacher, C and Lhomme, E and Moog, C}, title = {Deciphering HIV vaccine-induced Antibody response according to ethnicity.}, journal = {AIDS (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.1097/QAD.0000000000004196}, pmid = {40162984}, issn = {1473-5571}, abstract = {OBJECTIVE: One recurrent question is whether an HIV-1 preventive vaccine requires adaptation to geographic and/or ethnicity background. A recent attempt to improve the Thai RV144 vaccine efficacy in South Africa resulted in non-efficacy. The potential reasons for this disappointing outcome are probably multifactorial; the role of ethnicity could not be investigated given the trials' demographics.<br><br>DESIGN: To assess the role of ethnicity in the immune responses induced in HIV vaccine trials, we considered the HVTN 204 vaccine trial, which was conducted in the USA and South Africa.<br><br>METHODS: Univariate and multivariate analysis of antibody responses were conducted to assess ethnicity, geographic location, Fc-receptor polymorphism, sex at birth, age and geographic location.<br><br>RESULTS: We found that Black South Africans displayed higher total Immunoglobulins compared to White Americans. Noteworthy, Black South Africans showed lower HIV-specific binding IgG following vaccination. As they also showed lower background at baseline, differences between ethnic groups were narrowed after baseline background subtraction, referred to as delta values for the vaccine response outcome.<br><br>CONCLUSIONS: The observed modifications of HIV-specific Ab immune responses to the HVTN 204 vaccine according to genetic, geographic location and ethnic background warrants further investigation. Additional studies of immunological differences, especially with vaccine platforms inducing high HIV-specific antibodies that correlate with vaccine efficacy may help decipher the impact of ethnicity on HIV-vaccine efficacy.}, }
@article {pmid40162676, year = {2025}, author = {Wang, HH and Ono, Y and Paulson, TG and Grady, WM and Odze, RD}, title = {Gastric (Foveolar) Dysplasia in Barrett's Esophagus: A Clinical, Molecular and Long-Term Outcome Study.}, journal = {The American journal of gastroenterology}, volume = {}, number = {}, pages = {}, doi = {10.14309/ajg.0000000000003450}, pmid = {40162676}, issn = {1572-0241}, abstract = {BACKGROUND AND AIMS: The aim of this long-term progression study was to evaluate the clinical and pathologic features of gastric type dysplasia in Barrett's esophagus (BE).<br><br>METHODS: Baseline biopsies from 208 BE patients from the Seattle prospective cohort were evaluated for the type and grade of dysplasia (gastric or intestinal). Twenty-seven patients progressed to cancer and 181 did not over the long term follow up period. Patients with gastric or intestinal dysplasia were compared to each other with regard to their flow cytometric DNA content abnormalities and progression rates to cancer.<br><br>RESULTS: Of the 59 patients with dysplasia at baseline, 12 (20%) had gastric dysplasia only, 24 (41%) had mixed gastric and intestinal dysplasia, and 23 (39%) had intestinal dysplasia only. Patients with any gastric dysplasia component (alone or mixed with intestinal dysplasia) showed a significantly higher rate of high-grade dysplasia (72% vs 23%, P < 0.001) at baseline and cancer development (47% versus 22%, P = 0.05), and a significantly shorter time frame to cancer development (32 versus 64 months, P = 0.008), as well as a longer BE segment length (P = 0.05), and higher rate of aneuploidy (P = 0.04), compared to patients with pure intestinal dysplasia. By multivariable analysis, gastric dysplasia showed a higher hazard ratio of progression to cancer compared to intestinal dysplasia patients.<br><br>CONCLUSION: Gastric type dysplasia is common in BE. Our study suggests that this type of dysplasia may represent a more aggressive form of neoplastic precursor than conventional intestinal type dysplasia.}, }
@article {pmid40162240, year = {2025}, author = {Paredes, MI and Liang, C and Suen, SC and Holloway, IW and Garrigues, JM and Green, NM and Bedford, T and Müller, NF and Osmundson, J}, title = {Viral introductions and return to baseline sexual behaviors maintain low-level mpox incidence in Los Angeles County, USA, 2023-2024.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40162240}, support = {R35 GM119774/GM/NIGMS NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; U01 CK000357/CK/NCEZID CDC HHS/United States ; }, abstract = {In 2022, mpox clade llb disseminated around the world, causing outbreaks in more than 117 countries. Despite the decay of the 2022 epidemic and the expected accumulation of immunity within queer sexual networks, mpox continues to persist at low incidence in North America without extinction, raising concerns of future outbreaks. We combined phylodynamic inference and microsimulation modeling to understand the heterogeneous dynamics governing local mpox persistence in Los Angeles County (LAC) from 2023-2024. Our Bayesian phylodynamic analysis revealed a time-varying pattern of viral importations into the county that seeded a heavy-tailed distribution of mpox outbreak clusters that display a "stuttering chains" dynamic. Our phylodynamics-informed microsimulation model demonstrated that the persistent number of mpox cases in LAC can be explained by a combination of waves of viral introductions and a return to near-baseline sexual behaviors that were altered during the 2022 epidemic. Finally, our counterfactual scenario modeling showed that public health interventions that either promote increased isolation of symptomatic, infectious individuals or enact behavior-modifying campaigns during the periods with the highest viral importation intensity are both actionable and effective at curbing mpox cases. Our work highlights the heterogeneous factors that maintain present-day mpox dynamics in a large, urban US county and describes how to leverage these results to design timely and community-centered public health interventions.}, }
@article {pmid40161767, year = {2025}, author = {Vinueza, JL and Salisbury, NJH and Dye, KN and Roman, A and Galloway, DA}, title = {Delta-catenin is required for cell proliferation in virus positive Merkel cell carcinoma cell lines but not in human fibroblasts.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40161767}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R35 CA209979/CA/NCI NIH HHS/United States ; T32 AI083203/AI/NIAID NIH HHS/United States ; }, abstract = {Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer often driven by the integration of Merkel cell polyomavirus (MCPyV) into the host genome and the persistent expression of its viral oncoproteins, small tumor (ST) antigen and truncated large tumor (t-LT) antigen. While human fibroblasts support MCPyV replication, the cell of origin for MCC remains unknown. We hypothesized that MCPyV initially replicates in fibroblasts but, in rare cases, infects Merkel cell progenitors, contributing to MCC development. Using TurboID mass spectrometry, we identified δ-catenin as a novel ST interactor in fibroblasts. However, while ST binds δ-catenin in fibroblasts, this interaction is absent in virus-positive (VP)-MCC cell lines. Despite this, δ-catenin is essential for VP-MCC, but not for fibroblast, cell proliferation. We found that fibroblasts predominantly express δ-catenin isoform 1, whereas VP-MCC cells mainly express isoform 3. Overexpression of isoform 1 in VP-MCC failed to restore ST binding. δ-catenin promotes VP-MCC proliferation by regulating cell cycle gene expression through its interaction with Kaiso, a transcriptional repressor. Additionally, we found that LSD1 (KDM1A) regulates δ-catenin isoform 3 expression by modulating ESRP1, a δ-catenin splicing factor. Our findings reveal novel host factors involved in MCPyV infection and MCC tumorigenesis, suggesting that the host cell supporting viral replication and the MCC cell of origin may be distinct cell types.}, }
@article {pmid40161544, year = {2025}, author = {Safyan, RA and Zhang, K and Apisarnthanarax, S and Sham, JG and Pillarisetty, VG and Kugel, S and Dubard-Gault, M and Pritchard, CC and Konnick, EQ and Sahani, D and Chiorean, EG}, title = {Long-Term Survival Following Chemoradiation in Locoregional Recurrent Germline ATM Mutated Pancreatic Ductal Adenocarcinoma.}, journal = {Advances in radiation oncology}, volume = {10}, number = {4}, pages = {101742}, pmid = {40161544}, issn = {2452-1094}, }
@article {pmid40161439, year = {2025}, author = {Andrade Latino, A and Biggins, S}, title = {Analysis of a cancer-associated mutation in the budding yeast Nuf2 kinetochore protein.}, journal = {microPublication biology}, volume = {2025}, number = {}, pages = {}, pmid = {40161439}, issn = {2578-9430}, abstract = {The kinetochore is a highly conserved megadalton protein complex that ensures proper chromosome segregation via microtubule attachments. The NDC80 complex is one of the major conserved microtubule binding complexes in the kinetochore. NUF2, a protein within the NDC80 complex, has been identified as a cancer gene candidate because missense mutations, found across different tumor samples, cluster within NUF2's calponin homology domain. In this study, we examined a NUF2 cancer-associated mutation in a simple and well-studied organism, Saccharomyces cerevisiae , to elucidate its effects on cell division. We studied the budding yeast nuf2 [Q21A] mutation with the intention of extrapolating our results to the homologous cancer associated mutation in Homo sapiens NUF2 [R19H] (HsNUF2 [R19H]). Our studies demonstrate that the nuf2 [Q21A] mutant does not exhibit any growth defects or disrupt kinetochore composition. Additionally, it does not affect the Ndc80 complex's interactions with the Dam1 complex or with the Mps1 kinase. These results indicate that the yeast nuf2 [Q21A] mutant does not cause a significant defect in kinetochore function, and that the role of HsNUF2 [R19H] in cancer will need to be further investigated by directly studying the cancer-associated mutation in human cells.}, }
@article {pmid39808161, year = {2025}, author = {Parada, H and Agalliu, I and Sotres-Alvarez, D and Olshan, AF and Evenson, KR and Rohan, TE and Kaplan, RC and Thompson, CA and Gallo, LC and Penedo, FJ and Cai, J and Wassertheil-Smoller, S and Thyagarajan, B and Thomas, SN and Garcia-Bedoya, OL and Daviglus, ML and Talavera, GA}, title = {Cancer Incidence in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)-The Onco-SOL Ancillary Study.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {34}, number = {4}, pages = {491-499}, doi = {10.1158/1055-9965.EPI-24-1325}, pmid = {39808161}, issn = {1538-7755}, support = {P30 AG059299/AG/NIA NIH HHS/United States ; U54 CA285115/CA/NCI NIH HHS/United States ; U54 CA285117/CA/NCI NIH HHS/United States ; U54 MD012397/MD/NIMHD NIH HHS/United States ; K01 CA234317/CA/NCI NIH HHS/United States ; U54 MD012397/MD/NIMHD NIH HHS/United States ; U54 CA285117/CA/NCI NIH HHS/United States ; P30 AG059299/AG/NIA NIH HHS/United States ; BCRF-23-140//Breast Cancer Research Foundation (BCRF)/ ; U01 CA259208/CA/NCI NIH HHS/United States ; 5R01 CA227122//National Cancer Institute (NCI)/ ; N01-HC65233//National Heart, Lung, and Blood Institute (NHLBI)/ ; }, mesh = {Humans ; Female ; Male ; *Hispanic or Latino/statistics &amp; numerical data ; Incidence ; *Neoplasms/epidemiology/ethnology ; Middle Aged ; Adult ; Aged ; United States/epidemiology ; Cohort Studies ; Registries ; White ; }, abstract = {BACKGROUND: Few studies have examined how cancer incidence varies by the country of origin among US Hispanic/Latino adults. In this study, we describe the incidence rates (IR) of cancer overall and for screen-detectable, tobacco-related, and obesity-related cancers among 16,415 participants in the Hispanic Community Health Study/Study of Latinos, an ongoing population-based cohort study of Hispanic/Latino adults from diverse backgrounds.<br><br>METHODS: Cohort participant records were linked to the state cancer registries in New York, Florida, California, and Illinois to ascertain cancer incidence from baseline (2008-2011) through 2021. We estimated weighted age-adjusted IRs and age- and sex-adjusted HRs.<br><br>RESULTS: Over a mean follow-up of 10.7 (SD = 2.0) years, 715 incident invasive cancers were diagnosed including 118 female breast, 102 prostate, and 79 bronchus and lung cancers. The IR of all cancers combined was 26.2 [95% confidence interval (CI), 22.6-30.2] per 10,000 (10K) person-years (py). The IRs were lowest among persons of Mexican descent [IR, 19.0 (95% CI, 15.0-24.1) per 10K py] and highest for those of Puerto Rican [IR, 36.6 (95% CI, 28.4-47.0) per 10K py] descent. Compared with those of Mexican descent, those of Puerto Rican, Cuban, and Dominican descent had higher hazards of cancer incidence; the incidence of obesity-related (HR, 2.37; 95% CI, 1.43-3.95) and tobacco-related (HR, 3.00; 95% CI, 1.58-5.71) cancers was also the highest among Puerto Ricans.<br><br>CONCLUSIONS: Cancer IRs varied by Hispanic/Latino heritage and were masked when Hispanics/Latinos were aggregated into a single group.<br><br>IMPACT: Understanding disparities in cancer risk by Hispanic/Latino heritage may help tailor cancer prevention and control strategies.}, }
@article {pmid40160342, year = {2025}, author = {Haas, AL and Ma, A and Pham, J and Verma, P and Malhotra, U and Church, EC and Narita, M and Escuyer, V and Shakir, SM}, title = {Limitations of the MTB/RIF Assay: An Xpert Review of 4 Clinical Cases.}, journal = {Open forum infectious diseases}, volume = {12}, number = {4}, pages = {ofaf132}, pmid = {40160342}, issn = {2328-8957}, abstract = {Current U.S. Centers for Disease Control and Prevention tuberculosis (TB) guidelines recommend molecular testing for initial diagnosis of TB and detection of rifampin resistance to expedite initiation of proper treatment. The Cepheid Xpert MTB/RIF assay can detect members of the Mycobacterium tuberculosis complex and rifampin resistance by evaluating for mutations in the rpoB gene. However, false-positive and false-negative detection of M tuberculosis and rifampin resistance results can lead to incorrect treatment of patients, including overuse of second-line anti-TB drugs, and may result in patient harm and increased healthcare cost. We present a series of 4 cases to demonstrate the limitations of the Xpert MTB/RIF assay in the diagnosis of TB, emphasizing the importance of follow-up confirmatory testing and laboratory oversight in reporting accurate results.}, }
@article {pmid40159249, year = {2025}, author = {Fest, SN and Farland, LV and Doody, DR and Eliassen, AH and Rosner, BA and Fung, TT and Hankinson, SE and Kensler, TW and Willett, WC and Harris, HR}, title = {Hormone-associated dietary patterns and premenopausal breast cancer risk.}, journal = {Breast cancer research and treatment}, volume = {}, number = {}, pages = {}, pmid = {40159249}, issn = {1573-7217}, support = {U01 CA176726/NH/NIH HHS/United States ; R01 CA67262/NH/NIH HHS/United States ; U01 CA176726/NH/NIH HHS/United States ; }, abstract = {PURPOSE: Circulating levels of sex steroid hormones have previously been associated with premenopausal breast cancer risk. Few studies have considered the association between dietary patterns and premenopausal hormone levels. Our objective was to derive dietary patterns associated with premenopausal hormone levels and investigate the association between pattern scores and premenopausal breast cancer risk.<br><br>METHODS: Using reduced rank regression among a subset of participants from the Nurses' Health Study II (NHSII) (n&#x2009;=&#x2009;8,962), we identified dietary patterns correlated with premenopausal levels of five sex steroid hormones measured in the follicular and luteal phases. Then, in the full NHSII cohort (n&#x2009;=&#x2009;90,341), we used Cox proportional hazards models to calculate hazard ratios (HRs) for breast cancer risk associated with each dietary pattern score.<br><br>RESULTS: Dietary patterns were identified for luteal estradiol, luteal&#xa0;free estradiol, follicular estrone, luteal estrone, and free testosterone. However, these patterns explained a low percent variation in individual hormone levels, ranging from 2.5-4.1%. During 24&#xa0;years of follow-up, 1,956 premenopausal breast cancer&#xa0;cases were ascertained. Dietary patterns associated with luteal&#xa0;free estradiol (HR for fifth versus first quintile&#x2009;=&#x2009;1.29; 95% CI&#x2009;=&#x2009;1.11-1.49; Ptrend&#x2009;<&#x2009;0.01) and follicular estrone (HR for fifth versus first quintile&#x2009;=&#x2009;1.28; 95% CI&#x2009;=&#x2009;1.10-1.49; Ptrend&#x2009;<&#x2009;0.01) were positively associated with premenopausal breast cancer risk.<br><br>CONCLUSION: Our findings indicate that while some dietary factors may marginally influence premenopausal hormone levels, the relation between sex steroid hormones and premenopausal breast cancer risk is likely not driven by diet. Future studies should consider other mechanisms through which diet may impact breast cancer risk, including inflammatory processes.}, }
@article {pmid40155649, year = {2025}, author = {Dong, S and Banerjee, R and Khan, AM and Wang, M and Wang, X and Afghahi, A and Afrough, A and Janakiram, M and Wang, B and Cowan, AJ and Sperling, AS and Anderson, LD and Rajkumar, SV and Kaur, G}, title = {Carfilzomib prescribing patterns and outcomes for relapsed or refractory multiple myeloma: a real-world analysis.}, journal = {Blood cancer journal}, volume = {15}, number = {1}, pages = {48}, pmid = {40155649}, issn = {2044-5385}, mesh = {Humans ; *Multiple Myeloma/drug therapy/mortality ; *Oligopeptides/therapeutic use/administration &amp; dosage/adverse effects ; Male ; Female ; Aged ; Middle Aged ; Aged, 80 and over ; Practice Patterns, Physicians' ; Treatment Outcome ; Neoplasm Recurrence, Local/drug therapy ; Adult ; Drug Resistance, Neoplasm ; }, abstract = {Despite the widespread use of carfilzomib (K) in relapsed/refractory multiple myeloma (RRMM), there is no consensus on optimal K dose in milligrams per square meter (mg/m2) or dosing schedule. We assessed three modern K prescribing patterns in RRMM using a large United States electronic health record-derived database. Our final cohort (n = 486) included 136 patients (28.0%) who received K 56 mg/m2 once weekly (K56-1x), 86 (17.7%) who received 56 mg/m2 twice weekly (K56-2x), and 264 (54.3%) who received 70 mg/m2 once weekly (K70-1x). Between 2016 and 2023, once-weekly dosing became more common: K70-1x proportions changed from 21.1% in 2016 to 50.6% in 2023, K56-1x from 15.8% to 37.0%, and K56-2x from 63.2% to 12.3%. Median progression-free survival was 13.0 months [95% confidence interval (CI) 11.2-20.7] for K56-1x, 13.2 months (95% CI 9.0-28.1 months) for K56-2x, and 10.9 months (95% CI 9.9-15.3 months) for K70-1x; these differences were not statistically significant (log-rank p = 0.46). Rates of heart failure was comparable (<5% in all cohorts). In summary, our findings do not support improved outcomes with twice-weekly carfilzomib in RRMM. K56-1x may provide the best balance of efficacy, safety, and avoidance of time toxicity from frequent infusions.}, }
@article {pmid40155326, year = {2025}, author = {Saeed, A and Colby, S and Oberstein, PE and Duda, DG and Park, R and Agarwal, R and Figueroa-Moseley, C and Vaidya, R and Unger, JM and Guthrie, KA and Rocha, FG and Senthil, M and Safyan, RA and Wainberg, ZA and Iqbal, S and Chiorean, EG and Philip, PA}, title = {S2303: phase II/III trial of paclitaxel + ramucirumab ± nivolumab in gastric and esophageal adenocarcinoma (PARAMUNE).}, journal = {Future oncology (London, England)}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/14796694.2025.2485020}, pmid = {40155326}, issn = {1744-8301}, abstract = {NCT06203600.}, }
@article {pmid40154445, year = {2025}, author = {Pierce, AL and Okcu, I and Nowakowski, G and Tolu, S and Amengual, J and Ross, C and Graber, J and Bock, A and Hu, B and Ermann, D}, title = {HSR25-185: A Multicenter Retrospective Study of Treatment and Survival Outcomes of Patients With Secondary CNS Relapsed DLBCL in the Modern Era.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {23}, number = {3.5}, pages = {}, doi = {10.6004/jnccn.2024.7347}, pmid = {40154445}, issn = {1540-1413}, }
@article {pmid40153499, year = {2025}, author = {Page, CK and Shepard, JD and Ray, SD and Ferguson, JA and Rodriguez, AJ and Han, J and Jacob, JC and Rowe-Haas, DK and Akinpelu, JY and Friedman, LM and Hertz, T and Ward, AB and Tompkins, SM}, title = {Neuraminidase-specific antibodies drive differential cross-protection between contemporary FLUBV lineages.}, journal = {Science advances}, volume = {11}, number = {13}, pages = {eadu3344}, pmid = {40153499}, issn = {2375-2548}, mesh = {*Neuraminidase/immunology ; Animals ; *Cross Protection/immunology ; *Antibodies, Viral/immunology ; *Influenza B virus/immunology ; Orthomyxoviridae Infections/immunology/virology ; Humans ; Mice ; Influenza Vaccines/immunology ; Cross Reactions/immunology ; Influenza, Human/immunology/prevention &amp; control/virology ; }, abstract = {The two influenza B virus (FLUBV) lineages have continuously diverged from each other since the 1980s, with recent (post-2015) viruses exhibiting accelerated evolutionary rates. Emerging data from human studies and epidemiological models suggest that increased divergence in contemporary viruses may drive differential cross-protection, where infection with Yamagata lineage viruses provides limited immunity against Victoria lineage viruses. Here, we developed animal models to investigate the mechanisms behind asymmetric cross-protection between contemporary FLUBV lineages. Our results show that contemporary Victoria immunity provides robust cross-protection against the Yamagata lineage, whereas Yamagata immunity offers limited protection against the Victoria lineage. This differential cross-protection is driven by Victoria-elicited neuraminidase (NA)-specific antibodies, which show cross-lineage reactivity, unlike those from Yamagata infections. These findings identify a phenomenon in contemporary FLUBV that may help explain the recent disappearance of the Yamagata lineage from circulation, highlighting the crucial role of targeting NA in vaccination strategies to enhance cross-lineage FLUBV protection.}, }
@article {pmid40153422, year = {2025}, author = {Smibert, OC and Vogrin, S and Sinclair, M and Majumdar, A and Nasra, M and Pandey, D and Jahanabadi, H and Trubiano, JA and Markey, KA and Slavin, MA and Testro, A and Kwong, JC}, title = {Antibiotic Exposure and Risk of Allograft Rejection and Survival After Liver Transplant: An Observational Cohort Study From a Tertiary Referral Centre.}, journal = {Transplant infectious disease : an official journal of the Transplantation Society}, volume = {}, number = {}, pages = {e70026}, doi = {10.1111/tid.70026}, pmid = {40153422}, issn = {1399-3062}, support = {1191571//National Health and Medical Research Council/ ; #1173791//National Health and Medical Research Council Leadership Investigator/ ; }, abstract = {INTRODUCTION: Our goal is to understand whether there is an association between Abx exposure-and the inferred downstream damage to the intestinal microbiome-and the key patient outcomes of overall survival and rejection following liver transplant.<br><br>METHODS: We conducted a retrospective cohort study of 462 liver transplant recipients treated at a multistate liver transplant (LTx) service during a 7-year period. The association between antibiotic exposure and outcome was tested across models that addressed antibiotic spectrum, duration, and timing relative to transplant. Cox proportional hazard regression was used to evaluate the relationship between antibiotics with survival and rejection.<br><br>RESULTS: The observed 1-year survival in this cohort was 95% (95% CI: 93%, 97%), and 20.8% of patients (96/462) experienced rejection at 1&#xa0;year. In multivariable analyses, exposure to anaerobe-targeting antibiotics for longer than 14&#xa0;days pretransplant (p&#xa0;=&#xa0;0.055) or posttransplant (p&#xa0;=&#xa0;0.040) was significantly associated with reduced 1-year survival. In multivariable analyses, exposure to any anaerobe-targeting Abx posttransplant was significantly associated with an increased risk of rejection (p&#xa0;=&#xa0;0.001).<br><br>CONCLUSIONS: Exposure to anaerobic spectrum antibiotics either before or after LTx was associated with poor outcomes during the first year posttransplant and provides an impetus to further characterize the relationship between antibiotic use, microbiota disruption, and cellular immunity in liver transplantation.}, }
@article {pmid40153356, year = {2025}, author = {Suger, AH and Chen, H and Haas, CB and Fan, S and Scott, CG and Bolla, MK and Dennis, J and Dunning, AM and Michailidou, K and Wang, Q and Fasching, PA and Haeberle, L and Stone, J and Gago-Dominguez, M and Castelao, JE and Murphy, RA and Aronson, K and Couch, FJ and Yadav, S and Milne, RL and Hopper, JL and Norman, A and Eliassen, AH and Tapper, WJ and Eccles, DM and Evans, DG and Astley, S and Hall, P and Czene, K and Pharoah, PDP and Antoniou, AC and García-Closas, M and Berrington, A and Easton, DF and Gierach, GL and Tamimi, RM and Vachon, CM and Lindström, S and Harrison, TA}, title = {Interactions Between Genetic and Epidemiological Factors Influencing Mammographic Density.}, journal = {American journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/aje/kwaf067}, pmid = {40153356}, issn = {1476-6256}, abstract = {Studies have identified genetic and epidemiological factors associated with mammographic density (MD) phenotypes. However, MD-associated genetic variants only account for a small proportion of the total estimated heritability. Interrogating interactions between genetic and epidemiological factors could potentially identify additional MD-associated loci, expand our understanding of the genetic basis of MD phenotypes, and clarify how epidemiological factors modulate relationships between genetic variants and MD. We conducted six separate genome-wide, gene-environment (GxE) interaction analyses, applying 2 degrees of freedom (df) and 1df interaction tests, for each of three MD phenotypes (percent density (PD), dense area (DA), and non-dense area (NDA)). The six epidemiological factors considered were height, ever parous, parity, ever menopausal hormone therapy (MHT), ever breastfeeding, and months of breastfeeding. We included European ancestry participants from multiple studies within the Markers of Density (MODE) consortium and the Breast Cancer Association Consortium (BCAC) (n = 4,895 - 16,218 depending on specific analyses). We identified 11 loci with genome-wide significant (P < 5 × 10-8) interaction tests including two novel common genetic signals interacting with parity (8p21.2) and ever breastfeeding (19p13.2) for NDA. Our results suggest that epidemiological risk factors might influence relationships between common genetic variants and MD phenotypes at particular genomic loci.}, }
@article {pmid39589272, year = {2025}, author = {Han, YY and Chen, W and Forno, E and Perreira, KM and Oren, E and Daviglus, M and Garcia-Bedoya, O and Kaplan, R and Isasi, CR and Celedón, JC}, title = {Sociocultural Stressors and Asthma among Adults in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).}, journal = {Annals of the American Thoracic Society}, volume = {22}, number = {4}, pages = {549-559}, doi = {10.1513/AnnalsATS.202407-705OC}, pmid = {39589272}, issn = {2325-6621}, support = {R01 HL152475/HL/NHLBI NIH HHS/United States ; R01 HL168539/HL/NHLBI NIH HHS/United States ; HL152475//National Heart, Lung, and Blood Institute (National Heart, Lung, and Blood Institute)/United States ; HL168539//National Heart, Lung, and Blood Institute (National Heart, Lung, and Blood Institute)/United States ; }, mesh = {Humans ; *Asthma/ethnology/psychology/epidemiology ; Adult ; *Hispanic or Latino/psychology/statistics &amp; numerical data ; Male ; Female ; Middle Aged ; *Stress, Psychological/ethnology ; Cross-Sectional Studies ; Young Adult ; United States/epidemiology ; Aged ; Adolescent ; Acculturation ; Logistic Models ; Residence Characteristics ; Depression/ethnology/epidemiology ; Anxiety/ethnology/epidemiology ; Multivariate Analysis ; White ; }, abstract = {Rationale: Hispanic/Latino adults commonly experience high psychosocial stress; yet, little is known about the pathways linking sociocultural stressors and asthma in this population. Objectives: To study whether and how sociocultural stressors are associated with asthma in Hispanic/Latino adults. Methods: We conducted a cross-sectional study of 4,759 adults aged 18 to 74 years who participated in the Sociocultural Ancillary Study of the Hispanic Community Health Study/Study of Latinos. All participants completed a sociocultural assessment, including acculturative stress, perceived ethnic discrimination, neighborhood problems, neighborhood social cohesion, and a cumulative measure of all sociocultural stressors. Weighted multivariable logistic regression accounting for sampling design was used for the analysis of sociocultural stressors and current asthma or current asthma symptoms. A mediation analysis was conducted to estimate the contributions of depressive symptoms and anxiety to the cumulative sociocultural stressors-asthma association. Results: Acculturative stress and neighborhood problems were associated with 1.4 to 2.1 times higher odds of current asthma or current asthma symptoms, and perceived ethnic discrimination was associated with 1.4 times higher odds of current asthma symptoms. Neighborhood social cohesion was associated with 0.6 times lower odds of asthma. Cumulative sociocultural stressors were associated with 1.6 times higher odds of current asthma symptoms (odds ratio for below the median versus greater than or equal to the median value, 1.60; 95% confidence interval, 1.29, 1.99). Depressive symptoms and anxiety explained 26% and 22%, respectively, of the association between cumulative sociocultural stressors and asthma symptoms. Conclusions: Among Hispanic/Latino adults, sociocultural stressors were associated with current asthma or asthma symptoms. Depressive symptoms and anxiety partly mediated this association. Clinicians caring for Hispanic/Latino adults with asthma should be aware of potential stressors and comorbidities such as depression and anxiety.}, }
@article {pmid40152978, year = {2025}, author = {Orenduff, MC and Pieper, CF and Allott, EH and Coleman, MF and Jung, SY and Vitolins, MZ and Fenton, JI and Chen, C and Kroenke, CH and Tabung, FK and Barac, A and Paskett, ED and Pollak, MN and Hays-Grudo, J and Chang, S and Hursting, SD}, title = {Plasma Insulin-Like Growth Factor Binding Protein-7 is Positively Associated with Age, Obesity, Mortality, and Cancer in Postmenopausal Women.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-24-1644}, pmid = {40152978}, issn = {1538-7755}, abstract = {BACKGROUND: Predictors of premature death and cancer development are needed to more precisely identify individuals who may warrant preventive intervention. Circulating IGF binding protein-7 (IGFBP7) and, to lesser extent, the IGFBP7/IGF-1 ratio are emerging biomarkers of renal and cardiovascular morbidity. However, their relationships with aging, obesity, mortality and cancer risk remain unclear.<br><br>METHODS: This hypothesis-generating study investigated plasma IGFBP7, IGF-1, and their ratio as predictors of all-cause mortality, any cancer (excluding nonmelanoma skin cancer), obesity-related cancer (composite of 13 cancer types), and breast cancer incidence in a large longitudinal cohort of postmenopausal women. We assessed relationships of each biomarker with age, body mass index (BMI), and each outcome (bivariately and controlling for age, BMI, race, physical activity, education, income, marital status, alcohol intake, smoking, diabetes, and hormone therapy) in 793 Women's Health Initiative-Observational Study participants (mean 19.4 year follow-up).<br><br>RESULTS: In adjusted analyses, IGFBP7 increased with age and obesity, and was positively associated with risks of all-cause mortality [hazard ratio (HR)=2.42 (95% CI: 1.37-4.26), p=0.002], any cancer [HR=2.04 (1.05-3.94), p=0.035], and obesity-related cancer [HR=1.58 (0.99-2.51), p=0.053]. Also in adjusted analyses, the IGFBP7/IGF-1 ratio increased with age and was positively associated with all-cause mortality [HR=1.51 (1.14-1.99), p=0.004] and any cancer incidence [HR=5.44 (1.13-26.1), p=0.034].<br><br>CONCLUSIONS: Plasma IGFBP7 and the IGFBP7/IGF1 ratio are positively associated with age, obesity (IGFBP7 only), mortality, and cancer in postmenopausal women.<br><br>IMPACT: Plasma IGFBP7 may represent an age- and obesity-sensitive biomarker of increased risk of developing cancer and/or dying prematurely.}, }
@article {pmid40151933, year = {2025}, author = {Wang, X and Singh, P and Cejas, RB and Zhou, L and Sharafeldin, N and Trainor, PJ and Landier, W and Cheng, C and Hageman, L and Wang, F and Sapkota, Y and Yasui, Y and Hudson, MM and Chow, EJ and Armenian, SH and Neglia, JP and Hawkins, DS and Ginsberg, JP and Burridge, PW and Armstrong, GT and Bhatia, S}, title = {DNA Damage Response and Repair Genes and Anthracycline-Induced Cardiomyopathy in Childhood Cancer Survivors: A Report From the Children's Oncology Group and the Childhood Cancer Survivor Study.}, journal = {Circulation. Genomic and precision medicine}, volume = {}, number = {}, pages = {e004813}, doi = {10.1161/CIRCGEN.124.004813}, pmid = {40151933}, issn = {2574-8300}, abstract = {BACKGROUND: Anthracyclines induce cardiotoxicity via DNA double-strand breaks and reactive oxygen species formation, resulting in cardiomyocyte dysfunction. The role of DNA damage response/repair (DDR) genes in anthracycline-induced cardiomyopathy remains unstudied.<br><br>METHODS: We conducted a gene-based and pathway-based analysis to examine the main effect and gene-anthracycline interaction effect between DDR genes and anthracycline-induced cardiomyopathy. A discovery analysis performed with a matched case-control set of anthracycline-exposed non-Hispanic White childhood cancer survivors from Children's Oncology Group-ALTE03N1 (113 cases; 226 controls) was replicated using a cohort of anthracycline-exposed non-Hispanic White childhood cancer survivors from the Childhood Cancer Survivor Study cohort (n=1658; 97 cases). Functional analyses were performed by examining the response to doxorubicin of human-induced pluripotent stem cell-derived cardiomyocytes with CRISPR/Cas9-mediated knockout of prioritized genes.<br><br>RESULTS: Successfully replicated DDR genes demonstrating main-effect association included FANCC (P=0.037) and XRCC5 (P=0.001) and demonstrated gene-anthracycline interaction included MGMT (P=0.041). Knockouts of FANCC and MGMT in human-induced pluripotent stem cell-derived cardiomyocytes demonstrated significant resistance to doxorubicin, suggesting that these genes play a role in anthracycline-induced cardiotoxicity. Successfully replicated DDR pathways demonstrating main-effect association included base excision repair (P=2.7&#xd7;10[-4]); role of BRCA1 in DDR (P=9.2&#xd7;10[-5]); p53 signaling (P<1&#xd7;10[-16]); role of checkpoint kinases proteins in cell cycle checkpoint control (P<1&#xd7;10[-16]); mismatch repair (P<10[-16]); and double-strand break repair by homologous recombination (P<1&#xd7;10[-16]). Successfully replicated DDR pathways demonstrating significant interaction effects included role of BRCA1 in DDR (P=1.4&#xd7;10[-4]); p53 signaling (P<1&#xd7;10[-16]); the role of checkpoint kinases proteins in cell cycle checkpoint control (P<1&#xd7;10[-16]); mismatch repair (P<1&#xd7;10[-16]); cell cycle: G2/M DNA damage checkpoint regulation (P=0.002); double-strand break repair by homologous recombination (P=0.009); GADD45 signaling (P=4.8&#xd7;10[-4]); and cell cycle control of chromosomal replication (P=4.5&#xd7;10[-4]).<br><br>CONCLUSIONS: These findings provide evidence for the role of DDR genes and pathways in anthracycline-induced cardiomyopathy and provide a framework for targeted therapeutic interventions.}, }
@article {pmid40147465, year = {2025}, author = {Luetkemeyer, AF and Donnell, D and Cohen, SE and Dombrowski, JC and Grabow, C and Haser, G and Brown, C and Cannon, C and Malinski, C and Perkins, R and Nasser, M and Lopez, C and Suchland, RJ and Vittinghoff, E and Buchbinder, SP and Scott, H and Charlebois, ED and Havlir, DV and Soge, OO and Celum, C}, title = {Doxycycline to prevent bacterial sexually transmitted infections in the USA: final results from the DoxyPEP multicentre, open-label, randomised controlled trial and open-label extension.}, journal = {The Lancet. Infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1016/S1473-3099(25)00085-4}, pmid = {40147465}, issn = {1474-4457}, abstract = {BACKGROUND: Doxycycline post-exposure prophylaxis (doxy-PEP) is a promising intervention to reduce bacterial sexually transmitted infections (STIs). We evaluated the effect of doxy-PEP on STI incidence and antimicrobial resistance in men who have sex with men and transgender women for up to 12 months of follow-up, inlcuding an open-label extension.<br><br>METHODS: DoxyPEP, an open-label trial in Seattle (WA, USA) and San Francisco (CA, USA) among men who have sex with men and transgender women with at least one bacterial STI in the past year, randomly assigned participants by clinic (with computer-generated variable block sizes) 2:1 to doxy-PEP (200 mg doxycycline delayed-release tablets 24-72 h after condomless sex) or standard care. The independent endpoint adjudication committee was masked to group assignment. The primary outcome was presence of one or more bacterial STIs (Neisseria gonorrhoeae, Chlamydia trachomatis, or early syphilis) each quarter. This outcome was assessed in the modified intention-to-treat cohort, which included participants with at least one follow-up quarter (ie, &#x223c;3 months) in their as-randomised assignment. After early termination of the randomised phase for efficacy, all participants still enrolled were offered doxy-PEP in an open-label extension (OLE). We report quarterly incidence of bacterial STIs for the as-randomised and OLE periods. Safety was assessed in all participants with any follow-up data. The trial was registered with ClinicalTrials.gov (NCT03980223) and is completed.<br><br>FINDINGS: From Aug 19, 2020, to May 13, 2022, we enrolled 637 participants; 592 participants completed at least one follow-up quarter in the randomised phase (411 in the doxy-PEP group and 181 in the standard-care group) and 282 in the OLE phase (207 in the doxy-PEP group and 82 in the standard-care group). STIs were present in 129 (12&#xb7;0%) of 1077 quarters in the doxy-PEP group versus 139 (30&#xb7;5%) of 455 quarters in the standard-care group during the as-randomised period, showing an absolute difference of 19 percentage points and a relative risk of 0&#xb7;39 (95% CI 0&#xb7;31-0&#xb7;49, p<0&#xb7;0001). During the OLE, STIs were diagnosed in 51 (13%) of 388 quarters among those continuing doxy-PEP and 25 (17%) of 145 quarters among standard-care participants who initiated doxy-PEP. Throughout all quarters for participants on doxy-PEP, there was one grade 2 laboratory abnormality and five grade 3 adverse events that were possibly or probably related to doxy-PEP. No serious adverse events were attributed by site investigators to doxycycline. Of participants with positive gonorrhoea cultures during the study, eight (27%) of 29 taking doxy-PEP versus five (24%) of 21 not taking doxy-PEP had tetracycline resistance (minimum inhibitory concentration &#x2265;2 &#x3bc;g/mL).<br><br>INTERPRETATION: Doxy-PEP was effective in reducing bacterial STIs in this population of men who have sex with men and transgender women, including during an open-label extension when doxy-PEP efficacy was known. Doxy-PEP was well tolerated, highly acceptable, and with no new safety signals.<br><br>FUNDING: US National Institutes of Health.}, }
@article {pmid40147439, year = {2025}, author = {Dubocanin, D and Hartley, GA and Sedeño Cortés, AE and Mao, Y and Hedouin, S and Ranchalis, J and Agarwal, A and Logsdon, GA and Munson, KM and Real, T and Mallory, BJ and Eichler, EE and Biggins, S and O'Neill, RJ and Stergachis, AB}, title = {Conservation of dichromatin organization along regional centromeres.}, journal = {Cell genomics}, volume = {}, number = {}, pages = {100819}, doi = {10.1016/j.xgen.2025.100819}, pmid = {40147439}, issn = {2666-979X}, abstract = {The attachment of the kinetochore to the centromere is essential for genome maintenance, yet the highly repetitive nature of satellite regional centromeres limits our understanding of their chromatin organization. We demonstrate that single-molecule chromatin fiber sequencing (Fiber-seq) can uniquely co-resolve kinetochore and surrounding chromatin architectures along point centromeres, revealing largely homogeneous single-molecule kinetochore occupancy. In contrast, the application of Fiber-seq to regional centromeres exposed marked per-molecule heterogeneity in their chromatin organization. Regional centromere cores uniquely contain a dichotomous chromatin organization (dichromatin) composed of compacted nucleosome arrays punctuated with highly accessible chromatin patches. CENP-B occupancy phases dichromatin to the underlying alpha-satellite repeat within centromere cores but is not necessary for dichromatin formation. Centromere core dichromatin is conserved between humans and primates, including along regional centromeres lacking satellite repeats. Overall, the chromatin organization of regional centromeres is defined by marked per-molecule heterogeneity, buffering kinetochore attachment against sequence and structural variability within regional centromeres.}, }
@article {pmid40146127, year = {2025}, author = {Lee, CI and Lowry, KP}, title = {Identifying Who Is at Risk of Interval Breast Cancers.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaoncol.2025.0101}, pmid = {40146127}, issn = {2374-2445}, }
@article {pmid40146038, year = {2025}, author = {Unger, JM and McAneny, BL and Osarogiagbon, RU}, title = {Cancer in rural America: Improving access to clinical trials and quality of oncologic care.}, journal = {CA: a cancer journal for clinicians}, volume = {}, number = {}, pages = {}, doi = {10.3322/caac.70006}, pmid = {40146038}, issn = {1542-4863}, support = {UG1CA189974//National Institutes of Health, National Cancer Institute/ ; 5U10CA180819//National Institutes of Health, National Cancer Institute/ ; }, abstract = {Individuals from rural areas in the United States suffer higher rates of morbidity and mortality from cancer than their urban counterparts. This review is based on the idea that equity-the elimination of unnecessary and preventable differences between groups of individuals-should underlie access to cancer care resources for patients from rural areas. Access to cancer clinical trials serves as the framework for identifying and understanding barriers in access to quality oncologic care. The authors discuss the interplay between rural living, socioeconomic status, culture, and health; and they highlight how economic considerations in rural areas often limit access to clinical trials and oncologic care because economies of scale do not apply in these regions given the requirement for high-quality oncology care even with lower patient volumes. The authors propose solutions to enhance access to clinical trials and improve the quality of oncologic care in rural areas, viewing these aims as ethical and moral imperatives.}, }
@article {pmid40141440, year = {2025}, author = {Germain, A and Jaycox, JR and Emig, CJ and Ring, AM and Hanson, MR}, title = {An In-Depth Exploration of the Autoantibody Immune Profile in ME/CFS Using Novel Antigen Profiling Techniques.}, journal = {International journal of molecular sciences}, volume = {26}, number = {6}, pages = {}, pmid = {40141440}, issn = {1422-0067}, support = {U54NS105541/GF/NIH HHS/United States ; U54AI178855/GF/NIH HHS/United States ; UL1 TR 002384/GF/NIH HHS/United States ; 3P30CA016359-40S4//Yale Cancer Center Support/ ; DP5OD023088/GF/NIH HHS/United States ; T32GM007205//Yale Medical Scientist Training Program/ ; }, mesh = {Humans ; *Autoantibodies/immunology ; Female ; Male ; *Fatigue Syndrome, Chronic/immunology ; Middle Aged ; Adult ; Autoantigens/immunology ; }, abstract = {Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder characterized by serious physical and cognitive impairments. Recent research underscores the role of immune dysfunction, including the role of autoantibodies, in ME/CFS pathophysiology. Expanding on previous studies, we analyzed 7542 antibody-antigen interactions in ME/CFS patients using two advanced platforms: a 1134 autoantibody Luminex panel from Oncimmune and Augmenta Bioworks, along with Rapid Extracellular Antigen Profiling (REAP), a validated high-throughput method that measures autoantibody reactivity against 6183 extracellular human proteins and 225 human viral pathogen proteins. Unlike earlier reports, our analysis of 172 participants revealed no significant differences in autoantibody reactivities between ME/CFS patients and controls, including against GPCRs such as β-adrenergic receptors. However, subtle trends in autoantibody ratios between male and female ME/CFS subgroups, along with patterns of herpesvirus reactivation, suggest the need for broader and more detailed exploration.}, }
@article {pmid40140386, year = {2025}, author = {Beddows, I and Djirackor, S and Omran, DK and Jung, E and Shih, NN and Roy, R and Hechmer, A and Olshen, A and Adelmant, G and Tom, A and Morrison, J and Adams, M and Rohrer, DC and Schwartz, LE and Pearce, CL and Auman, H and Marto, JA and Drescher, CW and Drapkin, R and Shen, H}, title = {Impact of BRCA mutations, age, surgical indication, and hormone status on the molecular phenotype of the human Fallopian tube.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {2981}, pmid = {40140386}, issn = {2041-1723}, mesh = {Humans ; Female ; *Fallopian Tubes/metabolism/pathology ; *BRCA2 Protein/genetics/metabolism ; *BRCA1 Protein/genetics/metabolism ; Middle Aged ; Adult ; Aged ; Ovarian Neoplasms/genetics/metabolism ; Epigenesis, Genetic ; Germ-Line Mutation ; Fallopian Tube Neoplasms/genetics/metabolism/pathology ; Phenotype ; Mutation ; Age Factors ; Whole Genome Sequencing ; Proteomics/methods ; Heterozygote ; Pregnancy ; }, abstract = {The human Fallopian tube (FT) is an important organ in the female reproductive system and has been implicated as a site of origin for pelvic serous cancers, including high-grade serous tubo-ovarian carcinoma (HGSC). We have generated comprehensive whole-genome bisulfite sequencing, RNA-seq, and proteomic data of over 100 human FTs, with detailed clinical covariate annotations. Our results challenge existing paradigms that extensive epigenetic, transcriptomic and proteomic alterations exist in the FTs from women carrying heterozygous germline BRCA1/2 pathogenic variants. We find minimal differences between BRCA1/2 carriers and non-carriers prior to loss of heterozygosity. Covariates such as age and surgical indication can confound BRCA1/2-related differences reported in the literature, mainly through their impact on cell composition. We systematically document and highlight the degree of variations across normal human FT, defining five groups capturing major cellular and molecular changes across various reproductive stages, pregnancy, and aging. We are able to associate gene, protein, and epigenetic changes with these and other clinical covariates, but not heterozygous BRCA1/2 mutation status. This sheds new light into prevention and early detection of tumorigenesis in populations at high-risk for ovarian cancer.}, }
@article {pmid40139185, year = {2025}, author = {Tenthorey, JL and Del Banco, S and Ramzan, I and Klingenberg, H and Liu, C and Emerman, M and Malik, HS}, title = {Indels allow antiviral proteins to evolve functional novelty inaccessible by missense mutations.}, journal = {Cell genomics}, volume = {}, number = {}, pages = {100818}, doi = {10.1016/j.xgen.2025.100818}, pmid = {40139185}, issn = {2666-979X}, abstract = {Antiviral proteins often evolve rapidly at virus-binding interfaces to defend against new viruses. We investigated whether antiviral adaptation via missense mutations might face limits, which insertion or deletion mutations (indels) could overcome. Using high-throughput saturation missense mutagenesis, we identify one such case of a nearly insurmountable evolutionary challenge: the human anti-retroviral protein TRIM5α requires more than five missense mutations in its specificity-determining v1 loop to restrict a divergent simian immunodeficiency virus (SIV). However, through a novel saturating indel scanning methodology, we find that duplicating just one amino acid in v1 enables human TRIM5α to potently restrict SIV in a single evolutionary step. Moreover, natural primate TRIM5α v1 loops have evolved indels that confer novel antiviral specificities. Thus, indels enable antiviral proteins to overcome viral challenges otherwise inaccessible by missense mutations. Our findings reveal the potential of often-overlooked indel mutations in driving protein innovation.}, }
@article {pmid40138611, year = {2025}, author = {Aggarwal, RR and Vuky, J and VanderWeele, D and Rettig, M and Heath, EI and Quigley, D and Huang, J and Chumber, A and Cheung, A and Foye, A and Leung, S and Abbey, J and Dorr, A and Nasoff, M and Hunter, J and Wang, S and Flavell, RR and Fong, L and Liu, B and Small, EJ}, title = {Phase I, First-in-Human Study of FOR46 (FG-3246), an Immune-Modulating Antibody-Drug Conjugate Targeting CD46, in Patients With Metastatic Castration-Resistant Prostate Cancer.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2401989}, doi = {10.1200/JCO-24-01989}, pmid = {40138611}, issn = {1527-7755}, abstract = {PURPOSE: FOR46, a fully human antibody conjugated to monomethyl auristatin E, targets a tumor-selective epitope of CD46, which is overexpressed in metastatic castration-resistant prostate cancer (mCRPC). FOR46 demonstrates potent nonclinical activity in enzalutamide-resistant CRPC models.<br><br>PATIENTS AND METHODS: This was a phase I, first-in-human, dose escalation/expansion study in patients with progressive mCRPC after treatment with &#x2265;one androgen signaling inhibitors (ClinicalTrials.gov identifier: NCT03575819). The starting dose of FOR46 was 0.1 mg/kg given intravenously every 3 weeks. The primary objective was to determine the maximally tolerated dose (MTD). Whole-blood mass cytometry (cytometry by time of flight) was used to characterize peripheral immune response and CD46 expression in CRPC tissue that underwent central pathology review.<br><br>RESULTS: Fifty-six patients were enrolled. Dose-limiting toxicities included neutropenia (n = 4), febrile neutropenia (n = 1), and fatigue (n = 1). The MTD was 2.7 mg/kg using adjusted body weight. The most common grade &#x2265;3 adverse events across all dose levels were neutropenia (59%), leukopenia (27%), lymphopenia (7%), anemia (7%), and fatigue (5%). One grade 3 febrile neutropenia event was observed. There were no treatment-related deaths. In the efficacy evaluable subset (patients with adenocarcinoma treated with a starting dose &#x2265;1.2 mg/kg, n = 40), the median radiographic progression-free survival was 8.7 months (range, 0.1-33.9). Fourteen of 39 evaluable patients (36%) achieved a PSA50 response. The confirmed objective response rate was 20% (5 of 25 RECIST-evaluable patients). The median duration of response was 7.5 months. Responders had a significantly higher on-treatment frequency of circulating effector CD8[+] T cells.<br><br>CONCLUSION: FOR46 demonstrated encouraging preliminary clinical activity with a manageable safety profile. Targeting CD46 elicited an immune priming effect that was associated with clinical outcomes.}, }
@article {pmid40138497, year = {2025}, author = {Jana, S and Glabman, RA and Koehne, AL}, title = {Bridging the gap between histopathology and genomics: Spotlighting spatial omics.}, journal = {Veterinary pathology}, volume = {}, number = {}, pages = {3009858251322729}, doi = {10.1177/03009858251322729}, pmid = {40138497}, issn = {1544-2217}, abstract = {Spatial biology has emerged as a transformative field, offering insights into cellular interactions and organization within tissues. The field has evolved rapidly since the coining of the term "spatial omics." Now, the ability to spatially resolve proteins, RNA, chromatin, and lipids is becoming widespread, and the technologies are continually refined. Reagents to support the analysis of veterinary species are available and more are emerging. These new tools will allow pathologists and scientists to unravel the intricate interplay between tissue architecture and diverse cellular phenotypes. By integrating histological observations with spatially resolved genomic data, spatial biology holds immense potential for advancing diagnostic and therapeutic strategies in veterinary medicine. These tools will undoubtedly equip veterinary pathologists to better decipher complex disease processes and identify novel therapeutic targets.}, }
@article {pmid40138454, year = {2025}, author = {Hart, TM and Cui, Y and Telford, SR and Marín-López, A and Calloway, K and Dai, Y and Matias, J and DePonte, K and Jaycox, J and DeBlasio, M and Hoornstra, D and Belperron, AA and Cibichakravarthy, B and Johnson, EE and Alameh, MG and Dwivedi, G and Hovius, JWR and Bockenstedt, LK and Weissman, D and Ring, AM and Fikrig, E}, title = {Tick feeding or vaccination with tick antigens elicits immunity to the Ixodes scapularis exoproteome in guinea pigs and humans.}, journal = {Science translational medicine}, volume = {17}, number = {791}, pages = {eads9207}, doi = {10.1126/scitranslmed.ads9207}, pmid = {40138454}, issn = {1946-6242}, mesh = {Animals ; Guinea Pigs ; *Ixodes/immunology ; Humans ; *Antigens/immunology ; *Vaccination ; *Immunoglobulin G/immunology ; Mice ; Proteome/metabolism/immunology ; Tick Bites/immunology ; Lyme Disease/immunology/prevention &amp; control ; }, abstract = {Ixodes scapularis is a primary vector of tick-borne pathogens in North America. Repeated exposure to these ticks can induce a humoral response to tick antigens and acquired tick resistance. However, identifying antigens contributing to this resistance is challenging because of the vast number of I. scapularis proteins secreted during feeding. To address this, we developed I. scapularis rapid extracellular antigen monitoring (IscREAM), a technique to detect antibody responses to more than 3000 tick antigens. We validated IscREAM with immunoglobulin G (IgG) from guinea pigs vaccinated with tick antigens, including a cement antigen cocktail that induced tick resistance. Furthermore, we explored the natural response to tick bites by profiling antigens recognized by IgG isolated from a tick-resistant individual, as well as from others with Lyme disease and tick-bitten guinea pigs and mice, to identify 199 recognized antigens. We observed that several antigens contained histamine-binding domains. This work enhances our understanding of the host immune response to I. scapularis and defines immunogen candidates for future antitick vaccines.}, }
@article {pmid40133165, year = {2025}, author = {Astigarraga, CC and Mpms, K and Iovino, L and Milano, F}, title = {Haploidentical transplantation: An optimal platform for graft manipulation and cellular therapies.}, journal = {Blood reviews}, volume = {}, number = {}, pages = {101286}, doi = {10.1016/j.blre.2025.101286}, pmid = {40133165}, issn = {1532-1681}, abstract = {Allogeneic hematopoietic stem cell transplantation (allo-HCT) remains a curative therapeutic option for patients with high-risk hematologic malignancies. When a fully matched donor is unavailable, haploidentical hematopoietic stem cell transplantation (haplo-HCT) provides a viable alternative. Over time, haplo-HCT procedures have significantly evolved, improving outcomes in treatment related mortality (TRM), especially in graft-versus-host disease (GvHD). However, challenges such as delayed immune reconstitution and disease relapse persist. Advances in in vivo graft manipulation techniques, such as post-transplant cyclophosphamide (PTCy) and ex vivo approaches, including TCRα/β and CD19 depletion, have shown promise in reducing the risk of severe GvHD without increasing the relapse rates. Innovative strategies, such as haploidentical donor lymphocyte infusions, "suicide-switch" mechanisms, ORCA-Q product infusions, and CAR based therapies offer potential to further optimize outcomes. This review examines the graft manipulation modalities in the haplo-HCT setting, highlighting their role in advancing cellular therapies and providing new hope in the fight against life-threatening diseases.}, }
@article {pmid40132580, year = {2025}, author = {Larsen, BB and McMahon, T and Brown, JT and Wang, Z and Radford, CE and Crowe, JE and Veesler, D and Bloom, JD}, title = {Functional and antigenic landscape of the Nipah virus receptor-binding protein.}, journal = {Cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cell.2025.02.030}, pmid = {40132580}, issn = {1097-4172}, abstract = {Nipah virus recurrently spills over to humans, causing fatal infections. The viral receptor-binding protein (RBP or G) attaches to host receptors and is a major target of neutralizing antibodies. Here, we use deep mutational scanning to measure how all amino-acid mutations to the RBP affect cell entry, receptor binding, and escape from neutralizing antibodies. We identify functionally constrained regions of the RBP, including sites involved in oligomerization, along with mutations that differentially modulate RBP binding to its two ephrin receptors. We map escape mutations for six anti-RBP antibodies and find that few antigenic mutations are present in natural Nipah strains. Our findings offer insights into the potential for functional and antigenic evolution of the RBP that can inform the development of antibody therapies and vaccines.}, }
@article {pmid40131862, year = {2025}, author = {MacLean, F and Tsegaye, AT and Graham, JB and Swarts, JL and Vick, SC and Potchen, NB and Cruz Talavera, I and Warrier, L and Dubrulle, J and Schroeder, LK and Saito, A and Mar, C and Thomas, KK and Mack, M and Sabo, MC and Chohan, BH and Ngure, K and Mugo, NR and Lingappa, JR and Lund, JM}, title = {Bacterial vaginosis associates with dysfunctional T cells and altered soluble immune factors in the cervicovaginal tract.}, journal = {The Journal of clinical investigation}, volume = {}, number = {}, pages = {}, doi = {10.1172/JCI184609}, pmid = {40131862}, issn = {1558-8238}, abstract = {BACKGROUND: Bacterial vaginosis (BV) is a dysbiosis of the vaginal microbiome that is prevalent among reproductive-age females worldwide. Adverse health outcomes associated with BV include an increased risk of sexually-acquired HIV, yet the immunological mechanisms underlying this association are not well understood.<br><br>METHODS: To investigate BV-driven changes to cervicovaginal tract (CVT) and circulating T cell phenotypes, Kinga Study participants with or without BV provided vaginal tract (VT) and ectocervical (CX) tissue biopsies and PBMC samples.<br><br>RESULTS: High-parameter flow cytometry revealed an increased frequency of cervical conventional CD4+ T cells (Tconv) expressing CCR5. However, we found no difference in number of CD3+CD4+CCR5+ cells in the CX or VT of BV+ versus BV- individuals, suggesting that BV-driven increased HIV susceptibility may not be solely attributed to increased CVT HIV target cell abundance. Flow cytometry also revealed that individuals with BV have an increased frequency of dysfunctional CX and VT CD39+ Tconv and CX tissue-resident CD69+CD103+ Tconv, reported to be implicated in HIV acquisition risk and replication. Many soluble immune factor differences in the CVT further support that BV elicits diverse and complex CVT immune alterations.<br><br>CONCLUSION: Our comprehensive analysis expands on potential immunological mechanisms that may underlie the adverse health outcomes associated with BV including increased HIV susceptibility.}, }
@article {pmid40131369, year = {2025}, author = {Ito, S and Geramita, E and Ventura, K and Neupane, B and Bhise, S and Moore, EM and Furlan, S and Shlomchik, WD}, title = {IFN-γand donor leukocyte infusions for relapsed myeloblastic malignancies after allogeneic hematopoietic stem cell transplantation .}, journal = {JCI insight}, volume = {}, number = {}, pages = {}, doi = {10.1172/jci.insight.190655}, pmid = {40131369}, issn = {2379-3708}, abstract = {BACKGROUND: The graft-vs-leukemia (GVL) effect contributes to the efficacy of allogeneic stem cell transplantation (alloSCT). However, relapse, indicative of GVL failure, is the greatest single cause of treatment failure. Based on preclinical data showing that IFN-γ is important to sensitize myeloblasts to alloreactive T cells, we performed a phase I trial of IFN-γ combined with donor leukocyte infusions (DLI) in myeloblastic malignancies that relapsed post-HLA-matched alloSCT.<br><br>METHODS: Patients with relapsed acute myeloid leukemia or myelodysplastic syndrome after alloSCT were eligible. Patients self-administered IFN-&#x3b3; for 4 weeks (cohort 1) or 1 week (cohort 2), followed by DLI and concurrent IFN-&#x3b3; for a total of 12 weeks. Bone marrow samples were analyzed by single-cell RNA sequencing (scRNAseq) to assess in vivo responses to IFN-&#x3b3; by malignant myeloblasts.<br><br>RESULTS: IFN-&#x3b3; monotherapy was well tolerated by all subjects (n=7). Treatment-related toxicities after DLI included: grade I-II graft-versus-host disease (n=5), immune effector cell-associated neurotoxicity syndrome (n=2), and idiopathic pulmonary syndrome (n=1), all of which resolved with corticosteroids. Four of 6 DLI recipients achieved minimal residual disease-negative complete remissions and full donor hematopoietic recovery. Median overall survival was 579 days (range, 97-906) in responders. ScRNAseq confirmed in vivo activation of IFN-&#x3b3; response pathway in hematopoietic stem cell-like or myeloid progenitor cells after IFN-&#x3b3; in analyzed samples.<br><br>CONCLUSIONS: IFN-&#x3b3; was safe and well tolerated in this phase I study of IFN-&#x3b3; for relapsed AML/MDS post-alloSCT, with a promising efficacy signal when combined with DLI. Larger studies are needed to formally test the efficacy of this approach.TRIAL RESGISTRATION.<br><br>CLINICALTRIALS: gov NCT04628338.<br><br>FUNDING: The research was supported by The UPMC Hillman Cancer Center Cancer Immunology and Immunotherapy Program (CIIP) Pilot Award and Cure Within Reach: Drug Repurposing Clinical Trials to Impact Blood Cancers. Recombinant IFN-gamma (Actimmune&#xae;) was donated by Horizon Therapeutics.}, }
@article {pmid40130874, year = {2025}, author = {Dadonaite, B and Burrell, AR and Logue, J and Chu, HY and Payne, DC and Haslam, DB and Staat, MA and Bloom, JD}, title = {SARS-CoV-2 neutralizing antibody specificities differ dramatically between recently infected infants and immune-imprinted individuals.}, journal = {Journal of virology}, volume = {}, number = {}, pages = {e0010925}, doi = {10.1128/jvi.00109-25}, pmid = {40130874}, issn = {1098-5514}, abstract = {The immune response to viral infection is shaped by past exposures to related virus strains, a phenomenon known as imprinting. For severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), much of the population has been imprinted by a viral spike from an early strain, either through vaccination or infection during the early stages of the COVID-19 pandemic. As a consequence of this imprinting, infection with more recent SARS-CoV-2 strains primarily boosts cross-reactive antibodies elicited by the imprinting strain. Here we compare the neutralizing antibody specificities of imprinted individuals versus infants infected with a recent strain. Specifically, we use pseudovirus-based deep mutational scanning to measure how spike mutations affect neutralization by the serum antibodies of adults and children imprinted by the original vaccine versus infants with a primary infection by an XBB* variant. While the serum neutralizing activity of the imprinted individuals primarily targets the spike receptor-binding domain (RBD), the serum neutralizing activity of infants infected with only XBB* mostly targets the spike N-terminal domain. In these infants, secondary exposure to the XBB* spike via vaccination shifts more of the neutralizing activity toward the RBD, although the specific RBD sites targeted are different from imprinted adults. The dramatic differences in neutralization specificities among individuals with different exposure histories likely impact SARS-CoV-2 evolution.IMPORTANCEWe show that a person's exposure history to different SARS-CoV-2 strains strongly affects which regions on the viral spike that their neutralizing antibodies target. In particular, infants who have just been infected once with a recent viral strain make neutralizing antibodies that target different regions of the viral spike than adults or children who have been exposed to both older and more recent strains. This person-to-person heterogeneity means that the same viral mutation can have different impacts on the antibody immunity of different people.}, }
@article {pmid40127395, year = {2025}, author = {Lust, H and Schultz, LM and Kwon, S and Roloff, GW and Aldoss, I and Baggott, C and John, S and Rossoff, J and McNerney, KO and Fabrizio, VA and Talano, JA and Moskop, A and Curran, KJ and Phillips, CL and Karras, NA and Baumeister, SHC and Cooper, S and Hermiston, ML and Satwani, P and Qayed, M and Raikar, SS and MacMillan, ML and Hall, EM and Nguyen, K and Cassaday, RD and Kopmar, NE and Kota, VK and Mathews, J and Shaughnessy, PJ and Schwartz, MS and Ladha, A and Yaghmour, G and Kumaran, M and Bachanova, V and Tracy, SI and Othman, T and Luskin, MR and Chen, EC and Advani, AS and Jeyakumar, N and Miller, K and Zhang, A and Shah, BD and Muffly, LS and Faramand, RG}, title = {Real World Outcomes for Young Adult Patients Receiving CD19 CAR T-cell Therapy.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024014846}, pmid = {40127395}, issn = {2473-9537}, abstract = {Tisagenlecleucel (tisa-cel) and brexucabtagene autoleucel (brexu-cel) are approved CD19 CAR T products for young adults (YAs) with relapsed/refractory B-ALL. A distinct analysis of YAs receiving commercial CD19 CAR T has not been reported. Utilizing retrospective data from the Pediatric Real-World CAR T Consortium and the Real-World Outcomes of CAR T in Adult ALL collaboration, we describe efficacy and safety of tisa-cel and brexu-cel in 70 young adults (18-26 years; tisa-cel: 50, brexu-cel: 20). Cytokine release syndrome (CRS) and immune-effector cell associated neurotoxicity syndrome (ICANS) were observed more frequently for brexu-cel vs tisa-cel (CRS= 85% vs 56%, p=0.01; ICANS= 40% vs 18%, p=0.05). CR rates were similar between products at 80% for brexu-cel and 88% for tisa-cel (p=0.39). Relapse free survival (RFS) at 12 months was 46% for brexu-cel (95% CI 31-81%) and 36% for tisa-cel (95% CI 26-52%, p=0.79). Durability of remission over 12 months was 61% for brexu-cel (95% CI 41-93%) vs 41% for tisa-cel (95% CI 27-61%, p=0.12). 12-month overall survival (OS) for brexu-cel was 84% (95% CI 81-100) vs 68% for tisa-cel (95% CI 56-85, HR 1.9, p=0.35). In multivariate analysis, low disease burden was associated with improved OS (HR 0.23, 95% CI 0.06-0.86, p=0.03), while inotuzumab pre-CAR T was associated with inferior outcomes (OS HR 6.32, 95% CI 1.48-27, p=0.01; RFS HR 3.65, 95% CI 1.41-9.46, p=0.008). This study demonstrates comparable real-world efficacy among young adults receiving CD19 CAR T therapy irrespective of CAR T construct, however, rates of toxicity appear higher with brexu-cel.}, }
@article {pmid40124489, year = {2025}, author = {Bender Ignacio, RA and Chew, KW and Moser, C and Currier, JS and Eron, JJ and Javan, AC and Giganti, MJ and Ritz, J and Gibbs, M and Kouekam, HT and Esser, MT and Daar, ES and Choudhary, M and Deo, R and Fletcher, CV and Li, JZ and Hughes, MD and Smith, D and Wohl, DA and , }, title = {Tixagevimab/cilgavimab or placebo for COVID-19 in ACTIV-2: Safety, pharmacokinetics and neutralizing and anti-drug antibodies.}, journal = {iScience}, volume = {28}, number = {3}, pages = {111938}, pmid = {40124489}, issn = {2589-0042}, abstract = {Monoclonal antibodies have potential as rapidly developable agents for treatment and prevention of emerging viruses. The ACTIV-2 trial randomized persons with mild-moderate COVID-19 to the monoclonal antibody combination tixagevimab/cilgavimab via intramuscular injection (600 mg IM) or infusion (300 mg IV) versus placebo. We present final safety and laboratory outcomes; primary outcomes were previously reported. The analyzed IM group included 214 participants, and the IV group, 106 participants. Adverse events were not different between treatment and placebo. The half-life of both components was >90 days for IM or 75 days for IV. New anti-drug antibodies were about 3 times more likely in active vs. placebo recipients. SARS-CoV-2 neutralizing antibodies increased 157-fold at 7 days and 127-fold at 1 month (IM-treated) but were less robust in IV participants. These data can inform future development of monoclonal antibodies against SARS-CoV-2 and other viruses, even if this intervention is of low utility for contemporary SARS-CoV-2 variants.}, }
@article {pmid40122815, year = {2025}, author = {Thomson, RM and Cunningham, JA and Gatton, MM and Murphy, SC and de la Paz Ade, M and Ding, XC and Incardona, S and Legrand, E and Lucchi, N and Menard, D and Nsobya, SL and Saez, AC and Shrivastava, J and Chiodini, PL}, title = {WHO malaria nucleic acid amplification test external quality assessment scheme: results of eleven distributions over 6 years.}, journal = {Malaria journal}, volume = {24}, number = {1}, pages = {94}, pmid = {40122815}, issn = {1475-2875}, mesh = {*Nucleic Acid Amplification Techniques/standards/methods ; *Malaria/diagnosis ; Humans ; *World Health Organization ; Quality Control ; Plasmodium/isolation &amp; purification/genetics ; Molecular Diagnostic Techniques/standards/methods ; }, abstract = {BACKGROUND: The World Health Organization (WHO) recommends parasite-based diagnosis of malaria before treatment. The use of nucleic-acid amplification (NAAT) for detection of Plasmodium spp. has expanded rapidly in recent years, for epidemiological research globally and clinical care in high-resource settings. Data from NAATs are frequently used to inform policy decisions, so quality control is essential to ensure results are reliable and comparable. Therefore, robust quality control, including an external quality assessment (EQA) scheme targeting malaria NAATs, is essential. The WHO Global Malaria Programme and the UK National External Quality Assessment Service (UK NEQAS) have collaborated since 2017 to implement a global malaria NAAT EQA scheme.<br><br>METHODS: Panels of specimens containing five major species of human-infecting Plasmodium at various parasite concentrations and negative samples were created in lyophilized blood (LB) and dried blood spot (DBS) formats. Two distributions per year were sent, containing five LB and five DBS specimens. Samples were validated by expert referee laboratories prior to distribution. Between 37 and 51 laboratories participated in each distribution and submitted results online. Participants were scored based on their laboratory's stated capacity to identify Plasmodium species, and individual laboratory reports were sent which included performance comparison with anonymized peers. Change in performance over time was calculated using a generalized mixed model with a logit link function.<br><br>RESULTS: Participating laboratories were located in 42 countries. Sample format (DBS or LB) and parasite density were found to significantly affect performance, while referee labs performed better at identifying P. falciparum samples than non-referee labs. Performance of laboratories improved significantly over time, especially for lower density and P. falciparum samples.<br><br>CONCLUSIONS: Results from the first eleven distributions indicate that the EQA scheme has facilitated improved performance of laboratories over time, highlighting the value of implementing such programmes. EQA schemes are critical to safeguarding the reliability of data and diagnoses, especially in situations where NAAT methodologies and protocols are used. In future, funders should make participation in an EQA scheme a requirement for laboratories, and countries can take initiatives to embed such schemes into their own national assessment programmes.}, }
@article {pmid40119775, year = {2025}, author = {Rostad, CA and Campbell, JD and Paulsen, GC and Schnyder Ghamloush, S and Xu, W and Zheng, L and McElrath, MJ and De Rosa, SC and Girard, B and Das, R and Anderson, EJ and Creech, CB}, title = {Evaluation of Cellular Immune Responses After mRNA-1273 Vaccination in Children 6 Months to 11 Years of Age.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiaf144}, pmid = {40119775}, issn = {1537-6613}, abstract = {BACKGROUND: Cell-mediated immunity (CMI) may help protect against emerging SARS-CoV-2 variants that are less susceptible to neutralizing antibodies. We present CMI data after the mRNA-1273 primary series in a subset of participants aged 6 months to 11 years from the phase 2/3 KidCOVE trial.<br><br>METHODS: T-cell responses were assessed after 2 doses of mRNA-1273 (6 months-5 years: 25 &#x3bc;g; 6-11 years: 50 &#x3bc;g) or placebo administered 28 days apart. Magnitude, phenotype, and percentage of ancestral SARS-CoV-2 spike (S) protein T-cell responses to pooled peptides were assessed by intracellular cytokine staining and polyfunctionality analyses.<br><br>RESULTS: A total of 68 children aged 6 months to 11 years received either the 2-dose mRNA-1273 primary series or placebo (51:17, respectively) at 28-day interval. mRNA-1273 induced S protein-specific CD4+ T-cell responses exhibiting a type 1 T helper (Th1)-biased profile at Day 43 and Day 209 compared with placebo. S-protein-specific CD8+ T-cell responses were less frequently detected in children <5 years and undetectable in those <2 years. Compared with placebo, mRNA-1273 induced higher frequencies of S-specific polyfunctional CD4+ T cells at Day 43; frequencies declined but remained detectable at Day 209. Correlation between Th1 CD4+ responses and neutralizing antibodies was observed across age groups following mRNA-1273 vaccination.<br><br>CONCLUSIONS: The 2-dose mRNA-1273 primary series elicited robust and durable (&#x2265;6 months) Th1-biased CD4+ T-cell responses in children aged 6 months to 11 years. CD8+ T-cell responses varied by age.Trial registration number and URL NCT04796896 (https://clinicaltrials.gov/study/NCT04796896).}, }
@article {pmid40119478, year = {2025}, author = {Georgakis, MK and Malik, R and Bounkari, OE and Hasbani, NR and Li, J and Huffman, JE and Shakt, G and Tack, RWP and Kimball, TN and Asare, Y and Morrison, AC and Tsao, NL and Judy, R and Mitchell, BD and Xu, H and Montasser, ME and Do, R and Kenny, EE and Loos, RJF and Terry, JG and Carr, JJ and Bis, JC and Psaty, BM and Longstreth, WT and Young, KA and Lutz, SM and Cho, MH and Broome, J and Khan, AT and Wang, FF and Heard-Costa, N and Seshadri, S and Vasan, RS and Palmer, ND and Freedman, BI and Bowden, DW and Yanek, LR and Kral, BG and Becker, LC and Peyser, PA and Bielak, LF and Ammous, F and Carson, AP and Hall, ME and Raffield, LM and Rich, SS and Post, WS and Tracy, RP and Taylor, KD and Guo, X and Mahaney, MC and Curran, JE and Blangero, J and Clarke, SL and Haessler, JW and Hu, Y and Assimes, TL and Kooperberg, C and Bernhagen, J and Anderson, CD and Damrauer, SM and Zand, R and Rotter, JI and de Vries, PS and Dichgans, M}, title = {Rare damaging CCR2 variants are associated with lower lifetime cardiovascular risk.}, journal = {Genome medicine}, volume = {17}, number = {1}, pages = {27}, pmid = {40119478}, issn = {1756-994X}, mesh = {Humans ; *Receptors, CCR2/genetics ; Male ; Female ; Middle Aged ; Cardiovascular Diseases/genetics ; Genetic Predisposition to Disease ; Chemokine CCL2/genetics ; Aged ; Monocytes/metabolism ; }, abstract = {BACKGROUND: Previous work has shown a role of CCL2, a key chemokine governing monocyte trafficking, in atherosclerosis. However, it remains unknown whether targeting CCR2, the cognate receptor of CCL2, provides protection against human atherosclerotic cardiovascular disease.<br><br>METHODS: Computationally predicted damaging or loss-of-function (REVEL&#x2009;>&#x2009;0.5) variants within CCR2 were detected in whole-exome-sequencing data from 454,775 UK Biobank participants and tested for association with cardiovascular endpoints in gene-burden tests. Given the key role of CCR2 in monocyte mobilization, variants associated with lower monocyte count were prioritized for experimental validation. The response to CCL2 of human cells transfected with these variants was tested in migration and cAMP assays. Validated damaging variants were tested for association with cardiovascular endpoints, atherosclerosis burden, and vascular risk factors. Significant associations were replicated in six independent datasets (n&#x2009;=&#x2009;1,062,595).<br><br>RESULTS: Carriers of 45 predicted damaging or loss-of-function CCR2 variants (n&#x2009;=&#x2009;787 individuals) were at lower risk of myocardial infarction and coronary artery disease. One of these variants (M249K, n&#x2009;=&#x2009;585, 0.15% of European ancestry individuals) was associated with lower monocyte count and with both decreased downstream signaling and chemoattraction in response to CCL2. While M249K showed no association with conventional vascular risk factors, it was consistently associated with a lower risk of myocardial infarction (odds ratio [OR]: 0.66, 95% confidence interval [CI]: 0.54-0.81, p&#x2009;=&#x2009;6.1&#x2009;&#xd7;&#x2009;10[-5]) and coronary artery disease (OR: 0.74, 95%CI: 0.63-0.87, p&#x2009;=&#x2009;2.9&#x2009;&#xd7;&#x2009;10[-4]) in the UK Biobank and in six replication cohorts. In a phenome-wide association study, there was no evidence of a higher risk of infections among M249K carriers.<br><br>CONCLUSIONS: Carriers of an experimentally confirmed damaging CCR2 variant are at a lower lifetime risk of myocardial infarction and coronary artery disease without carrying a higher risk of infections. Our findings provide genetic support for the translational potential of CCR2-targeting as an atheroprotective approach.}, }
@article {pmid40119158, year = {2025}, author = {Cole, FM and Laszlo, GS and Lunn-Halbert, MC and Kehret, AR and Zweidler-McKay, PA and Rodríguez-Arbolí, E and Wu, D and Nyberg, K and Li, J and Lim, SYT and Pettenger-Willey, CM and Lakshmikanthan, S and Walter, RB}, title = {Preclinical characterization of the anti-leukemia activity of the CD123 antibody-drug conjugate, pivekimab sunirine (IMGN632).}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, pmid = {40119158}, issn = {1476-5551}, }
@article {pmid40117529, year = {2025}, author = {Wagner, MJ and Pimenta, EM and Sweeney, NW and Loggers, ET and Roberts, JL and Brinkman, E and Chen, EY and Ricciotti, R and Haddox, CL and Berg, R and Yilma, B and Stoppler, MC and Chen, JL and Cranmer, LD}, title = {Genomic Characterization of Chondrosarcoma Reveals Potential Therapeutic Targets.}, journal = {JCO precision oncology}, volume = {9}, number = {}, pages = {e2400592}, doi = {10.1200/PO-24-00592}, pmid = {40117529}, issn = {2473-4284}, mesh = {Humans ; *Chondrosarcoma/genetics ; Male ; Female ; Middle Aged ; Aged ; Adult ; Bone Neoplasms/genetics ; Aged, 80 and over ; Genomics ; Young Adult ; Mutation ; Isocitrate Dehydrogenase/genetics ; }, abstract = {PURPOSE: Chondrosarcomas are rare cancers of cartilage with limited systemic therapy options. To identify potential therapeutic targets, this study investigated the molecular and immune landscape of three chondrosarcoma subtypes using a large database of clinical-grade sequencing results.<br><br>METHODS: Deidentified records from patients with a histologic diagnosis of conventional, dedifferentiated, or mesenchymal chondrosarcoma sequenced by the Tempus xT DNA assay were included. Microsatellite instability (MSI) and tumor mutational burden (TMB) were determined from sequencing data. The expression of PD-L1 and mismatch repair enzymes was evaluated in cases with available immunohistochemistry (IHC) data.<br><br>RESULTS: Of the 149 patients, 103 had conventional chondrosarcoma, 31 dedifferentiated chondrosarcoma, and 15 mesenchymal chondrosarcoma. Across the cohort, 44% (n = 65) had an IDH1 or IDH2 mutation. No cases were MSI high. One conventional chondrosarcoma patient had a TMB >10 mut/Mb. Among 112 patients with available PD-L1 IHC, 10% of conventional (n = 7), 45% of dedifferentiated (n = 13), and 17% of mesenchymal cases (n = 2) were PD-L1-positive. The most common somatic alterations were in IDH1 (34%) and TP53 (28%) in conventional chondrosarcoma; TP53 (68%), TERT (65%), IDH1 (39%), IDH2 (39%), CDKN2A (35%), and CDKN2B (35%) in dedifferentiated chondrosarcoma; and HEY1-NCOA2 fusions (87%) and CDKN2A (20%) in mesenchymal chondrosarcoma. MTAP was deleted in >10% of each subtype, and potentially actionable PDGFRB mutations were identified in 13% of dedifferentiated chondrosarcomas.<br><br>CONCLUSION: These findings reinforce therapeutic efforts to target IDH signaling in chondrosarcoma, provide insight into varied subpopulation response to immune checkpoint inhibitors, and identify new potential therapeutic targets for clinical development in chondrosarcoma.}, }
@article {pmid40116910, year = {2025}, author = {Lewis, FM and Ganschow, P and Manst, D and Derry-Vick, H and Tercyak, KP and Griffith, KA and Oxford, M and Fukui, J and Gadi, VK and Phillips, F}, title = {Behavioral-Emotional Functioning of Children of Parents with Early Compared to Advanced Cancer.}, journal = {Journal of palliative medicine}, volume = {}, number = {}, pages = {}, doi = {10.1089/jpm.2024.0326}, pmid = {40116910}, issn = {1557-7740}, abstract = {Background: Parental cancer represents a substantial psychological threat to children, but little is known about the relative impact of advanced compared to early-stage cancer on children's behavioral-emotional functioning. Objectives: To compare the behavioral-emotional functioning in children of parents with early compared to advanced cancer. Design: Single occasion, two-group design with historical comparison group. Setting/Participants: Participants were recruited through cancer centers, oncologists, service organizations, and self-referrals in the United States. Eligible parents had advanced or early-stage cancer, a child 5-17 years old, and spoke and read English. The Child Behavior Checklist was administered to parents to assess their children's Internalizing and Externalizing Problems. Data were obtained from 236 diagnosed parents, 176 with early and 57 with advanced cancer. Results: Internalizing and Externalizing Problems and Anxious/Depressed Mood were significantly greater for children of parents with advanced compared to early-stage cancer, even after controlling for covariates. Differences in children's functioning were not affected by parents' anxiety, depressed mood, treatment, or measures of social determinants of health. Conclusions: This is the first study to systematically compare the effects of parents' stage of cancer on children's behavioral-emotional functioning while controlling for potential confounders. Results demonstrate significantly elevated levels of behavioral-emotional problems in children affected by advanced compared to early-stage cancer that were explained by parents' stage of cancer, not other sources. Future studies need to identify mutable protective and risk factors to reduce the threat of parental cancer.}, }
@article {pmid40116755, year = {2025}, author = {Yun, J and Indorf, AL}, title = {Optimizing intermittent dosing of oral small molecule inhibitors.}, journal = {Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners}, volume = {}, number = {}, pages = {10781552251327598}, doi = {10.1177/10781552251327598}, pmid = {40116755}, issn = {1477-092X}, abstract = {IntroductionWith recent expansion of oral small molecule inhibitors, the drug development studies need to provide insight into optimal dose selection for these agents with vastly different mechanism and pharmacokinetic considerations compared to our traditional chemotherapy agents. Currently there is one published meta-analysis that examines intermittent and alternative dosing of oral small molecule inhibitors and it is unclear what guidance is available for treatment personalization beyond package insert labeling for patients undergoing toxicities from treatment.MethodsA systematic review of oral small molecule inhibitors with intermittent dosing was conducted in the National Library of Medicine PubMed database. Studies were selected based on predefined inclusion/exclusion criteria. Data was extracted to summarize findings on available guidance for intermittent or alternative dosing of oral small molecule inhibitors. Studies were categorized based on food and drug administration (FDA) approved or non-FDA approved agents, and further characterized by comparison of different dosing schemas.ResultsFifty-five trials were included in the final review and data analysis. Thirty-three trials were phase 1 trials, 26 trials for FDA approved agents and 29 non-FDA approved agents. Most trials reported on agents used in solid tumors, particularly renal cell carcinoma, with most trials examining sunitinib. Of the 55 trials, 28 compared different dosing strategies with 26 of the 28 trials examining efficacy outcomes with 27 of the 28 trials examining safety outcomes.ConclusionsThis systematic review found limited guidance for clinicians in optimizing dosing for intermittently dosed oral small molecule inhibitors.}, }
@article {pmid40116305, year = {2025}, author = {Labaf, M and Han, W and Zhang, S and Liu, M and Patten, ND and Li, M and Patalano, S and Macoska, JA and Balk, SP and Han, D and Zarringhalam, K and Cai, C}, title = {Heterogeneous Responses to High-Dose Testosterone in Castration-Resistant Prostate Cancer Tumors with Mixed Rb-Proficient and Rb-Deficient Cells.}, journal = {Molecular cancer therapeutics}, volume = {}, number = {}, pages = {OF1-OF12}, doi = {10.1158/1535-7163.MCT-24-0716}, pmid = {40116305}, issn = {1538-8514}, support = {R01CA211350//National Cancer Institute (NCI)/ ; U54CA156734//National Cancer Institute (NCI)/ ; P50CA090381//National Cancer Institute (NCI)/ ; W81XWH-19-1-0361//U.S. Department of Defense (DOD)/ ; HT9425-24-1-0472//U.S. Department of Defense (DOD)/ ; }, abstract = {Androgen deprivation therapy remains a cornerstone in managing prostate cancer. However, its recurrence often leads to the more aggressive castration-resistant prostate cancer (CRPC). Although second-line androgen receptor signaling inhibition treatments such as enzalutamide and abiraterone are available, their effectiveness against CRPC is only transient. High-dose testosterone (Hi-T) has recently emerged as a promising treatment for CRPC, primarily through the suppression of E2F and MYC signaling. However, the roles of Rb family proteins in influencing this therapeutic response remain debated. In this study, we utilized a CRPC patient-derived xenograft model that includes both Rb pathway-proficient and -deficient cell populations based on the positive or negative expression of RB family genes. Single-cell RNA sequencing analysis revealed that Rb-proficient cells displayed a robust response to Hi-T, whereas Rb-deficient cells exhibited significant resistance. Notably, our analysis indicated increased enrichment of the hypoxia signature in the Rb-deficient cell population. Further studies in RB1-silenced CRPC cell lines showed that treatment with a hypoxia-inducible factor-1α inhibitor can restore the sensitivity of Rb-deficient cells to high-dose dihydrotestosterone treatment. In conclusion, our research provides new molecular insights into CRPC tumor cell responses to Hi-T and proposes a new strategy to resensitize Rb-deficient CRPC cells to Hi-T treatment.}, }
@article {pmid40115173, year = {2025}, author = {Ghobadi, A and Caimi, PF and Reese, JS and Goparaju, K and di Trani, M and Ritchey, J and Jackson, Z and Tomlinson, B and Schiavone, JM and Kleinsorge-Block, S and Zamborsky, K and Eissenberg, L and Schneider, D and Boughan, KM and Zabor, EC and Metheny, L and Gallogly, M and Kruger, W and Kadan, M and Worden A S, A and Sharma, A and Cooper, BW and Otegbeye, F and Sekaly, RP and Wald, DN and Carlo-Stella, C and DiPersio, J and Orentas, R and Dropulic, B and de Lima, M}, title = {Treatment of non-Hodgkin lymphoma with point-of-care manufactured CAR T cells: a dual institution, phase 1 trial.}, journal = {EClinicalMedicine}, volume = {81}, number = {}, pages = {103138}, pmid = {40115173}, issn = {2589-5370}, abstract = {BACKGROUND: Point-of-care manufacture of chimeric antigen receptor (CAR)-T cells can significantly reduce the time from apheresis to infusion. We conducted a dual-institution phase I trial aimed evaluating the safety and feasibility of this manufacturing model.<br><br>METHODS: CASE 2417 was a phase I clinical trial. Adults with relapsed or refractory CD19 positive non-Hodgkin lymphoma (R/R NHL) treated with &#x2265;2 prior systemic therapies were eligible. MB-CART-19 is an anti-CD19 CAR T-cell product manufactured using the CliniMACS Prodigy device with 4-1BB and CD3&#x3b6; costimulatory domains. Lymphodepletion included fludarabine 25&#xa0;mg/m[2] for 3 days and cyclophosphamide 60&#xa0;mg/kg for 1 day. Prophylactic tocilizumab was allowed. Three dose levels (0.5, 1.0 and 2.0&#xa0;&#xd7;&#xa0;10[6]&#xa0;cells/kg) were tested using a 3&#xa0;+&#xa0;3 dose-escalation schema. The primary outcome of this study was to determine the safety as defined by the dose limiting toxicities of MB-CART-19 in patients with relapsed and refractory NHL, co-primary outcome was determining the phase 2 dose of MB-CART-19. Secondary outcomes include defining the toxicity profile and to evaluate the initial efficacy of MB-CART-19 against relapsed or refractory NHL. This study was registered in ClinicalTrials.govNCT03434769.<br><br>FINDINGS: Thirty-one patients were enrolled between July 2018 and January 2021. Twenty-four (77%) had aggressive lymphoma, 7 (24%) had indolent lymphoma (follicular lymphoma and marginal zone lymphoma). The median number of previous therapies was 5 (range 2-13, interquartile range [IQR] 3-5). All enrolled patients received MB-CART-19. Median apheresis to infusion time was 13 days (range 9-20, IQR 9-13). One dose limiting toxicity (DLT) was observed in dose escalation (fatal cytokine release syndrome [CRS]), whereas one patient died in dose expansion secondary to hemophagocytic syndrome. Both deaths were considered treatment-related. Twenty (65%) patients had CRS, three (10%) grade &#x2265;3. Ten patients (32%) experienced immune effector cell neurotoxicity syndrome (ICANS), four (13%) grade &#x2265;3. Neutropenia (n&#xa0;=&#xa0;28, 90%), thrombocytopenia (n&#xa0;=&#xa0;15, 48%) and anaemia (n&#xa0;=&#xa0;13, 42%) were the most frequent grade &#x2265;3 adverse events. Twenty-five out of 29 (86%, 95% confidence interval [CI]: 68-96%) response-evaluable patients had disease response and 22 (76%, 95% CI: 56-90%) had complete response; the overall and complete response rates for response-evaluable aggressive lymphoma patients (n&#xa0;=&#xa0;22) were 82% (n&#xa0;=&#xa0;18, 95% CI: 60-95%) and 73% (n&#xa0;=&#xa0;16, 95% CI: 50-89%). Median follow up was 24.5 (IQR 17-32) months, median progression free survival (PFS) was 26 months (95% CI: 19-not reached [NR]) and median PFS was not reached (95% CI: 25 months-NR). Two-year estimates of PFS and overall survival (OS) were 63% (95% CI: 47-83%) and 68% (95% CI: 52-88%), respectively. Median PFS was 26 months (95% CI: 7-NR) for aggressive lymphoma patients with 2-year PFS estimate of 53% (95% CI: 36-78%), while median OS had not been reached for aggressive lymphoma patients (95% CI: 19 months-NR), and 2-year OS estimate was 60% (95% CI: 43-85%).<br><br>INTERPRETATION: Point-of-care CAR T-cell manufacture was feasible and replicable across sites. MB-CART-19 has a safety profile comparable to other CAR T-cell products and high response rates. The recommended phase 2 dose is 2&#xa0;&#xd7;&#xa0;10[6]&#xa0;MB-CART-19&#xa0;cells/kg. Short CAR T-cell manufacturing time permits treatment of patients with rapidly progressive lymphoma, a group of patients with high risk disease for whom access to autologous immune effector cellular therapies is usually limited.<br><br>FUNDING: This clinical trial was funded through University Hospitals Seidman Cancer Center and Washington University School of Medicine Institutional Funds. Correlative analyses were funded in part by the European Union-Next Generation EU-NRRP M6C2-Investment 2.1 Enhancement and strengthening of biomedical research in the NHS (project #PNRR-MAD-2022-12376059), and the Italian Ministry of Health Ricerca Finalizzata 2019 (project #RF-2019-12370243).}, }
@article {pmid40114218, year = {2025}, author = {Takeuchi, T and Flannery, AH and Liu, LJ and Ghazi, L and Cama-Olivares, A and Fushimi, K and Chen, J and Huen, SC and Tolwani, AJ and Neyra, JA}, title = {Epidemiology of sepsis-associated acute kidney injury in the ICU with contemporary consensus definitions.}, journal = {Critical care (London, England)}, volume = {29}, number = {1}, pages = {128}, pmid = {40114218}, issn = {1466-609X}, support = {K23DK128562/DK/NIDDK NIH HHS/United States ; R01DK128208//National Institute of Diabetes and Digestive and Kidney Diseases,United States/ ; }, mesh = {Humans ; *Acute Kidney Injury/epidemiology/etiology/diagnosis ; *Sepsis/epidemiology/complications ; *Intensive Care Units/organization &amp; administration/statistics &amp; numerical data ; Male ; Female ; Retrospective Studies ; Middle Aged ; Aged ; *Consensus ; Cohort Studies ; Hospital Mortality ; Adult ; }, abstract = {BACKGROUND: The definition of sepsis-associated acute kidney injury (SA-AKI) was updated in 2023. This study aims to describe the epidemiology of SA-AKI using updated consensus definition and to evaluate clinical outcomes.<br><br>METHODS: The study was a retrospective cohort analysis conducted at two academic medical centers. Adult patients admitted to intensive care units (ICU) between 2010 and 2022 were included and categorized as SA-AKI, sepsis alone, or AKI alone. SA-AKI was further classified by time of onset (early&#x2009;<&#x2009;2&#xa0;days from sepsis diagnosis vs. late 2-7&#xa0;days following sepsis diagnosis) and presence of septic shock. Clinical outcomes included hospital mortality and major adverse kidney events (MAKE&#x2009;=&#x2009;death, kidney replacement therapy, or reduced kidney function from baseline) at discharge.<br><br>RESULTS: 187,888 adult ICU patients were included, and SA-AKI was found in nearly half of sepsis patients and about 1 in 6 ICU admissions. 1 in 4 patients with SA-AKI died during hospitalization and 37.7% experienced at least one MAKE by hospital discharge. Compared to sepsis or AKI alone, SA-AKI was associated with higher mortality (adjusted HR 1.59; 95% CI 1.51-1.66) and higher odds of MAKE (adjusted OR 3.35; 95% CI 3.19-3.51). The early clinical phenotype of SA-AKI was most common, with incident AKI decreasing daily from sepsis onset. The presence of septic shock significantly worsened outcomes.<br><br>CONCLUSIONS: Applying updated consensus definitions highlights the high prevalence of SA-AKI in the ICU and its significant associated morbidity and mortality. Outcomes differ based on clinical phenotypes, including the timing of SA-AKI onset and the presence of shock.}, }
@article {pmid40112242, year = {2025}, author = {Abida, W and Beltran, H and Raychaudhuri, R}, title = {State of the Art: Personalizing Treatment for Patients With Metastatic Castration-Resistant Prostate Cancer.}, journal = {American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting}, volume = {45}, number = {3}, pages = {e473636}, doi = {10.1200/EDBK-25-473636}, pmid = {40112242}, issn = {1548-8756}, mesh = {Humans ; Male ; *Prostatic Neoplasms, Castration-Resistant/drug therapy/pathology ; *Precision Medicine ; Neoplasm Metastasis ; Biomarkers, Tumor ; Molecular Targeted Therapy ; }, abstract = {Until recently, the treatment of metastatic castration-resistant prostate cancer (mCRPC) relied exclusively on hormonal therapies and taxane chemotherapy. The advent of modern molecular profiling methods applied in the clinic, namely, next-generation sequencing and advanced positron emission tomography (PET) imaging, has allowed for the development of biomarker-driven therapeutics including anti-PD-L1 therapy for microsatellite instability-high or tumor mutation burden-high disease, poly(ADP-ribose) polymerase (PARP) inhibitors for patients with DNA damage repair mutations, and lutetium 177 vipivotide tetraxetan ([177]Lu-PSMA-617) for patients with prostate-specific membrane antigen (PSMA) PET-avid disease. While these targeted therapies have improved outcomes, there is an opportunity to refine biomarkers to optimize patient selection, understand resistance, and develop novel combination strategies. In addition, studies in the laboratory and in patient-derived samples have shown that a subset of mCRPC tumors lose expression of common prostate cancer markers such as prostate-specific antigen and PSMA because of lineage plasticity and the development of non-androgen receptor (AR)-driven disease. Non-AR-driven prostate cancer has been associated with aggressive behavior and poor prognosis, including in some cases histologic transformation to a poorly differentiated neuroendocrine prostate cancer (NEPC). The clinical management of NEPC typically follows the treatment paradigm for small cell lung cancer and increasingly relies on genomic and phenotypic characterization of disease, including loss of tumor suppressors and expression of cell surface markers such as DLL3. Therefore, both genomic subtyping and phenotypic subtyping are important to consider and can guide the clinical management of patients with advanced prostate cancer.}, }
@article {pmid40111318, year = {2025}, author = {Yeh, JM and Ward, ZJ and Stratton, KL and McMahon, MV and Taylor, CS and Armstrong, GT and Chow, EJ and Hudson, MM and Morton, LM and Oeffinger, KC and Diller, LR and Leisenring, WM}, title = {Accelerated Aging in Survivors of Childhood Cancer-Early Onset and Excess Risk of Chronic Conditions.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, pmid = {40111318}, issn = {2374-2445}, abstract = {IMPORTANCE: The lifetime risk of aging-related diseases among survivors of childhood cancer, accelerated by cancer treatment exposures, is unknown. Understanding this risk can provide a more comprehensive assessment of long-term health across the lifespan of survivors and guide adult care.<br><br>OBJECTIVE: To estimate the lifetime risks of 8 treatment-related cancers and cardiovascular conditions among childhood cancer survivors and compare them with the general population.<br><br>DESIGN, SETTING, PARTICIPANTS: Using data from the Childhood Cancer Survivor Study and national databases, this simulation modeling study projected long-term outcomes for 5-year survivors diagnosed between 1970 and 1999 based on treatment exposures and age-related risks. The general population comparator was simulated using age-, sex-, and calendar year-matched individuals who faced only age-related risks.<br><br>EXPOSURES: Treatment era (1970s, 1980s, 1990s), original cancer diagnosis, radiation treatment for primary diagnosis (any, none).<br><br>MAIN OUTCOMES AND MEASURES: Estimated lifetime risks of 8 health conditions (breast cancer, colorectal cancer, glial tumors, sarcomas, heart failure, coronary heart disease/myocardial infarction, stroke, and valvular disease). Risks were projected and compared with the general population, stratified by radiation exposure.<br><br>RESULTS: In the general population, 20% developed at least 1 health condition by age 65.0 years; in 5-year survivors this threshold was reached at age 47.3 years, representing a 17.7-year (95% uncertainty interval [UI], 14.0-21.0) acceleration in disease onset. By age 65 years, 55% of survivors were projected to develop at least 1 condition, indicating a 2.7-fold (95% UI, 2.2-3.5) higher relative risk and 34.2% (95% UI, 28.3-42.5) absolute excess risk compared with the general population. Risks were higher among those treated with radiation therapy for childhood cancer (22.0 years earlier onset [95% UI, 18.0-25.0]; 37.3% excess risk [95% UI, 31.6%-44.7%]) but still elevated for those without radiation exposure (13.5 years earlier onset [95% UI, 10.0-16.0]; 31.0% excess risk [95% UI, 23.9%-40.3%]). Reaching middle age was still associated with increased health risks. Compared with the general population, survivors who reached age 40 years had a 6.2-fold higher risk (95% UI, 4.8-9.4) of developing a new condition within 10 years.<br><br>CONCLUSIONS AND RELEVANCE: This study found that survivors of childhood cancer experience accelerated onset of aging-related diseases, regardless of prior radiation exposure. These findings underscore the importance of prioritizing cancer and cardiovascular disease prevention among survivors decades earlier than for the general population.}, }
@article {pmid40109220, year = {2025}, author = {Yeung, CC and Jones, DC and Woolston, DW and Seaton, B and Donato, EL and Lin, M and Backman, C and Oehler, V and Robinson, KL and Shimp, K and Kulikauskas, R and Long, AN and Sowerby, D and Elz, AE and Smythe, KS and Newell, EW}, title = {Spatial proteomics and transcriptomics characterization of tissue and multiple cancer types including decalcified marrow.}, journal = {Cancer biomarkers : section A of Disease markers}, volume = {42}, number = {1}, pages = {18758592241308757}, doi = {10.1177/18758592241308757}, pmid = {40109220}, issn = {1875-8592}, mesh = {Humans ; *Proteomics/methods ; *Bone Marrow/metabolism/pathology ; *Neoplasms/genetics/pathology/metabolism ; Transcriptome ; Gene Expression Profiling/methods ; Tissue Array Analysis/methods ; Biomarkers, Tumor/genetics/metabolism ; Immunohistochemistry/methods ; Decalcification Technique/methods ; Paraffin Embedding ; Tissue Fixation/methods ; }, abstract = {BackgroundRecent technologies enabling the study of spatial biology include multiple high-dimensional spatial imaging methods that have rapidly emerged with different capabilities evaluating tissues at different resolutions for different sample formats. Platforms like Xenium (10x Genomics) and PhenoCycler-Fusion (Akoya Biosciences) enable single-cell resolution analysis of gene and protein expression in archival FFPE tissue slides. However, a key limitation is the absence of systematic methods to ensure tissue quality, marker integrity, and data reproducibility.ObjectiveWe seek to optimize the technical methods for spatial work by addressing preanalytical challenges with various tissue and tumor types, including a decalcification protocol for processing FFPE bone marrow core specimens to preserve nucleic acids for effective spatial proteomics and transcriptomics. This study characterizes a multicancer tissue microarray (TMA) and a molecular- and protein-friendly decalcification protocol that supports downstream spatial biology investigations.MethodsWe developed a multi-cancer tissue microarray (TMA) and processed bone marrow core samples using a molecular- and protein-friendly decalcification protocol. PhenoCycler high-plex immunohistochemistry (IHC) generated spatial proteomics data, analyzed with QuPath and single-cell analysis. Xenium provided spatial transcriptomics data, analyzed via Xenium Explorer and custom pipelines.ResultsResults showed that PhenoCycler and Xenium platforms applied to TMA sections of tonsil and various tumor types achieved good marker concordance. Bone marrow decalcification with our optimized protocol preserved mRNA and protein markers, allowing Xenium analysis to resolve all major cell types while maintaining tissue morphology.ConclusionsWe have shared our preanalytical verification of tissues and demonstrate that both the PhenoCycler-Fusion high-plex spatial proteomics and Xenium spatial transcriptomics platforms work well on various tumor types, including marrow core biopsies decalcified using a molecular- and protein-friendly decalcificationprotocol. We also demonstrate our laboratory's methods for systematic quality assessment of the spatial proteomic and transcriptomic data from these platforms, such that either platform can provide orthogonal confirmation for the other.}, }
@article {pmid40109218, year = {2025}, author = {Tang, TM and Zhang, Y and Kenney, AM and Xie, C and Xiao, L and Siddiqui, J and Srivastava, S and Sanda, MG and Wei, JT and Feng, Z and Tosoian, JJ and Zheng, Y and Chinnaiyan, AM and Yu, B and , }, title = {A simplified MyProstateScore2.0 for high-grade prostate cancer.}, journal = {Cancer biomarkers : section A of Disease markers}, volume = {42}, number = {1}, pages = {18758592241308755}, doi = {10.1177/18758592241308755}, pmid = {40109218}, issn = {1875-8592}, mesh = {Humans ; Male ; *Prostatic Neoplasms/genetics/diagnosis ; *Biomarkers, Tumor/genetics ; *Neoplasm Grading ; Prostate-Specific Antigen/blood ; }, abstract = {Background: The limited diagnostic accuracy of prostate-specific antigen screening for prostate cancer (PCa) has prompted innovative solutions, such as the state-of-the-art 18-gene urine test for clinically-significant PCa (MyProstateScore2.0 (MPS2)). Objective: We aim to develop a non-invasive biomarker test, the simplified MPS2 (sMPS2), which achieves similar state-of-the-art accuracy as MPS2 for predicting high-grade PCa but requires substantially fewer genes than the 18-gene MPS2 to improve its accessibility for routine clinical care. Methods: We grounded the development of sMPS2 in the Predictability, Computability, and Stability (PCS) framework for veridical data science. Under this framework, we stress-tested the development of sMPS2 across various data preprocessing and modeling choices and developed a stability-driven PCS ranking procedure for selecting the most predictive and robust genes for use in sMPS2. Results: The final sMPS2 model consisted of 7 genes and achieved a 0.784 AUROC (95% confidence interval, 0.742-0.825) for predicting high-grade PCa on a blinded external validation cohort. This is only 2.3% lower than the 18-gene MPS2, which is similar in magnitude to the 1-2% in uncertainty induced by different data preprocessing choices. Conclusions: The 7-gene sMPS2 provides a unique opportunity to expand the reach and adoption of non-invasive PCa screening.}, }
@article {pmid40109190, year = {2025}, author = {Curran, E and Luskin, MR and Alachkar, H and Aldoss, I and Burke, PW and Cassaday, RD and Karol, SE and Perissinotti, AJ and Rank, CU and Schmiegelow, K and Webster, J and Douer, D}, title = {Recognition, prevention, and management of adverse events associated with asparaginase / pegaspargase treatment of acute lymphoblastic leukemia in adults: consensus of an expert panel.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2024.286744}, pmid = {40109190}, issn = {1592-8721}, abstract = {Asparaginase (ASNase)-based chemotherapy regimens significantly improve survival outcomes in children, adolescent and young adult (AYA), and even adults with acute lymphoblastic leukemia/lymphoma (ALL); however, the incidence and severity of ASNase-associated adverse events (AEs) in adults may differ significantly from those reported in children. Strategies to mitigate, monitor for, and manage toxicities that allow adult ALL patients to receive full ASNase courses are needed. A representative 12-member panel of experts who treat AYA and adult ALL patients, incorporate ASNase into their treatment regimens, and conduct related research was assembled to consider opportunities to optimize the use of pediatric-inspired ALL regimens in these adult patients. Following 2 systematic biomedical literature searches from April 2009 through April 2024, a modified Delphi method was used to distill expert opinion into clinical statements that met a standardized definition of consensus. After 2 iterative Delphi method surveys, 23 statements met the standardized definition of consensus, whereas 19 statements did not. Five statements were merged to avoid redundancy. The clinical statements were grouped into 5 distinct categories: 1) hepatotoxicity; 2) hypersensitivity reactions; 3) thromboembolic and coagulopathy complications; 4) pancreatitis and metabolic complications; and 5) dosing. The intent of these statements is to provide health care providers with information that will help them mitigate, monitor for, and manage the most common and/or unique ASNase-induced AEs in adult ALL patients, allowing these patients to receive more or all the planned ASNase doses and thereby improve outcomes.}, }
@article {pmid40108454, year = {2025}, author = {Pae, J and Schwan, N and Ottino-Loffler, B and DeWitt, WS and Garg, A and Bortolatto, J and Vora, AA and Shen, JJ and Hobbs, A and Castro, TBR and Mesin, L and Matsen, FA and Meyer-Hermann, M and Victora, GD}, title = {Transient silencing of hypermutation preserves B cell affinity during clonal bursting.}, journal = {Nature}, volume = {}, number = {}, pages = {}, pmid = {40108454}, issn = {1476-4687}, abstract = {In the course of antibody affinity maturation, germinal centre (GC) B cells mutate their immunoglobulin heavy- and light-chain genes in a process known as somatic hypermutation (SHM)[1-4]. Panels of mutant B cells with different binding affinities for antigens are then selected in a Darwinian manner, which leads to a progressive increase in affinity among the population[5]. As with any Darwinian process, rare gain-of-fitness mutations must be identified and common loss-of-fitness mutations avoided[6]. Progressive acquisition of mutations therefore poses a risk during large proliferative bursts[7], when GC B cells undergo several cell cycles in the absence of affinity-based selection[8-13]. Using a combination of in vivo mouse experiments and mathematical modelling, here we show that GCs achieve this balance by strongly suppressing SHM during clonal-burst-type expansion, so that a large fraction of the progeny generated by these bursts does not deviate from their ancestral genotype. Intravital imaging and image-based cell sorting of a mouse strain carrying a reporter of cyclin-dependent kinase 2 (CDK2) activity showed that B cells that are actively undergoing proliferative bursts lack the transient CDK2[low] 'G0-like' phase of the cell cycle in which SHM takes place. We propose a model in which inertially cycling B cells mostly delay SHM until the G0-like phase that follows their final round of division in the GC dark zone, thus maintaining affinity as they clonally expand in the absence of selection.}, }
@article {pmid40061317, year = {2025}, author = {Fuller, H and Agasaro, OP and Darst, BF}, title = {Pre-diagnostic circulating metabolomics and prostate cancer risk: A systematic review and meta-analysis.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40061317}, support = {P50 CA097186/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Metabolomic dysregulation contributes to prostate cancer (PCa) pathogenesis, and studies suggest that circulating metabolites have strong clinical potential to act as biomarkers. However, evidence of circulating metabolite associations has not been quantitively aggregated.<br><br>METHODS: Systematic searches were performed in PubMed and Embase (October 17[th], 2024) to identify pre-diagnostic untargeted serum metabolomic studies of PCa risk. After harmonizing metabolite names across studies, restricted maximum likelihood was used to conduct meta-analyses to quantify associations between metabolites and risk of overall PCa, low- to intermediate-risk PCa, high- to very high-risk PCa and lethal PCa, as defined by the NCCN. Statistical significance was defined as FDR-adjusted P<0.05. Enrichment analyses were conducted on significant metabolites to identify biologically relevant pathways. Correlation of effect estimates between PCa outcomes was assessed via Pearson correlation.<br><br>RESULTS: We identified 12 untargeted pre-diagnostic circulating metabolomic studies in a systematic review and meta-analyzed associations between up to 408 metabolites with four PCa outcomes. Three, eleven and nineteen metabolites were significantly associated with risk of overall, high/very high-risk and lethal PCa, respectively. Metabolites associated with high/very high-risk PCa were significantly enriched for lipids. Limited evidence of correlation between metabolite effects across outcomes was identified, highlighting potentially unique metabolite drivers of high-risk and lethal PCa. Follow-up analyses found that 13 of the significant metabolites were drug and/or dietary modifiable.<br><br>CONCLUSIONS: These findings suggest the strong potential for metabolites to inform risk of lethal PCa, which could inform risk-stratified screening strategies and facilitate the identification of targets for PCa prevention.}, }
@article {pmid40108332, year = {2025}, author = {Shah, BD and Cassaday, RD and Park, JH and Houot, R and Logan, AC and Boissel, N and Leguay, T and Bishop, MR and Topp, MS and O'Dwyer, KM and Tzachanis, D and Arellano, ML and Lin, Y and Baer, MR and Schiller, GJ and Subklewe, M and Abedi, M and Minnema, MC and Wierda, WG and DeAngelo, DJ and Stiff, P and Jeyakumar, D and Mao, D and Adhikary, S and Zhou, L and Hadjivassileva, T and Damico Khalid, R and Ghobadi, A and Oluwole, OO}, title = {Three-year analysis of adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia treated with brexucabtagene autoleucel in ZUMA-3.}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, pmid = {40108332}, issn = {1476-5551}, abstract = {Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 CAR T-cell therapy approved in the US to treat adults aged ≥18 years (≥26 years in the EU) with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). Brexu-cel showed an overall complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate of 73% (CR rate 60%) and median overall survival (OS) of 25.4 months in 78 patients with R/R B-ALL after 2 years in ZUMA-3. Here, we report updated outcomes after >3 years median follow-up. As of July 23, 2022, median follow-up in all patients (N = 78) was 41.6 months. Median OS (95% CI) was 25.6 months (1.2-47.0; N = 78) and was 38.9 months (25.4-not estimable) for responders (n = 58), with 9 patients in ongoing remission without subsequent therapies. Five deaths (none deemed brexu-cel-related) occurred since prior data cut. Benefits from brexu-cel were maintained regardless of age, prior therapies, and subsequent allogeneic stem cell transplantation (alloSCT). Subsequent alloSCT was not associated with survival benefit among responders versus responders without subsequent alloSCT. No secondary T-cell malignancies were reported in ZUMA-3 with long-term follow-up.}, }
@article {pmid40107155, year = {2025}, author = {Gupta, S and Climent Duran, MA and Sridhar, SS and Powles, T and Bellmunt, J and Park, SH and Gurney, H and Tsuchiya, N and Petrylak, DP and Tomita, Y and di Pietro, A and Manitz, J and Tyroller, K and Hoffman, J and Jacob, N and Grivas, P}, title = {Avelumab first-line maintenance for advanced urothelial carcinoma: long-term outcomes from the JAVELIN Bladder 100 trial in older patients.}, journal = {ESMO open}, volume = {10}, number = {4}, pages = {104506}, doi = {10.1016/j.esmoop.2025.104506}, pmid = {40107155}, issn = {2059-7029}, abstract = {BACKGROUND: In the JAVELIN Bladder 100 phase III trial, avelumab first-line (1L) maintenance plus best supportive care (BSC) significantly prolonged overall survival (OS) versus BSC alone in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) without progression following platinum-based chemotherapy. Older age (≥65 years) is a known risk factor for bladder cancer with a median age at diagnosis of 73.0 years. We report exploratory analyses in subgroups based on older age (≥65 years).<br><br>MATERIALS AND METHODS: Eligible patients with la/mUC without progression after 1L platinum-based chemotherapy were randomized to receive avelumab plus BSC (n&#xa0;= 350) or BSC alone (n&#xa0;= 350). This exploratory analysis included subgroups aged &#x2265;65 years, &#x2265;65-<75 years, &#x2265;75 years, and the subset aged &#x2265;80 years. OS (primary endpoint) and progression-free survival (PFS) from randomization were analyzed using the Kaplan-Meier method.<br><br>RESULTS: Of 700 patients, 464 (66.3%) were aged &#x2265;65 years. Median OS with avelumab plus BSC versus BSC alone was 26.1 versus 15.5 months (hazard ratio 0.70, 95% confidence interval 0.56-0.89) in all patients aged &#x2265;65 years and 28.7 versus 17.1, 24.0 versus 13.5, and 24.9 versus 10.0 months, respectively, in patients aged &#x2265;65-<75, &#x2265;75, and &#x2265;80 years. PFS analyses favored avelumab plus BSC versus BSC alone in all subgroups. No new safety concerns were identified in patients aged &#x2265;65 years, including those treated for &#x2265;12 months. Quality-adjusted time without symptoms or toxicity was 4.57 months longer with avelumab plus BSC versus BSC alone (a 30.35% relative improvement). Limitations include small sample size for the &#x2265;80-year age subgroup and the exploratory design.<br><br>CONCLUSIONS: These exploratory analyses support the efficacy and tolerability of avelumab 1L maintenance in patients aged &#x2265;65 years with la/mUC that has not progressed following chemotherapy, suggesting that older age should not solely prevent a patient from receiving avelumab 1L maintenance.}, }
@article {pmid40106531, year = {2025}, author = {Haring, B and Aragaki, AK and Shimbo, D and Rapp, SR and Eaton, CB and LaMonte, MJ and Wactawski-Wende, J and Allison, MA and Shadyab, AH and Rossouw, JE and Whitsel, EA and Franceschini, N and Kooperberg, C and Desai, P and Simon, MS and Böhm, M and Natarajan, P and Wassertheil-Smoller, S and Manson, JE}, title = {Clonal Hematopoiesis of Indeterminate Potential and Incident Hypertension: Results From the Women's Health Initiative.}, journal = {Hypertension (Dallas, Tex. : 1979)}, volume = {82}, number = {4}, pages = {e70-e72}, pmid = {40106531}, issn = {1524-4563}, support = {75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; R01 HL148565/HL/NHLBI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; }, }
@article {pmid40106482, year = {2025}, author = {Soneson, C and Shepherd, L and Ramos, M and Rue-Albrecht, K and Rainer, J and Pagès, H and Carey, VJ}, title = {Eleven quick tips for writing a Bioconductor package.}, journal = {PLoS computational biology}, volume = {21}, number = {3}, pages = {e1012856}, pmid = {40106482}, issn = {1553-7358}, }
@article {pmid40104982, year = {2025}, author = {Chen, YA and Kazerouni, AS and Phelps, MD and Hippe, DS and Youn, I and Lee, JM and Partridge, SC and Rahbar, H}, title = {Time to Enhancement Measured From Ultrafast Dynamic Contrast-Enhanced MRI for Improved Breast Lesion Diagnosis.}, journal = {Journal of breast imaging}, volume = {}, number = {}, pages = {}, doi = {10.1093/jbi/wbae089}, pmid = {40104982}, issn = {2631-6129}, support = {R01CA207290, R01CA203883, and K99CA293004/CA/NCI NIH HHS/United States ; }, abstract = {OBJECTIVE: Breast MRI affords high sensitivity with intermediate specificity for cancer detection. Ultrafast dynamic contrast-enhanced (DCE) MRI assesses early contrast inflow with potential to supplement or replace conventional DCE-MRI kinetic features. We sought to determine whether radiologist's evaluation of ultrafast DCE-MRI can increase specificity of a clinical MRI protocol.<br><br>METHODS: In this IRB-approved, HIPAA-compliant study, breast MRIs from March 2019 to August 2020 with a BI-RADS category 3, 4, or 5 lesion were identified. Ultrafast DCE-MRI was acquired during the first 40 seconds after contrast injection and before conventional DCE-MRI postcontrast acquisitions in the clinical breast MRI protocol. Three radiologists masked to outcomes retrospectively determined lesion time to enhancement (TTE) on ultrafast DCE-MRI. Interreader agreement, differences between benign and malignant lesion TTE, and TTE diagnostic performance were evaluated.<br><br>RESULTS: Ninety-five lesions (20 malignant, 75 benign) were included. Interreader agreement in TTE was moderate to substantial for both ultrafast source images and subtraction maximum intensity projections (overall &#x3ba;&#x2009;=&#x2009;0.63). Time to enhancement was greater across benign lesions compared with malignancies (P&#x2009;<.05), and all lesions demonstrating no enhancement during the ultrafast series were benign. With a threshold TTE&#x2009;&#x2265;40 seconds, ultrafast DCE-MRI yielded an average 40% specificity (95% CI, 30%-48%) and 92% sensitivity (95% CI, 81%-100%), yielding a potential reduction in 31% (95% CI, 23%-39%) of benign follow-ups based on conventional DCE-MRI.<br><br>CONCLUSION: Ultrafast imaging can be added to conventional DCE-MRI to increase diagnostic accuracy while adding minimal scan time. Future work to standardize evaluation criteria may improve interreader agreement and allow for more robust ultrafast DCE-MRI assessment.}, }
@article {pmid40103823, year = {2025}, author = {Tisoncik-Go, J and Lewis, TB and Whitmore, LS and Voss, K and Niemeyer, S and Dai, J and Kim, P and Hubbell, K and Iwayama, N and Ahrens, C and Wangari, S and Murnane, R and Edlefsen, PT and Guerriero, KA and Gale, M and Fuller, DH and O'Connor, MA}, title = {Persistent innate immune dysfunction and ZIKV replication in the gastrointestinal tract during SIV infection in pigtail macaques.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1535807}, pmid = {40103823}, issn = {1664-3224}, support = {P51 OD010425/OD/NIH HHS/United States ; U19 AI113173/AI/NIAID NIH HHS/United States ; U42 OD011123/OD/NIH HHS/United States ; R01 AI145296/AI/NIAID NIH HHS/United States ; K01 MH123258/MH/NIMH NIH HHS/United States ; UL1 TR000423/TR/NCATS NIH HHS/United States ; }, mesh = {Animals ; *Immunity, Innate ; *Simian Acquired Immunodeficiency Syndrome/immunology/virology ; *Simian Immunodeficiency Virus/immunology/physiology ; *Virus Replication ; *Zika Virus Infection/immunology/virology ; *Zika Virus/immunology/physiology ; *Gastrointestinal Tract/immunology/virology ; *Macaca nemestrina ; Viremia/immunology ; Disease Models, Animal ; Leukocytes, Mononuclear/immunology ; Coinfection/immunology ; Humans ; }, abstract = {Mosquito-borne flaviviruses, including dengue (DENV) and Zika (ZIKV) viruses, have caused widespread epidemics in areas with high HIV prevalence, partly due to the expanded geographic range of arthropod vectors. Despite the occurrence of large flavivirus outbreaks in areas with high HIV prevalence, little is known about the effects of flavivirus infection in people living with HIV (PLWH). Here, we use a pigtail macaque model of HIV/AIDS to investigate the impact of simian immunodeficiency virus (SIV)-induced immunosuppression on ZIKV replication and pathogenesis. During acute SIV infection, peripheral ZIKV cellular targets expanded and innate immune activation increased. In vitro, peripheral blood mononuclear cells (PBMC) from SIV infected pigtail macaques were less permissive to ZIKV infection. In vivo, ZIKV viremia was delayed and ZIKV was more persistent in the gastrointestinal tissues of SIV-ZIKV co-infected animals. This persistence was associated with changes in innate cellular (monocytes, neutrophils) recruitment to the blood and tissues, reduced anti-ZIKV immunity, and sustained expression of peripheral inflammatory and innate immune genes. Collectively, these findings uniquely suggest that untreated SIV infection may promote inflammatory cellular innate responses and create a state of persistent immune activation that contributes to prolonged ZIKV viremia and persistence in the gastrointestinal tract. Furthermore, these results suggest that PLWH and other immunocompromised individuals could be at higher risk for prolonged ZIKV infection, potentially extending the window of ZIKV transmission. These insights highlight the importance of including PLWH in strategies for deploying vaccines and treatments against ZIKV.}, }
@article {pmid40103753, year = {2025}, author = {Wolock, CJ and Gilbert, PB and Simon, N and Carone, M}, title = {Assessing variable importance in survival analysis using machine learning.}, journal = {Biometrika}, volume = {112}, number = {2}, pages = {asae061}, pmid = {40103753}, issn = {0006-3444}, abstract = {Given a collection of features available for inclusion in a predictive model, it may be of interest to quantify the relative importance of a subset of features for the prediction task at hand. For example, in HIV vaccine trials, participant baseline characteristics are used to predict the probability of HIV acquisition over the intended follow-up period, and investigators may wish to understand how much certain types of predictors, such as behavioural factors, contribute to overall predictiveness. Time-to-event outcomes such as time to HIV acquisition are often subject to right censoring, and existing methods for assessing variable importance are typically not intended to be used in this setting. We describe a broad class of algorithm-agnostic variable importance measures for prediction in the context of survival data. We propose a nonparametric efficient estimation procedure that incorporates flexible learning of nuisance parameters, yields asymptotically valid inference and enjoys double robustness. We assess the performance of our proposed procedure via numerical simulations and analyse data from the HVTN 702 vaccine trial to inform enrolment strategies for future HIV vaccine trials.}, }
@article {pmid40102030, year = {2025}, author = {Batalha, MA and LeCroy, MN and Lin, J and Peters, BA and Qi, Q and Wang, Z and Wang, T and Gallo, LC and Talavera, GA and McClain, AC and Thyagarajan, B and Daviglus, ML and Hou, L and Llabre, M and Cai, J and Kaplan, RC and Isasi, CR}, title = {Life-course socioeconomic position and the gut microbiome in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).}, journal = {Gut microbes}, volume = {17}, number = {1}, pages = {2479772}, doi = {10.1080/19490976.2025.2479772}, pmid = {40102030}, issn = {1949-0984}, mesh = {Humans ; *Gastrointestinal Microbiome ; *Hispanic or Latino/statistics &amp; numerical data ; Female ; Male ; Adult ; *Feces/microbiology ; Middle Aged ; United States/epidemiology ; Bacteria/classification/genetics/isolation &amp; purification ; Cohort Studies ; Young Adult ; Socioeconomic Factors ; Adolescent ; Child ; Social Class ; White ; }, abstract = {Socioeconomic position (SEP) in childhood and beyond may influence the gut microbiome, with implications for disease risk. Studies evaluating the relationship between life-course SEP and the gut microbiome are sparse, particularly among Hispanic/Latino individuals, who have a high prevalence of low SEP. We use the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a population-based cohort study conducted in four field centers in the United States (U.S.), to evaluate the association between life-course SEP and gut microbiome composition. Life-course SEP indicators included parental education (proxy of childhood SEP), current SEP (n = 2174), and childhood (n = 988) and current economic hardship (n = 994). Shotgun sequencing was performed on stool samples. Analysis of Compositions of Microbiomes was used to identify associations of life-course SEP indicators with gut microbiome species and functions. Parental education and current SEP were associated with the overall gut microbiome composition; however, parental education and current education explained more the gut microbiome variance than the current SEP. A lower parental education and current SEP were associated with a lower abundance of species from genus Bacteroides. In stratified analysis by nativity, we found similar findings mainly among foreign-born participants. Early-life SEP may have long-term effects on gut microbiome composition underscoring another biological mechanism linking early childhood factors to adult disease.}, }
@article {pmid40101246, year = {2025}, author = {Sorror, ML and Saber, W and Logan, BR and Geller, NL and Bellach, A and Kou, J and Wood, WA and McCarty, J and Knight, TG and Runaas, L and Johnston, LJ and Walston, JD and Nakamura, R and Jarrett, L and Mishra, A and Uberti, J and Dahi, PB and Saultz, JN and McCurdy, SR and Morris, LE and Imus, P and Hogan, WJ and Nadiminti, KVG and Bhatt, VR and Olin, RL and Maakaron, J and Sobecks, RM and Wall, SA and Mattila, D and Protz, B and Devine, SM and Horowitz, MM and Artz, AS}, title = {Novel Composite Health Assessment Risk Model for Older Allogeneic Transplant Recipients: BMT-CTN 1704.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025015793}, pmid = {40101246}, issn = {2473-9537}, abstract = {Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative for older adults with hematologic malignancies. Concerns about non-relapse mortality (NRM) in older adults limit allo-HCT utilization. We executed a prospective, observational study (BMT-CTN 1704) enrolling allo-HCT recipients aged ≥60 years from 49 centers in the U.S. We analyzed associations between 13 measurements of older adult health and NRM within 1-year to construct a comprehensive health assessment risk model (primary-CHARM) using amultivariate Fine-Gray model and grouped penalized variable selection. Two (Cox and pseudovalue Boosting) Machine-Learning (ML) models were also explored. Models' performances were compared using area under the receiver operating curve (AUC), with bootstrap and crossvalidation sampling to correct for optimism, decision-curve analysis (DCA), calibration, and Brierscores. Among 1105 patients with median age of 67 years (range 60-82) who received alloHCT, NRM was 14.4% and overall survival (OS), 71.7% at 1-year. Factors statistically selected for inclusion in primary-CHARM were: higher comorbidity-burden, lower albumin, higher Creactive protein, older age, higher weight loss percentage, lower patient-reported performance score, and cognitive impairment. Primary-CHARM scores were independently associated with higher NRM (hazard ratio [HR]:2.72, p<0.0001) and worse OS (HR:2.09, p<0.0001). Bootstrap bias-corrected AUC for primary-CHARM was 0.591. Comparing primary-CHARM to HCTcomorbidity index and 2 ML-CHARM models, calibration, Brier score, and DCA analysis favored primary-CHARM. The primary-CHARM, comprised of mostly simple and readily available parameters, risk-stratifies older adults for allo-HCT. Adopting primary-CHARM in practice maypromote broader use of HCT by quantifying risk and enhance the design of strategies to improve outcomes. Clinicaltrials.gov number: (NCT03992352).}, }
@article {pmid40100600, year = {2025}, author = {Graves, SS and Zellmer, E and Storb, R}, title = {Canine Hematopoietic Cell Transplantation for Graft-Versus-Host Disease.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2907}, number = {}, pages = {207-236}, pmid = {40100600}, issn = {1940-6029}, mesh = {*Graft vs Host Disease/therapy/prevention &amp; control ; Dogs ; Animals ; *Hematopoietic Stem Cell Transplantation/methods/adverse effects ; *Disease Models, Animal ; Transplantation Conditioning/methods ; Transplantation, Homologous/methods ; }, abstract = {Graft-versus-host disease (GVHD) is a risk of hematopoietic cell transplantation (HCT) in the clinical setting. The acute form of the disease is well managed, but the chronic form is more problematic. The canine HCT model, instrumental in establishing successful clinical HCT protocols, reproducibly recapitulates the clinical manifestations of GVHD. Thus, therapies for the prevention and treatment of GVHD in the canine model may be applicable to the clinic. Here, we present the methods necessary to establish both acute and chronic GVHD models in dogs.}, }
@article {pmid40093208, year = {2025}, author = {Zhao, K and Pershad, Y and Poisner, HM and Ma, X and Quade, K and Vlasschaert, C and Mack, T and Khankari, NK and von Beck, K and Brogan, J and Kishtagari, A and Corty, RW and Li, Y and Xu, Y and Reiner, AP and Scheet, P and Auer, PL and Bick, AG}, title = {Genetic drivers and clinical consequences of mosaic chromosomal alterations in 1 million individuals.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40093208}, support = {U01 HL120393/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; R01 AG083736/AG/NIA NIH HHS/United States ; T32 GM007347/GM/NIGMS NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; DP5 OD029586/OD/NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; }, abstract = {Mosaic chromosomal alterations of the autosomes (aut-mCAs) are large structural somatic mutations which cause clonal hematopoiesis and increase cancer risk. Here, we detected aut-mCAs in 1,011,269 participants across four biobanks. Through integrative analysis of the minimum critical region and inherited genetic variation, we found that proto-oncogenes exclusively drive chromosomal gains, tumor suppressors drive losses, and copy-neutral events can be driven by either. We identified three novel inherited risk loci in CHI3L2, HLA class II, and TERT that modulate aut-mCA risk and ten novel aut-mCA-specific loci. We found specific aut-mCAs are associated with cardiovascular, cerebrovascular, or kidney disease incidence. High-risk aut-mCAs were associated with elevated plasma protein levels of therapeutically actionable targets: NPM1, PARP1, and TACI. Participants with multiple high-risk features such as high clonal fraction, more than one aut-mCA, and abnormal red cell morphology had a 50% cumulative incidence of blood count abnormalities over 2 years. Leveraging inherited variation, we causally established aut-mCAs as premalignant lesions for chronic lymphocytic leukemia. Together, our findings provide a framework integrating somatic mosaicism, germline genetics, and clinical phenotypes to identify individuals who could benefit from preventative interventions.}, }
@article {pmid40093158, year = {2025}, author = {Latorre-Crespo, E and Robertson, NA and Kosebent, EG and MacGillivray, L and Murphy, L and Uddin, M and Whitsel, E and Honigberg, M and Bick, A and Reiner, AP and Orrù, V and Marongiu, M and Cucca, F and Fiorillo, E and Deary, IJ and Harris, S and Cox, S and Marioni, R and Schumacher, L and Chandra, T and Kirschner, K}, title = {Clinical progression of clonal hematopoiesis is determined by a combination of mutation timing, fitness, and clonal structure.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40093158}, issn = {2692-8205}, support = {/WT_/Wellcome Trust/United Kingdom ; U01 AG083829/AG/NIA NIH HHS/United States ; }, abstract = {Clonal hematopoiesis (CH) is characterized by expanding blood cell clones carrying somatic mutations in healthy aged individuals and is associated with various age-related diseases and all-cause mortality. While CH mutations affect diverse genes associated with myeloid malignancies, their mechanisms of expansion and disease associations remain poorly understood. We investigate the relationship between clonal fitness and clinical outcomes by integrating data from three longitudinal aging cohorts (n=713, observations=2,341). We demonstrate pathway-specific fitness advantage and clonal composition influence clonal dynamics. Further, the timing of mutation acquisition is necessary to determine the extent of clonal expansion reached during the host individual's lifetime. We introduce MACS120, a metric combining mutation context, timing, and variant fitness to predict future clonal growth, outperforming traditional variant allele frequency measurements in predicting clinical outcomes. Our unified analytical framework enables standardized clonal dynamics inference across cohorts, advancing our ability to predict and potentially intervene in CH-related pathologies.}, }
@article {pmid40093114, year = {2025}, author = {Visani, GM and Pun, MN and Minervina, AA and Bradley, P and Thomas, P and Nourmohammad, A}, title = {T-cell receptor specificity landscape revealed through de novo peptide design.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40093114}, issn = {2692-8205}, support = {R01 AI136514/AI/NIAID NIH HHS/United States ; R35 GM141457/GM/NIGMS NIH HHS/United States ; R35 GM142795/GM/NIGMS NIH HHS/United States ; }, abstract = {T-cells play a key role in adaptive immunity by mounting specific responses against diverse pathogens. An effective binding between T-cell receptors (TCRs) and pathogen-derived peptides presented on Major Histocompatibility Complexes (MHCs) mediate an immune response. However, predicting these interactions remains challenging due to limited functional data on T-cell reactivities. Here, we introduce a computational approach to predict TCR interactions with peptides presented on MHC class I alleles, and to design novel immunogenic peptides for specified TCR-MHC complexes. Our method leverages HERMES, a structure-based, physics-guided machine learning model trained on the protein universe to predict amino acid preferences based on local structural environments. Despite no direct training on TCR-pMHC data, the implicit physical reasoning in HERMES enables us to make accurate predictions of both TCR-pMHC binding affinities and T-cell activities across diverse viral epitopes and cancer neoantigens, achieving up to 72% correlation with experimental data. Leveraging our TCR recognition model, we develop a computational protocol for de novo design of immunogenic peptides. Through experimental validation in three TCR-MHC systems targeting viral and cancer peptides, we demonstrate that our designs-with up to five substitutions from the native sequence-activate T-cells at success rates of up to 50%. Lastly, we use our generative framework to quantify the diversity of the peptide recognition landscape for various TCR-MHC complexes, offering key insights into T-cell specificity in both humans and mice. Our approach provides a platform for immunogenic peptide and neoantigen design, opening new computational paths for T-cell vaccine development against viruses and cancer.}, }
@article {pmid40100459, year = {2025}, author = {Nguyen, NH and Nguyen, MP and Mai, HK and Do, ST and Pham, VH and Vuong, DTP and Maturi, JR and Le, HVT and Cluskey, PM and Pham, VT}, title = {The correlation of clinical and histopathological features of eyelid malignancies: a 5-year retrospective study in Vietnam.}, journal = {International ophthalmology}, volume = {45}, number = {1}, pages = {107}, pmid = {40100459}, issn = {1573-2630}, mesh = {Humans ; Retrospective Studies ; Male ; Female ; Middle Aged ; Vietnam/epidemiology ; *Eyelid Neoplasms/epidemiology/pathology/diagnosis ; Aged ; Adult ; Incidence ; *Carcinoma, Basal Cell/pathology/epidemiology/diagnosis ; Aged, 80 and over ; Eyelids/pathology ; Melanoma/epidemiology/pathology/diagnosis ; Young Adult ; Sebaceous Gland Neoplasms/pathology/epidemiology/diagnosis ; Adolescent ; }, abstract = {PURPOSE: To analyze the correlation between the clinical and histopathological features of eyelid malignancies in Vietnam.<br><br>METHODS: An observational retrospective study was conducted on 190 patients who were diagnosed histopathologically after surgery with eyelid malignancies between 2017 and 2021 at Vietnam National Eye Hospital. Demographic, clinical manifestations, pathological features and outcomes were analyzed.<br><br>RESULTS: Basal cell carcinoma was the most common histopathologic type, accounting for 57.9% of cases, followed by sebaceous gland carcinoma at 27.4%. The match between clinical diagnosis and pathological diagnosis was 57.4% across all cases. The majority of basal cell carcinoma cases presented on the lower eyelid, while the majority of sebaceous gland carcinoma cases presented on the upper eyelid. Clinical features with the highest clinical correlation were ulceration (76.4%) for basal cell carcinoma and ill-defined edges (84.6%) among malignant cutaneous melanoma.<br><br>CONCLUSION: Eyelid malignancies present significant challenges in clinical diagnosis, with only moderate concordance between clinical and histopathological findings. Basal cell carcinoma is the most common eyelid malignancy in Vietnam, though its incidence is significantly lower than in Western countries. Clinical findings with the most consistent clinical correlation were high rates of ulceration in basal cell carcinoma and ill-defined edges in malignant melanoma.}, }
@article {pmid40100220, year = {2025}, author = {Duncan, FC and Triplette, M}, title = {Adherence to Follow-Up Lung Cancer Screening-A Critical Target for Intervention.}, journal = {JAMA network open}, volume = {8}, number = {3}, pages = {e250949}, doi = {10.1001/jamanetworkopen.2025.0949}, pmid = {40100220}, issn = {2574-3805}, }
@article {pmid40099861, year = {2025}, author = {Othus, M and Sharon, E and Wu, MC and Sondak, VK and Ribas, A and Patel, SP}, title = {Design considerations for randomized comparisons of neoadjuvant-adjuvant versus adjuvant-only cancer immunotherapy when tumor measurement schedules do not align (SWOG S1801).}, journal = {Clinical trials (London, England)}, volume = {}, number = {}, pages = {17407745251321371}, doi = {10.1177/17407745251321371}, pmid = {40099861}, issn = {1740-7753}, abstract = {BackgroundIn 2022, SWOG S1801 was the first trial to demonstrate that single-agent anti-PD-1 checkpoint inhibition used as neoadjuvant-adjuvant therapy leads to significantly improved outcomes compared to adjuvant-only therapy. Endpoints in trials comparing neoadjuvant-adjuvant to adjuvant strategies need special consideration to ensure that event measurement timing is appropriately accounted for in analyses to avoid biased comparisons artificially favoring one arm over another.MethodsThe S1801 trial is used a case study to evaluate the issues involved in selecting endpoints for trials comparing neoadjuvant-adjuvant versus adjuvant-only strategies.ResultsDefinitions and timing of measurement of events is provided. Trial scenarios when recurrence-free versus event-free survival should be used are provided.ConclusionsIn randomized trials comparing neoadjuvant-adjuvant to adjuvant-only strategies, event-free survival endpoints measured from randomization are required for unbiased comparison of the arms. The time at which events can be measured on each arm needs to be carefully considered. If measurement of events occurs at different times on the randomized arms, modified definitions of event-free survival must be used to avoid bias.}, }
@article {pmid40099838, year = {2025}, author = {Lama, JR and Bender Ignacio, RA and Duerr, A}, title = {Acute retroviral syndrome.}, journal = {Current opinion in HIV and AIDS}, volume = {}, number = {}, pages = {}, doi = {10.1097/COH.0000000000000933}, pmid = {40099838}, issn = {1746-6318}, abstract = {PURPOSE OF REVIEW: To review the most important recent literature on the definition, epidemiology, clinical presentation, pathogenesis and treatment of the acute retroviral syndrome (ARS), a constellation of nonspecific symptoms and transient illness occuring in at least 50% of persons shortly after HIV acquisition. ARS is driven by initial rapid HIV viral replication and dissemination after acquisition, followed by immune activation and massive systemic inflammation. A more detailed understanding of ARS is important for the implementation of early detection efforts, treatment and public health strategies to control HIV.<br><br>RECENT FINDINGS: Recent research has provided deeper insights into ARS. Key findings include associations of ARS with heightened immune activation and elevated levels of IFN&#x3b3; and multiple other cytokines, particularly IP-10, as well as with higher viral load and more severe CD4+ depletion during acute infection. These negative impacts can be mitigated by early antiretroviral therapy initiation and long-term outcomes are generally similar in treated individals with or without ARS.<br><br>SUMMARY: Current findings underscore the importance of early detection and intervention in ARS to mitigate long-term health impacts and inform the development of targeted therapeutic strategies.}, }
@article {pmid40099002, year = {2025}, author = {Gong, E and Zawacki, L and Fan, X and Hippe, DS and Menon, AA and Remington, AJ and Lachance, K and Akaike, T and Tachiki, L and Park, SY and Nghiem, P}, title = {Immunotherapy response in immunosuppressed patients with Merkel cell carcinoma: analysis of 183 patients.}, journal = {BMJ oncology}, volume = {4}, number = {1}, pages = {e000654}, pmid = {40099002}, issn = {2752-7948}, abstract = {OBJECTIVE: Merkel cell carcinoma (MCC) is an aggressive skin cancer with poor outcomes in immunosuppressed patients. While immune checkpoint inhibitors (ICIs) achieve ~60% response rates in immunocompetent MCC patients, their efficacy in immunosuppressed patients remains unclear due to exclusion from trials. This study compares ICI outcomes, safety and the impact of immunosuppression subtypes between these groups.<br><br>METHODS AND ANALYSIS: This retrospective study analysed 183 advanced MCC patients on first-line ICIs from a Seattle-based data repository. Of these, 147 were immunocompetent, and 36 were immunosuppressed (chronic lymphocytic leukaemia (CLL) n=10, autoimmune disorders n=10, other haematologic malignancies n=9, solid organ transplants n=4 and HIV/AIDS n=3). Outcomes included objective response rate, disease progression, MCC-specific and overall survival probability, adjusted for age, sex and stage at ICI initiation.<br><br>RESULTS: Initial ICI response rates at 6 months were 50% in immunosuppressed and 61.5% in immunocompetent patients (HR=0.71, p=0.17). Immunosuppressed patients had higher risks of disease progression (2 years: 53.9% vs 42.1%, HR=1.65, p=0.05) and MCC-specific mortality (2&#x2009;years: 38.7% vs 24.4%, HR=1.85, p=0.04). CLL patients (n=10) had a particularly low response rate (response rate: 20.0% vs 61.5%, HR=0.18, p=0.02) and high progression risk (2&#x2009;years: 80.0% vs 42.1%, HR=4.09, p=0.01). Immunosuppressed patients faced higher rates of ICI toxicity (6-month risk: 51.6% vs 36.6%, HR=1.79, p=0.03).<br><br>CONCLUSIONS: ICIs provide meaningful benefits to immunosuppressed MCC patients, though their response rates are lower, and progression risk is higher compared with immunocompetent patients.}, }
@article {pmid40098997, year = {2025}, author = {Xia, T and Han, F and Wang, Y and Xie, X and Yuan, C and Lu, G and Xiao, W and Tu, B and Ren, H and Gong, W and Wang, Y}, title = {Inhibition of CD53 Reduces the Formation of ROS-Induced Neutrophil Extracellular Traps and Protects Against Inflammatory Injury in Acute Pancreatitis.}, journal = {Journal of inflammation research}, volume = {18}, number = {}, pages = {3725-3739}, pmid = {40098997}, issn = {1178-7031}, abstract = {BACKGROUND: The tetraspanin CD53 transmembrane protein is vital in immune cells like B cells and T cells, playing a crucial role in various inflammatory conditions. However, its involvement in neutrophils regarding inflammation remains uncertain. This study aims to examine the impact of CD53 on neutrophil extracellular traps (NETs) formation.<br><br>METHODS: Phorbol 12-myristate 13-acetate (PMA) was utilized to establish an in vitro classical NETs model to investigate the influence of CD53 on NETs formation and its regulatory mechanisms. Subsequently, the link between CD53 and acute pancreatitis (AP), a model of aseptic inflammatory responses connected to NETs, was verified. Peripheral blood neutrophils from clinical AP patients were collected to explore the role of CD53 in AP, while an AP mouse model induced by caerulein was employed to confirm the impact of CD53 inhibition on AP mice pancreatic tissue.<br><br>RESULTS: Our study has shown that CD53 is significantly elevated in in vitro NETs models and neutrophils from AP patients. The expression of CD53 is closely related to the clinical prognosis of AP patients. At the same time, CD53 neutralizing antibody (Anti-CD53) can significantly inhibit the formation of NETs in vitro, inflammatory injury in AP mice and the formation of NETs in damaged tissues. Mechanistically, CD53 can modulate the PI3K/AKT pathway and promote the formation of NETs. Finally, targeted regulation of CD53 can effectively reduce inflammatory injury and NETs formation in damaged tissues of AP mice.<br><br>CONCLUSION: The results of this study mark the first confirmation that CD53 plays a crucial role in NETs formation. Targeting CD53 inhibition could potentially serve as a novel therapeutic approach for the treatment of AP.}, }
@article {pmid40098681, year = {2025}, author = {Orouskhani, M and Rauniyar, S and Morella, N and Lachance, D and Minot, SS and Dey, N}, title = {Deep learning imaging analysis to identify bacterial metabolic states associated with carcinogen production.}, journal = {Discover imaging}, volume = {2}, number = {1}, pages = {2}, pmid = {40098681}, issn = {3004-9776}, abstract = {BACKGROUND: Colorectal cancer (CRC) is a globally prevalent cancer. Emerging research implicates the gut microbiome in CRC pathogenesis. Bacteria such as Clostridium scindens can produce the carcinogenic bile acid deoxycholic acid (DCA). It is unknown whether imaging methods can differentiate DCA-producing and DCA-non-producing C. scindens cells.<br><br>METHODS: Light microscopy images of anaerobically cultured C. scindens in four conditions were acquired at 100&#xd7; magnification using the Tissue FAX system: C. scindens in media alone (DCA-non-producing state), C. scindens in media with cholic acid (DCA-producing state), or C. scindens in co-culture with one of two Bacteroides species (intermediate DCA production states). We evaluated three approaches: whole-image classification, per-cell classification, and image segmentation-based classification. For whole-image classification, we used a custom Convolutional Neural Network (CNN), pre-trained DenseNet, pre-trained ResNet, and ResNet enhanced by integrating the Digital Images of Bacterial Species (DIBaS) dataset. For cell detection and classification, we applied thresholding (OTSU or adaptive thresholding) followed by a ResNet model. Finally, image segmentation-based classification was performed using nnU-Net.<br><br>RESULTS: For whole-image analysis, DIBaS-enhanced ResNet models achieved the best performance in distinguishing C. scindens states in monoculture (accuracy 0.89&#x2009;&#xb1;&#x2009;0.006) and in co-cultures (accuracy 0.86&#x2009;&#xb1;&#x2009;0.004). Per-cell analysis was optimal at a C constant value of 3, with the ResNet model achieving 62-74% accuracy for C. scindens states&#xa0;in monoculture. Segmentation-based analysis using nnU-Net resulted in Dice coefficients of 87% for C. scindens and 74-76% for the Bacteroides species.<br><br>CONCLUSIONS: This study demonstrates feasibility of image-based deep learning models in identifying health-relevant gut bacterial metabolic states.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s44352-025-00006-1.}, }
@article {pmid40098097, year = {2025}, author = {Berry, AA and Richie, TL and Church, LWP and Laurens, MB and Boyce, C and Kc, N and Joshi, S and Koudjra, AR and Butler, L and Chen, MC and Abebe, Y and Murshedkar, T and James, ER and Billingsley, PF and Sim, BKL and Hoffman, SL and Lyke, KE}, title = {Safety, tolerability and immunogenicity of a condensed, multi-dose prime regimen of PfSPZ Vaccine for the prevention of Plasmodium falciparum malaria infection.}, journal = {Malaria journal}, volume = {24}, number = {1}, pages = {88}, pmid = {40098097}, issn = {1475-2875}, support = {U44AI167783//National Institute of Allergy and Infectious Diseases,United States/ ; }, mesh = {*Malaria Vaccines/immunology/administration &amp; dosage/adverse effects ; Humans ; *Malaria, Falciparum/prevention &amp; control/immunology ; Adult ; Female ; Male ; *Plasmodium falciparum/immunology ; Double-Blind Method ; Young Adult ; Adolescent ; Middle Aged ; Vaccines, Attenuated/immunology/administration &amp; dosage/adverse effects ; Antibodies, Protozoan/blood ; Sporozoites/immunology ; }, abstract = {BACKGROUND: The World Health Organization (WHO) has called for new malaria vaccines with > 90% efficacy against Plasmodium falciparum infection to expand the anti-disease benefit provided by the RTS,S/AS01 and R21/Matrix M subunit vaccines currently administered to infants and young children in sub-Saharan Africa. Attenuated P. falciparum sporozoites (PfSPZ) are being developed as a traveller's vaccine and to fulfill WHO's call for high-level efficacy in endemic countries to support malaria elimination.<br><br>METHODS: PfSPZ Vaccine, comprised of radiation-attenuated PfSPZ, was compared with normal saline placebo in a randomized, double-blind trial targeting 60 malaria-naive US adults to assess safety, tolerability, immunogenicity, and efficacy against heterologous controlled human malaria infection three and twelve weeks after immunization. Pharmacists provided syringes to blinded clinicians using 3:1 (vaccine:placebo) blocked randomization, for administration by direct venous inoculation on days 1 and 8 (multidose prime) and day 29 (boost), a condensed regimen with superior efficacy. Primary outcomes included adverse events and antibody responses to the P. falciparum circumsporozoite protein (PfCSP).<br><br>RESULTS: 31 participants were screened, randomized and immunized twice (V1, V2) 5-7&#xa0;days apart, with one withdrawal after an intercurrent adverse event. A vial issue, later traced to the vial manufacturer, halted further immunizations. Solicited local and systemic adverse events recorded for 2 and 7&#xa0;days after immunizations, respectively, occurred with equal frequency and severity in the 23 vaccinees and 7 controls receiving two immunizations, as did unsolicited adverse events recorded for 28&#xa0;days and laboratory abnormalities 1 and 5&#xa0;weeks after V2. Four of 23 vaccinees and one of 7 controls (p&#x2009;=&#x2009;1.00) developed grade 2 adverse events including subjective fever, headache, malaise, fatigue, rigors, arthralgia and myalgia after V2 but not V1, these symptoms generally resolving within 24&#xa0;h. Twenty-two of 23 (96%) vaccinees developed IgG (median 99-fold increase over baseline) and IgM (median 1,110-fold increase) antibodies to PfCSP one week after V2. Antibody responses were not associated with reactogenicity.<br><br>CONCLUSIONS: The two-dose priming immunization regimen was safe, well tolerated and highly immunogenic. Larger studies may better define the adverse event profile of condensed regimens of PfSPZ Vaccine in malaria-naive adults.<br><br>TRIAL REGISTRATION NUMBER: clinicaltrial.gov NCT05604521.}, }
@article {pmid40097658, year = {2025}, author = {Simon, S and Bugos, G and Prins, R and Rajan, A and Palani, A and Heyer, K and Stevens, A and Zeng, L and Thompson, KA and Atilla, PA and Price, JP and Kluesner, MG and Jaeger-Ruckstuhl, CA and Shabaneh, TB and Olson, JM and Su, X and Riddell, SR}, title = {Design of sensitive monospecific and bispecific synthetic chimeric T cell receptors for cancer therapy.}, journal = {Nature cancer}, volume = {}, number = {}, pages = {}, pmid = {40097658}, issn = {2662-1347}, support = {R01 CA114536/CA/NCI NIH HHS/United States ; P01 CA18029//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; SCOR 1023-20//Leukemia and Lymphoma Society (Leukemia &amp; Lymphoma Society)/ ; SCOR 1023-20//Leukemia and Lymphoma Society (Leukemia &amp; Lymphoma Society)/ ; 3405-21//Leukemia and Lymphoma Society (Leukemia &amp; Lymphoma Society)/ ; SRA220501//Bristol-Myers Squibb (Bristol-Myers Squibb Company)/ ; }, abstract = {The adoptive transfer of T cells expressing chimeric antigen receptors (CARs) is effective in B cell malignancies. However, the persistence of cancer cells with low levels or complete absence of the target antigen, thereby evading detection by CAR T cells, leads to relapse. These evasion mechanisms highlight the need for receptors with enhanced sensitivity and multispecificity. We introduce a synthetic chimeric T cell receptor (ChTCR) that confers superior antigen sensitivity compared with CARS and previous hybrid TCR designs and is readily adapted for bispecific targeting. ChTCRs replicate the structure of natural TCRs, form classical immune synapses and demonstrate TCR-like signaling. T cells expressing bispecific ChTCRs (Bi-ChTCRs) are more effective than bispecific CAR T cells in eradicating tumors with heterogeneous antigen expression in vivo in female mice. The Bi-ChTCR architecture is resilient and can be designed to target pairs of B cell and multiple myeloma antigens. These findings provide a widely applicable strategy to combat tumor heterogeneity and prevent relapse.}, }
@article {pmid40095530, year = {2025}, author = {Gwin, WR and Hurvitz, SA}, title = {TOP-1 Priority: Advancing Biomarker-Driven Patient Selection for the use of ADCs.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-25-0166}, pmid = {40095530}, issn = {1557-3265}, abstract = {A recent study reports the emergence of TOP1 mutations as a potential mechanism of resistance to topoisomerase inhibitor-ADCs in advanced breast cancer. This is a crucial first step in identifying biomarkers to guide ADC therapy selection and underscores the need for caution when sequencing ADCs with similar payloads.}, }
@article {pmid40089329, year = {2025}, author = {Tseng, D and Lee, S}, title = {Tumor-Infiltrating Lymphocyte Therapy: A New Frontier.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {3S}, pages = {S599-S609}, doi = {10.1016/j.jtct.2024.11.014}, pmid = {40089329}, issn = {2666-6367}, mesh = {Humans ; *Lymphocytes, Tumor-Infiltrating/immunology/transplantation ; *Neoplasms/therapy/immunology ; *Immunotherapy, Adoptive/methods ; Immunotherapy/methods ; Animals ; Melanoma/therapy/immunology/pathology ; }, abstract = {In recent years, the successful use of tumor-infiltrating lymphocyte (TIL) therapy to treat melanoma not only culminated in a landmark Food and Drug Administration approval, but has also fueled the emergence of a new, rapidly growing field in TIL cellular immunotherapy surrounding novel enhancements in TIL design, refined manufacturing strategies to enrich for more potent TIL populations, as well as numerous clinical trials now investigating TIL therapy in additional solid tumor types beyond melanoma. This review provides a summary of the latest advances in TIL therapy and what lies ahead for the field. The first section explores several solid cancers that demonstrate the greatest potential for future indications of TIL therapy. The second section provides insight into the promising innovations for designing the next generation of TIL with greater specificity, persistence, safety, and function.}, }
@article {pmid40088973, year = {2025}, author = {Prentice, RL and Aragaki, AK and Zheng, C and Manson, JE and Tinker, LF and Schoeller, DA and Ravelli, MN and Raftery, D and Gowda, GAN and Navarro, SL and Huang, Y and Mossavar-Rahmani, Y and Wallace, RB and Johnson, KC and Lampe, JW and Neuhouser, ML}, title = {Energy intake is associated with dietary macronutrient densities: inversely with protein and monounsaturated fat and positively with polyunsaturated fat and carbohydrate among postmenopausal females.}, journal = {The American journal of clinical nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajcnut.2025.03.011}, pmid = {40088973}, issn = {1938-3207}, abstract = {BACKGROUND: Associations of the macronutrient composition of the diet with total energy intake (EI) are uncertain, as are associations of macronutrient composition with self-reported energy underreporting.<br><br>OBJECTIVES: We aim to estimate associations of biomarker-assessed EI with both biomarker-assessed and self-reported macronutrient component densities in a Women's Health Initiative (WHI) sub-cohort of postmenopausal U.S. females. Secondarily, we examine energy underreporting using food records, recalls and frequencies, for association with macronutrient densities.<br><br>DESIGN AND METHODS: We used a previously proposed EI biomarker equation based on doubly-labeled water (DLW) and updated biomarker equations for several macronutrient component densities, to estimate EI and macronutrient component densities in a WHI nutritional biomarkers sub-cohort (n=436; 2007-2009). We used linear regression of EI biomarker values on biomarker and self-reported macronutrient component densities, and of log-EI underreporting values on biomarker densities, to examine targeted associations.<br><br>RESULTS: Using biomarker assessments, the geometric mean (95% CI) for EI corresponding to a 20% increment in carbohydrate density was 2.0% (0.1%, 3.9%) higher, and for a 20% protein density increment was 2.1% (0.5%, 3.7%) lower. The former was attributable to added sugars. Similarly, EI values for 20% increments in polyunsaturated (PUFA), and monounsaturated (MUFA) fatty acids densities were respectively 1.4% (0.3%, 2.6%) higher, and 1.5% (0.1%, 2.9%) lower. Pertinent associations were either not detected or were substantially attenuated if instead self-reported macronutrient densities were used. Also, EI underreporting was strongly related to self-reported macronutrient densities using food records, recalls, or frequencies.<br><br>CONCLUSIONS: Among U.S. postmenopausal females lower EI was associated with diets relatively high in protein or MUFA, and higher EI was associated with diets relatively high in PUFA or added sugars. These associations are of public health importance, but are mostly missed using self-reported dietary density assessments. Self-reported energy underestimation is substantially associated with self-reported macronutrient densities. This study is registered with clinicaltrials.gov identifier: NCT00000611.}, }
@article {pmid40088909, year = {2025}, author = {Stranix-Chibanda, L and Hamilton, EL and Ngo, J and Jiao, Y and Hanscom, B and Choudhury, RP and Agyei, Y and Piwowar-Manning, E and Marzinke, M and Delany-Moretlwe, S and Mgodi, N and Siziba, B and Naidoo, I and Gati Mirembe, B and Kamira, B and McCoig, C and Adeyeye, A and Spiegel, HML and Hosek, S and , }, title = {Safety, tolerability, and acceptability of long-acting injectable cabotegravir for HIV prevention in cisgender female adolescents (HPTN 084-01): a single-arm, open-label, phase 2b trial.}, journal = {The lancet. HIV}, volume = {}, number = {}, pages = {}, doi = {10.1016/S2352-3018(24)00310-2}, pmid = {40088909}, issn = {2352-3018}, abstract = {BACKGROUND: Long-acting formulations of HIV pre-exposure prophylaxis (PrEP) appear particularly well suited to adolescents. We aimed to establish the safety, tolerability, and acceptability of long-acting injectable cabotegravir as PrEP in cisgender adolescent girls.<br><br>METHODS: HPTN 084-01 is a single-arm, open-label, phase 2b trial conducted at three clinical research sites in South Africa, Uganda, and Zimbabwe. Girls were recruited via community study-outreach teams, reproductive health clinics, and peer referral. Sexually active adolescent girls (younger than 18 years) willing to use long-acting contraception, weighing at least 35 kg, and able to participate with parental or guardian consent (unless an emancipated minor) were eligible. After an oral lead-in, if no adverse events occurred, participants received a 3 mL intramuscular gluteal injection (long-acting injectable cabotegravir 600 mg) at weeks 5, 9, 17, 25, and 33. The product was discontinued for grade 3 or higher toxic effects or pregnancy. The primary outcomes were safety, tolerability, and acceptability. Safety (ie, proportions of grade 2 or higher clinical and laboratory events) was assessed at weeks 6, 10, 18, 26, and 34 in all enrolled participants. Injection tolerability (ie, proportions of premature discontinuation due to intolerability, frequency of injections, or burden of study procedures) and product acceptability (ie, proportions of scheduled injections completed and participants preferring long-acting injectable cabotegravir for future use) were assessed in all participants who received at least one injection at study end. The trial was registered with ClinicalTrials.gov (NCT04824131) and is completed.<br><br>FINDINGS: Between Nov 1, 2020, and Aug 31, 2021, 69 participants were assessed for eligibility and 55 met inclusion criteria. The mean age was 16&#xb7;0 years (SD 1&#xb7;1), 39 (71%) had a recent primary sexual partner, 12 (22%) reported transactional sex, and 22 (40%) had sexually transmitted infections at baseline. Two participants dropped out and did not initiate long-acting injectable cabotegravir due to adverse events unrelated to the study drug during the oral lead-in. One participant stopped long-acting injectable cabotegravir after three injections due to pregnancy. 51 (93%) participants reported at least one adverse event of grade 2 or higher, mostly unrelated, transient laboratory abnormalities. There were no long-acting injectable cabotegravir discontinuations due to intolerability. Of the 52 participants who completed step 2, all scheduled injections were completed and 32 (62%) participants reported they would consider using long-acting injectable cabotegravir for HIV prevention in the future.<br><br>INTERPRETATION: Long-acting injectable cabotegravir is a safe, tolerable, and acceptable option for the prevention of HIV in adolescent girls. Our study findings expand the HIV prevention options available to adolescent girls.<br><br>FUNDING: National Institute of Allergy and Infectious Diseases, National Institute of Mental Health, National Institute on Drug Abuse, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, ViiV Healthcare, and The Bill &amp; Melinda Gates Foundation.}, }
@article {pmid40088674, year = {2025}, author = {Kumaraswamy, A and Mannan, R and Swaim, OA and Rodansky, E and Wang, XM and Udager, A and Mehra, R and Li, H and Morrissey, C and Corey, E and Haffner, MC and Nelson, PS and Chinnaiyan, AM and Yates, JA and Alumkal, JJ}, title = {LSD1+8a is an RNA biomarker of neuroendocrine prostate cancer.}, journal = {Neoplasia (New York, N.Y.)}, volume = {63}, number = {}, pages = {101151}, doi = {10.1016/j.neo.2025.101151}, pmid = {40088674}, issn = {1476-5586}, abstract = {BACKGROUND: Lysine-specific demethylase 1 (LSD1) is a histone demethylase and regulator of differentiation, including in cancer. A neuronal-specific isoform of LSD1-LSD1+8a-has been shown to play a key role in promoting neuronal differentiation in the developing brain. We previously determined that LSD1+8a transcripts were detected in an aggressive subtype of prostate cancer harboring a neuronal program-neuroendocrine prostate cancer (NEPC)-but not in prostate adenocarcinomas harboring a glandular program. However, the number of samples examined was limited.<br><br>METHODS: Using a large collection of prostate cancer patient cell lines and patient-derived xenografts (PDXs), we measured LSD1+8a using quantitative polymerase chain reaction (qPCR), RNA in situ hybridization (RNA-ISH), and protein detection methods. We then validated our findings using an independent cohort of patient tumor samples.<br><br>RESULTS: LSD1+8a mRNA expression was detected in every NEPC cell line and PDX examined by qPCR and RNA-ISH but in none of the prostate adenocarcinomas. We validated the RNA-ISH results in patient tumors, confirming that LSD1+8a was expressed in all NEPC tumors but in none of the adenocarcinomas. Finally, we generated a rabbit monoclonal antibody specific to LSD1+8a protein and confirmed its specificity using normal neuronal tissue samples. However, LSD1+8a protein was not detectable in NEPC tumors-likely due to the substantially lower levels of LSD1+8a mRNA in NEPC tumors vs. normal neuronal tissues.<br><br>CONCLUSIONS: Measuring LSD1+8a mRNA is a sensitive and specific method for the diagnosis of NEPC, which is often challenging.}, }
@article {pmid40088469, year = {2025}, author = {Banerjee, R and Richards, A and Midha, S and Afrough, A and Anwer, F and Atanackovic, D and Atrash, S and Bachanova, V and Beitinjaneh, AM and Ouchveridze, E and Castaneda Puglianini, O and Chhabra, S and Cicero, KI and Davis, JA and Dhakal, B and Dima, D and Ferreri, CJ and Forsberg, PA and Freeman, CL and Herr, MM and Jain, T and Janakiram, M and Khouri, J and Kocoglu, MH and Kumar, AD and Liu, Y and Locke, FL and McGuirk, JP and Mikkilineni, L and Nadeem, O and Parrondo, RD and Pasvolsky, O and Peres, LC and Purvey, S and Raza, S and Reshef, R and Richard, S and Rossi, AC and Sborov, DW and Shune, L and Wagner, CB and Zanwar, SS and Sidana, S and Patel, KK and Hansen, DK and Kumar, SK and Lin, Y and Martin, TG and Voorhees, PM and Anderson, LD and Cowan, AJ and Kaur, G}, title = {Universal driving restrictions beyond 4 weeks appear unnecessary following CAR-T therapy in multiple myeloma.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025016131}, pmid = {40088469}, issn = {2473-9537}, }
@article {pmid40086733, year = {2025}, author = {Antonarelli, G and Pérez-García, JM and Gion, M and Rugo, H and Schmid, P and Bardia, A and Hurvitz, S and Harbeck, N and Tolaney, SM and Curigliano, G and Llombart-Cussac, A and Cortés, J}, title = {Redefining Clinical Trial Strategic Design to Support Drug Approval in Medical Oncology.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.annonc.2025.03.005}, pmid = {40086733}, issn = {1569-8041}, abstract = {Randomized clinical trials represent the gold standard for the introduction of innovative therapies in medical oncology, and they provide the highest level of evidence to ascertain the clinical activity of new drugs or novel combinations. However, the current infrastructure of clinical trials supporting innovative drug approvals is challenged by an increased body of knowledge concerning tumor biology and therapy resistance, a fast-growing armamentarium of novel anti-cancer compounds, an impressively upscaled data analysis capacity, as well as increasing costs related to clinical trials' management. In this scenario, modern clinical trial designs need to evolve to expedite new drug approvals by tailoring patients' treatment strategies according to their medical needs. Balanced, patient-oriented, clinical trial designs are eagerly warranted to increase their efficiency, to include the fast-pace of technological innovations and scientific discoveries, and ultimately to face the challenges of the modern medical oncology field.}, }
@article {pmid40086461, year = {2025}, author = {Diallo, F and Haidara, FC and Tapia, MD and Dominguez Islas, CP and Alderson, MR and Hausdorff, WP and Martellet, L and Hosken, N and Kapse, D and Kulkarni, PS and Townsend-Payne, K and Vanni, F and Posavad, CM and Sow, SO and Kotloff, KL and Chen, WH and , }, title = {Safety and immunogenicity of a pentavalent meningococcal conjugate vaccine targeting serogroups A, C, W, Y, and X when co-administered with routine childhood vaccines at ages 9 months and 15 months in Mali: a single-centre, double-blind, randomised, controlled, phase 3, non-inferiority trial.}, journal = {Lancet (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.1016/S0140-6736(25)00046-7}, pmid = {40086461}, issn = {1474-547X}, abstract = {BACKGROUND: Invasive meningococcal disease is a devastating public health problem for the African meningitis belt. We assessed the safety and immunogenicity of a pentavalent meningococcal conjugate vaccine targeting serogroups A, C, Y, W, and X (NmCV-5) relative to a licensed, quadrivalent meningococcal conjugate vaccine (MenACWY-TT) when co-administered with routine childhood vaccines at ages 9 months and 15 months.<br><br>METHODS: In this single-centre, double-blind, randomised, controlled, phase 3, non-inferiority trial, children aged 9-11 months who had completed their local infant Expanded Program on Immunization (EPI) vaccines were recruited at the Centre pour le D&#xe9;veloppement des Vaccins in Bamako, Mali. Participants were randomly assigned (1:1&#xb7;2) at their 9-month EPI visits to receive a meningococcal vaccine at either their 9-month or 15-month EPI vaccination visits. At each participant's designated EPI visit, they were randomly assigned a second time (2:1) to receive either NmCV-5 or MenACWY-TT. Study vaccines and designated EPI vaccines were prepared and administered by assigned unmasked study personnel. Parents or guardians, investigators, and all other trial staff were masked to meningococcal vaccine assignments. The meningococcal vaccines were co-administered with a measles and rubella vaccine (first dose) and a yellow fever vaccine at age 9 months or with a measles and rubella vaccine (second dose) at age 15 months. The primary endpoint, seroprotective response, was defined as a rabbit complement serum bactericidal antibody titre of 8 or higher, with the estimand, given as the difference in the proportions of participants for each of the five meningococcal serogroups who showed this response 28 days after vaccination, assessed in the per-protocol population. The prespecified non-inferiority margin was -10% for all five serogroups in both age groups. The non-inferiority of the NmCV-5 seroprotective response to serogroup X was evaluated in comparison with the lowest seroprotective response for MenACWY-TT among serogroups A, C, W, or Y. Safety was a secondary endpoint, assessed over 6 months in a modified intention-to-treat population that included all participants who received a randomly assigned meningococcal vaccine. This trial is registered with ClinicalTrials.gov, NCT05093829.<br><br>FINDINGS: Between March 24 and Aug 15, 2022, 1325 participants were enrolled and randomly assigned to receive a meningococcal vaccine at either age 9 months (n=602) or age 15 months (n=723). Meningococcal vaccines were administered to 600 of the 602 participants assigned to the 9-month vaccination group during that same period. Between Sept 27, 2022, and Feb 6, 2023, 600 participants received meningococcal vaccines at their 15-month visits. In both groups, 400 participants received NmCV-5 and 200 participants received MenACWY-TT. The per-protocol population assessed in the non-inferiority analysis included 564 participants vaccinated at age 9 months (373 who received NmCV-5 and 191 who received MenACWY-TT) and 549 participants vaccinated at age 15 months (367 who received NmCV-5 and 182 who received MenACWY-TT). Among the participants in the per-protocol population who received NmCV-5 at age 9 months, the difference in seroprotection prevalence for NmCV-5 relative to MenACWY-TT was 0&#xb7;0% (95% CI -1&#xb7;0 to 2&#xb7;0) for serogroup A, -0&#xb7;5% (-2&#xb7;3 to 1&#xb7;9) for serogroup C, -3&#xb7;0% (-6&#xb7;3 to 0&#xb7;8) for serogroup W, and -3&#xb7;0% (-5&#xb7;4 to -0&#xb7;4) for serogroup Y. For serogroup X, non-inferiority was assessed relative to seroprotection for serogroup W in participants who received MenACWY-TT, with a difference of 2&#xb7;3% (95% CI 0&#xb7;3 to 4&#xb7;7). The difference in the prevalence of seroprotection among the participants who received NmCV-5 at age 15 months relative to participants who received MenACWY-TT at age 15 months was 0&#xb7;8% (95% CI -0&#xb7;6 to 3&#xb7;7) for serogroup A, -0&#xb7;8% (-3&#xb7;3 to 2&#xb7;5) for serogroup C, 0&#xb7;3% (-1&#xb7;8 to 3&#xb7;5) for serogroup W, and 1&#xb7;4% (-0&#xb7;6 to 4&#xb7;8) for serogroup Y. For serogroup X, non-inferiority was assessed in relation to seroprotection for serogroup Y in participants who received MenACWY-TT, with a difference of 1&#xb7;9% (95% CI 0&#xb7;0 to 4&#xb7;4). NmCV-5 responses in both age groups were non-inferior to MenACWY-TT responses for all five serogroups. Six serious adverse events were recorded but none were deemed related to vaccination.<br><br>INTERPRETATION: When compared with a licensed, quadrivalent meningococcal conjugate vaccine, and given alongside other routine vaccines, a single dose of NmCV-5 was safe and elicited a non-inferior immune response in infants aged 9 months and young children aged 15 months.<br><br>FUNDING: US National Institutes of Health, UK Foreign, Commonwealth &amp; Development Office, and Serum Institute of India.}, }
@article {pmid40086122, year = {2025}, author = {Dale, R and He, H and Chen, Y}, title = {Absorbing Markov chain model of PrEP drug adherence to estimate adherence decay rate and probability distribution in clinical trials.}, journal = {Journal of theoretical biology}, volume = {604}, number = {}, pages = {112086}, doi = {10.1016/j.jtbi.2025.112086}, pmid = {40086122}, issn = {1095-8541}, abstract = {Pre-exposure prophylaxis (PrEP) is increasingly used to prevent the transmission of H.I.V. in at-risk populations. However, PrEP users may discontinue use of the medicine due to side effects, lower perceived risk, or other reasons. The usage metrics of 594 individuals was tracked over 350 days using the Wisepill electronic monitoring system. We model the PrEP drug adherence level using an absorbing Markov chain with a unique absorbing state. The transition matrix T obtained from the Wisepill data will have a trivial eigenvector (eigendistribution) associated with the first (i.e., largest) eigenvalue 1. The 2nd eigenvalue(s) then become important in determining the asymptotic behavior of the Markov chain, dictating how fast the Markov chain decays to the absorbing state. Under a fairly general assumption, we prove that the second positive eigenvalue is unique and the corresponding eigenvector will have nonnegative entries with exceptions at absorbing states. In addition, we define the asymptotic half life of the absorbing Markov chain directly from the 2nd eigenvalue. We then determine the 2nd eigenvalue of T and the asymptotic half life of the Markov chain, which turns out to be very close to the real half life of the Markov chain. Finally, we interpret the 2nd eigenvector as the relative probability distribution of X∞ with respect to the decay rate of the 2nd eigenvalue. By applying these methods to the Wisepill data, we estimate the half-life of population adherence to be 46 weeks. The bi-weekly decay rate observed in these data from 90 to 100 % adherence is 3 %. This work produces an estimate at which adherence falls over time, given no external intervention is applied. These results suggest an eigenvector-based approach to estimate adherence trends, as well as the timing of interventions to improve adherence.}, }
@article {pmid40084542, year = {2025}, author = {Cox, SN and Roychoudhury, P and Frivold, C and Acker, Z and Babu, TM and Boisvert, CL and Carone, M and Ehmen, B and Englund, JA and Feldstein, LR and Gamboa, L and Grindstaff, S and Grioni, HM and Han, PD and Hoffman, KL and Kim, HG and Kuntz, JL and Lo, NK and Lockwood, CM and McCaffrey, K and Mularski, RA and Hatchie, TL and Reich, SL and Schmidt, MA and Smith, N and Starita, LM and Varga, A and Yetz, N and Naleway, AL and Weil, AA and Chu, HY}, title = {Household Transmission and Genomic Diversity of Respiratory Syncytial Virus (RSV) in the United States, 2022-2023.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciaf048}, pmid = {40084542}, issn = {1537-6591}, support = {75D30121C12297/CC/CDC HHS/United States ; }, abstract = {BACKGROUND: Household transmission of respiratory viruses may drive community spread. Few recent studies have examined household respiratory syncytial virus (RSV) transmission in the United States.<br><br>METHODS: We conducted a prospective community-based cohort study from 1 June 2022 to 31 May 2023. Participants had blood samples collected and completed nasal swabs and surveys at least weekly, irrespective of symptoms. We tested serum for RSV antibody, nasal swabs by quantitative reverse transcription polymerase chain reaction (RT-qPCR), and performed whole genome sequencing. We evaluated secondary RSV transmission and associated risk factors based on a log-linear Poisson regression model.<br><br>RESULTS: RSV was detected among 310 (10%) participants within 200 (20%) households. Most (94%) index cases were symptomatic. We identified 37 cases of potential secondary transmission within 14 days of a distinct index case (10%, 95% confidence interval [CI]: 7%, 14%); median age of index and secondary cases were 6 (interquartile range [IQR]: 3-10) and 35 (7-41) years, respectively, with 89% (24/27) of index cases aged 6 months to 12 years. Factors associated with increased risk of RSV transmission included index case viral detection &#x2265;1 week and contact age &#x2264;12 years. Of 120 sequenced specimens, the main lineages represented were A.d.5.2 (n = 37) and A.d.1 (n = 30). Sequenced viruses from households with &#x2265;2 RSV infections were similar when occurring within &#x2264;14 days (mean pairwise difference 4 [range 0-13], n = 17 households), compared to those >14 days (137 [37-236], n = 2).<br><br>CONCLUSIONS: Most RSV household transmission occurs from infants and young children to adults. Viral genome sequencing demonstrated that multiple household infections within a 14-day period are likely due to within-household transmission.}, }
@article {pmid40084371, year = {2025}, author = {Santiago-Torres, M and Westmaas, JL and Ostroff, JS and Mull, KE and Sullivan, BM and Unger, JM and Bricker, JB}, title = {Overcoming challenges of recruiting cancer patients into clinical trials: insights from a randomized trial of app-based smoking cessation interventions.}, journal = {American journal of cancer research}, volume = {15}, number = {2}, pages = {601-617}, pmid = {40084371}, issn = {2156-6976}, support = {R01 CA253975/CA/NCI NIH HHS/United States ; }, abstract = {Behavioral clinical trials among cancer patients often fail to meet recruitment goals - especially for underrepresented groups. Comparing recruitment strategies on participant accrual and cost can inform the use of cost-effective recruitment strategies for enrollment of diverse populations of cancer patients. In this study, we compared social media, internet sites, and clinic-based recruitment on accrual, cost, and characteristics of cancer patients (i.e., sociodemographic, cancer type/stage, and smoking habits) enrolled in a randomized trial of app-based smoking cessation interventions. Fisher's exact tests for categorical variables and analysis of variance for continuous variables were used to compared data between recruitment strategies. In 35 months, 427 cancer patients from 45 US states enrolled in the trial out of 3,936 screened (rate of participation, 10.8%). Social media recruited over eight times the number of enrolled participants (n=340, 79.6%) compared with Internet sites (n=43, 10.1%) and clinics (n=42, 9.8%). Most (80.1%) participants were women, with mean age 52.3 years. About 20.4% of participants were from underrepresented racial/ethnic backgrounds, 23.0% were rural residents, and 23.7% were uninsured. Over 32 cancer types and all cancer stages were represented. Breast cancer was the most common diagnosis (n=129/427, 30.2%), followed by lung cancer (n=96/427, 23.8%). Internet recruitment generated a higher proportion of men (30.2% vs. 26.2% clinics vs. 17.4% social media, P=.005). Clinics generated a higher proportion of Hispanic participants (9.5% vs. 7.0% Internet vs. 2.6% social media, P=.04) and cancer patients aged 65 and older (28.6% vs. 11.5% social media vs. 4.7% Internet, P=.01). Social media recruited a higher proportion of participants with low income (<$20,000: 39.1% vs. 23.3% Internet vs. 19.0% clinics, P<.001), who tended to have later stage cancers (stage IV: 17.4% vs. 14.0% Internet vs. 7.1% clinics, P=.05). Cost per randomized participant ranged from $270 via social media to $454 via Internet sites to $2,240 via clinic-based recruitment. In conclusion, social media was the most efficient and cost-effective method for recruiting a quality sample of racially/ethnically, geographically, socioeconomically, and clinically diverse sample of cancer patients into a smoking cessation clinical trial. Social media has solid potential for recruiting cancer patients into behavioral clinical trials.}, }
@article {pmid40083364, year = {2025}, author = {Selby, LD and Wallner, K and Hall, E and Mayr, N and Chvetsov, A and Stacey, AW}, title = {Simultaneous conjunctival melanomas in one eye treated with both adjuvant brachytherapy and proton beam radiotherapy.}, journal = {American journal of ophthalmology case reports}, volume = {38}, number = {}, pages = {102281}, pmid = {40083364}, issn = {2451-9936}, abstract = {PURPOSE: We describe a rare case of two simultaneous primary conjunctival melanomas in the same eye that were treated sequentially with both plaque brachytherapy and proton beam radiotherapy following wide surgical excision.<br><br>OBSERVATIONS: A 66-year-old male presented with two pigmented lesions that were concerning for conjunctival melanoma. One of the lesions was on the bulbar conjunctiva near the corneal limbus, and the other in the lower fornix. The lesions were surgically removed using the "no touch" technique, and pathology confirmed invasive melanoma in two separate locations on the same eye. The two lesions were then treated separately with two different forms of adjuvant radiation therapy. The forniceal tumor was treated with proton beam radiotherapy and the limbal lesion was treated with plaque brachytherapy. 30 months after radiation therapy was completed, there were no signs of local recurrence.<br><br>CONCLUSIONS AND IMPORTANCE: The appropriate treatment for two primary malignancies in the same eye can be determined independently and, in some cases, can involve two different forms of radiation therapy.}, }
@article {pmid40082827, year = {2025}, author = {He, Y and Xiao, H and Liu, F and Dai, X and Wang, H and Yang, H and Liu, Z and Unger, JM}, title = {Healthcare utilization in the departments of obstetrics and gynecology during the first two years of the COVID-19 pandemic: time series analysis in Jining, China.}, journal = {BMC public health}, volume = {25}, number = {1}, pages = {996}, pmid = {40082827}, issn = {1471-2458}, support = {82204132//National Natural Science Foundation of China/ ; 2021J01721//Natural Science Foundation of Fujian Province/ ; XRCZX2020007//Startup Fund for High-level Talents of Fujian Medical University/ ; }, mesh = {Humans ; *COVID-19/epidemiology ; China/epidemiology ; Female ; *Interrupted Time Series Analysis ; *Obstetrics and Gynecology Department, Hospital/statistics &amp; numerical data ; *Patient Acceptance of Health Care/statistics &amp; numerical data ; Adult ; Pregnancy ; Gynecology/statistics &amp; numerical data ; Obstetrics/statistics &amp; numerical data ; Hospitalization/statistics &amp; numerical data ; Pandemics ; SARS-CoV-2 ; Tertiary Care Centers ; }, abstract = {INTRODUCTION: Healthcare utilization in China decreased precipitously during the initial outbreak of the COVID-19 pandemic, and women were disproportionately affected. As the COVID-19 pandemic has proven to be far more pervasive and persistent than many first surmised, a vital question is whether the utilization of non-COVID related healthcare has remained low under China's dynamic zero-COVID policy. This study aimed to estimate the initial and enduring collateral effects of the COVID-19 pandemic on the utilization of obstetrics and gynecology care at a tertiary hospital in Jining, Shandong Province, China.<br><br>METHODS: An interrupted time series analysis was conducted to estimate the impact of the COVID-19 pandemic and mobility restrictions on monthly counts of outpatient visits, inpatient admissions, and surgeries in the obstetrics and gynecology departments at a tertiary hospital in Jining, China. Outpatient visits and surgery volume were abstracted from the hospital's monthly healthcare delivery report, while inpatient admissions were obtained from de-identified individual electronic medical records of inpatients admitted between January 1, 2017 to December 31, 2021. Incidence Rate Ratios (IRRs) representing monthly service counts compared with counterfactual counts (had the pandemic not happened) and the volume (number) of patients lost due to the pandemic were estimated.<br><br>RESULTS: During the study period, there were a total of 1 181 120 outpatient visits, 89 550 inpatient admissions and 49 056 surgeries in the obstetrics department; and 847 124 outpatient visits, 42 644 inpatient admissions and 39 653 surgeries of these totals occurred in the gynecology department. Compared to the expected estimates had the pandemic not occurred, a 55.4% (95% CI: 52.6-57.9%; p&#x2009;<&#x2009;0.001), 31.1% (95% CI: 27.2 -&#x2009;34.7%; p&#x2009;<&#x2009;0.001), and 27.6% (95% CI: 23.2- 31.8%; p&#x2009;<&#x2009;0.001) decrease was observed in obstetric outpatient visits, inpatient admissions, and surgeries, respectively in the month of February 2020 when the lockdown was enforced; and a 87.4% (95% CI: 86.0 -&#x2009;88.4%; p&#x2009;<&#x2009;0.001), 74.6% (95% CI: 71.0 -79.2%; p&#x2009;<&#x2009;0.001), and 75.5% (95% CI: 70.9 -&#x2009;77.8%; p&#x2009;<&#x2009;0.001) decrease was observed in gynecologic outpatient visits, inpatient admissions, and surgeries, respectively. As of December 2021, outpatient (IRR&#x2009;=&#x2009;0.86; 95% CI: 0.80-0.94; p&#x2009;<&#x2009;0.001), surgery (IRR&#x2009;=&#x2009;0.88; 95% CI: 0.82-0.95; p&#x2009;<&#x2009;0.001), and inpatient (IRR&#x2009;=&#x2009;0.73; 95% CI: 0.68-0.79; p&#x2009;<&#x2009;0.0001) services in the obstetrics department, and outpatient visits (IRR&#x2009;=&#x2009;0.90; 95% CI: 0.82-0.89; p&#x2009;=&#x2009;0.007) in the gynecology department had not fully recovered to pre-pandemic levels. Rural residents experienced a larger immediate decrease in inpatient care utilization in both obstetrics and gynecology in the month of February 2020, and the return to pre-pandemic levels in care utilization was also slower than that of urban residents.<br><br>CONCLUSIONS: The COVID-19 pandemic led to sizable disruptions in routine delivery and utilization of obstetrics and gynecology care. Disruptions were particularly substantial during the initial wave of the outbreak, and full recovery to pre-pandemic levels has not yet been achieved. The impact was more dramatic for women from rural areas, highlighting the need for policies and programs that address inequities in pandemic response and preparedness.}, }
@article {pmid40082098, year = {2025}, author = {Ramirez, M and Shah, PD and Chu, HY and Garza, L and Linde, S and Garrison, MM and Zhou, C and Bishop, S and Ibarra, G and Ko, LK}, title = {Corrigendum to "Reopening schools safely and educating youth (ROSSEY) study: Protocol for a community-based, cluster randomized controlled trial" [Contemporary Clinical Trials, 139 (2024) 107480].}, journal = {Contemporary clinical trials}, volume = {}, number = {}, pages = {107873}, doi = {10.1016/j.cct.2025.107873}, pmid = {40082098}, issn = {1559-2030}, }
@article {pmid40080774, year = {2025}, author = {Banegas, MP and Nightingale, CL and Dressler, EV and Cooley, ME and Kamen, C and Wagner, LI and Kittel, CA and Flores, EJ and Carlos, R and Milton, A and Park, E and Parsons, SK and Wood, EG and Loh, KP and Ramsey, S and ,  and , }, title = {Screening and Referral for Health-Related Social Needs and Financial Distress: Current Processes Among National Cancer Institute Community Oncology Research Program Practices.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2400902}, doi = {10.1200/OP-24-00902}, pmid = {40080774}, issn = {2688-1535}, abstract = {PURPOSE: Health-related social needs (HRSNs) are associated with adverse cancer health outcomes. We assessed the processes for screening and responding to both HRSNs and financial distress and described the methods used across National Cancer Institute Community Oncology Research Program (NCORP) practices.<br><br>METHODS: The NCORP 2022 Landscape Assessment survey focused on services to screen for and respond to HRSNs and financial distress within a national network of community oncology practices. We calculated the proportions of oncology practices that screened for and responded to HRSNs and financial distress, separately, and described the staff, tools, and methods used for each process. Multivariable logistic regression models estimated the associations between oncology practice characteristics and screening for HRSNs and financial distress.<br><br>RESULTS: The majority of community oncology practices reported screening for HRSNs (79%), and of those, most inquired about transportation (96%), family and social support (93%), housing (80%), and food security (80%). Most oncology practices reported screening for financial distress (78%). Social worker evaluation was the most common method used to screen for both HRSNs (77%) and financial distress (65%). Most oncology practices reported social work referral as the method for responding to HRSNs (89%) and financial distress (96%). Oncology practice characteristics such as having a survivorship clinic and geographic region were associated with screening for HRSNs and financial distress.<br><br>CONCLUSION: Research is needed to understand the impact of different HRSN screening and referral approaches on care delivery, clinic costs, care quality, and health outcomes of patients with cancer. These efforts are critical to generate evidence to inform best practices, clinical guidelines, and novel interventions aimed to improve cancer health equity.}, }
@article {pmid40080017, year = {2025}, author = {Gupta, A and Till, C and Vaidya, R and Hershman, DL and Unger, JM}, title = {Health Care Contact Days for Older Adults Enrolled in Cancer Clinical Trials.}, journal = {JAMA network open}, volume = {8}, number = {3}, pages = {e250778}, pmid = {40080017}, issn = {2574-3805}, mesh = {Humans ; Aged ; Male ; Female ; United States ; Aged, 80 and over ; *Neoplasms/therapy ; *Clinical Trials as Topic/statistics &amp; numerical data ; Cohort Studies ; Medicare/statistics &amp; numerical data ; }, abstract = {IMPORTANCE: Contact days-days with health care contact outside the home-are a measure of how much of a patient's life is consumed by health care. Clinical trials, with a more uniform patient mix and protocolized care, provide a unique opportunity to assess whether burdens differ by individuals' sociodemographic backgrounds.<br><br>OBJECTIVE: To characterize patterns of contact days for older adults with cancer participating in clinical trials.<br><br>In this cohort study, data from 6 SWOG Cancer Research Network trials across prostate, lung, and pancreatic cancers that recruited patients aged 65 years or older from 1999 to 2014 were linked with Medicare claims data. Data were analyzed from December 14, 2023, to September 26, 2024.<br><br>EXPOSURES: Demographic variables, including age, sex, self-reported race and ethnicity, and insurance status; clinical factors, such as cancer type and study-specific prognostic risk score; and social factors, such as neighborhood socioeconomic deprivation.<br><br>MAIN OUTCOMES AND MEASURES: Number of contact days, defined as number of days with contact with the health care system, percentage of health care contact days (number of contact days divided by follow-up), and sources of contact days (eg, ambulatory or inpatient) in the first 12 months after trial enrollment. Sociodemographic and clinical factors associated with contact days were examined using negative binomial regression, including an offset variable for duration of observation.<br><br>RESULTS: The study included 1429 patients (median age, 71 years [range, 65-91 years]; 1123 men [78.6%]; and 332 patients [23.5%] with rural residence). The median number of contact days was 48 (IQR, 26-71), of a median of 350 days (IQR, 178-365 days) of observation; the median percentage of contact days was 19% (IQR, 13%-29%). The most common sources of contact days were ambulatory clinician visits (median, 17 [IQR, 7-25]), tests (median, 12 [IQR, 3-24]), and treatments (median, 11 [IQR, 3-22]). A median of 70% (IQR, 50%-88%) of ambulatory contact days had only a single service performed on that day (eg, only tests). In multivariable regression, factors associated with increased contact days included age (relative risk [RR] per year, 1.02 [95% CI, 1.01-1.02]), insurance type (Medicare alone or with Medicaid or private insurance vs other: RR, 2.47 [95% CI, 2.16-2.83]), prognostic risk score (above the median vs at or below the median: RR, 1.14 [95% CI, 1.04-1.25]), and type of cancer (pancreatic vs prostate cancer: RR, 1.69 [95% CI, 1.51-1.89]; lung vs prostate cancer: RR, 1.69 [95% CI, 1.54-1.85]).<br><br>CONCLUSIONS AND RELEVANCE: In this cohort study of older adults with advanced stage cancer participating in phase 3 randomized clinical trials, patients spent nearly 1 in 5 days with health care contact. These findings highlight the need to simplify trial requirements to minimize participant burden.}, }
@article {pmid40061351, year = {2025}, author = {Siegel, SJ and DeWolf, S and Schmalz, J and Saber, W and Dong, J and Martens, MJ and Logan, B and Albanese, A and Iovino, L and Chen, E and Kaminski, J and Neuberg, D and Hebert, K and Keskula, P and Zavistaski, J and Steinberg, L and Schichter, I and Cagnin, L and Hernandez, V and Warren, M and Applegate, K and Bar, M and Chhabra, S and Choi, SW and Clark, W and Das, S and Jenq, R and Jones, RJ and Levine, JE and Murthy, H and Rashidi, A and Riches, M and Sandhu, K and Sung, AD and Larkin, K and Al Malki, MM and Gooptu, M and Elmariah, H and Alousi, A and Runaas, L and Shaffer, B and Rezvani, A and El Jurdi, N and Loren, AW and Scheffey, D and Sanders, C and Hamadani, M and Dudakov, J and Bien, S and Robins, H and Horowitz, M and Bolaños-Meade, J and Holtan, S and Bhatt, AS and Perales, MA and Kean, LS}, title = {Graft-versus-host disease prophylaxis shapes T cell biology and immune reconstitution after hematopoietic cell transplant.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40061351}, support = {U10 HL069294/HL/NHLBI NIH HHS/United States ; U24 HL138660/HL/NHLBI NIH HHS/United States ; }, abstract = {Successful hematopoietic cell transplant requires immunosuppression to prevent graft-versus-host disease (GVHD), a lethal, T-cell-mediated post-transplant complication. The phase 3 BMT CTN 1703 trial demonstrated superior GVHD-free/relapse-free survival for post-transplant cyclophosphamide (PT-Cy)-based GVHD prophylaxis versus tacrolimus/methotrexate (Tac/MTX), but did not improve overall survival. To compare T-cell biology between GVHD prophylaxis regimens, 324 patients were co-enrolled onto BMT CTN 1801 (NCT03959241). We quantified T-cell immune reconstitution using multi-modal analysis, including T-cell receptor (TCR) sequencing of 2,359 longitudinal samples (180,432,350 T-cells). Compared to Tac/MTX, PT-Cy was associated with an early, substantial reduction in TCR diversity that was sustained for 2 years. PT-Cy led to a T-cell reconstitution bottleneck, including reduced thymic output and virus-associated TCRs. Decreased D+14 TCR diversity predicted prevention of chronic GVHD, but also correlated with increased moderate-to-severe infections. This study reveals how distinct immunosuppression strategies have significant effects on the global immune repertoire, underpinning post-transplant clinical outcomes.}, }
@article {pmid40060686, year = {2025}, author = {Singh, S and Islam, SMS and Liu, R and Adeniji, OS and Giron, LB and Saini, P and Danesh, A and Denton, PW and Jones, B and Xiao, H and Abdel-Mohsen, M}, title = {HIV-Induced Sialoglycans on Infected Cells Promote Immune Evasion from Myeloid Cell-Mediated Killing.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40060686}, issn = {2692-8205}, support = {R01 AA029859/AA/NIAAA NIH HHS/United States ; R15 AI178516/AI/NIAID NIH HHS/United States ; R01 DK123733/DK/NIDDK NIH HHS/United States ; R01 NS117458/NS/NINDS NIH HHS/United States ; R01 AI165079/AI/NIAID NIH HHS/United States ; R01 AG062383/AG/NIA NIH HHS/United States ; P20 GM103427/GM/NIGMS NIH HHS/United States ; }, abstract = {Sialic acid-containing glycans (sialoglycans) on pathological cells interact with Siglecs, glycol-immune checkpoint receptors expressed on myeloid cells such as monocytes and neutrophils. This interaction suppresses the cytotoxic functions of these immune cells. We show that HIV infection reprograms the glycosylation machinery of infected cells to increase the expression of specific sialoglycan ligands for Siglecs-3, -7, and -9. These ligands engage Siglecs on myeloid cells, impairing their ability to target HIV-infected cells. Selective disruption of these interactions using 10-1074-Sia, an HIV-specific antibody conjugated to sialidase-an enzyme that removes sialic acids-significantly enhances monocyte- and neutrophil-mediated killing of HIV-infected cells in autologous assays. Treatment with 10-1074-Sia in humanized mice infected with HIV reduces viral load and decreases inflammation. These findings reveal a novel immune evasion mechanism exploited by HIV to evade myeloid cell immune surveillance and highlight the potential of targeting sialoglycan-Siglec interactions to improve immune clearance of HIV-infected cells.}, }
@article {pmid40060420, year = {2025}, author = {Rosero, M and Bai, J}, title = {AFD Thermosensory Neurons Mediate Tactile-Dependent Locomotion Modulation in C. elegans.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40060420}, issn = {2692-8205}, support = {R01 NS115974/NS/NINDS NIH HHS/United States ; F31 NS129545/NS/NINDS NIH HHS/United States ; T32 GM136534/GM/NIGMS NIH HHS/United States ; R01 NS109476/NS/NINDS NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P40 OD010440/OD/NIH HHS/United States ; }, abstract = {Sensory neurons drive animal behaviors by detecting environmental stimuli and relaying information to downstream circuits. Beyond their primary roles in sensing, these neurons often form additional synaptic connections outside their main sensory modality, suggesting broader contributions to behavior modulation. Here, we uncover an unexpected role for the thermosensory neuron AFD in coupling tactile experience to locomotion modulation in Caenorhabditis elegans. We show that while AFD employs cGMP signaling for both thermotaxis and tactile-dependent modulation, the specific molecular components of the cGMP pathway differ between these two processes. Interestingly, disrupting the dendritic sensory apparatus of AFD, which is essential for thermotaxis, does not impair tactile-based locomotion modulation, indicating that AFD can mediate tactile-dependent behavior independently of its thermosensory apparatus. In contrast, ablating the AFD neuron eliminates tactile-dependent modulation, pointing to an essential role for AFD itself, rather than its sensory dendritic endings. Further, we find tactile-dependent modulation requires the AIB interneuron, which connects AFD to touch circuits via electrical synapses. Removing innexins expressed in AFD and AIB abolishes this modulation, while re-establishing AFD-AIB connections with engineered electrical synapses restores it. Collectively, these findings uncover a previously unrecognized function of AFD beyond thermosensation, highlighting its influence on context-dependent neuroplasticity and behavioral modulation through broader circuit connectivity.}, }
@article {pmid40060404, year = {2025}, author = {Park, L and Tsai, YT and Lim, HK and Faulhaber, LD and Burleigh, K and Faulhaber, EM and Bose, M and Shih, AY and Hirayama, AY and Turtle, CJ and Annesley, CE and Gardner, RA and Gustafson, HH and Gust, J}, title = {Cytokine-mediated increase in endothelial-leukocyte interaction mediates brain capillary plugging during CAR T cell neurotoxicity.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40060404}, issn = {2692-8205}, support = {K08 NS118138/NS/NINDS NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R37 CA275954/CA/NCI NIH HHS/United States ; }, abstract = {CD19-directed CAR T cells treat cancer, but also cause immune effector cell associated neurotoxicity syndrome (ICANS). Despite strong epidemiologic links between cytokine release syndrome and ICANS, it is uncertain how elevated systemic cytokines and activated immune cells cause brain dysfunction. We previously showed that leukocytes plug brain capillaries in an immunocompetent mouse model of CD19-CAR neurotoxicity. Here, we used the same model to explore how integrin activation and endothelial adhesion molecule expression contribute to capillary plugging. In vivo two-photon imaging revealed increased expression of ICAM-1 on brain capillaries, with spatially restricted VCAM-1 increases. TNF, IFN-γ, and IL-1β at concentrations equivalent to CAR T cell patient blood levels upregulated ICAM-1 and VCAM-1 in brain microendothelial cells. In mice, CAR T cells strongly upregulated VLA-4 (integrin α4β1) affinity to VCAM-1, but not affinity of LFA-1 (integrin αLβ2) to ICAM-1. Blocking integrin α4 but not integrin αL improved ICANS behavior in mice. In human CAR T cell patients, increased soluble ICAM-1 and VCAM-1 are associated with ICANS, and integrin α4 but not integrin αL is upregulated in CAR T cells after infusion. Our study highlights that cytokine-driven upregulation of endothelial-leukocyte adhesion may be sufficient to induce neurovascular dysfunction in CAR T cell patients.}, }
@article {pmid40079983, year = {2025}, author = {Gomez-Castillo, L and Cushing-Haugen, KL and Useche, M and Norouzi, A and Rizvi, Z and Ferrandino, R and Futran, N and Marchiano, E and Rodriguez, T and Harris, HR and Barber, B}, title = {High Sugar-Sweetened Beverage Intake and Oral Cavity Cancer in Smoking and Nonsmoking Women.}, journal = {JAMA otolaryngology-- head &amp; neck surgery}, volume = {}, number = {}, pages = {}, pmid = {40079983}, issn = {2168-619X}, abstract = {IMPORTANCE: The incidence of oral cavity cancer (OCC) is increasing among nonsmokers and young individuals without traditional risk factors worldwide. High sugar-sweetened beverage (SSB) intake is associated with various gastrointestinal cancers, but its association with OCC has not been explored.<br><br>OBJECTIVE: To evaluate the association between SSB intake and the risk of OCC among smoking and nonsmoking women participating in the Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII).<br><br>This longitudinal cohort study analyzed data from women in the NHS (follow-up, 1986-2016) and NHSII (follow-up, 1991-2017) after excluding those with a history of cancer, implausible caloric intake, or missing SSB intake data. Participants were followed up until the diagnosis of OCC. Data analysis was performed from July 2023 to June 2024.<br><br>EXPOSURE: SSB intake, quantified by frequency of consumption ranging from less than 1 SSB monthly to 1 or more SSBs daily.<br><br>MAIN OUTCOME AND MEASURE: Cox proportional hazards regression models with age and questionnaire period as the time scale were used to estimate hazard ratios (HRs) and 95% CIs associated with the development of OCC for each category of SSB intake, with less than 1 SSB per month as the reference group.<br><br>RESULTS: A total of 162&#x202f;602 women (mean [SD] age, 43.0 [9.9] years) were evaluated. During 30 years of follow-up, 124 invasive OCC cases were documented. In multivariable-adjusted models, participants consuming 1 or more SSB daily (5 people per 100&#x202f;000 population) had a 4.87 times (95% CI, 2.47-9.60 times) higher risk of OCC compared with those consuming less than 1 SSB monthly (2 people per 100&#x202f;000 population), increasing the rate of OCC to 3 more people per 100&#x202f;000 population. When restricted to both nonsmokers or light smokers and nondrinkers or light drinkers, the risk of OCC was 5.46 times (95% CI, 1.75-17.07 times) higher, increasing the rate of OCC to 3 more people per 100&#x202f;000 population.<br><br>CONCLUSIONS AND RELEVANCE: In this study, high SSB intake was associated with a significantly increased risk of OCC in women, regardless of smoking or drinking habits, yet with low baseline risk. Additional studies are needed in larger cohorts, including males, to validate the impact of these findings.}, }
@article {pmid40079097, year = {2025}, author = {Portuguese, AJ and Huang, JJ and Jeon, Y and Taheri, M and Albittar, A and Liang, EC and Hirayama, AV and Kimble, EL and Iovino, L and Poh, C and Gopal, AK and Shadman, M and Till, BG and Milano, F and Chapuis, AG and Otegbeye, F and Cassaday, RD and Basom, RS and Wu, QV and Maloney, DG and Gauthier, J}, title = {Real-world comparison of lisocabtagene maraleucel and axicabtagene ciloleucel in large B-cell lymphoma: an inverse probability of treatment weighting analysis with 3-year follow up.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2024.287010}, pmid = {40079097}, issn = {1592-8721}, abstract = {Lisocabtagene maraleucel (liso-cel) and axicabtagene ciloleucel (axi-cel) are FDA- and EMAapproved chimeric antigen receptor (CAR) T-cell therapies for relapsed/refractory large B-cell lymphoma (LBCL). However, comparative real-world analyses of their efficacy and toxicity with extended follow-up are lacking. We conducted a retrospective study of 160 LBCL patients treated at the Fred Hutchinson Cancer Center with commercial liso-cel or axi-cel per standard of care. Using inverse probability of treatment weighting (IPTW) to mitigate treatment allocation bias and multivariable adjustments to minimize other sources of confounding, we assessed the impact of CAR T-cell product type on outcomes. Axi-cel was associated with significantly higher rates of cytokine release syndrome (CRS; G1+: adjusted OR [aOR] 4.27, p=0.004; G2+: aOR 2.88, p=0.006), immune effector cell-associated neurotoxicity syndrome (ICANS; G1+: aOR 2.10, p=0.048), and immune effector cell-associated hematotoxicity (ICAHT; G1+: aOR 8.09, p.}, }
@article {pmid40075650, year = {2025}, author = {Bar, M and El Anbari, M and Rinchai, D and Toufiq, M and Kizhakayil, D and Manjunath, HS and Mathew, R and Cavattoni, I and Forer, S and Recla, M and Bibawi, H and Alater, A and Yahia, R and Brown, C and Miles, NL and Vo, P and Bedognetti, D and Tomei, S and Saleh, A and Cugno, C and Chaussabel, D and Deola, S}, title = {Whole-Blood Longitudinal Molecular Profiling Maps the Road of Graft Versus Host Disease (GVHD).}, journal = {Cancers}, volume = {17}, number = {5}, pages = {}, pmid = {40075650}, issn = {2072-6694}, support = {NPRP13S-0107-200023 to Sara Deola//QNRF/ ; }, abstract = {Background: Graft versus host disease (GVHD) and the graft versus tumor (GVT) effect after allogeneic hematopoietic cell transplantation (allo-HCT) result from complex interactions between the donor immune system and the recipient environment. High-temporal longitudinal monitoring might be necessary to identify triggering events of GVHD and GVT and to intercept these events before their occurrence. But it would require an overall considerable amount of blood by venipuncture, which is unfeasible in such a fragile population. Methods: In this study, we implemented a targeted multiplex microfluidics q-PCR-based transcriptional fingerprint assay (TFA) on 50 µL of blood collected by a simple fingerstick to evaluate post-allo-HCT systemic immune perturbations associated with the development of GVHD. Fluctuations of a panel of 264 genes were measured in 31 allo-HCT patients by frequent (weekly or biweekly) analysis of 50 µL serial blood samples. Cross-sectional and longitudinal analyses correlated with detailed clinical annotations were performed. Results: Signatures of neutrophil activation and interferon (IFN) characterized the onset of acute GVHD, while an ongoing cytotoxic response was modulated in chronic mild GVHD and protein-synthesis and B-cell-related signatures characterized late acute/overlap GVHD. An unexpected erythroid signature distinguished patients with acute and mild chronic GVHD. Conclusions: Our micro-invasive approach unveiled the molecular heterogeneity of GVHD and identified hierarchically important biological processes conducive to different forms of GVHD. These findings increase our understanding of GVHD and reveal potentially targetable alterations. This approach might be implemented clinically to intercept GVHD before its occurrence and to modulate therapeutic interventions accordingly.}, }
@article {pmid40075647, year = {2025}, author = {Roeker, LE and Burke, JM and Rhodes, JM and Emechebe, N and Jawaid, D and Manzoor, BS and Jensen, CE and Ryland, L and Liu, Y and Marx, SE and Sinai, W and Roser, J and Shadman, M}, title = {Real-World Effectiveness of Frontline Treatments Among Patients with Chronic Lymphocytic Leukemia: Results from ConcertAI.}, journal = {Cancers}, volume = {17}, number = {5}, pages = {}, pmid = {40075647}, issn = {2072-6694}, support = {N/A//AbbVie (United States)/ ; }, abstract = {Background: The long-term follow-up of clinical trials of novel first-line (1L) therapies for chronic lymphocytic leukemia (CLL) demonstrates 6-10-year progression-free survival. We describe the effectiveness of 1L CLL treatments in real-world settings, with an emphasis on the important real-world outcome of time to next treatment or death (TTNT-D). Methods: This retrospective, observational study utilized de-identified electronic health records from the ConcertAI RWD360™ database with linked administrative open claims. Adults with CLL who initiated an approved 1L CLL therapy (June 2019-March 2023) were included. Duration of therapy (DoT), TTNT-D, and overall survival were assessed. Results: At 1L, 39.8% of 1843 patients received first-generation covalent Bruton tyrosine kinase inhibitors (cBTKis), 23.0% second-generation cBTKis, 12.4% venetoclax-obinutuzumab (VenO), 7.4% chemotherapy/chemoimmunotherapy (CT/CIT), and 17.4% anti-CD20 monotherapy. Median (range) follow-up in months was 24.9 (13.1-36.6) for first-generation cBTKis, 13.4 (7.3-21.7) for second-generation cBTKis, 16.0 (8.4-27.8) for VenO, 21.8 (11.2-32.7) for CT/CIT, and 19.7 (10.0-33.4) for anti-CD20 monotherapy. Median (range) DoT was 11.5 (4.2-25.0) and 8.6 (3.0-16.1), 9.1 (5.9-12.2), 5.6 (3.2-5.8), and 1.6 (1.6-4.5) months for first- and second-generation cBTKis, VenO, CT/CIT, and anti-CD20 monotherapy, respectively. Regarding TTNT-D, at 2 years' follow-up, 69.1%, 82.5%, 86.3%, 79.1%, and 53.0% of patients treated with first- and second-generation cBTKis, VenO, CT/CIT, and anti-CD20 monotherapy, respectively, had not initiated subsequent treatment or experienced death. Conclusions: TTNT-D is an important real-world outcome in CLL. Our findings demonstrated the utility of time-limited VenO, with potentially more time off treatment, relative to continuous 1L cBTKi therapies.}, }
@article {pmid40074150, year = {2025}, author = {Paulson, KG and Park, SY and Bhatia, S and Hippe, DS and Nghiem, P}, title = {Improved survival at the population level for patients with advanced Merkel cell carcinoma following availability of immunotherapy.}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2025.03.006}, pmid = {40074150}, issn = {1097-6787}, abstract = {BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive skin cancer with poor survival rates. Immune checkpoint inhibitors (ICIs) were FDA-approved for advanced MCC in 2017, but their real-world survival impact remains unclear.<br><br>OBJECTIVE: Evaluate whether ICI introduction in the US corresponded with improved survival.<br><br>METHODS: This cohort study analyzed SEER data for MCC patients diagnosed from 2010 to 2021, grouped by 3-year periods, to calculate 2-year overall and relative survival.<br><br>RESULTS: For 453 patients with metastatic MCC, 2-year relative survival improved from 23% (2010-2012) to 37% (2013-2015), 42% (2016-2018), and 54% (2019-2021) (p < 0.001). Median overall survival also increased from 9 to 16 months among these patients. In 4,786 MCC patients overall, 2-year relative survival rose from 73% (2010-2012) to 81% (2019-2021) (p = 0.004), while overall survival improved from 67% to 72% (p = 0.012).<br><br>LIMITATIONS: SEER lacks case-level data to link ICI treatment directly to survival, although ICIs represent the major recent treatment advance for MCC.<br><br>CONCLUSIONS: The introduction of ICIs aligns with a >2-fold increase in survival for advanced MCC patients at the population level, translating to &#x223c;220 fewer deaths per year in the U.S.}, }
@article {pmid40073862, year = {2025}, author = {Khyzha, N and Ahmad, K and Henikoff, S}, title = {Profiling transcriptome composition and dynamics within nuclear compartments using SLAM-RT&amp;Tag.}, journal = {Molecular cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.molcel.2025.02.012}, pmid = {40073862}, issn = {1097-4164}, abstract = {Nuclear compartments are membrane-less regions enriched in functionally related molecules. RNA is a major component of many nuclear compartments, but the identity and dynamics of transcripts within nuclear compartments are poorly understood. Here, we applied reverse transcribe and tagment (RT&amp;Tag) to human cell lines to identify the transcript populations of Polycomb domains and nuclear speckles. We also developed SLAM-RT&amp;Tag, which combines RNA metabolic labeling with RT&amp;Tag, to quantify transcript dynamics within nuclear compartments. We observed unique transcript populations with differing structures and dynamics within each compartment. Intriguingly, exceptionally long genes are transcribed adjacent to Polycomb domains and are transiently associated with chromatin. By contrast, nuclear speckles act as quality control checkpoints that transiently confine incompletely spliced polyadenylated transcripts and facilitate their post-transcriptional splicing. In summary, we demonstrate that transcripts at Polycomb domains and nuclear speckles undergo distinct RNA processing mechanisms, highlighting the pivotal role of compartmentalization in RNA maturation.}, }
@article {pmid40073837, year = {2025}, author = {Gajjar, A and Mahajan, A and Bale, T and Bowers, DC and Canan, L and Chi, S and Cluster, A and Cohen, K and Cole, B and Coven, S and Darlington, W and Dorris, K and Elster, J and Ermoian, R and Franson, A and George, E and Helgager, J and Landi, D and Lin, C and Metrock, L and Nanda, R and Palmer, J and Partap, S and Plant, A and Pruthi, S and Reynolds, R and Stearns, D and Storm, P and Wang, A and Wang, LD and Whipple, N and Zaky, W and McMillian, N and Ramakrishnan, S}, title = {Pediatric Central Nervous System Cancers, Version 2.2025, NCCN Clinical Practice Guidelines In Oncology.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {23}, number = {3}, pages = {113-130}, doi = {10.6004/jnccn.2025.0012}, pmid = {40073837}, issn = {1540-1413}, mesh = {Humans ; Child ; *Central Nervous System Neoplasms/therapy/diagnosis ; Adolescent ; *Medical Oncology/standards/methods ; Glioma/therapy/diagnosis/pathology ; Medulloblastoma/therapy/diagnosis/pathology ; Child, Preschool ; }, abstract = {The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pediatric Central Nervous System Cancers provide multidisciplinary diagnostic workup, staging, and treatment recommendations for diffuse high-grade gliomas and medulloblastomas in children and adolescents. This article summarizes the studies and panel discussion that serve as the rationale for comprehensive care recommendations included in the NCCN Guidelines for Pediatric Central Nervous System Cancers.}, }
@article {pmid40073835, year = {2025}, author = {Greenberg, PL and Stone, RM and Abaza, Y and Al-Kali, A and Anand, S and Ball, B and Bennett, JM and Borate, U and Brunner, AM and Chai-Ho, W and Curtin, P and DeZern, AE and Gaensler, K and Gahvari, Z and Garcia-Manero, G and Griffiths, EA and Haque, T and Jacoby, M and Jonas, BA and Keel, S and Khanal, R and Kishtagari, A and Madanat, Y and Maness, LJ and McCurdy, SR and McMahon, C and Odenike, O and Osman, A and Reddy, VV and Sallman, DA and Sayar, H and Shallis, R and Singh, A and Tanaka, T and Thota, S and Kovach, E and Nguyen, J and Hochstetler, C}, title = {NCCN Guidelines® Insights: Myelodysplastic Syndromes, Version 2.2025.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {23}, number = {3}, pages = {66-75}, doi = {10.6004/jnccn.2025.0013}, pmid = {40073835}, issn = {1540-1413}, mesh = {*Myelodysplastic Syndromes/diagnosis/therapy ; Humans ; Prognosis ; Disease Management ; }, abstract = {The NCCN Guidelines for Myelodysplastic Syndromes (MDS) provide recommendations for the evaluation, diagnosis, and comprehensive care of patients with MDS based on a review of recent clinical evidence that has led to important advances in treatment or has yielded new information on biologic factors that may have prognostic significance in MDS. The multidisciplinary panel of MDS experts is convened at least on an annual basis. During the annual meeting, the panel evaluates new and emerging data to inform their recommendations. These NCCN Guidelines Insights review the recent updates, including treatment recommendations both for lower-risk and higher-risk MDS, preference stratification of therapeutic agents, and emerging data on novel therapeutics.}, }
@article {pmid40073834, year = {2025}, author = {Narkhede, M and Ujjani, CS}, title = {Immune Dysfunction and Consequences in Chronic Lymphocytic Leukemia.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {23}, number = {3}, pages = {}, doi = {10.6004/jnccn.2024.7090}, pmid = {40073834}, issn = {1540-1413}, mesh = {Humans ; *Leukemia, Lymphocytic, Chronic, B-Cell/immunology/therapy ; }, abstract = {Infectious complications are among the leading causes of mortality in chronic lymphocytic leukemia (CLL). Over the past decade, several advances have been made in treating CLL through inhibition of Bruton tyrosine kinase and the antiapoptotic protein BCL-2. As mortality from CLL progression is expected to decline in the next several years, mortality from severe infections is anticipated to increase. Therefore, understanding the nature of immune defects in CLL and developing strategies to augment the impaired immune system are needed to keep pace with advancements in treatment. This review article summarizes the available data on immune dysfunctions, their clinical consequences, therapeutic implications, and current strategies to enhance immune function in patients with CLL.}, }
@article {pmid40073280, year = {2025}, author = {Barros, M and Leon, A and Crivera, C and Cusson, E and Kodjamanova, P and Bagnall, R and Panch, SR}, title = {Literature review of occurrence, effectiveness, safety, and hospitalization burden of blood transfusion in the management of warm autoimmune hemolytic anemia.}, journal = {Hematology (Amsterdam, Netherlands)}, volume = {30}, number = {1}, pages = {2472489}, doi = {10.1080/16078454.2025.2472489}, pmid = {40073280}, issn = {1607-8454}, mesh = {Humans ; *Anemia, Hemolytic, Autoimmune/therapy ; *Hospitalization ; Erythrocyte Transfusion/adverse effects ; Blood Transfusion/methods ; }, abstract = {INTRODUCTION: Cases of warm autoimmune hemolytic anemia (wAIHA) often present with life-threatening levels of hemoglobin requiring red blood cell (RBC) transfusion support.<br><br>AIM: This literature review assessed the occurrence, safety, effectiveness, and hospitalization burden of RBC transfusions in the management of patients with wAIHA.<br><br>METHODS: Electronic databases (Embase, MEDLINE) were searched from inception to December 2021 along with additional searches conducted up to March 2024.<br><br>RESULTS: Of the 1478 articles screened, 17 observational studies and reviews were included. These studies demonstrated the use of 1-50 red blood cell transfusions to reach clinically acceptable hemoglobin levels in patients with wAIHA. In general, pre-transfusion hemoglobin levels were 6&#x2005;g/dL and increased by an average 1.2&#x2005;g/dL following a transfusion. Approximately 50% of patients with primary or secondary wAIHA suffered relapses. No data was available to distinguish between RBC transfusions used at initial presentation versus during relapse. Five studies found no increase in hemolysis or serious adverse reactions following transfusions and two studies reported mild transfusion-related adverse effects. Limited data was available regarding the hospitalization burden of RBC transfusion. Patients with wAIHA requiring transfusions had a median hospital stay from 15 to 17 days, which is considerably higher than all causes hospitalization of 4.5 days for 2023 U.S.<br><br>CONCLUSION: In patients with wAIHA, data supports wide variability in occurrence, but relative safety and effectiveness of RBC transfusions as supportive therapy. Additional studies are needed to assess the occurrence, safety, and hospitalization burden of RBC transfusions relative to other therapies in chronic relapsing wAIHA.}, }
@article {pmid40072429, year = {2025}, author = {Heng, F and Sun, Y and Li, L and B Gilbert, P}, title = {Estimation and Hypothesis Testing of Strain-Specific Vaccine Efficacy With Missing Strain Types With Application to a COVID-19 Vaccine Trial.}, journal = {Statistics in medicine}, volume = {44}, number = {6}, pages = {e10345}, pmid = {40072429}, issn = {1097-0258}, support = {R37 AI054165/AI/NIAID NIH HHS/United States ; AI068635/NH/NIH HHS/United States ; U01 AI068635/AI/NIAID NIH HHS/United States ; DMS1915829//National Science Foundation/ ; R37AI054165/NH/NIH HHS/United States ; }, mesh = {Humans ; *COVID-19 Vaccines/immunology ; *SARS-CoV-2/immunology/genetics ; *COVID-19/prevention &amp; control ; *Computer Simulation ; *Vaccine Efficacy ; Genotype ; Randomized Controlled Trials as Topic ; Models, Statistical ; }, abstract = {Based on data from a randomized, controlled vaccine efficacy trial, this article develops statistical methods for assessing vaccine efficacy (VE) to prevent COVID-19 infections by a discrete set of genetic strains of SARS-CoV-2. Strain-specific VE adjusting for possibly time-varying covariates is estimated using augmented inverse probability weighting to address missing viral genotypes under a competing risks model that allows separate baseline hazards for different risk groups. Hypothesis tests are developed to assess whether the vaccine provides at least a specified level of VE against some viral genotypes and whether VE varies across genotypes. Asymptotic properties providing analytic inferences are derived and finite-sample properties of the estimators and hypothesis tests are studied through simulations. This research is motivated by the fact that previous analyses of COVID-19 vaccine efficacy did not account for missing genotypes, which can cause severe bias and efficiency loss. The theoretical properties and simulations demonstrate superior performance of the new methods. Application to the Moderna COVE trial identifies several SARS-CoV-2 genotype features with differential vaccine efficacy across genotypes, including lineage (Reference, Epsilon, Gamma, Zeta), indicators of residue match vs. mismatch to the vaccine-strain residue at Spike amino acid positions (identifying signatures of differential VE), and a weighted Hamming distance to the vaccine strain. The results show VE decreases against genotypes more distant from the vaccine strain, highlighting the need to update COVID-19 vaccine strains.}, }
@article {pmid40071691, year = {2025}, author = {Huang, Y and Kwan, ML and Heckbert, SR and Smith, NL and Othus, M and Laurent, CA and Roh, JM and Rillamas-Sun, E and Lee, VS and Kolevska, T and Cheng, RK and Irribarren, C and Nguyen-Huynh, M and Hershman, DL and Kushi, LH and Greenlee, H}, title = {Endocrine therapy and risk of cardiovascular disease and mortality in postmenopausal breast cancer survivors.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djaf063}, pmid = {40071691}, issn = {1460-2105}, abstract = {BACKGROUND: There are increasing concerns of cardiovascular safety related to endocrine therapy use in women with breast cancer (BC). We examined risk of cardiovascular disease (CVD) events and mortality associated with endocrine therapy use in postmenopausal women with early-stage BC.<br><br>METHODS: Postmenopausal women diagnosed with stage I-III hormone receptor-positive BC from 2005 to 2013 were included (n&#x2009;=&#x2009;8,495). Women were classified as aromatase inhibitor (AI) users, tamoxifen users, and non-users of endocrine therapy in the 12&#x2009;months after BC diagnosis. Likelihood ratio tests examined whether the association of endocrine therapy use with CVD and mortality outcomes varied by body mass index (BMI) and history of CVD before BC diagnosis.<br><br>RESULTS: Over a median follow-up of 7.5&#x2009;years, women who used AIs were less likely to develop major adverse cardiovascular events (MACE) (HR&#x2009;=&#x2009;0.84, 95% CI: 0.73-0.97) and heart failure (HR&#x2009;=&#x2009;0.81, 95% CI: 0.66-0.99) compared with non-users of endocrine therapy. No associations between tamoxifen use and CVD outcomes were observed. AI use was associated with lower risk all-cause, CVD-related, and non-CVD-related mortality, compared with non-use of endocrine therapy. Tamoxifen use was associated with lower risk of all-cause mortality and non-CVD-related mortality, compared with non-use of endocrine therapy, and the association was modified by BMI (P for interaction <0.05).<br><br>CONCLUSION: Our findings suggest endocrine therapy use reduces all-cause mortality risk and may not increase CVD risk in postmenopausal women with early-stage hormone receptor-positive BC.}, }
@article {pmid40071498, year = {2025}, author = {Mehta, RS and Choe, H and Saultz, J and Gong, Z and Sharma, P and Al-Juhaishi, T and Petitto, GS and Lazaryan, A and Singh, A and Xue, E and Dimitrova, D and Hyder, M and McCurdy, S and Im, A and Huber, B and Aljawai, YM and Kanakry, J and Milano, F and Kanakry, CG}, title = {Impact of Donor Age and Donor Cytomegalovirus Serostatus on Outcomes After Related Donor Allogeneic Hematopoietic Stem Cell Transplantation.}, journal = {American journal of hematology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ajh.27662}, pmid = {40071498}, issn = {1096-8652}, abstract = {Cytomegalovirus (CMV) infection post-hematopoietic cell transplantation (HCT) remains a significant cause of morbidity and mortality. While letermovir prophylaxis is available for CMV-seropositive recipients, optimal donor selection for CMV-seronegative recipients remains unclear, with donor age often prioritized over CMV serostatus. We investigated the relative impact of donor age and CMV serostatus in CMV-seronegative recipients (n = 1013) with either CMV-seropositive (n = 318) or CMV-seronegative donors (n = 695), who underwent HCT with HLA-matched sibling donors with calcineurin inhibitor-based or post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease prophylaxis, or haploidentical donors with PTCy. Multiple conventional and machine-learning approaches were employed to account for confounding factors. Across all analyses, CMV-seropositive donor status was consistently associated with significantly inferior overall survival (OS) and disease-free survival, primarily driven by increased non-relapse mortality (NRM). Older donor age showed a statistically significant association with OS and DFS in some but not all models, and its effect size was small (about 1% increased hazard per year in Cox proportional hazard model) compared to the substantial impact of CMV-seropositive donors (about 27%-33% increased hazards for worse OS, approximately 50%-60% higher NRM in Cox proportional hazard model). However, our machine learning model revealed a more nuanced and complex non-linear effect of donor age, further demonstrating the adverse impact of donor CMV serostatus. Our findings suggest that prioritizing a CMV-seronegative donor may be associated with improved outcomes in CMV-seronegative recipients. Further research is needed to validate these findings and explore underlying mechanisms.}, }
@article {pmid40071446, year = {2025}, author = {Julceus, EF and Liese, AD and Alfalki, AM and Brown, AD and Pihoker, C and Qu, P and Malik, FS and Jones-Smith, JC and Crow, S and Loots, B and Reboussin, BA and Dolan, LM and Igudesman, D and Sauder, KA and Shapiro, ALB and Turley, CB and Mendoza, JA}, title = {The Association of Levels of Food Insecurity and Disordered Eating Behaviors Among Youth and Young Adults With Diabetes: The SEARCH for Diabetes in Youth Study.}, journal = {The International journal of eating disorders}, volume = {}, number = {}, pages = {}, doi = {10.1002/eat.24411}, pmid = {40071446}, issn = {1098-108X}, support = {1UC4DK108173/DK/NIDDK NIH HHS/United States ; R01DK117461/DK/NIDDK NIH HHS/United States ; /CC/CDC HHS/United States ; }, abstract = {OBJECTIVE: To examine the relationship between levels of household food insecurity and disordered eating behaviors (DEB) among youth and young adults with youth-onset type 1 (T1D) and type 2 diabetes (T2D).<br><br>METHOD: We used cross-sectional data from the multicenter SEARCH for Diabetes in Youth Study (2015-2020). The Household Food Security Survey Module and the Diabetes Eating Problem Survey-Revised (DEPS-R) were utilized to measure household food insecurity and continuous scores for DEB. In each stratum of diabetes type, we evaluated the association of household food insecurity levels with DEB through linear regression adjusting for potential confounders.<br><br>RESULTS: Participants (n&#x2009;=&#x2009;2669) were on average 21.5&#x2009;&#xb1;&#x2009;5.1&#x2009;years old and had a mean diabetes duration of 11.2&#x2009;&#xb1;&#x2009;3.3&#x2009;years; 54.2% were female, 64.0% non-Hispanic white, and respectively 12.9%, 11.1%, and 8.43% experienced marginal, low, and very low food security. The overall unadjusted mean DEPS-R score was 13.5&#x2009;&#xb1;&#x2009;9.5, with scores of 18.6&#x2009;&#xb1;&#x2009;11.8 and 21.1&#x2009;&#xb1;&#x2009;11.7 among T1D and T2D participants with very low food security, and scores of 11.5&#x2009;&#xb1;&#x2009;8.9 and 15.2&#x2009;&#xb1;&#x2009;8.8 among T1D and T2D participants with high food security. Compared to participants who reported high food security, adjusted DEPS-R scores among those with very low food security were 5.8 points (95% CI: 4.3, 7.4) and 6.6 points (95% CI: 3.3, 9.2) higher, respectively, in those with T1D (n&#x2009;=&#x2009;2274) and T2D (n&#x2009;=&#x2009;395). Less severe levels of household food insecurity showed similar associations with smaller effect sizes.<br><br>DISCUSSION: Addressing household food insecurity may decrease DEB and future adverse health outcomes for youth and young adults with diabetes.}, }
@article {pmid40070357, year = {2025}, author = {Gust, J and Cole, BL and Ronsley, R and Wilson, AL and Seidel, K and Wendler, J and Pattabhi, S and Brown, C and Rawlings-Rhea, SD and Shtanukhina, N and Browd, SR and Hauptman, JS and Lee, A and Ojemann, JG and Crotty, EE and Leary, SES and Perez, FA and Wright, JN and Albert, CM and Pinto, N and Gardner, RA and Vitanza, NA and Jensen, MC and Park, JR}, title = {Locoregional Infusion of EGFR806-CAR T Cells for Recurrent or Refractory Pediatric CNS Tumors: Results of the Completed BrainChild02 Phase 1 Clinical Trial.}, journal = {Neuro-oncology}, volume = {}, number = {}, pages = {}, doi = {10.1093/neuonc/noaf064}, pmid = {40070357}, issn = {1523-5866}, abstract = {BACKGROUND: Relapsed/refractory pediatric CNS tumors have a poor prognosis. EGFR is commonly overexpressed, but EGFRvIII mutations are uncommon. To target these tumors, we used chimeric antigen receptor (CAR) T cells with a binder based on mAb806 which recognizes ectopically expressed wild-type EGFR and EGFRvIII.<br><br>METHODS: In this open-label phase 1 clinical trial, patients age 1-26 years with EGFR+ CNS tumors received weekly infusions of 1-2.5 x 107 CAR T cells into the tumor resection bed or the lateral ventricle via an implanted catheter. No lymphodepletion was used.<br><br>RESULTS: Eleven patients were enrolled. Four (3 with high-grade glioma, 1 with atypical teratoid-rhabdoid tumor) were treated and received 5-10 CAR T cell infusions without dose-limiting toxicities. The trial closed prior to reaching planned dose regimens. All treatment-related adverse events were no higher than CTCAE grade 2. The most common were headache and nausea. One patient had a grade 1 seizure, and three had new sensory changes, weakness and/or urinary changes (grade 1-2) that were possibly related to CAR T cell infusion. Three of the four treated patients had progressive disease. One patient with spinal cord diffuse midline glioma had progressive peritumoral edema that could not be conclusively attributed to either progression or pseudoprogression and was therefore defined as stable disease, followed by a complete response to subsequent chemotherapy.<br><br>CONCLUSIONS: Intracranially infused EGFR806-CAR T cells were tolerable at tested doses, with a best response of stable disease. EGFR is a potentially useful target for cellular therapy against pediatric brain tumors, particularly high-grade gliomas.}, }
@article {pmid40067465, year = {2025}, author = {Nelson, JL and Lambert, NC}, title = {The when, what, and where of naturally-acquired microchimerism.}, journal = {Seminars in immunopathology}, volume = {47}, number = {1}, pages = {20}, pmid = {40067465}, issn = {1863-2300}, support = {117737/HL/NHLBI NIH HHS/United States ; 45659//Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases/ ; }, mesh = {Humans ; *Chimerism ; Pregnancy ; Female ; Maternal-Fetal Exchange/immunology ; HLA Antigens/genetics/immunology ; Autoimmune Diseases/etiology/immunology ; Animals ; }, abstract = {Naturally acquired microchimerism (Mc) is increasingly recognized as an aspect of normal biology. Maternal-fetal bi-directional exchange during pregnancy creates a Mc legacy for the long-term in both individuals. Maternal Mc in her offspring and Mc of fetal origin in women with previous births are best studied. Other sources include from a known or vanished twin, miscarriage or pregnancy termination, older sibling, or previous maternal pregnancy loss. Mc is pleotropic and protean, present in diverse forms, and changing over time as other aspects of biology. Mc acquired from multiple sources, at different lifespan times, and taking on an array of diverse forms, creates a "forward, reverse, and horizontal inheritance" Mc landscape. Mc is found in adaptive and innate immune cells, as resident tissue-specific cells in a wide variety of human tissues, and among other forms as extracellular vesicles. HLA molecules function in a myriad of ways as key determinants for health and are of central importance in interactions between genetically disparate individuals. Studies of autoimmune disease have firmly established a primary role of HLA molecules. Studies of iatrogenic chimerism have established benefit of donor-recipient HLA-disparity against recurrent malignancy after transplantation. HLA molecules and HLA-relationships of families are therefore of particular interest in seeking to understand the role(s) of Mc at the interface of auto-immunity and healthy allo-immunity. This review will begin by providing perspective on Mc in biology followed by a primary focus on persistent Mc according to the human lifespan, in healthy individuals and with illustrative examples of autoimmune diseases.}, }
@article {pmid40067336, year = {2025}, author = {Shadman, M and Fakhri, B and Jain, N}, title = {Consensus in CLL: global needs matter.}, journal = {Blood advances}, volume = {9}, number = {5}, pages = {1210-1212}, doi = {10.1182/bloodadvances.2024015355}, pmid = {40067336}, issn = {2473-9537}, }
@article {pmid40060430, year = {2025}, author = {Colegrove, HL and Monnat, RJ and Feder, AF}, title = {Epithelial competition determines gene therapy potential to suppress Fanconi Anemia oral cancer risk.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40060430}, issn = {2692-8205}, support = {DP2 CA280623/CA/NCI NIH HHS/United States ; }, abstract = {Fanconi Anemia (FA) is a heritable syndrome characterized by DNA damage repair deficits, frequent malformations and a significantly elevated risk of bone marrow failure, leukemia, and mucosal head and neck squamous cell carcinomas (HNSCC). Hematopoietic stem cell gene therapy can prevent marrow failure and lower leukemia risk, but mucosal gene therapy to lower HNSCC risk remains untested. Major knowledge gaps include an incomplete understanding of how rapidly gene-corrected cellular lineages could spread through the oral epithelium, and which delivery parameters are critical for ensuring efficient gene correction. To answer these questions, we extended an agent-based model of the oral epithelium to include the delivery of gene correction in situ to FA cells and the competitive dynamics between cellular lineages with and without gene correction. We found that only gene-corrected lineages with substantial proliferative advantages (probability of resisting displacement out of the basal layer ≥ 0.1) could spread on clinically relevant timelines, and that these lineages were initially at high risk of loss in the generations following correction. Delivering gene correction to many cells minimizes the risk of loss, while delivery to many distinct locations within a tissue maximizes the rate of spread. To determine the impact of mucosal gene therapy in preventing the clonal expansion of pre-cancerous mutations, we compared the expected burden of T P 53 mutations in simulated tissue sections with and without gene correction. We found that when FA cells have elevated genome instability or a T P 53 -dependent proliferative advantage, gene correction can substantially reduce the accumulation of pro-tumorigenic mutations. This model illustrates the power of computational frameworks to identify critical determinants of therapeutic success to enable experimental optimization and support novel and effective gene therapy applications.}, }
@article {pmid40067123, year = {2025}, author = {Wuliji, N and Jones, SMW and Gooley, TA and Gerds, AT and Medeiros, BC and Shami, PJ and Galvin, JP and Adekola, KUA and Luger, SM and Baer, MR and Rizzieri, DA and Wildes, T and Wang, ES and Sekeres, MA and Mukherjee, S and Smith, J and Garrison, M and Kojouri, K and Appelbaum, JS and Percival, MM and Sandmaier, BM and Lee, SJ and Appelbaum, F and Rouce, RH and Sorror, ML}, title = {Social Determinants of Health and Access to Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024027543}, pmid = {40067123}, issn = {1528-0020}, abstract = {Whether allogeneic hematopoietic cell transplant (allo-HCT) to treat acute myeloid leukemia (AML) is equitably accessible regardless of social determinants of health (SDOH) remains unknown. We examined associations of SDOH with access to allo-HCT and other outcomes. Patients presenting for treatment (n=692) at 13 AML treatment centers were prospectively recruited to a registered clinical trial (#NCT01929408). Various patient, AML, and SDOH specific variables were collected. Outcomes included mortality without allo-HCT, receipt of allo-HCT, and mortality after allo-HCT. Individual multivariable models (Fine-Gray for the first two outcomes, Cox regression for the third) were fit for each SDOH variable, adjusting for relevant patient- and AML-specific variables. Allo-HCT was used to treat 46% of patients. A 10% increase in the proportion with less than a high-school education, in households receiving Supplemental Nutrition Assistance Program, receiving Supplemental Security Income, or in poverty led to modeled adjusted hazard ratios (aHRs) of 1.21 (0.99-1.46), 1.13 (0.97-1.31), 1.41 (1.01-1.97), and 1.16 (0.96-1.39) for death without allo-HCT. The aHRs were 0.67 (0.55-0.83), 0.88 (0.76-1.01), 0.71 (0.48-1.05), and 0.91 (0.75-1.09), for lessened receipt of allo-HCT. Among those who received allo-HCT, aHRs for mortality were 1.18 (0.87-1.60), 1.13 (0.92-1.38), 1.21 (0.81-1.82), and 1.04 (0.79-1.36). Results highlight increased mortality without allo-HCT and decreased access to allo-HCT, but lesser magnitude of increased mortality after allo-HCT, among patients from lower resourced areas due to limited education and/or increased poverty. Targeted interventions and policy changes are needed to ensure that marginalized patient populations have equitable chances for AML cure compared to others.}, }
@article {pmid40066650, year = {2025}, author = {Donzella, SM and Bryer, BN and VoPham, T and Weaver, MD and Watson, NF and Zhong, C and Patel, AV and Phipps, AI}, title = {Chronotype, sleep timing, sleep regularity, and cancer risk: A systematic review.}, journal = {Sleep}, volume = {}, number = {}, pages = {}, doi = {10.1093/sleep/zsaf059}, pmid = {40066650}, issn = {1550-9109}, abstract = {Sleep is a multidimensional modifiable lifestyle factor related to cancer risk. Prior research has primarily focused on sleep duration, despite the increasing importance of sleep timing and sleep regularity in the health research field. The objective of this systematic review was to synthesize the existing literature on the relationship of chronotype, sleep timing, and sleep regularity with cancer risk. We searched four databases (PubMed, CINAHL, PsychInfo, and Embase) in October 2024. The sleep exposures of interest included sleep timing, sleep regularity, sleep midpoint, social jetlag, chronotype, and weekend catch-up sleep, and the outcome of interest was cancer incidence (overall or site-specific). A total of 22 studies were included, of which 18 investigated chronotype, two investigated social jetlag, two investigated sleep midpoint, and one investigated weekend catch-up sleep as the sleep exposure. The majority of studies assessed sleep using self-reported questionnaires (95%) and investigated site-specific cancer incidence (91%). We found no consistent evidence linking late chronotype, later sleep midpoint, increased social jetlag, or weekend catch-up sleep to elevated risk of cancer. This review highlights the heterogeneity in how sleep timing and sleep regularity are assessed. Future research should standardize measures on how to quantify sleep timing and sleep regularity and replication studies in diverse populations are needed. Current evidence on linking sleep timing, sleep regularity, and chronotype with cancer risk remains inconclusive.}, }
@article {pmid40065283, year = {2025}, author = {Venkataraman, A and Jia, T and Ruderman, SA and Haas, CB and Nance, RM and Mixson, LS and Mayer, KH and Saag, MS and Chander, G and Moore, RD and Jacobson, J and Napravnik, S and Christopolous, K and Lee, WJ and Whitney, BM and Peter, I and Crane, HM and Delaney, JAC and Lindström, S}, title = {A genome-wide association study of methamphetamine use among people with HIV.}, journal = {BMC medical genomics}, volume = {18}, number = {1}, pages = {46}, pmid = {40065283}, issn = {1755-8794}, support = {R01 HG010649/HG/NHGRI NIH HHS/United States ; R24 AI067039/AI/NIAID NIH HHS/United States ; R24AI067039/AA/NIAAA NIH HHS/United States ; R01HG010649/NH/NIH HHS/United States ; }, mesh = {Humans ; *Methamphetamine/adverse effects ; *Genome-Wide Association Study ; *HIV Infections/genetics ; *Polymorphism, Single Nucleotide ; Male ; Female ; Adult ; Amphetamine-Related Disorders/genetics ; Middle Aged ; Cohort Studies ; }, abstract = {BACKGROUND: Amphetamine-like stimulants are the most used psychostimulants in the world; methamphetamine use is the most prevalent in people with HIV. Prolonged methamphetamine use can cause lasting damage to the heart, gut, and brain, as well as auditory hallucinations and paranoid thinking. However, relatively little is known about methamphetamine use and its genetic contributors.<br><br>METHODS: Using genetic information from the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort, we conducted a multi-ancestry genome-wide association study (GWAS) of methamphetamine use among people with HIV (n&#x2009;=&#x2009;1,196 reported ever use, n&#x2009;=&#x2009;4,750 reported never use).<br><br>RESULTS: No single nucleotide polymorphism was statistically associated with methamphetamine use at the genome-wide level (p&#x2009;<&#x2009;5 * 10[-8]) in our study. Further, we did not replicate previously suggested genetic variants from other studies (all p&#x2009;>&#x2009;0.05 in our analysis).<br><br>DISCUSSION: Our study suggests that there is no single strong genetic contributor to lifetime use of methamphetamine in people with HIV enrolled in CNICS. Larger studies with more refined outcome assessment are warranted to further understand the contribution of genetics to methamphetamine use and use disorder. Investigation into social and environmental contributors to methamphetamine use are similarly necessary.}, }
@article {pmid40064621, year = {2025}, author = {Salerno, S and Yang, E and Dahlerus, C and Hirth, RA and Han, P and Xu, T and Eckard, A and Agbenyikey, W and Horton, GM and Clark, S and Messana, JM and Li, Y}, title = {Adding New Components to a Composite Quality Metric: How Good Is Good Enough?.}, journal = {Medical care}, volume = {63}, number = {4}, pages = {293-299}, doi = {10.1097/MLR.0000000000002116}, pmid = {40064621}, issn = {1537-1948}, mesh = {Humans ; Reproducibility of Results ; *Quality Indicators, Health Care ; Renal Dialysis/standards ; Quality of Health Care/standards ; United States ; }, abstract = {OBJECTIVES: This study illustrates how the statistical reliability of an individual measure relates to the overall reliability of a composite metric, as understanding this relationship provides additional information when evaluating measures for endorsement.<br><br>BACKGROUND: National quality measure endorsement processes typically evaluate individual metrics on criteria such as importance and scientific acceptability (eg, reliability). In practice, quality measures may be used in composite rating systems, which aid in the interpretation of overall quality differences.<br><br>METHODS: We define an individual measure's reliability by its intraclass correlation and analytically establish the relationship between a composite's reliability and the reliability of its components. We use real data to confirm this relationship under various scenarios. We are motivated by 8 quality measures, which comprise the Quality of Patient Care Star Ratings on Dialysis Facility Care Compare. These measure 4 primary outcomes (mortality, hospitalizations, readmissions, and blood transfusions), vascular access (2 measures), and facility processes (2 measures).<br><br>RESULTS: Depending on the reliability of the individual measures, their respective weights in the composite, and their pairwise correlations, there are circumstances when adding a new measure, even if it is less reliable, increases the composite's reliability. For the dialysis facility Star Ratings, we find that the combined reliability of measures grouped within certain domains of care exceeded the reliability of the individual measures within those domains.<br><br>CONCLUSIONS: New quality measures may add utility to a composite rating system under certain circumstances-a consideration that should, in part, factor into quality measure endorsement processes.}, }
@article {pmid40064297, year = {2025}, author = {Ahmed, S and Pfeiffer, RM and Volesky-Avellaneda, K and Blosser, CD and Snyder, JJ and Israni, AK and Lynch, CF and Qiao, B and Rees, JR and Zwald, F and Yu, KJ and Engels, EA}, title = {Real-world evidence regarding cancer, mortality, and graft failure risk with de novo belatacept use among kidney transplant recipients in the United States.}, journal = {American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajt.2025.03.004}, pmid = {40064297}, issn = {1600-6143}, abstract = {Belatacept is a selective T-cell co-stimulation blocker used in maintenance immunosuppression for kidney transplant recipients (KTRs), but evidence on cancer risk and other outcomes is limited. This retrospective cohort study used linked US transplant and cancer registry data on KTRs treated with belatacept (N=1514) or tacrolimus (N=7570) as initial maintenance therapy. We used multivariable Cox regression models to compare incidence of invasive cancer, cutaneous squamous cell carcinoma (cSCC), posttransplant lymphoproliferative disorder (PTLD), death, and graft failure/retransplantation (GF/RT) between belatacept and tacrolimus users. Overall, cancer incidence was 10.1 and 12.6 per 1000 person-years in belatacept and tacrolimus users, respectively. We did not find increased risk with belatacept for cancer overall (adjusted hazard ratio [HR] 0.83, 95% confidence interval [95%CI] 0.53-1.30), individual cancer types, or cSCC. Belatacept was associated with increased risk of death (adjusted HR 1.22, 95%CI 1.04-1.43) but lower risk of GF/RT more than four years after transplantation (0.54, 0.35-0.83). PTLD risk was increased among EBV-seropositive KTRs (adjusted HR 1.96, 95%CI 1.03-3.73). This study provides reassurance that belatacept does not increase cancer risk among KTRs, and there was a long-term protective association for GF/RT. However, we found evidence suggesting a potential increased risk of PTLD and death with belatacept use.}, }
@article {pmid40064296, year = {2025}, author = {Blosser, CD and Marks, LJ and Dharnidharka, VR}, title = {PTLD - It's Best to Face This Growing Challenge at the Start.}, journal = {American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajt.2025.03.006}, pmid = {40064296}, issn = {1600-6143}, }
@article {pmid40063180, year = {2025}, author = {Pete, D and Farris, PE and Adsul, P and Bea, JW and Decker, D and Ingram, J and Semprini, J and Baker, H and Yellowhair, M and Blackwater, C and Dee, C and Briant, KJ and Parker, M and Zahnd, WE and Nash, SH}, title = {The inclusion of tribes and American Indian and Alaska Native People in State comprehensive cancer control plans.}, journal = {Cancer causes &amp; control : CCC}, volume = {}, number = {}, pages = {}, pmid = {40063180}, issn = {1573-7225}, support = {K00CA253685/CA/NCI NIH HHS/United States ; 5P30CA069533/NH/NIH HHS/United States ; P30CA015704/NH/NIH HHS/United States ; P30CA015704/NH/NIH HHS/United States ; P30CA015704/NH/NIH HHS/United States ; 3P30CA086862//National Institutes of Health,United States/ ; 3P30CA086862//National Institutes of Health,United States/ ; }, abstract = {PURPOSE: State and District Comprehensive Cancer Control (CCC) plans often do not include priorities for all individuals within their state or district borders. In particular, American Indian and Alaska Native (AI/AN) people experience persistent cancer disparities, yet their inclusion in CCC plans has not been examined. Our study systematically reviewed state and district CCC plans for the inclusion of Tribal-specific cancer control strategies and priorities.<br><br>METHODS: A collaborative team of researchers from Tribal serving organizations, cancer centers, and academic institutions conducted a content analysis of state CCC plans to assess terms, concepts, context, and goals related to Tribal populations across twelve domains.<br><br>RESULTS: Seventy-three percent (n&#x2009;=&#x2009;37) of state CCC plans addressed at least one of twelve domain criteria, while 14 states (27%) did not mention Tribal data or priorities. Specifically, the terms "Indigenous or Native" (n&#x2009;=&#x2009;29) or "American Indian, Indian Country, Reservations, or Indian Health Service" (n&#x2009;=&#x2009;27) were referenced most often. Three states met the highest domain criteria (New Mexico, California, Montana). Six states with federally recognized tribes within their borders did not meet any domains (Alabama, Florida, Massachusetts, Missouri, Texas, Virginia).<br><br>CONCLUSION: By highlighting state and Tribal CCC plans' best practices and incorporating Tribal priorities within state and district CCC plans and programs, we underscore the importance of addressing cancer in Tribal populations across the U.S. and offer examples of inclusive CCC plan development and implementation.}, }
@article {pmid40063046, year = {2025}, author = {Raychaudhuri, R and Lin, DW and Montgomery, RB}, title = {Prostate Cancer: A Review.}, journal = {JAMA}, volume = {}, number = {}, pages = {}, doi = {10.1001/jama.2025.0228}, pmid = {40063046}, issn = {1538-3598}, abstract = {IMPORTANCE: Prostate cancer is the most common nonskin cancer in men in the US, with an estimated 299 010 new cases and 35 250 deaths in 2024. Prostate cancer is the second most common cancer in men worldwide, with 1 466 680 new cases and 396 792 deaths in 2022.<br><br>OBSERVATIONS: The most common type of prostate cancer is adenocarcinoma (&#x2265;99%), and the median age at diagnosis is 67 years. More than 50% of prostate cancer risk is attributable to genetic factors; older age and Black race (annual incidence rate, 173.0 cases per 100&#x202f;000 Black men vs 97.1 cases per 100&#x202f;000 White men) are also strong risk factors. Recent guidelines encourage shared decision-making for prostate-specific antigen (PSA) screening. At diagnosis, approximately 75% of patients have cancer localized to the prostate, which is associated with a 5-year survival rate of nearly 100%. Based on risk stratification that incorporates life expectancy, tumor grade (Gleason score), tumor size, and PSA level, one-third of patients with localized prostate cancer are appropriate for active surveillance with serial PSA measurements, prostate biopsies, or magnetic resonance imaging, and initiation of treatment if the Gleason score or tumor stage increases. For patients with higher-risk disease, radiation therapy or radical prostatectomy are reasonable options; treatment decision-making should include consideration of adverse events and comorbidities. Despite definitive therapy, 2% to 56% of men with localized disease develop distant metastases, depending on tumor risk factors. At presentation, approximately 14% of patients have metastases to regional lymph nodes. An additional 10% of men have distant metastases that are associated with a 5-year survival rate of 37%. Treatment of metastatic prostate cancer primarily relies on androgen deprivation therapy, most commonly through medical castration with gonadotropin-releasing hormone agonists. For patients with newly diagnosed metastatic prostate cancer, the addition of androgen receptor pathway inhibitors (eg, darolutamide, abiraterone) improves survival. Use of abiraterone improved the median overall survival from 36.5 months to 53.3 months (hazard ratio, 0.66 [95% CI, 0.56-0.78]) compared with medical castration alone. Chemotherapy (docetaxel) may be considered, especially for patients with more extensive disease.<br><br>CONCLUSIONS AND RELEVANCE: Approximately 1.5 million new cases of prostate cancer are diagnosed annually worldwide. Approximately 75% of patients present with cancer localized to the prostate, which is associated with a 5-year survival rate of nearly 100%. Management includes active surveillance, prostatectomy, or radiation therapy, depending on risk of progression. Approximately 10% of patients present with metastatic prostate cancer, which has a 5-year survival rate of 37%. First-line therapies for metastatic prostate cancer include androgen deprivation and novel androgen receptor pathway inhibitors, and chemotherapy for appropriate patients.}, }
@article {pmid40062652, year = {2025}, author = {Zhang, X and Hery, C and McLaughlin, EM and Woods, NF and Neuhouser, ML and Harris, H and Gower, EW and Wactawski-Wende, J and Shadyab, AH and Wallace, RB and Paskett, ED}, title = {The Association of Long COVID-19 Symptoms, Physical Function, and Activities of Daily Living Among Older Women.}, journal = {Journal of the American Geriatrics Society}, volume = {}, number = {}, pages = {}, doi = {10.1111/jgs.19434}, pmid = {40062652}, issn = {1532-5415}, support = {/HL/NHLBI NIH HHS/United States ; /NH/NIH HHS/United States ; //U.S. Department of Health and Human Services/ ; K00CA253745/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: The impact of COVID-19 on physical function (PF) outcomes among older adults remains unclear. We examined the long-term association between COVID, PF, and Activities of Daily Living (ADLs) among women from the Women's Health Initiative (WHI).<br><br>METHODS: Participants from the WHI who completed the COVID-19 survey (2021-2022) and annual survey (2022) were included. Self-reported data on COVID-19 testing and symptoms (2021-2022) were used. PF score and ADLs were evaluated pre- and post-COVID-19 survey by the 36-Item Short Form Survey PF subscale, the Lawton Instrumental Activities of Daily Living, and the Katz Index of Independence in ADL. Multivariable linear regression and logistic regression were used and adjusted for pre-COVID functioning to examine the association between COVID status, PF, and ADLs. The interaction between pre-COVID functioning and COVID status was tested.<br><br>RESULTS: Among the 13,933 WHI participants, 71.4% were aged &#x2265;&#x2009;80&#x2009;years, and 88.6% were Non-Hispanic White. Only 8.7% tested positive for COVID-19 (n&#x2009;=&#x2009;1210), with 35.1% having long COVID (n&#x2009;=&#x2009;425). The most common long COVID symptoms were fatigue (18.2%), malaise (12.2%), memory problems (12.1%), and brain fog (11.2%). Women who tested COVID+ had lower PF scores (60 vs. 65, p&#x2009;=&#x2009;0.045) and were less likely to be able to do all ADLs without help (74% vs. 79.2%, p&#x2009;=&#x2009;0.015) compared to those who never tested COVID+. After controlling for covariates, post-COVID PF scores did not differ by COVID status (p&#x2009;=&#x2009;0.30), although pre-COVID PF scores were significantly linked to post-COVID scores (p&#x2009;<&#x2009;0.001). Similarly, the odds of being able to do all ADLs without any help did not differ by COVID status (p&#x2009;=&#x2009;0.31), with pre-COVID ADLs significantly associated with post-COVID ADLs (p&#x2009;<&#x2009;0.001).<br><br>CONCLUSIONS: In older women, after accounting for pre-COVID functional status, the association between long COVID and lower functioning became nonsignificant. Our findings highlight the importance of preserving physical functioning among older women.}, }
@article {pmid40059038, year = {2025}, author = {Cuadrado, A and Cazalla, E and Bach, A and Bathish, B and Naidu, SD and DeNicola, GM and Dinkova-Kostova, AT and Fernández-Ginés, R and Grochot-Przeczek, A and Hayes, JD and Kensler, TW and León, R and Liby, KT and López, MG and Manda, G and Shivakumar, AK and Hakomäki, H and Moerland, JA and Motohashi, H and Rojo, AI and Sykiotis, GP and Taguchi, K and Valverde, &#xc1;M and Yamamoto, M and Levonen, AL}, title = {Health position paper and redox perspectives - Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases.}, journal = {Redox biology}, volume = {}, number = {}, pages = {103569}, doi = {10.1016/j.redox.2025.103569}, pmid = {40059038}, issn = {2213-2317}, abstract = {Nuclear factor erythroid 2-related factor 2 (NRF2) is a redox-activated transcription factor regulating cellular defense against oxidative stress, thereby playing a pivotal role in maintaining cellular homeostasis. Its dysregulation is implicated in the progression of a wide array of human diseases, making NRF2 a compelling target for therapeutic interventions. However, challenges persist in drug discovery and safe targeting of NRF2, as unresolved questions remain especially regarding its context-specific role in diseases and off-target effects. This comprehensive review discusses the dualistic role of NRF2 in disease pathophysiology, covering its protective and/or destructive roles in autoimmune, respiratory, cardiovascular, and metabolic diseases, as well as diseases of the digestive system and cancer. Additionally, we also review the development of drugs that either activate or inhibit NRF2, discuss main barriers in translating NRF2-based therapies from bench to bedside, and consider the ways to monitor NRF2 activation in vivo.}, }
@article {pmid40058159, year = {2025}, author = {Gadalla, SM and Katki, HA and Lai, TP and Auer, PL and Dagnall, CL and Bupp, C and Hutchinson, AA and Anderson, JJ and Mendez, KJW and Spellman, SR and Stewart, V and Savage, SA and Lee, SJ and Levine, JE and Saber, W and Aviv, A}, title = {Donor telomeres and their magnitude of shortening post-allogeneic haematopoietic cell transplant impact survival for patients with early-stage leukaemia or myelodysplastic syndrome.}, journal = {EBioMedicine}, volume = {114}, number = {}, pages = {105641}, doi = {10.1016/j.ebiom.2025.105641}, pmid = {40058159}, issn = {2352-3964}, abstract = {BACKGROUND: Donor selection is a key success factor in allogeneic haematopoietic cell transplant (HCT). We evaluated the potential impact of donor leucocyte telomere length (LTL) and LTL shortening in recipients at three-month post-HCT (LTL-3MS) on the two-year HCT outcomes.<br><br>METHODS: We identified a cohort of 384 HCT recipients for early-stage leukaemia or myelodysplastic syndrome in the Blood and Marrow Transplant Clinical Trial Network protocol#1202 with blood samples collected three-month post-HCT. Blood samples from respective donors were available at the Centre for International Blood and Marrow Transplant Research biorepository. We used Cox proportional hazards models for statistical analyses.<br><br>FINDINGS: A better two-year overall survival (OS) was associated with longer donor LTL (adjusted-hazard ratio [HR]&#xa0;=&#xa0;0.60, 95% confidence interval [CI]&#xa0;=&#xa0;0.37-0.96, for LTL &#x2265;6.7&#xa0;kb vs LTL< 6.7&#xa0;kb, p&#xa0;=&#xa0;0.03), and higher LTL-3MS (HR&#xa0;=&#xa0;0.52, 95% CI&#xa0;=&#xa0;0.34-0.80, for LTL-3MS&#xa0;&#x2265;&#xa0;230 vs&#xa0;<&#xa0;230 bp, p&#xa0;=&#xa0;0.003). Longer donor LTL was associated with a lower risk of non-relapse mortality (NRM; HR&#xa0;=&#xa0;0.48, p&#xa0;=&#xa0;0.05), while higher LTL-3MS was associated with lower relapse risk (HR for relapse risk&#xa0;=&#xa0;0.53, p&#xa0;=&#xa0;0.008). The adjusted 2-year cumulative risk of all-cause mortality was reduced by about half for patients with both donor LTL &#x2265;6.7&#xa0;kb and LTL-3MS&#xa0;&#x2265;&#xa0;230 bp vs patients with neither characteristic (21% vs 41%, respectively; p&#xa0;<&#xa0;0.0001).<br><br>INTERPRETATION: Selection of donors with longer LTL may improve HCT outcomes. Limited LTL shortening in recipients post-HCT may guide relapse prediction.<br><br>FUNDING: The NCI intramural research program and NIH grant U01AG066529.}, }
@article {pmid40057520, year = {2025}, author = {Wen, X and Hu, AK and Presnell, SR and Ford, ES and Koelle, DM and Kwok, WW}, title = {Longitudinal single cell profiling of epitope specific memory CD4+ T cell responses to recombinant zoster vaccine.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {2332}, pmid = {40057520}, issn = {2041-1723}, support = {HHSN272201400049C/AI/NIAID NIH HHS/United States ; }, mesh = {*CD4-Positive T-Lymphocytes/immunology ; *Herpes Zoster Vaccine/immunology ; Humans ; *Immunologic Memory/drug effects ; *Single-Cell Analysis ; *Vaccines, Synthetic/immunology ; Memory T Cells/immunology ; Epitopes, T-Lymphocyte/immunology ; Herpes Zoster/prevention &amp; control/immunology ; Viral Envelope Proteins/immunology ; Female ; Herpesvirus 3, Human/immunology ; Vaccination ; Male ; Lymphocyte Activation/immunology ; Middle Aged ; }, abstract = {Vaccination leads to rapid expansion of antigen-specific T cells within in the first few days. However, understanding of transcriptomic changes and fates of antigen-specific T cells upon vaccination remains limited. Here, we investigate the fate of memory CD4+ T cells upon reactivation to recombinant zoster vaccine for shingles at cellular and transcriptional levels. We show that glycoprotein E-specific memory CD4+ T cells respond strongly, their frequencies remain high, and they retain markers of cell activation one year following vaccination. Memory T cells with the most dominant TCR clonotype pre-vaccination remain prevalent at year one post-vaccination. These data implicate a major role for pre-existing memory T cells in perpetuating immune repertoires upon re-encountering cognate antigens. Differential gene expression indicates that cells post-vaccination are distinct from cells at baseline, suggesting committed memory T cells display transcriptional changes upon vaccination that could alter their responses against cognate immunogens.}, }
@article {pmid40057187, year = {2025}, author = {Han, YY and Gaietto, K and Chen, W and Perreira, KM and Oren, E and Pirzada, A and Garcia-Bedoya, O and Kaplan, R and Isasi, CR and Celedón, JC}, title = {Life stressors, resilience resources, and asthma among adults in the Hispanic Community Health Study/ Study of Latinos (HCHS/SOL).}, journal = {The journal of allergy and clinical immunology. In practice}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaip.2025.02.031}, pmid = {40057187}, issn = {2213-2201}, abstract = {BACKGROUND: Whether life stressors and resiliency interact on asthma risk in adults is largely unknown.<br><br>OBJECTIVE: To examine life stressors, resiliency, and asthma in Hispanic/Latino adults.<br><br>METHODS: Cross-sectional study of 4,747 adults aged 18-74 years in the Sociocultural Ancillary Study of the Hispanic Community Health Study/Study of Latinos. Participants completed questionnaires on life stressors (adverse childhood experiences [ACE], traumatic stress exposure (TSE), and chronic stressors [for >6 months]) and resilience resources (family cohesion, perceived social support, and spiritual well-being). Logistic regression was used for the multivariable analyses of current asthma and current asthma symptoms.<br><br>RESULTS: Any ACE and any chronic stressor were associated with 54%-69% increased odds of asthma and asthma symptoms in all individuals, with stronger associations for ACE in men and for chronic stressors in women. In a separate analysis, high family cohesion and high spiritual well-being were each associated with 35%-36% reduced odds of asthma symptoms. There was suggestive evidence of interactions: any TSE was associated with increased odds of asthma in adults with low family cohesion (adjusted odds ratio [aOR]=2.40, 95% CI=1.01-5.73) but not in others, and any chronic stressor was associated with increased odds of asthma symptoms in adults with low spiritual well-being (aOR=2.24, 95% CI=1.20-4.20) but not in others.<br><br>CONCLUSION: In Hispanic/Latino adults, ACE and chronic stress were associated with higher odds of asthma or asthma symptoms, while family cohesion and spiritual well-being were linked to lower odds of asthma or asthma symptoms. Further, resiliency may interact with life stressors on asthma.}, }
@article {pmid40056061, year = {2025}, author = {Mehta, RS and Sparapani, R and Wang, T and Spellman, S and Lee, SJ and Petersdorf, EW}, title = {Donor Age Matters for Haploidentical HCT Patients Even After Adjusting for HLA Factors: A Machine Learning Approach.}, journal = {American journal of hematology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ajh.27648}, pmid = {40056061}, issn = {1096-8652}, support = {U24CA076518/CA/NCI NIH HHS/United States ; /HL/NHLBI NIH HHS/United States ; //National Institute of Allergy and Infectious Diseases/ ; 75R60222C00011/HRSA/HRSA HHS/United States ; N00014-21-1-2954//Office of Naval Research/ ; N00014-23-1-2057//Office of Naval Research/ ; //National Marrow Donor Program/ ; //Medical College of Wisconsin/ ; }, }
@article {pmid40055795, year = {2025}, author = {Skalland, TM and de Dieu Tapsoba, J and Zangeneh, SZ and Floyd, S and Ayles, H and Bock, P and Fidler, S and Eshleman, SH and Hayes, RJ and Donnell, D and , }, title = {A survey weighted analysis of HPTN 071 (PopART) primary outcome of HIV incidence.}, journal = {AIDS research and therapy}, volume = {22}, number = {1}, pages = {30}, pmid = {40055795}, issn = {1742-6405}, mesh = {Humans ; *HIV Infections/epidemiology ; Incidence ; Female ; Male ; Adult ; Zambia/epidemiology ; South Africa/epidemiology ; Young Adult ; Adolescent ; Middle Aged ; HIV Testing/statistics &amp; numerical data ; Anti-HIV Agents/therapeutic use ; }, abstract = {INTRODUCTION: HPTN 071 (PopART) implemented a comprehensive HIV prevention package which aimed to reduce HIV incidence within 21 communities of Zambia and South Africa: Arm A, PopART intervention of universal HIV testing and treatment; Arm B, PopART intervention of universal HIV testing with ART provided according to local guidelines; and Arm C, standard of care. Analyses so far have not accounted for the sampling design of the enrolled cohort. We performed a sample-weighted re-analysis of the primary outcome of the PopART trial to derive a population-based estimate of the intervention effect.<br><br>METHODS: Enrollment used a two-stage sampling design: household and adult participant within each household. We constructed post-stratification weights to match the age and sex distribution of the target population in these communities. Weighted Poisson regression was used to estimate community-level HIV incidence. The PopART intervention effect was estimated using log-transformed community-level incidence estimates in an ANCOVA model.<br><br>RESULTS: The analysis based on community-level incidence shows a 25% reduction in incidence for Arm B communities compared to standard of care (RR: 0.75, 95% CI: 0.56-1.02, p&#x2009;=&#x2009;0.06) while Arm A communities show no difference in HIV incidence compared to standard of care (RR: 1.08, 95% CI: 0.81-1.46, p&#x2009;=&#x2009;0.56).<br><br>CONCLUSIONS: Our re-analysis shows 25% reduction in HIV incidence comparing Arm B to Arm C communities. No effect was observed comparing Arm A communities to Arm C communities. These results align with the primary results of the PopART trial.<br><br>CLINICALTRIALS: gov number, NCT01900977, HPTN 071 [PopArt].}, }
@article {pmid40054143, year = {2025}, author = {Carter, JJ and Smith, RA and Scherer, EM and Skibinski, DAG and Sankaranarayanan, S and Luxembourg, A and Kollmann, T and Marty, KD and Sadarangani, M and Dobson, S and Galloway, DA}, title = {Corrigendum to "Long-Term immune memory responses to human papillomavirus (HPV) vaccination following 2 versus 3 doses of HPV vaccine" [Vaccine, Volume 50, 19 March 2025, 126,817].}, journal = {Vaccine}, volume = {54}, number = {}, pages = {126974}, doi = {10.1016/j.vaccine.2025.126974}, pmid = {40054143}, issn = {1873-2518}, }
@article {pmid40053727, year = {2025}, author = {Benjet, C and Zainal, NH and Albor, Y and Alvis-Barranco, L and Carrasco Tapia, N and Contreras-Ibáñez, CC and Cortés-Morelos, J and Cudris-Torres, L and de la Peña, FR and González, N and Gutierrez-Garcia, RA and Vargas-Contreras, E and Medina-Mora, ME and Patiño, P and Gildea, SM and Kennedy, CJ and Luedtke, A and Sampson, NA and Petukhova, MV and Zubizarreta, JR and Cuijpers, P and Kazdin, AE and Kessler, RC}, title = {The Effect of Predicted Compliance With a Web-Based Intervention for Anxiety and Depression Among Latin American University Students: Randomized Controlled Trial.}, journal = {JMIR mental health}, volume = {12}, number = {}, pages = {e64251}, doi = {10.2196/64251}, pmid = {40053727}, issn = {2368-7959}, mesh = {Humans ; Female ; Male ; *Students/psychology ; Universities ; *Cognitive Behavioral Therapy/methods ; *Internet-Based Intervention ; Young Adult ; Adult ; *Depression/therapy ; Anxiety/therapy ; Patient Compliance ; Colombia ; Mexico ; Adolescent ; }, abstract = {BACKGROUND: Web-based cognitive behavioral therapy (wb-CBT) is a scalable way to reach distressed university students. Guided wb-CBT is typically superior to self-guided wb-CBT over short follow-up periods, but evidence is less clear over longer periods.<br><br>OBJECTIVE: This study aimed to compare short-term (3 months) and longer-term (12 months) aggregate effects of guided and self-guided wb-CBT versus treatment as usual (TAU) in a randomized controlled trial of Colombian and Mexican university students and carry out an initially unplanned secondary analysis of the role of differential predicted compliance in explaining these differences.<br><br>METHODS: The 1319 participants, recruited either through email and social media outreach invitations or from waiting lists of campus mental health clinics, were undergraduates (1038/1319, 78.7% female) with clinically significant baseline anxiety (Generalized Anxiety Disorder-7 score&#x2265;10) or depression (Patient Health Questionnaire-9 score&#x2265;10). The intervention arms comprised guided wb-CBT with weekly asynchronous written human feedback, self-guided wb-CBT with the same content as the guided modality, and TAU as provided at each university. The prespecified primary outcome was joint remission (Generalized Anxiety Disorder-7 score=0-4 and Patient Health Questionnaire-9 score=0-4). The secondary outcome was joint symptom reduction (mean scores on the Patient Health Questionnaire Anxiety and Depression Scale) at 3 and 12 months after randomization.<br><br>RESULTS: As reported previously, 3-month outcomes were significantly better with guided wb-CBT than self-guided wb-CBT (P=.02) or TAU (P=.02). However, subsequent follow-up showed that 12-month joint remission (adjusted risk differences=6.0-6.5, SE 0.4-0.5, and P<.001 to P=.007; adjusted mean differences=2.70-2.69, SE 0.7-0.8, and P<.001 to P=.001) was significantly better with self-guided wb-CBT than with the other interventions. Participants randomly assigned to the guided wb-CBT arm spent twice as many minutes logged on as those in the self-guided wb-CBT arm in the first 12 weeks (mean 12.5, SD 36.9 vs 5.9, SD 27.7; &#x3c7;[2]1=107.1, P<.001), whereas participants in the self-guided wb-CBT arm spent twice as many minutes logged on as those in the guided wb-CBT arm in weeks 13 to 52 (mean 0.4, SD 7.5 vs 0.2, SD 4.4; &#x3c7;[2]1=10.5, P=.001). Subgroup analysis showed that this longer-term superiority of self-guided wb-CBT was confined to the 40% (528/1319) of participants with high predicted self-guided wb-CBT compliance beyond 3 months based on a counterfactual nested cross-validated machine learning model. The 12-month outcome differences were nonsignificant across arms among other participants (all P>.05).<br><br>CONCLUSIONS: The results have important practical implications for precision intervention targeting to maximize longer-term wb-CBT benefits. Future research needs to investigate strategies to increase sustained guided wb-CBT use once guidance ends.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT04780542; https://www.clinicaltrials.gov/study/NCT04780542.<br><br>RR2-10.1186/s13063-022-06255-3.}, }
@article {pmid40034763, year = {2025}, author = {Orchard, P and Blackwell, TW and Kachuri, L and Castaldi, PJ and Cho, MH and Christenson, SA and Durda, P and Gabriel, S and Hersh, CP and Huntsman, S and Hwang, S and Joehanes, R and Johnson, M and Li, X and Lin, H and Liu, CT and Liu, Y and Mak, ACY and Manichaikul, AW and Paik, D and Saferali, A and Smith, JD and Taylor, KD and Tracy, RP and Wang, J and Wang, M and Weinstock, JS and Weiss, J and Wheeler, HE and Zhou, Y and Zoellner, S and Wu, JC and Mestroni, L and Graw, S and Taylor, MRG and Ortega, VE and Johnson, CW and Gan, W and Abecasis, G and Nickerson, DA and Gupta, N and Ardlie, K and Woodruff, PG and Zheng, Y and Bowler, RP and Meyers, DA and Reiner, A and Kooperberg, C and Ziv, E and Ramachandran, VS and Larson, MG and Cupples, LA and Burchard, EG and Silverman, EK and Rich, SS and Heard-Costa, N and Tang, H and Rotter, JI and Smith, AV and Levy, D and ,  and ,  and Aguet, F and Scott, L and Raffield, LM and Parker, SCJ}, title = {Cross-cohort analysis of expression and splicing quantitative trait loci in TOPMed.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40034763}, abstract = {Most genetic variants associated with complex traits and diseases occur in non-coding genomic regions and are hypothesized to regulate gene expression. To understand the genetics underlying gene expression variability, we characterize 14,324 ancestrally diverse RNA-sequencing samples from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and integrate whole genome sequencing data to perform cis and trans expression and splicing quantitative trait locus (cis-/trans-e/sQTL) analyses in six tissues and cell types, most notably whole blood (N=6,454) and lung (N=1,291). We show this dataset enables greater detection of secondary cis-e/sQTL signals than was achieved in previous studies, and that secondary cis-eQTL and primary trans-eQTL signal discovery is not saturated even though eGene discovery is. Most TOPMed trans-eQTL signals colocalize with cis-e/sQTL signals, suggesting many trans signals are mediated by cis signals. We fine-map European UK BioBank GWAS signals from 164 traits and colocalize the resulting 34,107 fine-mapped GWAS signals with TOPMed e/sQTL signals, finding that of 10,611 GWAS signals with a colocalization, 7,096 GWAS signals colocalize with at least one secondary e/sQTL signal. These results demonstrate that larger e/sQTL analyses will continue to uncover secondary e/sQTL signals, and that these new signals will benefit GWAS interpretation.}, }
@article {pmid40053601, year = {2025}, author = {Binkowski, B and Klamer, Z and Gao, C and Staal, B and Repesh, A and Tran, HL and Brass, DM and Bartlett, P and Gallinger, S and Blomqvist, M and Morrow, JB and Allen, P and Shi, C and Singhi, A and Brand, R and Huang, Y and Hostetter, G and Haab, BB}, title = {Multiplexed glycan immunofluorescence identification of pancreatic cancer cell subpopulations in both tumor and blood samples.}, journal = {Science advances}, volume = {11}, number = {10}, pages = {eadt0029}, doi = {10.1126/sciadv.adt0029}, pmid = {40053601}, issn = {2375-2548}, mesh = {Humans ; *Polysaccharides/metabolism/blood ; *Pancreatic Neoplasms/blood/metabolism/pathology/diagnosis ; *Carcinoma, Pancreatic Ductal/blood/metabolism/diagnosis/pathology ; *Biomarkers, Tumor/blood/metabolism ; *Fluorescent Antibody Technique ; Cell Line, Tumor ; }, abstract = {Pancreatic ductal adenocarcinoma (PDAC) tumor heterogeneity impedes the development of biomarker assays for early disease detection. We hypothesized that PDAC cell subpopulations could be identified by aberrant glycan signatures in both tumor tissue and blood samples. We used multiplexed glycan immunofluorescence to distinguish between PDAC and noncancer cell subpopulations within tumor tissue, and we developed hybrid glycan sandwich assays to determine whether the aberrant glycan signatures could be detected in blood samples. We found that PDAC cells were identified by signatures of glycans detected by four glycan-binding proteins (VVL, CA19-9, sTRA, and GM2) and that there are three types of glycan-defined PDAC tumors: sTRA type, CA19-9 type, and intermixed. In patient-matched tumor and blood samples, the PDAC tumor type could be determined by the aberrant glycans in the blood. As a result, the combined assays of aberrant glycan signatures were more sensitive and specific than any individual assay. Our results demonstrate a methodology to detect and stratify PDAC.}, }
@article {pmid40051480, year = {2024}, author = {Back, A and Myers, S and Guy, J and Perez, J and Lazar Thorn, L and McGregor, B}, title = {Evolving Guidelines for the Use of Touch During a Clinical Trial of Group Psilocybin-Assisted Therapy.}, journal = {Psychedelic medicine (New Rochelle, N.Y.)}, volume = {2}, number = {4}, pages = {187-191}, pmid = {40051480}, issn = {2831-4433}, abstract = {For a new clinical trial testing a group retreat-based format of psilocybin-assisted therapy, our research team created an initial set of practice guidelines that aimed to describe facilitator use of touch in a way that is ethical, supportive, and minimizes harm. In our first three retreats, however, we had two unexpected experiences with touch that led us to iterate our initial guidelines into a new version of guidelines. In this Technical Report, we describe our evolving guidelines specifying acceptable practices for facilitator use of touch to ensure a safe, supportive, and therapeutic participant experience. Our primary goal with these guidelines is to create a haptic experience during the psilocybin session that reinforces the participants' sense of safety and supports their own experience during the psilocybin session. Our secondary goal is to allow the facilitator team to notice and maintain therapeutic boundaries and to respond to participant experiences with empathy and openness in the context of those boundaries (Clinical Trials No: NCT05847686).}, }
@article {pmid40049206, year = {2025}, author = {Morris, ZS and Demaria, S and Monjazeb, AM and Formenti, SC and Weichselbaum, RR and Welsh, J and Enderling, H and Schoenfeld, JD and Brody, JD and McGee, HM and Mondini, M and Kent, MS and Young, KH and Galluzzi, L and Karam, SD and Theelen, WSME and Chang, JY and Huynh, MA and Daib, A and Pitroda, S and Chung, C and Serre, R and Grassberger, C and Deng, J and Sodji, QH and Nguyen, AT and Patel, RB and Krebs, S and Kalbasi, A and Kerr, C and Vanpouille-Box, C and Vick, L and Aguilera, TA and Ong, IM and Herrera, F and Menon, H and Smart, D and Ahmed, J and Gartrell, RD and Roland, CL and Fekrmandi, F and Chakraborty, B and Bent, EH and Berg, TJ and Hutson, A and Khleif, S and Sikora, AG and Fong, L}, title = {Proceedings of the National Cancer Institute Workshop on combining immunotherapy with radiotherapy: challenges and opportunities for clinical translation.}, journal = {The Lancet. Oncology}, volume = {26}, number = {3}, pages = {e152-e170}, doi = {10.1016/S1470-2045(24)00656-9}, pmid = {40049206}, issn = {1474-5488}, support = {R37 CA262557/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Immunotherapy/methods ; *Neoplasms/radiotherapy/immunology/therapy ; United States ; *National Cancer Institute (U.S.) ; *Translational Research, Biomedical ; Animals ; Combined Modality Therapy ; }, abstract = {Radiotherapy both promotes and antagonises tumour immune recognition. Some clinical studies show improved patient outcomes when immunotherapies are integrated with radiotherapy. Safe, greater than additive, clinical response to the combination is limited to a subset of patients, however, and how radiotherapy can best be combined with immunotherapies remains unclear. The National Cancer Institute-Immuno-Oncology Translational Network-Society for Immunotherapy of Cancer-American Association of Immunology Workshop on Combining Immunotherapy with Radiotherapy was convened to identify and prioritise opportunities and challenges for radiotherapy and immunotherapy combinations. Sessions examined the immune effects of radiation, barriers to anti-tumour immune response, previous clinical trial data, immunological and computational assessment of response, and next-generation radiotherapy-immunotherapy combinations. Panel recommendations included: developing and implementing patient selection and biomarker-guided approaches; applying mechanistic understanding to optimise delivery of radiotherapy and selection of immunotherapies; using rigorous preclinical models including companion animal studies; embracing data sharing and standardisation, advanced modelling, and multidisciplinary cross-institution collaboration; interrogating clinical data, including negative trials; and incorporating novel clinical endpoints and trial designs.}, }
@article {pmid40048931, year = {2025}, author = {Moore, M and Anderson, L and Schiffer, JT and Matrajt, L and Dimitrov, D}, title = {Durability of COVID-19 vaccine and infection induced immunity: A systematic review and meta-regression analysis.}, journal = {Vaccine}, volume = {54}, number = {}, pages = {126966}, doi = {10.1016/j.vaccine.2025.126966}, pmid = {40048931}, issn = {1873-2518}, abstract = {BACKGROUND: Despite the success of mRNA vaccines, COVID-19 remains a significant public health threat. Waning of immune memory and the emergence of new variants can degrade population-level protection and contribute to ongoing morbidity.<br><br>METHODS: In this systematic review and meta-regression, we searched for studies in PubMed, medRxiv and bioRxiv published January 1, 2020 - January 1, 2023 measuring vaccine effectiveness as the reduction in infection, symptomatic disease, and severe disease (resulting in hospitalization and/or death) conferred by mRNA-based vaccination and prior SARS-CoV-2 infections relative to na&#xef;ve individuals. We excluded studies that did not distinguish between mRNA and non-mRNA vaccines or had less than 1000 participants. Using a multi-level model, we quantified the initial effectiveness and change over four to six months following vaccination or infection. Model covariates were COVID variant, number of vaccine doses, and the number and variant of prior infection. Our estimates were adjusted for the age of the study population.<br><br>FINDINGS: Of 828 screened, we included 123 studies in our analysis. Vaccine effectiveness against infection and disease declined both over time and with the emergence of Omicron, regardless of booster doses, though protection against severe outcomes was more durable. Booster doses reduced severe Omicron infections by 90.5&#xa0;% (95&#xa0;% confidence interval 87.1-93.8) and 77.6&#xa0;% (70.5-84.7) at two and 26&#xa0;weeks post-vaccination, respectively. Protection conferred by hybrid immunity was more durable than that from either vaccination or prior infection alone, but protection against Omicron reinfection was only 50.1&#xa0;% (32.5-67.8) at 26&#xa0;weeks following vaccination. Individuals with hybrid immunity had 80.6&#xa0;% protection (70.0-91.2) following booster doses declining to 36.9&#xa0;% (19.3-54.6) after 16&#xa0;weeks.<br><br>INTERPRETATION: Our results suggest that timely deployment of pre-existing boosters can greatly mitigate seasonal COVID outbreaks even in populations with prior infection and vaccination.<br><br>FUNDING: Centers for Disease Control and Prevention (NU38OT000297-03).}, }
@article {pmid40048743, year = {2025}, author = {Nath, K and Zhang, MJ and Bye, M and Abid, MB and Benjamin, C and Betts, BC and Bhatt, NS and Arrieta-Bolaños, E and Bolon, YT and Gadalla, SM and Grunwald, MR and Krem, MM and Lee, SJ and Marsh, SGE and Martino, R and Mehta, PA and Milano, F and Prestidge, T and Saultz, JN and Shaw, BE and Spellman, SR and Choe, HK and Shaffer, BC}, title = {Transplant Outcomes Using Older Matched Sibling Donors Compared to Young Alternative Donors: A CIBMTR Analysis.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024014858}, pmid = {40048743}, issn = {2473-9537}, abstract = {Whether younger donors should be prioritized over HLA-matching for allogeneic hematopoietic cell transplantation (allo-HCT) when using post-transplant cyclophosphamide (PTCy)-based graft versus host disease (GvHD) prophylaxis is unclear. To address this, we compared outcomes of allo-HCT recipients aged ≥50-years using PTCy-based GvHD prophylaxis from an older (≥50-years) matched sibling donor (MSD) to those of younger alternative donors ≤35-years: HLA-matched unrelated donors (MUD), HLA-mismatched unrelated donors (MMUD), and haploidentical (haplo)-related donors reported to the Center for International Blood &amp; Marrow Transplant Research between 2014-2021. Young MUD and older MSD receiving calcineurin inhibitor (CNI)-based allo-HCT that met study criteria were concurrently examined. The primary endpoint was overall survival (OS). Among 14,662 HCT recipients, 3,746 received PTCy- and 10,916 CNI-based GvHD prophylaxis. The median follow-up was 47 months. In patients treated with PTCy, the adjusted 5-year OS was not significantly different at 44% for MSD compared with 52% for MUD (multivariable hazard ratio [HR]: 1.20, 95%CI: 1.03-1.41, p=0.09), 45% for haplo (HR: 1.02, 0.88-1.18, p=1.00) and 46% for MMUD (HR: 1.00, 0.83-1.21, p=1.00). Compared to MSDs, receipt of younger MUD associated with improved disease-free survival (DFS) both with PTCy (HR: 1.21, 1.05-1.40, p=0.048) and CNI (HR 1.09, 1.04-1.15, p<0.01) based prophylaxis. Haplo-donor recipients associated with similar OS to MSD, but worse OS compared to MUD recipients with PTCy (HR: 1.18, 1.05-1.33, p=0.04). These data suggest that older MSDs result in similar OS compared to younger alternative donors in older-aged recipients. Younger MUDs may be preferred for older patients due to improved DFS when available.}, }
@article {pmid40048671, year = {2025}, author = {Rajdev, L and King, GG and Lieu, CH and Cohen, SA and Pant, S and Uboha, NV and Deming, D and Malla, M and Kasi, A and Klute, K and Spencer, KR and Dasari, A and Morris, VK and Botta, G and Lowy, AM and O'Hara, MH and Eads, J and King, D and Shah, MA and Hong, TS and Parikh, A and Klempner, SJ and Jabbour, SK and Chawla, A and Molena, D and George, TJ and Gibson, MK and Allegra, C and Goodman, K and Eng, C and Philip, PA}, title = {Incorporating Circulating Tumor DNA Testing Into Clinical Trials: A Position Paper by the National Cancer Institute GI Oncology Circulating Tumor DNA Working Group.}, journal = {JCO precision oncology}, volume = {9}, number = {}, pages = {e2400489}, doi = {10.1200/PO-24-00489}, pmid = {40048671}, issn = {2473-4284}, mesh = {Humans ; *Circulating Tumor DNA/blood/genetics ; *Gastrointestinal Neoplasms/genetics/blood ; United States ; *National Cancer Institute (U.S.) ; *Clinical Trials as Topic ; }, abstract = {PURPOSE: Circulating tumor DNA (ctDNA) is an emerging tool in the evaluation of GI cancers. Challenges remain in defining its utility and role as a primary end point in therapeutic trials. The National Cancer Institute (NCI) ctDNA GI working group was created to evaluate current data and provide guidance on the inclusion of ctDNA in GI cancer trials.<br><br>METHODS: The NCI GI steering committee assigned four task force members to serve as co-chairs for the working group. Co-chairs identified experts within each GI disease group to form a panel that convened to review data and provide recommendations. The group focused on ctDNA's role as a potential surrogate for assessing prognosis and guiding treatment decisions that may enhance GI cancer trials. A manuscript was drafted, circulated, revised, and voted on by the panel. The final draft was reviewed by the Cancer Therapy Evaluation Program.<br><br>RESULTS: Further data are required to support ctDNA as a primary end point for late-phase therapeutic trials, particularly in studies that could change the standard-of-care. However, the group supports ctDNA as a primary efficacy end point for phase II studies and as a noninvasive evaluation strategy for new drug development. Incorporation of ctDNA as a biomarker in trial design must consider the specific context of disease biology of the GI cancer subtypes. ctDNA should be incorporated as an exploratory end point across a variety of disease settings and indications. Several practical considerations were identified to optimize the incorporation of ctDNA in future trial design.<br><br>CONCLUSION: Prospective trials are required to clarify the role of ctDNA as a valid surrogate end point for progression-free or overall survival in GI cancers.}, }
@article {pmid40045233, year = {2025}, author = {Yilmaz, S and Aryal, K and King, J and Bischof, JJ and Hong, AS and Wood, N and Gould Rothberg, BE and Hudson, MF and Heinert, SW and Wattana, MK and Coyne, CJ and Reyes-Gibby, C and Todd, K and Lyman, G and Klotz, A and Abar, B and Grudzen, C and Bastani, A and Baugh, CW and Henning, DJ and Bernstein, S and Rico, JF and Ryan, RJ and Yeung, SJ and Qdaisat, A and Padela, A and Madsen, TE and Liu, R and Adler, D}, title = {Understanding oncologic emergencies and related emergency department visits and hospitalizations: a systematic review.}, journal = {BMC emergency medicine}, volume = {25}, number = {1}, pages = {40}, pmid = {40045233}, issn = {1471-227X}, mesh = {Humans ; *Emergency Service, Hospital/statistics &amp; numerical data ; *Neoplasms/therapy/epidemiology ; *Hospitalization/statistics &amp; numerical data ; Emergencies/epidemiology ; Emergency Room Visits ; }, abstract = {BACKGROUND: Patients with cancer frequently visit the emergency department (ED) and are at high risk for hospitalization due to severe illness from cancer progression or treatment side effects. With an aging population and rising cancer incidence rates worldwide, it is crucial to understand how EDs and other acute care venues manage oncologic emergencies. Insights from other nations and health systems may inform resources necessary for optimal ED management and novel care delivery pathways. We described clinical management of oncologic emergencies and their contribution to ED visits and hospitalizations worldwide.<br><br>METHODS: We performed a systematic review of peer-reviewed original research studies published in the English language between January 1st, 2003, to December 31st, 2022, garnered from PubMed, Web of Science, and EMBASE. We included all studies investigating adult (&#x2265;&#x2009;18&#xa0;years) cancer patients with emergency visits. We examined chief complaints or predictors of ED use that explicitly defined oncologic emergencies.<br><br>RESULTS: The search strategy yielded 49 articles addressing cancer-related emergency visits. Most publications reported single-site studies (n&#x2009;=&#x2009;34/49), with approximately even distribution across clinical settings- ED (n&#x2009;=&#x2009;22/49) and acute care hospital/ICU (n&#x2009;=&#x2009;27/49). The number of patient observations varied widely among the published studies (range: 9 - 87,555 patients), with most studies not specifying the cancer type (n&#x2009;=&#x2009;33/49), stage (n&#x2009;=&#x2009;41/49), or treatment type (n&#x2009;=&#x2009;36/49). Most studies (n&#x2009;=&#x2009;31/49) examined patients aged&#x2009;&#x2265;&#x2009;60&#xa0;years. Infection was the most common oncologic emergency documented (n&#x2009;=&#x2009;22/49), followed by pain (n&#x2009;=&#x2009;20/49), dyspnea (n&#x2009;=&#x2009;19/49), and gastrointestinal (GI) symptoms (n&#x2009;=&#x2009;17/49). Interventions within the ED or hospital ranged from pharmacological management with opioids (n&#x2009;=&#x2009;11/49), antibiotics (n&#x2009;=&#x2009;9/49), corticosteroids (n&#x2009;=&#x2009;5/49), and invasive procedures (e.g., palliative stenting; n&#x2009;=&#x2009;13/49) or surgical interventions (n&#x2009;=&#x2009;2/49).<br><br>CONCLUSION: Limited research specifically addresses oncologic emergencies despite the international prevalence of ED presentations among cancer patients. Patients with cancer presenting to the ED appear to have a variety of complaints which could result from their cancers and thus may require tailored diagnostic and intervention pathways to provide optimal acute care. Further acute geriatric oncology research may clarify the optimal management strategies to improve the outcomes for this vulnerable patient population.}, }
@article {pmid40044856, year = {2025}, author = {Tran-Kiem, C and Paredes, MI and Perofsky, AC and Frisbie, LA and Xie, H and Kong, K and Weixler, A and Greninger, AL and Roychoudhury, P and Peterson, JM and Delgado, A and Halstead, H and MacKellar, D and Dykema, P and Gamboa, L and Frazar, CD and Ryke, E and Stone, J and Reinhart, D and Starita, L and Thibodeau, A and Yun, C and Aragona, F and Black, A and Viboud, C and Bedford, T}, title = {Fine-scale patterns of SARS-CoV-2 spread from identical pathogen sequences.}, journal = {Nature}, volume = {}, number = {}, pages = {}, pmid = {40044856}, issn = {1476-4687}, abstract = {Pathogen genomics can provide insights into underlying infectious disease transmission patterns[1,2], but new methods are needed to handle modern large-scale pathogen genome datasets and realize this full potential[3-5]. In particular, genetically proximal viruses should be highly informative about transmission events as genetic proximity indicates epidemiological linkage. Here we use pairs of identical sequences to characterize fine-scale transmission patterns using 114,298 SARS-CoV-2 genomes collected through Washington State (USA) genomic sentinel surveillance with associated age and residence location information between March 2021 and December 2022. This corresponds to 59,660 sequences with another identical sequence in the dataset. We find that the location of pairs of identical sequences is highly consistent with expectations from mobility and social contact data. Outliers in the relationship between genetic and mobility data can be explained by SARS-CoV-2 transmission between postcodes with male prisons, consistent with transmission between prison facilities. We find that transmission patterns between age groups vary across spatial scales. Finally, we use the timing of sequence collection to understand the age groups driving transmission. Overall, this study improves our ability to use large pathogen genome datasets to understand the determinants of infectious disease spread.}, }
@article {pmid40043139, year = {2025}, author = {Rubio, AA and Baharani, VA and Dadonaite, B and Parada, M and Abernathy, ME and Wang, Z and Lee, YE and Eso, MR and Phung, J and Ramos, I and Chen, T and El Nesr, G and Bloom, JD and Bieniasz, PD and Nussenzweig, MC and Barnes, CO}, title = {Bispecific antibodies targeting the N-terminal and receptor binding domains potently neutralize SARS-CoV-2 variants of concern.}, journal = {Science translational medicine}, volume = {17}, number = {788}, pages = {eadq5720}, doi = {10.1126/scitranslmed.adq5720}, pmid = {40043139}, issn = {1946-6242}, mesh = {*Antibodies, Bispecific/immunology/pharmacology ; *SARS-CoV-2/immunology ; Animals ; Humans ; *Antibodies, Neutralizing/immunology ; *COVID-19/virology/immunology ; Mice ; Spike Glycoprotein, Coronavirus/immunology/chemistry/metabolism ; Antibodies, Viral/immunology ; Protein Domains ; Epitopes/immunology ; Protein Binding ; Neutralization Tests ; Female ; Binding Sites ; Cryoelectron Microscopy ; }, abstract = {The ongoing emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that reduce the effectiveness of antibody therapeutics necessitates development of next-generation antibody modalities that are resilient to viral evolution. Here, we characterized amino-terminal domain (NTD)- and receptor binding domain (RBD)-specific monoclonal antibodies previously isolated from coronavirus disease 2019 (COVID-19) convalescent donors for their activity against emergent SARS-CoV-2 VOCs. Among these, the NTD-specific antibody C1596 displayed the greatest breadth of binding to VOCs, with cryo-electron microscopy structural analysis revealing recognition of a distinct NTD epitope outside of the site i antigenic supersite. Given C1596's favorable binding profile, we designed a series of bispecific antibodies (bsAbs), termed CoV2-biRNs, that featured both NTD and RBD specificities. Two of the C1596-inclusive bsAbs, CoV2-biRN5 and CoV2-biRN7, retained potent in vitro neutralization activity against all Omicron variants tested, including XBB.1.5, BA.2.86, and JN.1, contrasting the diminished potency of parental antibodies delivered as monotherapies or as a cocktail. Furthermore, prophylactic delivery of CoV2-biRN5 reduced the viral load within the lungs of K18-hACE2 mice after challenge with SARS-CoV-2 XBB.1.5. In conclusion, NTD-RBD bsAbs offer promising potential for the design of resilient, next-generation antibody therapeutics against SARS-CoV-2 VOCs.}, }
@article {pmid40042432, year = {2025}, author = {Gao, F and Janes, H and Buchbinder, S and Donnell, D}, title = {Active-Controlled Trial Design for HIV Prevention Trials With a Counterfactual Placebo.}, journal = {Statistics in medicine}, volume = {44}, number = {6}, pages = {e70022}, doi = {10.1002/sim.70022}, pmid = {40042432}, issn = {1097-0258}, support = {R37AI029168/NH/NIH HHS/United States ; R01AI177078/NH/NIH HHS/United States ; S10OD028685/NH/NIH HHS/United States ; UM1AI068617/NH/NIH HHS/United States ; }, mesh = {Humans ; *HIV Infections/prevention &amp; control/drug therapy ; *Pre-Exposure Prophylaxis/methods ; Placebos ; Research Design ; Anti-HIV Agents/therapeutic use ; Models, Statistical ; Controlled Clinical Trials as Topic/ethics/methods ; }, abstract = {In the quest for enhanced HIV prevention methods, the advent of antiretroviral drugs as pre-exposure prophylaxis (PrEP) has marked a significant stride forward. However, the ethical challenges in conducting placebo-controlled trials for new PrEP agents against a backdrop of highly effective existing PrEP options necessitate innovative approaches. This manuscript delves into the design and implementation of active-controlled trials that incorporate a counterfactual placebo estimate-a theoretical estimate of what HIV incidence would have been without effective prevention. We introduce a novel statistical framework for regulatory approval of new PrEP agents, predicated on the assumption of an available and consistent counterfactual placebo estimate. Our approach aims to assess the absolute efficacy (i.e., against placebo) of the new PrEP agent relative to the absolute efficacy of the active control. We propose a two-step procedure for hypothesis testing and further develop an approach that addresses potential biases inherent in non-randomized comparisons to counterfactual placebos. By exploring different scenarios with moderately and highly effective active controls and counterfactual placebo estimates from various sources, we demonstrate how our design can significantly reduce sample sizes compared to traditional non-inferiority trials and offer a robust framework for evaluating new PrEP agents. This work contributes to the methodological repertoire for HIV prevention trials and underscores the importance of adaptability in the face of ethical and practical challenges.}, }
@article {pmid40027810, year = {2025}, author = {Newsom, OJ and Sullivan, LB}, title = {Defined media reveals the essential role of lipid scavenging to support cancer cell proliferation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40027810}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R35 GM147118/GM/NIGMS NIH HHS/United States ; }, abstract = {Fetal bovine serum (FBS) is a nearly ubiquitous, yet undefined additive in mammalian cell culture media whose functional contributions to promoting cell proliferation remain poorly understood. Efforts to replace serum supplementation in culture media have been hindered by an incomplete understanding of the environmental requirements fulfilled by FBS in culture. Here, we use a combination of live-cell imaging and liquid chromatography-mass spectrometry to elucidate the role of serum in supporting proliferation. We show that serum provides consumed factors that enable proliferation and demonstrate that the serum metal and lipid components are crucial to sustaining proliferation in culture. Importantly, despite access to a wide range of lipid classes, albumin-bound lipids are the primary species consumed during cancer cell proliferation. Furthermore, we find that combinations of the additive ITS, containing necessary metals, and albumin-associated lipid classes are sufficient to replace FBS in culture media. We show that serum-free media enables sensitive quantification of lipid consumption dynamics during cell proliferation, which indicate that fatty acids (FA) are consumed through a mass-action mechanism, with minimal competition from other lipid classes. Finally, we find that pharmacologic disruption of FA activation and incorporation into the cellular lipidome reduces uptake from the environment and impairs cell proliferation. This work therefore identifies metabolic contributions of serum in cell culture settings and provides a framework for building cell culture systems that sustain cell proliferation without the variable and undefined contributions of FBS.}, }
@article {pmid40027790, year = {2025}, author = {Li, S and Song, K and Sun, H and Tao, Y and Huang, A and Bhatia, V and Hanratty, B and Patel, RA and Long, HW and Morrissey, C and Haffner, MC and Nelson, PS and Graeber, TG and Lee, JK}, title = {Defined cellular reprogramming of androgen receptor-active prostate cancer to neuroendocrine prostate cancer.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40027790}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; P50 CA092131/CA/NCI NIH HHS/United States ; DP2 CA271301/CA/NCI NIH HHS/United States ; R01 CA266452/CA/NCI NIH HHS/United States ; P01 CA163227/CA/NCI NIH HHS/United States ; R01 CA222877/CA/NCI NIH HHS/United States ; }, abstract = {Neuroendocrine prostate cancer (NEPC) arises primarily through neuroendocrine transdifferentiation (NEtD) as an adaptive mechanism of therapeutic resistance. Models to define the functional effects of putative drivers of this process on androgen receptor (AR) signaling and NE cancer lineage programs are lacking. We adapted a genetically defined strategy from the field of cellular reprogramming to directly convert AR-active prostate cancer (ARPC) to AR-independent NEPC using candidate factors. We delineated critical roles of the pioneer factors ASCL1 and NeuroD1 in NEtD and uncovered their abilities to silence AR expression and signaling by remodeling chromatin at the somatically acquired AR enhancer and global AR binding sites with enhancer activity. We also elucidated the dynamic temporal changes in the transcriptomic and epigenomic landscapes of cells undergoing acute lineage conversion from ARPC to NEPC which should inform future therapeutic development. Further, we distinguished the activities of ASCL1 and NeuroD1 from the inactivation of RE-1 silencing transcription factor (REST), a master suppressor of a major neuronal gene program, in establishing a NEPC lineage state and in modulating the expression of genes associated with major histocompatibility complex class I (MHC I) antigen processing and presentation. These findings provide important, clinically relevant insights into the biological processes driving NEtD of prostate cancer.}, }
@article {pmid40046543, year = {2023}, author = {Nayak, S and Waters, A and Warsi, M and Hegde, A and Chu, ES}, title = {Inpatient Physician and Nurse Experience During the COVID-19 Crisis at a Public Safety Net Hospital.}, journal = {The Brown journal of hospital medicine}, volume = {2}, number = {1}, pages = {57694}, pmid = {40046543}, issn = {2831-5553}, abstract = {BACKGROUND: The COVID-19 pandemic has been associated with front line health care provider burnout, depression, and post-traumatic stress disorder. We sought to better understand how nurses and physicians of differing genders may have been affected differently by the COVID-19 crisis.<br><br>METHODS: Between July 17, 2020, and October 31, 2020, we surveyed nurses and physicians caring for COVID-19 patients at a large, academic, public safety net hospital in the southern United States. Survey questions were adapted from validated questionnaires used to determine quality of life, assess levels of anxiety, and determine how COVID-19 may have affected our nurses' and physicians' work, home and social lives.<br><br>RESULTS: Overall, 120 (41.7%) providers responded, including 39 (50%) physicians and 81 (38.6%) nurses. 69.3% reported disruption to their home/family, 76.3% to their social lives, and 29.8% worried about financial strain. More nurses than physicians worried about being excluded from social gatherings (59.7% v 35.1%, p=0.01). Similarly, 70.1% of nurses and 46.0% of physicians expressed concern of exposing others to COVID-19 (p=0.01). Nurses also expressed greater concern about being treated differently by others when compared to physicians (64.5% v 37.8%, p= 0.01). Female physicians reported greater difficulty separating their personal lives from their professional lives than male physicians and either male or female nurses (84.6%% vs 35% vs 33.3% vs 35.9%, p <0.05). Most physicians (89.7%) and nurses (93.8%) reported some level of anxiety, with 31.5% of respondents experiencing moderate or severe anxiety.<br><br>CONCLUSION: Healthcare workers on the frontline of COVID-19 pandemic, regardless of profession, reported increased anxiety that extended beyond the hospital into their homes and social lives. Physicians and nurses, as well as men and women, reported different sources and degrees of stress and disruption to their work, home and social lives.}, }
@article {pmid40041932, year = {2025}, author = {Yuan, JM and Kensler, TW and Dacic, S and Hartman, DJ and Wang, R and Balogh, PA and Sufka, P and Turner, MA and Fuhrer, K and Seigh, L and Pham, YT and Adams-Haduch, J and Valacchi, G and Singh, SV and Herman, JG and Wilson, DO}, title = {Randomized phase II clinical trial of sulforaphane in former smokers at high risk for lung cancer.}, journal = {Cancer prevention research (Philadelphia, Pa.)}, volume = {}, number = {}, pages = {}, doi = {10.1158/1940-6207.CAPR-24-0386}, pmid = {40041932}, issn = {1940-6215}, abstract = {Experimental studies have shown dietary isothiocyanates reduced cellular proliferative marker Ki-67 and increased apoptotic markers Caspase-3 and TUNEL in animals, but human data are lacking. The present study was to assess whether sulforaphane would stop/reverse the progression of bronchial histopathology, reduce Ki-67 index and/or increase Caspase-3 and TUNEL indices in humans. A randomized clinical trial (NCT03232138) was conducted in former smokers. Forty-three subjects were randomly assigned to the placebo or the treatment with a potential daily dose of 95 µmol sulforaphane for 12 months. The endpoints were the changes of histopathology scores, and Ki-67, Caspase-3 and TUNEL indices in post- vs. pre-treatment bronchial biopsies. Thirty-seven participants (17 in the sulforaphane and 20 in the placebo group) completed the study. Supplementation of sulforaphane did not show significant impact on bronchial histopathology, but significantly reduced Ki-67 index with a 20% decrease in the sulforaphane group and a 65% increase in the placebo (p = 0.014). The difference was even greater in high-density (3+) positive Ki-67, with a 44% decrease in the sulforaphane group compared with a 71% increase in the placebo (p = 0.004). Higher bioavailability of sulforaphane was correlated with greater reduction of Ki-67 index (P for trend = 0.019). Sulforaphane treatment had no impact on Caspase-3 or TUNEL index in bronchial biopsies. No severe adverse event was observed in the study participants. The findings of oral sulforaphane that significantly reduced Ki-67 index in bronchial tissue support further development as a potential chemopreventive agent against lung cancer development.}, }
@article {pmid40040586, year = {2025}, author = {Owens, L and Fung, A and Shuhendler, J and Glick, J and Ryser, MD and Gulati, R and Etzioni, R}, title = {Trends in Young-Onset Cancer Incidence: A Modeling Perspective.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djaf050}, pmid = {40040586}, issn = {1460-2105}, abstract = {BACKGROUND: Recent increases in the diagnosis of certain cancers among younger individuals are generating intense concern. Many studies attribute the increase in so-called "young-onset" cancer to an etiologic cause but questions have also arisen about the role of earlier diagnosis.<br><br>METHODS: We simulate incidence trends from a natural history model that includes healthy, preclinical, and clinical disease states, where transitions from a healthy to a preclinical state represent disease onset and transitions from the preclinical to the clinical state represent diagnosis. We superimpose birth cohort effects on the rate of disease onset and period effects on the rate of disease diagnosis to identify those that match patterns of relative incidence by age group and five-year calendar interval from 2000-2019 for six "young-onset" cancers (colon, rectum, female breast, gastric, pancreas, kidney).<br><br>RESULTS: Two types of effects are broadly consistent with the observed increasing incidence trends in younger individuals: (1) A birth-cohort effect on disease onset that begins around 1970 and becomes more pronounced in later birth years, or (2) A period effect consistent with progressive reduction over time in the duration of preclinical disease. An earlier, protective birth cohort effect is consistent with recent declining trends in incidence in older individuals for colon, rectal, and gastric cancers.<br><br>DISCUSSION: A disease model provides clues about the possible drivers of cancer incidence trends, suggests constraints on the patterns of exposures that might be implicated etiologically, and indicates that the role of diagnostic changes warrants consideration alongside potential etiologic explanations.}, }
@article {pmid40038837, year = {2025}, author = {Yousefiasl, M and Soltanattar, A and Ezzatollahi Tanha, A and Azami, P and Alaei, M and Alamdari, AA and Esmailsorkh, F and Habibzadeh, A and Khanmohammadi, S}, title = {Association of triglyceride-glucose index with bone mineral density and fracture: a systematic review.}, journal = {Diabetology &amp; metabolic syndrome}, volume = {17}, number = {1}, pages = {77}, pmid = {40038837}, issn = {1758-5996}, abstract = {BACKGROUND AND AIM: Studies have found inconsistent results regarding triglyceride-glucose (TyG) index and bone health. This systematic review aims to synthesize the existing evidence on the association between the (TyG) index, bone mineral density (BMD), and bone fractures.<br><br>METHOD: A comprehensive search of PubMed, Scopus, Web of Science, and Embase databases was performed for studies published up to December 26, 2024. Inclusion criteria encompassed human studies examining the TyG index in relation to BMD or fractures. The risk of bias was assessed using the Newcastle-Ottawa Scale (NOS). Data synthesis included both qualitative and descriptive statistical analyses.<br><br>RESULTS: From 201 studies identified, 12 met the inclusion criteria comprising 817,242 participants. Most studies reported a significant association between TyG index and bone fractures. The studies reported inconsistent findings regarding the association between the TyG index and BMD. While some studies found no correlation between the TyG index and BMD in individuals aged&#x2009;&#x2265;&#x2009;50 years, studies on the general population aged&#x2009;&#x2265;&#x2009;18 years demonstrated a significant correlation between the TyG index and BMD. Variations in the age of study populations, the presence of diabetes, BMI, and adjustment factors likely contributed to these discrepancies. Further research is needed to clarify the role of the TyG index in bone health and its potential utility as a surrogate marker.<br><br>CONCLUSION: The TyG index is associated with bone fractures and can serve as a surrogate marker for osteoporosis in the general populations rather than exclusively for the elderly.}, }
@article {pmid40038122, year = {2025}, author = {Javid, SH and Kilgore, MR and Austin, EJ and Parker, EU and Alvarez, R and Flanagan, MR and Brewer, EG and Gibbons, C and Holt, SK and Lee, JM and Donlan, AW and DeStefano, LM and Gore, JL}, title = {The development and comparative effectiveness of a patient-centered pathology report for breast cancer care: a randomized clinical trial.}, journal = {Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer}, volume = {33}, number = {3}, pages = {248}, pmid = {40038122}, issn = {1433-7339}, mesh = {Humans ; *Breast Neoplasms/pathology/therapy/psychology ; Female ; Middle Aged ; *Patient-Centered Care ; Adult ; *Self Efficacy ; Aged ; Health Knowledge, Attitudes, Practice ; Decision Making ; Surveys and Questionnaires ; Comparative Effectiveness Research ; }, abstract = {PURPOSE: Pathology reports contain complex medical terminology that may be confusing or overwhelming for patients newly diagnosed with breast cancer. We evaluated the effectiveness of patient-centered pathology reports (PCPRs), which translate pathology results into patient-friendly language.<br><br>METHODS: Sixty-six participants newly diagnosed with breast cancer were randomized to receive either a PCPR and standard pathology report (intervention arm) or a standard pathology report alone (control arm). Patients were surveyed at initial pathology disclosure and 1 month later to assess breast cancer knowledge and ratings of decisional confidence, conflict, and self-efficacy for treatment decision-making. Knowledge was assessed for four pathology domains independently.<br><br>RESULTS: Accuracy of breast cancer knowledge across all domains trended higher for the intervention group compared with the control group (66% vs. 50%, p&#x2009;=&#x2009;0.11); cancer type and surgical margin status knowledge domains exceeded 75% accuracy for the intervention group. No significant differences between groups were observed for patient-reported ratings of communication, decisional conflict, and decision self-efficacy.<br><br>CONCLUSIONS: PCPRs in lay language appeared to improve patients' knowledge of their breast cancer diagnosis, were acceptable to patients and providers, and have the potential to be broadly applied in an effort to improve patient knowledge and improve the patient experience surrounding a breast cancer diagnosis.}, }
@article {pmid40037704, year = {2025}, author = {Wang, MF and Li, MY and Yang, YC and Chuang, YC and Tsai, CY and Binder, MN and Ma, L and Lin, SW and Li, HW and Smith, GR and Chi, P}, title = {Mug20-Rec25-Rec27 binds DNA and enhances meiotic DNA break formation via phase-separated condensates.}, journal = {Nucleic acids research}, volume = {53}, number = {5}, pages = {}, pmid = {40037704}, issn = {1362-4962}, support = {MOST 111-2311-B-002-006-MY3//Ministry of Science and Technology/ ; //National Science and Technology Council/ ; NIH R35 GM118120/NH/NIH HHS/United States ; R35 GM118120/GM/NIGMS NIH HHS/United States ; //Cellular Imaging Shared Resource/ ; }, mesh = {*Meiosis/genetics ; *DNA Breaks, Double-Stranded ; *Schizosaccharomyces/genetics/metabolism ; *Schizosaccharomyces pombe Proteins/metabolism/chemistry ; *DNA, Fungal/metabolism/genetics/chemistry ; DNA-Binding Proteins/metabolism/chemistry ; Protein Binding ; Nuclear Proteins/metabolism/chemistry ; Homologous Recombination ; }, abstract = {During meiosis, programmed DNA double-strand breaks (DSBs) are formed at hotspots to initiate homologous recombination, which is vital for reassorting genetic material. In fission yeast, the linear element (LinE) proteins Mug20, Rec25, and Rec27 interdependently bind chromosomal hotspots with high specificity and are necessary for high-level DSB formation. However, their mechanistic role in regulating the meiotic DSB machinery remains unknown. Here, using purified Mug20-Rec25-Rec27 (MRR) complex and functional intracellular analyses, we reveal that the MRR-DNA nucleoprotein complex assembles phase-separated condensates that compact the DNA. Notably, MRR complex formation is a prerequisite for DNA binding and condensate assembly, with Rec27 playing a pivotal role in directly binding DNA. Consistent with this finding, failure to form MRR-DNA condensates results in defective intracellular meiotic DSB formation and recombination. Our results provide mechanistic insights into how LinEs enhance meiotic DSB formation and provide a paradigm for studies in other species.}, }
@article {pmid40036963, year = {2025}, author = {Coronado, G and Rutter, C}, title = {Response to McElroy and Everett.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djaf042}, pmid = {40036963}, issn = {1460-2105}, }
@article {pmid40036318, year = {2025}, author = {Alagoz, O and Caswell-Jin, JL and de Koning, HJ and Huang, H and Huang, X and Lee, SJ and Li, Y and Plevritis, SK and Sarkar, S and Schechter, CB and Stout, NK and Trentham-Dietz, A and van Ravesteyn, N and Lowry, KP and , }, title = {Mathematical Modeling to Address Questions in Breast Cancer Screening: An Overview of the Breast Cancer Models of the Cancer Intervention and Surveillance Modeling Network.}, journal = {Journal of breast imaging}, volume = {}, number = {}, pages = {}, doi = {10.1093/jbi/wbaf003}, pmid = {40036318}, issn = {2631-6129}, support = {U01CA253911, P30CA014520/NH/NIH HHS/United States ; 21-078-01-CPSH//American Cancer Society/ ; }, abstract = {The National Cancer Institute-funded Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer mathematical models have been increasingly utilized by policymakers to address breast cancer screening policy decisions and influence clinical practice. These well-established and validated models have a successful track record of use in collaborations spanning over 2 decades. While mathematical modeling is a valuable approach to translate short-term screening performance data into long-term breast cancer outcomes, it is inherently complex and requires numerous inputs to approximate the impacts of breast cancer screening. This review article describes the 6 independently developed CISNET breast cancer models, with a particular focus on how they represent breast cancer screening and estimate the contribution of screening to breast cancer mortality reduction and improvements in life expectancy. We also describe differences in structures and assumptions across the models and how variation in model results can highlight areas of uncertainty. Finally, we offer insight into how the results generated by the models can be used to aid decision-making regarding breast cancer screening policy.}, }
@article {pmid40036070, year = {2025}, author = {Zhao, LP and Papadopoulos, GK and Skyler, JS and Kwok, WW and Bondinas, GP and Moustakas, AK and Wang, R and Pyo, CW and Nelson, WC and Geraghty, DE and Lernmark, &#xc5;}, title = {Two DRB3 residues predictively associate with the progression to type 1 diabetes among DR3 carriers.}, journal = {JCI insight}, volume = {}, number = {}, pages = {}, doi = {10.1172/jci.insight.184348}, pmid = {40036070}, issn = {2379-3708}, abstract = {HLA-DR genes are associated with the progression from stage 1 and stage 2 to onset of stage 3 type 1 diabetes (T1D), after accounting HLA-DQ genes with which they are in high linkage-disequilibrium. Based on an integrated cohort of participants from two completed clinical trials, this investigation finds that sharing a haplotype with the DRB1*03:01 (DR3) allele, DRB3*01:01:02 and *02:02:01 have respectively negative and positive associations with the progression. Further, we uncovered two residues (β11, β26, participating in pockets 6 and 4, respectively) on the DRB3 molecule responsible for the progression among DR3 carriers, i.e. motif RY and LF respectively delay and promote the progression (Hazard Ratio = 0.73 and 2.38, p-value = 0.039 and 0.017, respectively). Two anchoring pockets 6 and 4 probably bind differential autoantigenic epitopes. We further investigated the progression association with the motifs RY and LF among carriers of DR3 and found that carriers of the motif LF have significantly faster progression than carriers of RY (HR = 1.48 and p = 0.019 in unadjusted analysis; HR = 1.39, p = 0.047 in adjusted analysis). New insights provide an impetus to examine the possible role of specific DRB3-binding peptides in the progression to T1D.}, }
@article {pmid40035770, year = {2025}, author = {Haberman, M and Kamyshinsky, R and Reznik, N and Yeshaya, N and Khmelnitsky, L and Plender, EG and Eichler, EE and Fass, D}, title = {MUC5AC filaments illuminate the structural diversification of respiratory and intestinal mucins.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {10}, pages = {e2419717122}, doi = {10.1073/pnas.2419717122}, pmid = {40035770}, issn = {1091-6490}, support = {2660/20//Israel Science Foundation (ISF)/ ; 101097867//EC | ERC | HORIZON EUROPE European Research Council (ERC)/ ; }, mesh = {*Mucin 5AC/metabolism/genetics/chemistry ; Humans ; Mucin-2/metabolism/chemistry/genetics ; Mucin-5B/metabolism/genetics/chemistry ; Intestinal Mucosa/metabolism ; Models, Molecular ; Mucins/metabolism/chemistry ; Amino Acid Sequence ; von Willebrand Factor/metabolism/chemistry/genetics ; Respiratory Mucosa/metabolism ; }, abstract = {Secreted mucins are multimegadalton glycoprotein polymers that share the function of protecting mucosal tissues but diversified for activities in different organs of the body. Structural studies of secreted mucins are complicated by the enormous sizes, flexibility, and complex supramolecular assembly modes of these glycoproteins. The two major respiratory mucins are MUC5AC and MUC5B. Here, we present structures of a large amino-terminal segment of MUC5AC in the form of helical filaments. These filaments differ from filamentous and tubular structures observed previously for the intestinal mucin MUC2 and the partial mucin homolog VWF. Nevertheless, the MUC5AC helical filaments support the proposed mechanism, based on MUC2 and VWF, for how noncovalent interactions between mucin monomers guide disulfide crosslinking to form polymers. The high-resolution MUC5AC structures show how local and limited changes in amino acid sequence can profoundly affect higher-order assembly while preserving the overall folds and polymerization activity of mucin glycoproteins. Differences in supramolecular assembly are likely to be functionally significant considering the divergence of mechanical properties and physiological requirements between respiratory and intestinal mucins. Determining the high-resolution structures of respiratory mucins provides a foundation for understanding the mechanisms by which they clean and protect the lungs. Moreover, the MUC5AC structure enables visualization of the sites of human amino acid sequence variation and disease-associated mutations.}, }
@article {pmid40027747, year = {2025}, author = {Hart, ML and Davidsen, K and Danquah, S and Zheng, E and Sokolov, D and Sullivan, LB}, title = {Succinate Dehydrogenase loss causes cascading metabolic effects that impair pyrimidine biosynthesis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40027747}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R35 GM147118/GM/NIGMS NIH HHS/United States ; T32 GM007270/GM/NIGMS NIH HHS/United States ; U54 CA132381/CA/NCI NIH HHS/United States ; }, abstract = {Impaired availability of the amino acid aspartate can be a metabolic constraint of cell proliferation in diverse biological contexts. However, the kinetics of aspartate depletion, and its ramifications on downstream metabolism and cell proliferation, remain poorly understood. Here, we deploy the aspartate biosensor jAspSnFR3 with live cell imaging to resolve temporal relationships between aspartate and cell proliferation from genetic, pharmacological, and nutritional manipulations. In cells with impaired aspartate acquisition from mitochondrial complex I inhibition or constrained uptake in aspartate auxotrophs, we find that the proliferation defects lag changes in aspartate levels and only manifest once aspartate levels fall below a critical threshold, supporting the functional link between aspartate levels and cell proliferation in these contexts. In another context of aspartate synthesis inhibition, impairing succinate dehydrogenase (SDH), we find a more complex metabolic interaction, with initial aspartate depletion followed by a rebound of aspartate levels over time. We find that this aspartate rebound effect results from SDH inhibition disproportionately impairing pyrimidine synthesis by inhibiting aspartate transcarbamoylase (ATCase) through the dual effect of diminishing aspartate substrate availability while accumulating succinate, which functions as a competitive inhibitor of aspartate utilization. Finally, we uncover that the nucleotide imbalance from SDH inhibition causes replication stress and introduces a vulnerability to ATR kinase inhibition. Altogether, these findings identify a mechanistic role for succinate in modulating nucleotide synthesis and demonstrate how cascading metabolic interactions can unfold to impact cell function.}, }
@article {pmid39989965, year = {2025}, author = {Nicholas, JC and Katz, DH and Tahir, UA and Debban, CL and Aguet, F and Blackwell, T and Bowler, RP and Broadaway, KA and Chen, J and Clish, CB and Coresh, J and Cornell, E and Cruz, DE and Deo, R and Doyle, MF and Durda, P and Ekunwe, L and Floyd, JS and Gill, D and Guo, X and Hoogeveen, RC and Johnson, C and Lange, LA and Li, Y and Manning, A and Meigs, JB and Mi, MY and Mychaleckyj, JC and Olson, NC and Pratte, KA and Psaty, BM and Reiner, AP and Ruan, P and Sevilla-Gonzalez, M and Shah, AM and Sun, Q and Tracy, RP and Wen, J and Wood, AC and Wilson, JG and Young, KL and Yu, B and Rooney, MR and Manichaikul, A and Dubin, R and Mohlke, KL and Rich, SS and Rotter, JI and Ganz, P and Gerszten, RE and Taylor, KD and Raffield, LM}, title = {Cross-Ancestry Comparison of Aptamer and Antibody Proteomics Measures.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39989965}, issn = {2693-5015}, support = {U54 HG003067/HG/NHGRI NIH HHS/United States ; UL1 TR001079/TR/NCATS NIH HHS/United States ; T32 ES007018/ES/NIEHS NIH HHS/United States ; R01 HL071250/HL/NHLBI NIH HHS/United States ; N01HC95159/HL/NHLBI NIH HHS/United States ; N01HC95167/HL/NHLBI NIH HHS/United States ; R01 HL071205/HL/NHLBI NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; R01 HL071258/HL/NHLBI NIH HHS/United States ; OT3 HL142478/HL/NHLBI NIH HHS/United States ; UL1 RR033176/RR/NCRR NIH HHS/United States ; 75N92020D00002/HL/NHLBI NIH HHS/United States ; HHSN268201500003C/HL/NHLBI NIH HHS/United States ; T32 GM135128/GM/NIGMS NIH HHS/United States ; 75N92020D00005/HL/NHLBI NIH HHS/United States ; N01HC95160/HL/NHLBI NIH HHS/United States ; R01 HL071251/HL/NHLBI NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; R01 HL071259/HL/NHLBI NIH HHS/United States ; N01HC95163/HL/NHLBI NIH HHS/United States ; 75N92020D00001/HL/NHLBI NIH HHS/United States ; N01HC95169/HL/NHLBI NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; R01 DK072193/DK/NIDDK NIH HHS/United States ; N01HC95164/HL/NHLBI NIH HHS/United States ; OT3 HL142481/HL/NHLBI NIH HHS/United States ; N01HC95162/HL/NHLBI NIH HHS/United States ; OT3 HL147154/HL/NHLBI NIH HHS/United States ; 75N92020D00003/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; N01HC95168/HL/NHLBI NIH HHS/United States ; R01 HL146860/HL/NHLBI NIH HHS/United States ; P30 DK063491/DK/NIDDK NIH HHS/United States ; R01 HL071051/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; U01 AG082042/AG/NIA NIH HHS/United States ; R01 HL159081/HL/NHLBI NIH HHS/United States ; N01HC95165/HL/NHLBI NIH HHS/United States ; N01HC95161/HL/NHLBI NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; 75N92020D00004/HL/NHLBI NIH HHS/United States ; OT3 HL142480/HL/NHLBI NIH HHS/United States ; 75N92020D00007/HL/NHLBI NIH HHS/United States ; HHSN268201500014C/HL/NHLBI NIH HHS/United States ; R01 HL133870/HL/NHLBI NIH HHS/United States ; HHSN268201500003I/HL/NHLBI NIH HHS/United States ; OT3 HL142479/HL/NHLBI NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; R01 HL151855/HL/NHLBI NIH HHS/United States ; UM1 DK078616/DK/NIDDK NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; 75N92020D00006/HL/NHLBI NIH HHS/United States ; N01HC95166/HL/NHLBI NIH HHS/United States ; }, abstract = {Measures from affinity-proteomics platforms often correlate poorly, challenging interpretation of protein associations with genetic variants (pQTL) and phenotypes. Here, we examined 2,157 proteins measured on both SomaScan 7k and Olink Explore 3072 across 1,930 participants with genetic similarity to European, African, East Asian, and Admixed American ancestry references. Inter-platform correlation coefficients for these 2,157 proteins followed a bimodal distribution (median r=0.30). Protein measures from each platform were associated with genetic variants (pQTLs), and one-third of the pQTL signals were driven by protein-altering variants (PAVs). We highlight 80 proteins that correlate differently across ancestry groups likely due to differing PAV frequencies by ancestry. Furthermore, adjustment for PAVs with opposite directions of effect by platform improved inter-platform protein measure correlation and resulted in more concordant genetic and phenotypic associations. Hence, PAVs need to be accounted for across ancestries to facilitate platform-concordant and accurate protein measurement.}, }
@article {pmid39989958, year = {2025}, author = {von Delft, F and Ni, X and Richardson, R and Godoy, A and Ferla, M and Kikawa, C and Scheen, J and Hannon, W and Capkin, E and Lahav, N and Balcomb, B and Marples, P and Fairhead, M and Wang, S and Williams, E and Tomlinson, C and Aschenbrenner, J and Lithgo, R and Winokan, M and Giroud, C and Chandran, A and Walsh, M and Thompson, W and Bloom, J and Barr, H and Kirkegaard, K and Koekemoer, L and Fearon, D and Evans, M}, title = {Crystallographic fragment screening and deep mutational scanning of Zika virus NS2B-NS3 protease enable development of resistance-resilient inhibitors.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39989958}, issn = {2693-5015}, support = {U19 AI171399/AI/NIAID NIH HHS/United States ; }, abstract = {The Zika viral protease NS2B-NS3 is essential for the cleavage of viral polyprotein precursor into individual structural and non-structural (NS) proteins and is therefore an attractive drug target. Generation of a robust crystal system of co-expressed NS2B-NS3 protease has enabled us to perform a crystallographic fragment screening campaign with 1076 fragments. 47 fragments with diverse scaffolds were identified to bind in the active site of the protease, with another 6 fragments observed in a potential allosteric site. To identify binding sites that are intolerant to mutation and thus suppress the outgrowth of viruses resistant to inhibitors developed from bound fragments, we performed deep mutational scanning of NS2B-NS3 protease. Merging fragment hits yields an extensive set of 'mergers', defined as synthetically accessible compounds that recapitulate constellations of observed fragment-protein interactions. In addition, the highly sociable fragment hits enable rapid exploration of chemical space via algorithmic calculation and thus yield diverse possible starting points that maximally explore the binding opportunities to NS2B-NS3 protease, facilitating its resistance-resilient antiviral development.}, }
@article {pmid40034245, year = {2025}, author = {Apolo, A and Baumann, BC and Al-Ahmadie, H and Ballas, L and Bangs, R and Brothers, K and Greenberg, SC and Delacroix, S and Dignam, JJ and Efstathiou, JA and Feldman, AS and Foster, JC and Hahn, NM and Hall, E and Hansel, DE and Hoffman-Censits, J and Kamat, AM and Kamran, SC and Khani, F and Lerner, SP and Lipman, R and Mann, B and McConkey, D and McKiernan, J and Rose, TL and Smith, AB and Tangen, C and Amiri, AT and Weinstock, C and West, PJ and Milowsky, MI and Black, PC}, title = {Summary from the NCI clinical trials planning meeting on next generation of clinical trials in non-muscle invasive bladder cancer.}, journal = {Bladder cancer (Amsterdam, Netherlands)}, volume = {11}, number = {1}, pages = {23523735251319185}, pmid = {40034245}, issn = {2352-3735}, abstract = {The National Cancer Institute organized a virtual Clinical Trials Planning Meeting (CTPM) on 'Defining the next generation of clinical trials with combination therapies in non-muscle invasive bladder cancer (NMIBC)' led by the Bladder Cancer Task Force of the NCI Genitourinary Cancers Steering Committee. The purpose of this meeting was to accelerate advances in clinical trials for patients with high-risk NMIBC. The meeting delivered a multidisciplinary expert consensus on optimal strategies for next-generation clinical trial designs in NMIBC with prioritization of combination therapies. Two clinical trial concepts were developed for potential implementation within the National Clinical Trials Network.}, }
@article {pmid40032074, year = {2025}, author = {Kinoshita, H and Walti, CS and Webber, K and Pezzella, G and Jensen-Wachspress, M and Lang, H and Shuey, K and Boonyaratanakornkit, J and Pergam, SA and Chu, HY and Bollard, CM and Keller, MD and Hill, JA}, title = {T cell immune response to influenza vaccination when administered prior to and following autologous CAR-T cell therapy.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.02.019}, pmid = {40032074}, issn = {2666-6367}, abstract = {BACKGROUND: Chimeric antigen receptor-modified T (CAR-T) cell therapies are gaining wider use in relapsed and refractory malignancies. However, data on vaccination in this population is lacking. We evaluated T cell responses in an established cohort of CAR-T recipients and healthy controls before and after 2019-2020 influenza vaccination.<br><br>METHODS: Peripheral blood mononuclear cells were isolated from healthy controls and patients who received the 2019-2020 influenza vaccine pre- or post-CD19, CD20 or B cell maturation antigen (BCMA) CAR-T. T cells were expanded in vitro for 10 days with peptide libraries for hemagglutinin (HA) and nucleoprotein (NP) from the 2019-2020 vaccine influenza A strains and analyzed by flow cytometry following IFN&#x3b3;/TNF&#x3b1; intracellular staining. Antibody response was evaluated by a hemagglutination-inhibition (HAI) assay.<br><br>RESULTS: Twenty-nine participants, including eight immunocompetent adults, seven pre-CAR-T and 14 post-CAR-T patients, were evaluated. IFN&#x3b3;[+]/TNF&#x3b1;[+] T cell responses after influenza vaccination in healthy controls varied with an increased response to HA-Kansas after vaccination in 7/8 individuals. In the pre-CAR-T cohort, there was a rise in CD4+ T cell response to HA-Brisbane in 6/7 patients after vaccination that remained detectable in 3/4 evaluable patients 90 days post-CAR-T. Five of six patients who lacked an antibody response nonetheless demonstrated a T cell response to HA-Brisbane. There was no association between time since CAR-T administration, baseline IgG or absolute lymphocyte count and change in CD4+ T cell IFN&#x3b3;[+]/TNF&#x3b1;[+] response pre- to post-vaccine for the post-CART cohort.<br><br>CONCLUSION: These data demonstrate that cell-mediated immunity to the influenza vaccine can be elicited in patients vaccinated pre-CAR-T and sustained post-CAR-T, filling an important gap from lack of humoral responses.}, }
@article {pmid40030014, year = {2025}, author = {Torgbor, C and Sohn, H and Dizon, BLP and Mutic, EC and George, R and Kwak, K and Akkaya, M and Ulker, EB and Traver, M and Brzostowski, J and Galloway, DA and Thompson, CD and Çuburu, N and Schiller, JT and Pierce, SK}, title = {In the activation of HPV-specific human B cells HPV-VLP vaccines mimic membrane-associated antigens.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {10}, pages = {e2414514122}, doi = {10.1073/pnas.2414514122}, pmid = {40030014}, issn = {1091-6490}, mesh = {Humans ; *Papillomavirus Vaccines/immunology ; *B-Lymphocytes/immunology/metabolism ; *Ion Channels/metabolism/immunology ; Cell Membrane/metabolism ; Papillomavirus Infections/immunology/prevention &amp; control/virology ; Antigen Presentation/immunology ; Papillomaviridae/immunology ; Lymphocyte Activation/immunology ; Antigens, Viral/immunology ; }, abstract = {B cell responses to membrane-presented antigens appear to be strongly favored over soluble antigens in vivo suggesting that vaccines that mimic membrane-presented antigens may be highly efficacious. We recently demonstrated that human B cell responses to membrane-associated but not to soluble antigens in vitro depended on the expression and activity of the plasma membrane mechanosensitive ion channel, Piezo1. Here, we provide evidence that the efficacy of the current human papillomavirus virus-like particle (HPV VLP) vaccines may be due in part to their inherent ability to mimic Piezo1-dependent membrane presentation of antigens to B cells. We compared HPV-specific human B cell responses to HPV VLPs versus soluble HPV pentameric capsomeres and showed that although both induced calcium responses, only HPV VLP-induced responses were blocked by Piezo1 inhibitors. The kinetics of internalization of HPV-VLP and capsomeres into HPV-specific B cells were similar and neither required Piezo1 function as shown by small interfering RNA (siRNA)-mediated knockdown of Piezo. However, trafficking of HPV-VLPs into intracellular major histocompatibility complex (MHC) class II, lysosomal associated membrane protein 1 (LAMP1)[+] antigen-processing compartments was Piezo1-dependent, whereas trafficking of capsomeres was not. In addition, a time course of intracellular trafficking suggested that colocalization of HPV-VLP with MHC classII was more stable over time as compared to capsomeres. Taken together these findings suggest that the ability of HPV-VLP vaccines to mimic Piezo1-dependent membrane antigen presentation may be exploited in the design of highly effective human vaccines.}, }
@article {pmid40029972, year = {2025}, author = {Sommers, J and Dizon, DS and Lewis, MA and Stone, E and Andreoli, R and Henderson, V}, title = {Assessing Health Information Seeking Behaviors Among Targeted Social Media Users Using an Infotainment Video About a Cancer Clinical Trial: Population-Based Descriptive Study.}, journal = {JMIR cancer}, volume = {11}, number = {}, pages = {e56098}, doi = {10.2196/56098}, pmid = {40029972}, issn = {2369-1999}, mesh = {Humans ; *Social Media ; *Information Seeking Behavior ; Female ; *Clinical Trials as Topic ; Breast Neoplasms/psychology ; Adult ; Middle Aged ; Video Recording ; Neoplasms ; }, abstract = {BACKGROUND: The lack of information and awareness about clinical trials, as well as misconceptions about them, are major barriers to cancer clinical trial participation. Digital and social media are dominant sources of health information and offer optimal opportunities to improve public medical awareness and education by providing accurate and trustworthy health information from reliable sources. Infotainment, material intended to both entertain and inform, is an effective strategy for engaging and educating audiences that can be easily disseminated using social media and may be a novel way to improve awareness of and recruitment in clinical trials.<br><br>OBJECTIVE: The purpose of this study was to evaluate whether an infotainment video promoting a clinical trial, disseminated using social media, could drive health information seeking behaviors.<br><br>METHODS: As part of a video series, we created an infotainment video focused on the promotion of a specific cancer clinical trial. We instituted a dissemination and marketing process on Facebook to measure video engagement and health information seeking behaviors among targeted audiences who expressed interest in breast cancer research and organizations. To evaluate video engagement, we measured reach, retention, outbound clicks, and outbound click-through rate. Frequencies and descriptive statistics were used to summarize each measure.<br><br>RESULTS: The video substantially increased health information seeking behavior by increasing viewership from 1 visitor one month prior to launch to 414 outbound clicks from the video to the clinical trial web page during the 21-day social media campaign period.<br><br>CONCLUSIONS: Our study shows that digital and social media tools can be tailored for specific target audiences, are scalable, and can be disseminated at low cost, making it an accessible educational, recruitment, and retention strategy focused on improving the awareness of clinical trials.}, }
@article {pmid40029708, year = {2025}, author = {Johnson, ACM and Zager, RA}, title = {Veverimer, a Non-Absorbed Gastrointestinal Tract HCl Binder, Decreases Renal Ammoniagenesis and Mitigates Nephrotoxic Serum Nephritis.}, journal = {Kidney360}, volume = {}, number = {}, pages = {}, doi = {10.34067/KID.0000000743}, pmid = {40029708}, issn = {2641-7650}, abstract = {BACKGROUND: Increased tubular ammoniagenesis is an adaptive response to progressive kidney disease, facilitating net acid excretion. However, excess ammonia production can also exacerbate kidney disease progression, in part, by activating the alternative complement cascade. Oral Na bicarbonate therapy can decrease the systemic H+ burden, limiting ammonia production. However, poor compliance limits bicarbonate's efficacy. Veverimer is an oral, Na+ free, non-absorbed polymer that binds H+ within the gastrointestinal (GI) tract. This stimulates GI carbonic anhydrase-mediated bicarbonate production and systemic bicarbonate uptake. Hence, the goals of this study were to: test whether GI HCl binding decreases renal tubular ammoniagenesis; assess whether decreased complement activation results; and determine whether these changes can mitigate nephrotoxic serum (NTS) nephritis in which complement activation may play a role.<br><br>METHODS: A normal diet &#xb1; veverimer (4.5% w/w) was fed to normal mice for &#x223c;1 week. Veverimer's impact on plasma bicarbonate, blood/urinary pH, urinary ammonia excretion, and tubular H+ transporter, NHE3, density were assessed. Additional mice were fed the normal or veverimer diet following NTS injection. Urine protein, albumin, ammonia, C5b-9 excretion, and plasma C3a levels were measured at 1 and/or 2 weeks post NTS injection. Renal histologic changes (H/E stain; C5b-9, CD45 immunohistochemistry), and selected injury mediators/biomarkers (NGAL, IL-6, MCP-1, TGF beta 1, endothelin-1 mRNAs) were also assessed.<br><br>RESULTS: Veverimer increased plasma bicarbonate/urinary pH, reduced urinary ammonia, and decreased NHE3 in normal mice. Veverimer also reduced NTS-induced proteinuria/albuminura, urinary ammonia, and C5b-9 excretion (by &#x223c;60%, &#x223c;75%, &#x223c;50%, respectively). Significant reductions in NTS-induced glomerular/ tubulointerstitial injury, inflammatory/profibrotic gene expression, renal C5b-9 deposition, and suppressed plasma C3a levels were observed. Oral bicarbonate also conferred protection, implicating bicarbonate in veverimer's beneficial effect.<br><br>CONCLUSIONS: Veverimer-mediated bicarbonate generation can suppress renal ammoniagenesis and complement activation. These findings suggest a potential benefit of veverimer/ bicarbonate therapy in selected complement-mediated renal diseases.}, }
@article {pmid40029702, year = {2025}, author = {Lee, CI and Elmore, JG}, title = {FDA Breast Density Reporting Requirements and Evidence-Based Medical Practice.}, journal = {JAMA}, volume = {}, number = {}, pages = {}, doi = {10.1001/jama.2025.0001}, pmid = {40029702}, issn = {1538-3598}, }
@article {pmid40028765, year = {2025}, author = {Henikoff, S and Levens, DL}, title = {The plusses and minuses of DNA torsion.}, journal = {eLife}, volume = {14}, number = {}, pages = {}, pmid = {40028765}, issn = {2050-084X}, mesh = {*RNA Polymerase II/metabolism/genetics ; *DNA/genetics ; Humans ; Nucleic Acid Conformation ; }, abstract = {A new method for mapping torsion provides insights into the ways that the genome responds to the torsion generated by RNA polymerase II.}, }
@article {pmid39990346, year = {2025}, author = {Prodanov, T and Plender, EG and Seebohm, G and Meuth, SG and Eichler, EE and Marschall, T}, title = {Locityper: targeted genotyping of complex polymorphic genes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39990346}, issn = {2692-8205}, support = {R01 HG002385/HG/NHGRI NIH HHS/United States ; }, abstract = {The human genome contains numerous structurally-variable polymorphic loci, including several hundred disease-associated genes, almost inaccessible for accurate variant calling. Here we present Locityper, a tool capable of genotyping such challenging genes using short and long-read whole genome sequencing. For each target, Locityper recruits and aligns reads to locus haplotypes, for instance extracted from a pangenome, and finds the likeliest haplotype pair by optimizing read alignment, insert size and read depth profiles. Locityper accurately genotypes up to 194 of 256 challenging medically relevant loci (95% haplotypes at QV33), an 8.8-fold gain compared to 22 genes achieved with standard variant calling pipelines. Furthermore, Locityper provides access to hyperpolymorphic HLA genes and other gene families, including KIR, MUC and FCGR. With its low running time of 1h10m per sample at 8 threads, Locityper is scalable to biobank-sized cohorts, enabling association studies for previously intractable disease-relevant genes.}, }
@article {pmid40028346, year = {2025}, author = {Weinfurtner, K and Tischfield, D and McClung, G and Crainic, J and Gordan, J and Jiao, J and Furth, EE and Li, W and Supan, ET and Nadolski, GJ and Hunt, SJ and Kaplan, DE and Gade, TPF}, title = {Human GM-CSF/IL-3 enhance tumor immune infiltration in humanized HCC patient-derived xenografts.}, journal = {JHEP reports : innovation in hepatology}, volume = {7}, number = {3}, pages = {101264}, pmid = {40028346}, issn = {2589-5559}, abstract = {BACKGROUND &amp; AIMS: Response to immunotherapy in hepatocellular carcinoma (HCC) is suboptimal with no biomarkers to guide patient selection. "Humanized" mice represent promising models to address this deficiency but are limited by variable chimerism and underdeveloped myeloid compartments. We hypothesized that expression of human GM-CSF and IL-3 increases tumor immune cell infiltration, especially myeloid-derived cells, in humanized HCC patient-derived xenografts.<br><br>MATERIAL AND METHODS: NOG (NOD/Shi-scid/IL-2R&#x3b3;[null]) and NOG-EXL (huGM-CSF/huIL-3 NOG) mice conditioned with busulfan underwent i.v. injection of human CD34+ cells. HCC patient-derived xenograft tumors were then implanted subcutaneously or orthotopically. Following serial blood sampling, mice were euthanized at defined tumor sizes. Tumor, blood, liver, and spleen were analyzed by flow cytometry and immunohistochemistry.<br><br>RESULTS: Humanized NOG-EXL mice demonstrated earlier and higher levels of human chimerism compared to humanized NOG mice (82.1% vs. 43.8%, p <0.0001) with a greater proportion of human monocytes (3.2% vs. 1.1%, p&#xa0;= 0.001) and neutrophils (0.8% vs. 0.3%, p&#xa0;= 0.02) in circulation. HCC tumors in humanized NOG-EXL mice exhibited greater human immune cell infiltration (57.6% vs. 30.2%, p&#xa0;= 0.04) with higher proportions of regulatory T cells (14.6% vs. 6.8%, p&#xa0;= 0.04), CD4+ PD-1 expression (84.7% vs. 32.0%, p <0.01), macrophages (1.2% vs. 0.6%, p&#xa0;= 0.02), and neutrophils (0.5% vs. 0.1%, p <0.0001). No differences were observed in tumor engraftment or growth latency in subcutaneous tumors, but orthotopic tumors required implantation at 2 rather than 4 weeks post-humanization for successful engraftment. Finally, utilizing adult bone marrow instead of fetal livers enabled partial HLA-matching to HCC tumors but required more CD34+ cells.<br><br>CONCLUSIONS: Human GM-CSF and IL-3 expression in humanized mice resulted in features more closely approximating the immune microenvironment of human disease, providing a promising model for investigating critical questions in immunotherapy for HCC.<br><br>IMPACT AND IMPLICATIONS: This study introduces a unique mouse model at a critical point in the evolution of treatment paradigms for patients with hepatocellular carcinoma (HCC). Immunotherapies have become the first-line treatment for advanced HCC; however, response rates remain low with no clear predictors of response to guide patient selection. In this context, animal models that recapitulate human disease are greatly needed. Leveraging xenograft tumors derived from patients with unresectable HCCs and a commercially available immunodeficient mouse strain that expresses human GM-CSF and IL-3, we demonstrate a novel but accessible approach for modeling the HCC tumor microenvironment.}, }
@article {pmid40027237, year = {2025}, author = {Le, C and Tatunay, K and Liu, W and Lu, H and Rodis, NA and Nam, T and Laurino, MY and Dubard-Gault, ME}, title = {Lessons learned in migrating from one commercial genetics clinical decision-making tool to another: Assessment of data integrity and utilization.}, journal = {Genetics in medicine open}, volume = {3}, number = {}, pages = {101913}, pmid = {40027237}, issn = {2949-7744}, abstract = {PURPOSE: Rapid advancements in information technology have greatly influenced clinicians' engagement with patient data for health maintenance. The electronic health record often contains multiple ways to record risk factors and to identify patients at an elevated genetic risk for cancer. However, these variables exist in multiple forms and disparate locations in each commercial electronic health record solution resulting in significant variations in how family history or genetic data is codified. Furthermore, there is pressure to migrate from one commercial solution to another at times, prompting the need for a process ensuring data integrity during such a transition.<br><br>METHODS: Between July and December 2023, the genetics team migrated a family history database from one commercial software solution to another. After the data migration of 13,000 patient records, we reviewed 500 randomly selected charts in both support tools to measure the rate of concordance of information transferred.<br><br>RESULTS: A total of 461 patient charts were reviewed. Of these, 425 (92.2%) were noted to be concordant. Of the 36 charts that were discordant, 9 had incorrect genetic testing results entered, 19 had missing information, 5 charts contained data recorded on paper before 2017 (legacy data), and 3 had additional information transferred.<br><br>CONCLUSION: There was high data integrity after migration from one commercial software solution to another. Although these results can ease clinicians' concerns after such support tool transitions, our effort also highlights areas for improvement in how family and patient genetic data are recorded and utilized for clinical care and research within an institution.}, }
@article {pmid40026777, year = {2025}, author = {Hartlage, W and Castillo, AY and Kassamali Escobar, Z and Bajenov, M and Martinez-Paz, N and Lynch, JB and Bryson-Cahn, C and Chan, JD}, title = {Stewarding the inappropriate diagnosis and treatment of urinary tract infection: leveraging the urinalysis to understand true antibiotic overuse.}, journal = {Antimicrobial stewardship &amp; healthcare epidemiology : ASHE}, volume = {5}, number = {1}, pages = {e49}, pmid = {40026777}, issn = {2732-494X}, abstract = {We evaluated 249 asymptomatic patients receiving antibiotics for urinary infection: 222 had asymptomatic pyuria and/or nitrituria (ASPN) and 133 had asymptomatic bacteriuria (ASB, growth ≥10[5] colony forming units/ml). ASPN identified 40% more cases of unnecessary antibiotics compared to ASB and may be a more comprehensive measure of unnecessary antibiotic use.}, }
@article {pmid40025499, year = {2025}, author = {Fang, H and Tronco, AR and Bonora, G and Nguyen, T and Thakur, J and Berletch, JB and Filippova, GN and Henikoff, S and Shendure, J and Noble, WS and Duan, Z and Disteche, CM and Deng, X}, title = {CTCF-mediated insulation and chromatin environment modulate Car5b escape from X inactivation.}, journal = {BMC biology}, volume = {23}, number = {1}, pages = {68}, pmid = {40025499}, issn = {1741-7007}, support = {U54DK107979/GF/NIH HHS/United States ; UM1HG011586/GF/NIH HHS/United States ; UM1 HG011586/HG/NHGRI NIH HHS/United States ; GM131745/GF/NIH HHS/United States ; GM1273727/GF/NIH HHS/United States ; }, mesh = {*CCCTC-Binding Factor/metabolism/genetics ; Animals ; *X Chromosome Inactivation/genetics ; Mice ; *Chromatin/metabolism ; Female ; Binding Sites ; Repressor Proteins/metabolism/genetics ; }, abstract = {BACKGROUND: Genes that escape X-chromosome inactivation (XCI) in female somatic cells vary in number and levels of escape among mammalian species and tissues, potentially contributing to species- and tissue-specific sex differences. CTCF, a master chromatin conformation regulator, is enriched at escape regions and may play an important role in regulating escape, but the molecular mechanisms remain elusive.<br><br>RESULTS: CTCF binding profiles and epigenetic features were systematically examined at escape genes (escapees) using mouse allelic systems with skewed XCI to distinguish the inactive X (Xi) and active X (Xa) chromosomes. We found that six constitutive and two facultative escapees are located inside 30-800&#xa0;kb domains marked by convergent arrays of CTCF binding sites, consistent with the formation of chromatin loops. Facultative escapees show clear differences in CTCF binding depending on their XCI status in specific cell types/tissues. In addition, sets of strong and in some cases divergent CTCF binding sites located at the boundary between an escapee and its adjacent neighbors subject to XCI would also help insulate domains. Indeed, deletion but not inversion of a CTCF binding site at the boundary between the facultative escapee Car5b and its silent neighbor Siah1b results in a dramatic reduction of Car5b escape. This is associated with reduced CTCF and cohesin binding, which indicates loss of looping and insulation and is supported by 3C combined with Hi-C analysis. In addition, enrichment in the repressive mark H3K27me3 invades the Car5b domain in deleted cells, consistent with loss of expression from the Xi. In contrast, cells with an inversion of the CTCF binding site retain CTCF and cohesin binding, as well as looping, in line with persistence of escape. Interestingly, the levels of escape increase in cells with deletion of either Dxz4, which disrupts the Xi-specific compact 3D structure, or Firre, which results in lower H3K27me3 enrichment on the Xi, indicating that the structural and epigenetic features of the Xi constrain escape from XCI in wild type conditions.<br><br>CONCLUSIONS: Taken together, our findings support the idea that escape from XCI in female somatic cells is modulated by both the topological insulation of domains via CTCF binding and the surrounding heterochromatin environment.}, }
@article {pmid39990799, year = {2025}, author = {Chen, KY and Toro-Moreno, M and Subramaniam, AR}, title = {GitHub is an effective platform for collaborative and reproducible laboratory research.}, journal = {ArXiv}, volume = {}, number = {}, pages = {}, pmid = {39990799}, issn = {2331-8422}, support = {R01 AT012826/AT/NCCIH NIH HHS/United States ; R35 GM119835/GM/NIGMS NIH HHS/United States ; }, abstract = {Laboratory research is a complex, collaborative process that involves several stages, including hypothesis formulation, experimental design, data generation and analysis, and manuscript writing. Although reproducibility and data sharing are increasingly prioritized at the publication stage, integrating these principles at earlier stages of laboratory research has been hampered by the lack of broadly applicable solutions. Here, we propose that the workflow used in modern software development offers a robust framework for enhancing reproducibility and collaboration in laboratory research. In particular, we show that GitHub, a platform widely used for collaborative software projects, can be effectively adapted to organize and document all aspects of a research project's lifecycle in a molecular biology laboratory. We outline a three-step approach for incorporating the GitHub ecosystem into laboratory research workflows: 1. designing and organizing experiments using issues and project boards, 2. documenting experiments and data analyses with a version control system, and 3. ensuring reproducible software environments for data analyses and writing tasks with containerized packages. The versatility, scalability, and affordability of this approach make it suitable for various scenarios, ranging from small research groups to large, cross-institutional collaborations. Adopting this framework from a project's outset can increase the efficiency and fidelity of knowledge transfer within and across research laboratories. An example GitHub repository based on this approach is available at https://github.com/rasilab/github_demo and a template repository that can be copied is available at https://github.com/rasilab/github_template.}, }
@article {pmid40025364, year = {2025}, author = {Javid, SH and Kazerouni, AS and Hippe, DS and Hirano, M and Schnuck-Olapo, J and Biswas, D and Bryant, ML and Li, I and Xiao, J and Kim, AG and Guo, A and Dontchos, B and Kilgore, M and Kim, J and Partridge, SC and Rahbar, H}, title = {Correction: Preoperative MRI to Predict Upstaging of DCIS to Invasive Cancer at Surgery.}, journal = {Annals of surgical oncology}, volume = {}, number = {}, pages = {}, doi = {10.1245/s10434-025-17029-x}, pmid = {40025364}, issn = {1534-4681}, }
@article {pmid40023656, year = {2025}, author = {Sullivan, KM and Sanders, JE}, title = {The Cure of Thalassemia and the Angst of a Junior Attending.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {3}, pages = {113-117}, doi = {10.1016/j.jtct.2025.02.006}, pmid = {40023656}, issn = {2666-6367}, }
@article {pmid40022306, year = {2025}, author = {Zhou, P and Yeshoua, BJ and Konuthula, N and Pan, CJ and Ferrandino, RM and Holte, SE and Rizvi, Z and Marchiano, EM and Futran, ND and Barber, BR}, title = {Association of Oral Health Determinants With Oral Squamous Cell Carcinoma in Never-Smoking Adults.}, journal = {Head &amp; neck}, volume = {}, number = {}, pages = {}, doi = {10.1002/hed.28119}, pmid = {40022306}, issn = {1097-0347}, support = {//RFPU-NW research award/ ; }, abstract = {BACKGROUND: The incidence of oral cavity squamous cell carcinoma (OCSCC) is increasing among non-smokers. This study investigates the association between local and systemic oral health determinants and OCSCC in never-smoking adults.<br><br>METHODS: A case-control study using the National Institutes of Health All of Us database was conducted. Lifetime exposures to periodontal disease, acquired absence of teeth, hyperlipidemia, hyperglycemia, HIV, oral-related autoimmune diseases, depression, and eating disorders were analyzed. Multivariate logistic regression estimated odds ratios (ORs) and 95% confidence intervals to identify independent OCSCC risk factors.<br><br>RESULTS: Several risk factors were independently associated with OCSCC: periodontal disease (OR 4.99), hyperlipidemia (OR 1.53), HIV infection (OR 2.96), oral-related autoimmune diseases (OR 2.40), depression (OR 1.51), and eating disorders (OR 8.46). Acquired absence of teeth and hyperglycemia did not show statistical significance.<br><br>CONCLUSIONS: This study highlights the complex pathophysiology of OCSCC in never-smoking adults and underscores the need for comprehensive risk assessment and prevention strategies.}, }
@article {pmid40022201, year = {2025}, author = {Jennings-Shaffer, C and Rich, DH and Macaulay, M and Karcher, MD and Ganapathy, T and Kiami, S and Kooperberg, A and Zhang, C and Suchard, MA and Matsen, FA}, title = {Finding high posterior density phylogenies by systematically extending a directed acyclic graph.}, journal = {Algorithms for molecular biology : AMB}, volume = {20}, number = {1}, pages = {2}, pmid = {40022201}, issn = {1748-7188}, support = {R01 AI162611/AI/NIAID NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; S10OD028685/RI/ORIP NIH HHS/United States ; AI162611/NH/NIH HHS/United States ; }, abstract = {Bayesian phylogenetics typically estimates a posterior distribution, or aspects thereof, using Markov chain Monte Carlo methods. These methods integrate over tree space by applying local rearrangements to move a tree through its space as a random walk. Previous work explored the possibility of replacing this random walk with a systematic search, but was quickly overwhelmed by the large number of probable trees in the posterior distribution. In this paper we develop methods to sidestep this problem using a recently introduced structure called the subsplit directed acyclic graph (sDAG). This structure can represent many trees at once, and local rearrangements of trees translate to methods of enlarging the sDAG. Here we propose two methods of introducing, ranking, and selecting local rearrangements on sDAGs to produce a collection of trees with high posterior density. One of these methods successfully recovers the set of high posterior density trees across a range of data sets. However, we find that a simpler strategy of aggregating trees into an sDAG in fact is computationally faster and returns a higher fraction of probable trees.}, }
@article {pmid40019842, year = {2025}, author = {Kronenberger, DW and Zimmers, TA and Ralston, RK and Runco, DV}, title = {Circulating Growth Differentiation Factor 15 (GDF15) in Paediatric Disease: A Systematic Review.}, journal = {Journal of cachexia, sarcopenia and muscle}, volume = {16}, number = {2}, pages = {e13712}, pmid = {40019842}, issn = {2190-6009}, mesh = {*Growth Differentiation Factor 15/blood ; Humans ; Child ; *Biomarkers/blood ; Child, Preschool ; Infant, Newborn ; Infant ; Adolescent ; }, abstract = {BACKGROUND: Growth Differentiation Factor 15 (GDF15), a nonspecific inflammatory marker and member of the TGF-β superfamily, has a well-established role in both inflammation and metabolic modulation, but lacks a comprehensive paediatric literature review. In several adult disease states, including cancer cachexia and pregnancy, circulation and expression of GDF15 has been of clinical and scientific interest, but little published paediatric data exists. As such, we aim to summarize existing paediatric studies.<br><br>METHODS: This review follows the PRISMA-ScR guidelines for reporting and aims to summarize existing paediatric studies including GDF15, describe disease entities in which GDF15 has been investigated including existing reference ranges, and identify literature gaps to present future clinical and research direction. Our search strategy queried Ovid MEDLINE, Ovid Embase, Cochrane Library and Scopus databases to find original scientific articles measuring GDF15 from birth through children up to age 18. Data relating to study participant demographic and disease pathology, GDF15 measurement methods and clinical outcomes of interest were extracted.<br><br>RESULTS: Sixty-two studies were included, classified as cardiac, endocrine, mitochondrial, hematologic, neonatal, oncologic, infectious, rheumatologic, renal, neurologic or healthy. While several entities demonstrated elevated GDF15, the highest median GDF15 levels were observed in cardiac arrest 7089&#x2009;pg/mL (interquartile range 3805-13&#x2009;306) and mitochondrial diseases 4640&#x2009;pg/mL (1896-14&#x2009;064). In certain conditions, including cardiac stress, polycystic ovarian syndrome (PCOS), Kawasaki Disease (KD) and certain mitochondrial myopathies GDF15 can normalize with disease treatment or resolution. Of healthy children studied, GDF15 levels were highest in healthy neonates and followed a predictable pattern, decreasing over time. Mean and standard deviation values of GDF15 in healthy children were 343.8&#x2009;&#xb1;&#x2009;221.0&#x2009;pg/mL, with a range of 90-1134&#x2009;pg/mL for study averages.<br><br>CONCLUSIONS: Circulating GDF15 has been studied in a variety of paediatric diseases. However, variable evaluated outcome measures and GDF15 measurement methodologies prevent generalizability and direct comparison of these published studies. Validating normal GDF15 levels in children with standardized and reproducible methodology will help clarify GDF15's utility as a diagnostic marker of disease, a necessary step to elucidate clinical implications of GDF15 over expression and its potential as a therapeutic target.}, }
@article {pmid40019493, year = {2025}, author = {Fasching, PA and Slamon, D and Nowecki, Z and Kukielka-Budny, B and Stroyakovskiy, D and Yardley, DA and Huang, CS and Chan, A and Chia, S and Martín, M and Rugo, HS and Loi, S and Hurvitz, S and Untch, M and Afenjar, K and Fresco, R and Danyliv, A and Ferrusi, I and Li, Z and Hortobagyi, G}, title = {Health-related quality of life in patients with HR+/HER2- early breast cancer treated with ribociclib plus a nonsteroidal aromatase inhibitor: results from the NATALEE trial.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-24-1724}, pmid = {40019493}, issn = {1557-3265}, abstract = {PURPOSE: The phase 3 NATALEE trial reported a statistically significant invasive disease-free survival benefit with ribociclib plus nonsteroidal aromatase inhibitor (NSAI) versus an NSAI alone in stage II/III hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) early breast cancer (EBC). Here we report health-related quality of life (HRQOL) data from NATALEE.<br><br>PATIENTS AND METHODS: Patients were randomized to receive ribociclib plus NSAI or NSAI alone. Patient-reported outcome scores (EORTC QLQ-C30 global health status and physical, social, and emotional functioning domains; EORTC QLQ-BR23 breast-symptoms scale; health on a visual analog scale of EQ-5D-5L; and the Hospital Anxiety and Depression Scale) were assessed. The prespecified primary HRQOL endpoint was physical functioning. Mean scores and time-categorical and prespecified linear-time repeated-measure models were used to evaluate HRQOL changes during treatment.<br><br>RESULTS: HRQOL was evaluated in all patients in the ribociclib plus NSAI (n = 2549) and NSAI alone (n = 2552) arms. Compliance was high in both arms (&#x2248;93%-97%). Mean scores did not differ meaningfully from baseline for any analyzed domain. Likewise, neither a meaningful change from baseline (in either treatment arm) nor a difference between arms was observed during treatment in the time-categorical, model-adjusted mean scores for any HRQOL domains-using published thresholds for interpreting longitudinal and between-group differences, with all values being within 0.5 SD of their baseline values. Linear-time regression analysis confirmed these findings.<br><br>CONCLUSIONS: These analyses of NATALEE show that adding adjuvant ribociclib to an NSAI does not negatively impact HRQOL in patients with HR+/HER2- EBC.}, }
@article {pmid40019453, year = {2025}, author = {Di, M and Maurer, MJ and Flowers, CR}, title = {End points and Outcomes in Follicular Lymphoma: What should we measure, how, and why?.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024026978}, pmid = {40019453}, issn = {1528-0020}, abstract = {Overall survival (OS) and quality of life (QoL) are clinically relevant outcomes/endpoints during examination of therapies. However, with median OS approaching 20 years for patients with follicular lymphoma (FL), it is often not feasible to use OS as a primary endpoint in clinical studies. While validated tools for assessing QoL in patient with lymphoma exist, QoL data are rarely the sole basis for drug approvals in FL. Therefore, other survival endpoints, surrogates, and intermediate clinical endpoints have all been used to measure outcomes in FL trials. In this review, we discuss the strengths and limitations of these commonly used traditional endpoints in FL trials and examine the current gaps, including delayed availability of results and suboptimal sensitivity in distinguishing difference in therapeutic effects. To help address the gaps identified, well-validated surrogates, such as complete remission 30 months after starting frontline immunochemotherapy (CR30), may be used as the primary or co-primary endpoint in confirmatory randomized trials. Emerging intermediate endpoints like minimal residual disease, may be useful in early phase trials and in guiding accelerated approvals after appropriate validation. As patient preference plays a crucial role in treatment decisions in FL, it is critical to include QoL as an important secondary trial endpoint and to measure non-medical burdens, including time and financial toxicities. Endpoints that are clinically relevant, timely, and patient-centered may identify new drugs that help patients with FL live longer and better lives.}, }
@article {pmid40016020, year = {2025}, author = {Indorf, A and Kwok, M and Jao, M and Chen, A and Baek, GT and Banerjee, R and Cicero, KI and Cowan, AJ and Portuguese, AJ and Yoon, L and Segal, EM}, title = {Enhancing Multiple Myeloma Care: Implementation of Pharmacist-Led Prescribing of Immunomodulatory Drugs in an Academic Medical Setting.}, journal = {Clinical lymphoma, myeloma &amp; leukemia}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.clml.2025.01.013}, pmid = {40016020}, issn = {2152-2669}, abstract = {BACKGROUND: The oncology healthcare landscape has transformed and has demonstrated the need for efficient care delivery models due to improved survival resulting in larger patient panels. Pharmacists can prescribe oral anticancer agents (OAA), laboratory orders, and supportive care treatments as licensed independent practitioners (LIP) under their pharmacist license. Using immunomodulators (IMiDs) for patients with multiple myeloma (MM) has complexities with regulatory requirements for prescribing. At our institution, the care team was spending about 240 hours per month satisfying regulatory activities. We aim to characterize the effectiveness of pharmacist LIPs for patients with MM receiving IMiD treatment.<br><br>METHODS: A multidisciplinary quality improvement team implemented a model for OAA management with pharmacist LIPs. Patients were evaluated for IMiD adherence. Medication possession ratios (MPR) were collected using fill history for patients with 6 months of fill history pre and postpharmacist LIPs involvement, and paired McNemar's Test assessed differences in adherence. A care team survey gauged satisfaction.<br><br>RESULTS: The pharmacist patient panel comprised 246 patients. There were similar adherence rates, with an MPR of 96% preintervention and 96.55% postintervention. All survey participants recommended the pharmacist prescriber for IMiDs and reported positive reviews of pharmacist involvement.<br><br>CONCLUSION: Management of OAAs by pharmacist LIPs is viable clinical model. The care team reduced their administrative burden while empowering pharmacists to practice at the top of their license. This framework serves as a guide for institutions to adapt and optimize OAA management in an increasingly complex therapeutic landscape.}, }
@article {pmid40015292, year = {2025}, author = {Haidar, G and Thomas, S and Loubet, P and Baker, RI and Benfield, T and Boonyaratanakornkit, J and Kiertiburanakul, S and Kim, AHJ and Longbrake, EE and Molina, JM and Paredes, R and Tucker, D and Uriel, A and Weinmann-Menke, J and Aksyuk, AA and Clegg, LE and Currie, A and Yang, H and Flyrin, K and Gibbs, M and Shroff, M and Perez, JL and Chang, LJ and Cohen, TS and , }, title = {Efficacy and safety of sipavibart for prevention of COVID-19 in individuals who are immunocompromised (SUPERNOVA): a randomised, controlled, double-blind, phase 3 trial.}, journal = {The Lancet. Infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1016/S1473-3099(24)00804-1}, pmid = {40015292}, issn = {1474-4457}, abstract = {BACKGROUND: Sipavibart is an anti-spike monoclonal antibody that neutralises SARS-CoV-2 with exceptions, including Phe456Leu-containing variants (eg, KP.2* and KP.3*). This trial assessed sipavibart efficacy and safety for prevention of symptomatic COVID-19 in participants who are immunocompromised.<br><br>METHODS: In this ongoing, double-blind, international, phase 3 trial, we enrolled participants who were immunocompromised and aged 12 years or older at 197 hospitals, university health centres, and clinical trial units in 18 countries. Participants were randomly allocated 1:1 to a sipavibart group (intramuscular sipavibart 300 mg on days 1 and 181) or a comparator group (tixagevimab 300 mg-cilgavimab 300 mg on day 1 and placebo on day 181 or placebo on days 1 and 181), stratified by previous COVID-19 vaccination and infection status and use of tixagevimab-cilgavimab. The primary efficacy outcomes were symptomatic COVID-19 caused by any variant or symptomatic COVID-19 caused by non-Phe456Leu-containing variants within 181 days of dosing, assessed in the SARS-CoV-2-negative set, comprising all participants without a positive RT-PCR test for SARS-CoV-2 at baseline and who received at least one trial intervention dose. Safety outcomes for adverse events were assessed 90 days following the first dose and for serious adverse events throughout the study in the safety analysis set (ie, all participants who received at least one injection of sipavibart or comparator). This study is registered with ClinicalTrials.gov, NCT05648110.<br><br>FINDINGS: Participants were screened from March 31 to Oct 27, 2023; 3349 participants (56&#xb7;8% female) were randomly assigned: 1674 to the sipavibart group (five no first dose; 1669 sipavibart) and 1675 to the comparator group (nine no first dose; 1105 tixagevimab-cilgavimab and 561 placebo). Within 181 days of dosing, 122 (7&#xb7;4%) of 1649 participants in the sipavibart group and 178 (10&#xb7;9%) of 1631 participants in the comparator group had symptomatic COVID-19 due to any variant (relative risk reduction [RRR] 34&#xb7;9% [97&#xb7;5% CI 15&#xb7;0 to 50&#xb7;1]; p=0&#xb7;0006), 54 (3&#xb7;3%) participants in the sipavibart group and 90 (5&#xb7;5%) participants in the comparator group had symptomatic COVID-19 due to non-Phe456Leu-containing variants (RRR 42&#xb7;9% [95% CI 19&#xb7;9 to 59&#xb7;3]; p=0&#xb7;0012), and 47 (2&#xb7;9%) participants in the sipavibart group and 64 (3&#xb7;9%) participants in the comparator group had symptomatic COVID-19 due to Phe456Leu-containing variants (30&#xb7;4% [-1&#xb7;8 to 52&#xb7;5]). Adverse events occurred in 833 (49&#xb7;9%) of 1671 participants in the sipavibart group and 857 (51&#xb7;5%) of 1663 participants in the comparator group within 3 months of the first dose. One COVID-19-related death occurred in the comparator group. Serious adverse events considered related to trial intervention occurred in two (0&#xb7;1%) of 1671 participants in the sipavibart group and seven (0&#xb7;4%) of 1663 participants in the comparator group (none fatal). No serious cardiovascular or thrombotic events were considered to be related to sipavibart.<br><br>INTERPRETATION: The primary analysis showed efficacy and safety of sipavibart in preventing symptomatic COVID-19 in participants who are immunocompromised when susceptible (ie, non-Phe456Leu-containing) variants dominated, although no efficacy was shown against resistant (ie, Phe456Leu-containing) variants that dominate as of November, 2024.<br><br>FUNDING: AstraZeneca.}, }
@article {pmid40014858, year = {2025}, author = {Nudy, M and Aragaki, AK and Jiang, X and Manson, JE and Shadyab, AH and Jung, SY and Martin, LW and Wild, RA and Womack, C and Mouton, CP and Rossouw, JE and Schnatz, PF}, title = {Long-Term Changes to Cardiovascular Biomarkers After Hormone Therapy in the Women's Health Initiative Hormone Therapy Clinical Trials.}, journal = {Obstetrics and gynecology}, volume = {}, number = {}, pages = {}, pmid = {40014858}, issn = {1873-233X}, abstract = {OBJECTIVE: To assess the long-term changes in cardiovascular biomarkers during the WHI (Women's Health Initiative) hormone therapy (HT) clinical trials of conjugated equine estrogens (CEE) alone and CEE plus medroxyprogesterone acetate (MPA).<br><br>METHODS: HT trial participants from the CEE alone (n=1,188, 0.625 mg/d CEE or placebo) and the CEE+MPA (n=1,508, 0.625 mg/d CEE plus continuous 2.5 mg/d MPA or placebo) trials provided blood samples at baseline and after 1, 3, and 6 years. Low-density lipoprotein cholesterol (LDL-C; primary endpoint), high-density lipoprotein cholesterol (HDL-C), triglycerides, total cholesterol, lipoprotein(a), glucose, insulin, and homeostatic model assessment for insulin resistance were measured. Repeated-measures regression models estimated the geometric means of each log-transformed biomarker by restricted maximum likelihood. A constant treatment effect across visits was used to estimate the overall effect, expressed as a ratio of geometric means, and was complemented with geometric means (95% CIs) by randomization group and corresponding ratios of geometric means (95% CI; HT vs placebo) at each visit.<br><br>RESULTS: During the intervention phase of the CEE-alone trial, randomization to CEE reduced LDL-C by 11% over 6 years (ratio of geometric means 0.89, 95% CI, 0.88-0.91, P<.001). The overall reduction in LDL-C was similar for CEE+MPA relative to placebo (ratio of geometric means 0.88, 95% CI, 0.86-0.89, P<.001). Relative to placebo, HDL-C and triglycerides were 13.0% and 7.0% higher with CEE and CEE+MPA, respectively. The homeostatic model assessment for insulin resistance decreased by 14.0% and 8.0% for CEE-alone and CEE+MPA trial participants, respectively. Relative to placebo, lipoprotein(a) decreased by 15.0% and 20.0% for participants randomized to CEE alone and CEE+MPA, respectively.<br><br>CONCLUSION: Lipoprotein(a), LDL-C, and homeostatic model assessment for insulin resistance were lower and HDL-C levels were higher for HT compared with placebo. Triglycerides increased in both the CEE and CEE+MPA trials, however. Future research should assess whether other progestogens attenuate the effect of estrogen on HDL-C. These results may be used to counsel younger menopausal women with bothersome symptoms who are deciding whether to initiate oral HT within the context of published effects of oral HT on rates of cardiovascular events.<br><br>CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00000611.}, }
@article {pmid40014323, year = {2025}, author = {Hirayama, AV and Bleakley, M}, title = {Competition for CD19 binding may accelerate CAR efficacy.}, journal = {Blood}, volume = {145}, number = {9}, pages = {902-903}, doi = {10.1182/blood.2024027469}, pmid = {40014323}, issn = {1528-0020}, }
@article {pmid40013681, year = {2025}, author = {Childers, CP and Petty, AM and Selzer, DJ and Senkowski, CK}, title = {Obesity and Work in Abdominal Surgery.}, journal = {Journal of the American College of Surgeons}, volume = {}, number = {}, pages = {}, doi = {10.1097/XCS.0000000000001367}, pmid = {40013681}, issn = {1879-1190}, abstract = {BACKGROUND: Recent analyses have shown that Modifier 22 does not reimburse surgeons for the increased work required to care for the most complex patients. New strategies are needed to identify patients that require additional work to create a financial system that ensures equitable access. Obesity has been identified as a growing and potentially reliable patient risk factor that could be used to identify cases that require additional work.<br><br>STUDY DESIGN: Using 2022 ACS NSQIP data, this study evaluated 10 common general surgery operations (appendectomy, cholecystectomy, colon/rectal operations, hernia repairs). The primary predictor was BMI category (Normal: 18.5-25, overweight: 25-29.9, class I obesity: 30-34.9, class II obesity: 35-39.9, class III obesity 40-49.9, extreme obesity >=50). Primary outcomes were operative time and composite measures of complications.<br><br>RESULTS: The final sample included 158,692 operations. Across the entire cohort, 22.2% were normal weight and 76.3% were overweight or obese. Overall, operative time was increased by 5.6% (95% CI 4.8-6.3%) for overweight, by 10.6% (CI 9.8-11.5%) for class I obesity, by 14.7% (CI 13.6-15.8%) for class II obesity, by 18.9% (CI 17.6-20.2%) for class III obesity, and by 26.8% (CI 14.1-29.6%) for extreme obesity compared to those with normal BMI. Obesity was associated with higher odds of any complication or serious complication, driven by wound complications, pulmonary emboli, and renal insufficiency.<br><br>CONCLUSION: Obesity is a growing challenge in abdominal surgery and is associated with increase operative time and risk of complications. The consistency of the magnitude of effect makes it an ideal target for a modifier or add-on code that could identify cases requiring additional work.}, }
@article {pmid40013392, year = {2025}, author = {Haney, M and Ashraf, A and Lake, KE and Strecker, L and Myers, KC and Towe, C and Walkup, L and Woods, J and Edwards, SL and Cooper, R and Lehmann, LE and Cisneros, GS and Freedman, JL and Baker, KS and Doherty, E and MacMillan, ML and Goldfarb, SB and Davies, SM and Koo, J and Groups, T}, title = {Community respiratory viruses are generally well-tolerated in hematopoietic stem cell transplant recipients: a brief report from the TRANSPIRE study.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2024.287107}, pmid = {40013392}, issn = {1592-8721}, abstract = {Not available.}, }
@article {pmid40009771, year = {2025}, author = {Collin, LJ and Cushing-Haugen, KL and Terry, KL and Goode, EL and Wu, AH and Harris, HR and Sasamoto, N and Cramer, DW and Modugno, F and Elishaev, E and Fu, Z and Moysich, KB and Fasching, PA and Pearce, CL and Menon, U and Gentry-Maharaj, A and Gayther, SA and Wentzensen, N and Goodman, MT and George, J and Talhouk, A and Anglesio, MS and Ramus, SJ and Bowtell, DD and Tworoger, SS and Schildkraut, JM and Webb, PM and Doherty, JA}, title = {Patterns of associations with epidemiologic factors by high grade serous ovarian cancer gene expression subtypes.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-24-1143}, pmid = {40009771}, issn = {1538-7755}, abstract = {BACKGROUND: Ovarian high-grade serous carcinomas (HGSC) comprise four distinct molecular subtypes based on mRNA expression patterns, with differential survival. Understanding risk factor associations is important to elucidate the etiology of HGSC. We investigated associations between different epidemiologic risk factors and HGSC molecular subtypes.<br><br>METHODS: We pooled data from 11 case-control studies with epidemiologic and tumor gene expression data from custom NanoString CodeSets developed through a collaboration within the Ovarian Tumor Tissue Analysis Consortium. The PrOTYPE validated NanoString-based 55 gene classifier was used to assign HGSC gene expression subtypes. We examined associations between epidemiologic factors and HGSC subtypes in 2,070 cases and 16,633 controls using multivariable-adjusted polytomous regression models.<br><br>RESULTS: Among the 2,070 HGSC cases, 556 (27%) were classified as C1.MES, 340 (16%) as C5.PRO, 538 (26%) as C2.IMM, and 636 (31%) as C4.DIF. Key factors, including oral contraceptive use, parity, breastfeeding, and family history of ovarian cancer, were similarly associated with all subtypes. Heterogeneity was observed for several factors. Former smoking (OR=1.25, 95%CI: 1.03, 1.51) and genital powder use (OR=1.42, 95%CI: 1.08, 1.86) were uniquely associated with C2.IMM. History of endometriosis was associated with C5.PRO (OR=1.46, 95%CI: 0.98, 2.16) and C4.DIF (OR=1.27, 95%CI: 0.94, 1.71) only. Family history of breast cancer (OR=1.44, 95%CI: 1.16, 1.78) and current smoking (OR=1.40, 95%CI: 1.11, 1.76) were associated with C4.DIF only.<br><br>CONCLUSIONS: This study observed heterogeneous associations of epidemiologic and modifiable factors with HGSC molecular subtypes.<br><br>IMPACT: The different patterns of associations may provide key information about the etiology of the four subtypes.}, }
@article {pmid40007996, year = {2025}, author = {Crotty, EE and Sato, AA and Abdelbaki, MS}, title = {Integrating MAPK pathway inhibition into standard-of-care therapy for pediatric low-grade glioma.}, journal = {Frontiers in oncology}, volume = {15}, number = {}, pages = {1520316}, pmid = {40007996}, issn = {2234-943X}, abstract = {Pediatric low-grade gliomas (pLGG) are a group of tumors largely driven by alterations in a single genetic pathway, known as the RAS-RAF-mitogen-activated protein kinase (MAPK) pathway. Recent biologic insights and therapeutic targeting of MAPK-alterations have dramatically shifted the treatment approach in pLGG. While chemotherapy remains front-line therapy for unresectable pLGG in most scenarios (with the notable exception of BRAF [V600E]-altered tumors), many patients recur following cytotoxic agents and require further treatment. Inhibitors of the MAPK pathway, primarily MEK and RAF kinase inhibitors, have emerged as effective and tolerable second-line or later therapy for pLGG. As familiarity with these targeted agents increases, their indications for use continue to expand and Phase 3 clinical trials investigating their utility in the front-line setting are ongoing. We have adopted mitigation strategies for their associated toxicities; skin toxicity, in particular, is now managed by prevention strategies and early dermatologic intervention. This review highlights current approaches for the clinical implementation of MEK and RAF kinase inhibitors for pLGG, focusing on the practical aspects of drug administration, toxicity management, response monitoring, and distribution to patients experiencing geographic or financial barriers to care. Additionally, we review important considerations for the off-label use of these agents while contemporaneous clinical trials assessing front-line efficacy are ongoing. We discuss the potential for more expansive or histology-agnostic tumor targeting using MEK inhibitors, harnessing their biologic relevance for other RAS-altered conditions.}, }
@article {pmid40006680, year = {2025}, author = {Shen, X and Korber, B and Spreng, RL and Sawant, SS and deCamp, A and McMillan, AS and Mathura, R and Zolla-Pazner, S and Pinter, A and Parks, R and Bowman, C and Sutherland, L and Scearce, R and Yates, NL and Montefiori, DC and Haynes, BF and Tomaras, GD}, title = {A Pentavalent HIV-1 Subtype C Vaccine Containing Computationally Selected gp120 Strains Improves the Breadth of V1V2 Region Responses.}, journal = {Vaccines}, volume = {13}, number = {2}, pages = {}, pmid = {40006680}, issn = {2076-393X}, support = {HHSN27201100016C/AI/NIAID NIH HHS/United States ; AI067854//Center for HIV/AIDS Vaccine Immunology/ ; AI100645//Duke Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery/ ; P30AI064518//Duke Center for AIDS Research/ ; }, abstract = {BACKGROUND: HIV-1 envelope (Env) variable loops 1 and 2 (V1V2) directed non-neutralizing antibodies were a correlate of decreased transmission risk in the RV144 vaccine trial. Thus, the elicitation and breadth of antibody responses against the V1V2 of HIV-1 Env are important considerations for HIV-1 vaccine candidates. The V1V2 region's highly variable nature and the extensive diversity of subtype C HIV-1 Envelopes (Envs) make the V1V2 response breadth a high priority for HIV-1 vaccine regimens aiming for V1V2-mediated protection in Southern Africa. Here, we determined whether the breadth of the anti-V1V2 vaccine response can be broadened by including HIV-1 Env strains computationally designed to enhance the coverage of subtype C V1V2 sequence diversity.<br><br>METHODS: Three subtype C Env strains were selected to maximize antibody binding coverage while complementing subtype C vaccine gp120s that were given in human clinical trials in South Africa, as well as to improve epitope accessibility. Humoral immunogenicity of a novel trivalent gp120 vaccine immunogen, a bivalent gp120 boost already in clinical trials (1086C and TV1), and a pentavalent (all five gp120s combined) were evaluated in a preclinical immunization study in guinea pigs. The pentavalent combination was further evaluated with alum versus glucopyranosyl lipid adjuvants formulated in squalene-in-water emulsion (GLA-SE) adjuvants in non-human primates. The breadth of the anti-V1V2 response was assessed using an array of cross-subtype variable loops 1&amp;2 (V1V2) scaffold proteins and linear V2 peptides.<br><br>RESULTS: The breadth of the IgG response against V1V2 antigens of the trivalent and pentavalent groups was comparable, and both were greater than the breadth of the bivalent group. Linear epitope mapping showed that two linear epitopes in V2 were targeted by the vaccinated animals: the V2 hotspot focused at [169]K that potentially correlated with decreased HIV-1 risk in RV144 and the V2.2 site ([179]LDV/I[181]) that is part of the integrin &#x3b1;4&#x3b2;7 binding site. The bivalent vaccine elicited a significantly higher magnitude of binding to the V2 hotspot compared to the trivalent vaccine whereas the trivalent vaccine elicited significantly higher binding to the V2.2 epitope compared to the bivalent vaccine, while the pentavalent recognized both regions.<br><br>CONCLUSIONS: These results demonstrate that the three new computationally selected subtype C Envs successfully complemented 1086C and TV1 for broader V1V2 antibody responses, and, in concert with adjuvants that stimulate V1V2 responses, can be considered as part of a rationale immunogen design to improve V1V2 IgG coverage in future vaccine trials in South Africa.}, }
@article {pmid39990376, year = {2025}, author = {Wang, Y and Gornalusse, GG and Siegel, DA and Barbehenn, A and Hoh, R and Martin, J and Hecht, F and Pilcher, C and Semenova, L and Murdoch, DM and Margolis, DM and Levy, CN and Jerome, KR and Rudin, CD and Hladik, F and Deeks, SG and Lee, SA and Browne, EP}, title = {NF-κB dependent gene expression and plasma IL-1β, TNFα and GCSF drive transcriptomic diversity and CD4:CD8 ratio in people with HIV on ART.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39990376}, issn = {2692-8205}, support = {R01 DA054994/DA/NIDA NIH HHS/United States ; K23 GM112526/GM/NIGMS NIH HHS/United States ; R01 AI143381/AI/NIAID NIH HHS/United States ; R01 AI184122/AI/NIAID NIH HHS/United States ; KL2 TR002317/TR/NCATS NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; UM1 AI164567/AI/NIAID NIH HHS/United States ; UM1 AI126623/AI/NIAID NIH HHS/United States ; }, abstract = {Despite antiretroviral therapy (ART), people with HIV (PWH) on ART experience higher rates of morbidity and mortality vs. age-matched HIV negative controls, which may be driven by chronic inflammation due to persistent virus. We performed bulk RNA sequencing (RNA-seq) on peripheral CD4+ T cells, as well as quantified plasma immune marker levels from 154 PWH on ART to identify host immune signatures associated with immune recovery (CD4:CD8) and HIV persistence (cell-associated HIV DNA and RNA). Using a novel dimension reduction tool - Pairwise Controlled Manifold Approximation (PaCMAP), we defined three distinct participant transcriptomic clusters. We found that these three clusters were largely defined by differential expression of genes regulated by the transcription factor NF-κB. While clustering was not associated with HIV reservoir size, we observed an association with CD4:CD8 ratio, a marker of immune recovery and prognostic factor for mortality in PWH on ART. Furthermore, distinct patterns of plasma IL-1β, TNF-α and GCSF were also strongly associated with the clusters, suggesting that these immune markers play a key role in CD4+ T cell transcriptomic diversity and immune recovery in PWH on ART. These findings reveal novel subgroups of PWH on ART with distinct immunological characteristics, and define a transcriptional signature associated with clinically significant immune parameters for PWH. A deeper understanding of these subgroups could advance clinical strategies to treat HIV-associated immune dysfunction.}, }
@article {pmid39975454, year = {2025}, author = {Xie, T and Richman, H and Gao, J and Matsen, FA and Zhang, C}, title = {PhyloVAE: Unsupervised Learning of Phylogenetic Trees via Variational Autoencoders.}, journal = {ArXiv}, volume = {}, number = {}, pages = {}, pmid = {39975454}, issn = {2331-8422}, support = {R01 AI162611/AI/NIAID NIH HHS/United States ; }, abstract = {Learning informative representations of phylogenetic tree structures is essential for analyzing evolutionary relationships. Classical distance-based methods have been widely used to project phylogenetic trees into Euclidean space, but they are often sensitive to the choice of distance metric and may lack sufficient resolution. In this paper, we introduce phylogenetic variational autoencoders (PhyloVAEs), an unsupervissed learning framework designed for representation learning and generative modeling of tree topologies. Leveraging an efficient encoding mechanism inspired by autoregressive tree topology generation, we develop a deep latent-variable generative model that facilitates fast, parallelized topology generation. PhyloVAE combines this generative model with a collaborative inference model based on learnable topological features, allowing for high-resolution representations of phylogenetic tree samples. Extensive experiments demonstrate PhyloVAE's robust representation learning capabilities and fast generation of phylogenetic tree topologies.}, }
@article {pmid39975229, year = {2025}, author = {Shi, Z and Tsuge, M and Collier, N and Takeuchi, Y and Uchida, T and Rutter, CM and Teraoka, Y and Uprichard, S and Ishida, Y and Tateno, C and Ozik, J and Dahari, H and Chayama, K}, title = {Modeling of hepatitis B virus infection spread in primary human hepatocytes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39975229}, issn = {2692-8205}, support = {R01 AI144112/AI/NIAID NIH HHS/United States ; R01 AI146917/AI/NIAID NIH HHS/United States ; }, abstract = {Chronic hepatitis B virus (HBV) infection poses a significant global health threat, causing severe liver diseases including cirrhosis and hepatocellular carcinoma. We characterized HBV DNA kinetics in primary human hepatocytes (PHH) over 32 days post-inoculation (pi) and used agent-based modeling (ABM) to gain insights into HBV lifecycle and spread. Parallel PHH cultures were mock-treated or HBV entry inhibitor Myr-preS1 (6.25 μg/mL) was initiated 24h pi. In untreated PHH, 3 viral DNA kinetic patterns were identified: (1) an initial decline, followed by (2) rapid amplification, and (3) slower amplification/accumulation. In the presence of Myr-preS1, viral DNA and infected cell numbers in phase 3 were effectively blocked, with minimal to no increase. This suggests that phase 2 represents viral amplification in initially infected cells, while phase 3 corresponds to viral spread to naïve cells. The ABM reproduced well the HBV kinetic patterns observed and predicted that the viral eclipse phase lasts between 18 and 38 hours. After the eclipse phase, the viral production rate increases over time, starting with a slow production cycle of 1 virion per day, which gradually accelerates to 1 virion per hour after 3 days. Approximately 4 days later, virion production reaches a steady state production rate of 4 virions/hour. The estimated median efficacy of Myr-preS1 in blocking HBV spread was 91% (range: 90-92%). The HBV kinetics and the predicted estimates of the HBV eclipse phase duration and HBV production cycles in PHH are similar of those predicted in uPA/SCID mice with human livers.}, }
@article {pmid39975131, year = {2025}, author = {Barrero, DJ and Hedouin, S and Mao, Y and Asbury, CL and Stergachis, A and O'Toole, E and Biggins, S}, title = {Centromeres in the thermotolerant yeast K. marxianus mediate attachment to a single microtubule.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39975131}, issn = {2692-8205}, support = {DP5 OD029630/OD/NIH HHS/United States ; R35 GM134842/GM/NIGMS NIH HHS/United States ; R35 GM149357/GM/NIGMS NIH HHS/United States ; }, abstract = {Eukaryotic chromosome segregation requires spindle microtubules to attach to chromosomes through kinetochores. The chromosomal locus that mediates kinetochore assembly is the centromere and is epigenetically specified in most organisms by a centromeric histone H3 variant called CENP-A. An exception to this is budding yeast which have short, sequenced-defined point centromeres. In S. cerevisiae, a single CENP-A nucleosome is formed at the centromere and is sufficient for kinetochore assembly. The thermophilic budding yeast Kluyveromyces marxianus also has a point centromere but its length is nearly double the S. cerevisiae centromere and the number of centromeric nucleosomes and kinetochore attachment sites is unknown. Purification of native kinetochores from K. marxianus yielded a mixed population, with one subpopulation that appeared to consist of doublets, making it unclear whether K. marxianus shares the same attachment architecture as S. cerevisiae. Here, we demonstrate that though the doublet kinetochores have a functional impact on kinetochore strength, kinetochore localization throughout the cell cycle appears conserved between these two yeasts. In addition, whole spindle electron tomography demonstrates that a single microtubule binds to each chromosome. Single-molecule nucleosome mapping analysis suggests the presence of a single centromeric nucleosome. Taken together, we propose that the K. marxianus point centromere assembles a single centromeric nucleosome that mediates attachment to one microtubule.}, }
@article {pmid39973981, year = {2025}, author = {Gustav, M and van Treeck, M and Reitsam, NG and Carrero, ZI and Loeffler, CML and Meneghetti, AR and Märkl, B and Boardman, LA and French, AJ and Goode, EL and Gsur, A and Brezina, S and Gunter, MJ and Murphy, N and Hönscheid, P and Sperling, C and Foersch, S and Steinfelder, R and Harrison, T and Peters, U and Phipps, A and Kather, JN}, title = {Assessing Genotype-Phenotype Correlations with Deep Learning in Colorectal Cancer: A Multi-Centric Study.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39973981}, support = {75N92021D00002/HL/NHLBI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA107333/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; U01 CA137088/CA/NCI NIH HHS/United States ; P20 CA252733/CA/NCI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; HHSN268201700006C/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; HHSN261201000032C/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Deep Learning (DL) has emerged as a powerful tool to predict genetic biomarkers directly from digitized Hematoxylin and Eosin (H&amp;E) slides in colorectal cancer (CRC). However, few studies have systematically investigated the predictability of biomarkers beyond routinely available alterations such as microsatellite instability (MSI), and BRAF and KRAS mutations.<br><br>METHODS: Our primary dataset comprised H&amp;E slides of CRC tumors across five cohorts totaling 1,376 patients who underwent comprehensive panel sequencing, with an additional 536 patients from two public datasets for validation. We developed a DL model using a single transformer model to predict multiple genetic alterations directly from the slides. The model's performance was compared against conventional single-target models, and potential confounders were analyzed.<br><br>FINDINGS: The multi-target model was able to predict numerous biomarkers from pathology slides, matching and partly exceeding single-target transformers. The Area Under the Receiver Operating Characteristic curve (AUROC, mean &#xb1; std) on the primary external validation cohorts was: BRAF (0&#xb7;78 &#xb1; 0&#xb7;01), hypermutation (0&#xb7;88 &#xb1; 0&#xb7;01), MSI (0&#xb7;93 &#xb1; 0&#xb7;01), RNF43 (0&#xb7;86 &#xb1; 0&#xb7;01); this biomarker predictability was mirrored across metrics and co-occurrence analyses. However, biomarkers with high AUROCs largely correlated with MSI, with model predictions depending considerably on MSI-associated morphology upon pathological examination.<br><br>INTERPRETATION: Our study demonstrates that multi-target transformers can predict the biomarker status for numerous genetic alterations in CRC directly from H&amp;E slides. However, their predictability is mainly associated with MSI phenotype, despite indications of slight biomarker-inherent contributions to a phenotype. Our findings underscore the need to analyze confounders in AI-based oncology biomarkers. To enable this, we developed a validated model applicable to other cancers and larger, diverse datasets.<br><br>FUNDING: The German Federal Ministry of Health, the Max-Eder-Programme of German Cancer Aid, the German Federal Ministry of Education and Research, the German Academic Exchange Service, and the EU.}, }
@article {pmid39786430, year = {2025}, author = {Lee, SM and Hamid, O and Jotte, R and Zakharia, Y and Medina, T and Gillespie-Twardy, A and Mehmi, I and Chandra, S and Watson, G and Ward, P and Chaney, M and Lu, H and Berndt, J and O'Connor, BP and Rathi, K and Shaikh, E and Cowey, CL}, title = {Phase II Open-Label Trial of Brentuximab Vedotin with Pembrolizumab in PD-1-Pretreated Metastatic Non-Small Cell Lung Cancer and Metastatic Cutaneous Melanoma.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {31}, number = {5}, pages = {848-859}, doi = {10.1158/1078-0432.CCR-24-1478}, pmid = {39786430}, issn = {1557-3265}, support = {//Pfizer Foundation/ ; }, mesh = {Humans ; *Antibodies, Monoclonal, Humanized/administration &amp; dosage/therapeutic use/adverse effects ; Female ; Male ; Middle Aged ; *Melanoma/drug therapy/pathology/mortality ; Aged ; *Carcinoma, Non-Small-Cell Lung/drug therapy/pathology/mortality ; Adult ; *Skin Neoplasms/drug therapy/pathology/mortality ; *Lung Neoplasms/drug therapy/pathology/secondary/mortality ; Aged, 80 and over ; *Brentuximab Vedotin/therapeutic use/administration &amp; dosage ; *Programmed Cell Death 1 Receptor/antagonists &amp; inhibitors ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Melanoma, Cutaneous Malignant ; }, abstract = {PURPOSE: Brentuximab vedotin (BV) is hypothesized to selectively deplete T regulatory cells that express CD30 and resensitize tumors to anti-PD-1 therapy. This study evaluated responses to BV + pembrolizumab after PD-1 therapy and explored corresponding biomarkers.<br><br>PATIENTS AND METHODS: A total of 55 patients with metastatic non-small cell lung cancer and 58 patients with metastatic cutaneous melanoma received &#x2265;1 dose of BV + pembrolizumab. Patients had received a median of 2.0 prior lines of systemic therapies (range, 1-7). The primary endpoint was confirmed objective response rate (ORR). Exploratory endpoints included overall survival (OS) and biomarker analysis in blood and tumor.<br><br>RESULTS: For the secondary refractory metastatic non-small cell lung cancer cohort (RECIST v1.1), the ORR was 14%, median progression-free survival (PFS) was 5.85 months, and median OS was 14.4 months. For the secondary refractory metastatic cutaneous melanoma cohort (immune RECIST), the ORR was 24%, median PFS was 4.44 months, and median OS was 21.9 months. Overall, the median duration of OS follow-up was 17.2 months (95% confidence interval, 14.62-22.87). No new safety signals were identified. No treatment-related grade 5 toxicity was seen. Longitudinal immune phenotyping in peripheral blood demonstrated a transient decrease in T regulatory cells. Paired tumor biopsies from baseline and cycle 3 day 1 showed a trend of increased CD8 T-cell infiltration, especially in responding patients.<br><br>CONCLUSIONS: BV + pembrolizumab in solid tumor malignancies resulted in clinically meaningful, durable responses with encouraging OS and PFS rates supportive of the immunomodulatory activity of this combination. Stronger antitumor activity was observed in secondary refractory cohorts. The safety profile of this combination was consistent with the individual drug risk profiles.}, }
@article {pmid40006664, year = {2025}, author = {Gwin, WR and Salazar, LG and Dai, JY and Higgins, D and Coveler, AL and Childs, JS and Blancas, R and Dang, Y and Reichow, J and Slota, M and Lu, H and Disis, ML}, title = {A Phase II Study of Denileukin Diftitox in Patients with Advanced Treatment Refractory Breast Cancer.}, journal = {Vaccines}, volume = {13}, number = {2}, pages = {}, pmid = {40006664}, issn = {2076-393X}, abstract = {Background/Objectives: Regulatory T cells (Treg) suppress immunity in the tumor microenvironment, are linked to poor prognosis across breast cancer subtypes, and suppress the cytolytic function of cytotoxic CD8+ T cells. Denileukin diftitox, a diphtheria toxin (DT)/IL-2 fusion protein, targets and depletes Tregs. This Phase II study aimed to assess the safety of denileukin diftitox and its effect on Tregs and tumor growth in patients with advanced breast cancer. Methods: This single-arm Phase II study of denileukin diftitox enrolled patients with refractory stage IV breast cancer. Patients received denileukin diftitox 18 mcg/kg/day IV for Days 1-5 every 21 days for up to six cycles. Toxicity was assessed using CTCAE v3.0 and tumor response was evaluated per RECIST criteria. Blood samples were collected to analyze Tregs by flow cytometry and anti-DT antibodies by ELISA. Results: Fifteen patients with stage IV breast cancer were enrolled. Four patients completed all planned denileukin diftitox infusions and achieved stable disease (27%, 95% CI [0.08, 0.55]). Two patients (13%) discontinued due to toxicity, and nine patients (60%) discontinued due to progressive disease. Eleven patients experienced at least one grade 3 or 4 adverse event. Although there was a general reduction in peripheral blood Tregs, the difference in CD4+CD25+FOXP3+ Tregs levels post-treatment was not statistically significant (p = 0.10). Six patients (40%) achieved ≥25% reductions in Tregs. A significant increase in anti-DT IgG antibodies was observed post-treatment (p < 0.005). Conclusions: Denileukin diftitox demonstrated moderate toxicity in this advanced breast cancer cohort. Denileukin diftitox modulated regulatory T cells. However, the majority of patients experienced disease progression in the study.}, }
@article {pmid40004846, year = {2025}, author = {Costa, BA and Dima, D and Mark, T and Sadek, NL and Ijioma, S and Ray, D and Goel, U and Dranitsaris, G and Sheng, T and Moshier, E and Mouhieddine, TH and Khouri, J and Rossi, A}, title = {Impact of Prior Selinexor Exposure on Outcomes of Chimeric Antigen Receptor T-Cell Therapy for Relapsed/Refractory Multiple Myeloma: An Exploratory Analysis.}, journal = {Journal of clinical medicine}, volume = {14}, number = {4}, pages = {}, pmid = {40004846}, issn = {2077-0383}, support = {NA//Karyopharm Therapeutics/ ; }, abstract = {Background/Objectives: Chimeric antigen receptor T-cell therapy (CAR-T) has become a key treatment option for relapsed/refractory multiple myeloma (RRMM), but factors impairing T-cell fitness may diminish efficacy. Our exploratory analysis aimed to evaluate the impact of prior treatment with a selinexor-containing regimen on CAR-T outcomes for RRMM patients. Methods: Data for this retrospective cohort study were sourced from electronic medical records at two US academic centers. Kaplan-Meier estimates assessed duration of response (DOR), progression-free survival (PFS), and overall survival (OS), reported as medians with interquartile ranges (IQRs). Cox proportional hazards regression analyzed factors potentially associated with PFS and OS, reported as hazard ratios (HRs) with 95% confidence intervals (CIs). Results: Among 45 patients exposed to selinexor before undergoing BCMA-directed CAR-T, median therapy line numbers for selinexor use and CAR-T were 7 and 9, respectively, with 24.4% receiving selinexor as part of bridging. At median follow-up of 68 months, median PFS and OS post CAR-T were 8.0 (IQR 3.1-39.5) and 35.9 (IQR 14.2-NR) months, respectively. Overall response rate to CAR-T was 89%, with a median DOR of 8.1 months (IQR 2.9-39.0). In our multivariable model, patients who received a selinexor-based regimen in the line of therapy preceding CAR-T showed a trend toward reduced risk of death (HR = 0.08; 95% CI 0.02-0.46) and/or disease progression (HR = 0.40; 95% CI 0.14-1.09). Conclusions: Prior selinexor exposure does not appear to compromise CAR-T outcomes in heavily pretreated RRMM, suggesting potential T-cell sparing. Our findings warrant larger, prospective studies to determine whether preemptive selinexor treatment can optimize CAR-T efficacy.}, }
@article {pmid40000903, year = {2025}, author = {Itkin, T and Houghton, S and Schreiner, R and Lin, Y and Badwe, CR and Voisin, V and Murison, A and Seyedhassantehrani, N and Kaufmann, KB and Garcia-Prat, L and Booth, GT and Geng, F and Liu, Y and Gomez-Salinero, JM and Shieh, JH and Redmond, D and Xiang, JZ and Josefowicz, SZ and Trapnell, C and Pietras, EM and Spencer, JA and Levine, R and Xiao, W and Zangi, L and Hadland, B and Dick, JE and Xie, SZ and Rafii, S}, title = {Transcriptional activation of regenerative hematopoiesis via microenvironmental sensing.}, journal = {Nature immunology}, volume = {}, number = {}, pages = {}, pmid = {40000903}, issn = {1529-2916}, abstract = {Transition between activation and quiescence states in hematopoietic stem and progenitor cells (HSPCs) is tightly governed by cell-intrinsic means and microenvironmental co-adaptation. Although this balance is fundamental for lifelong hematopoiesis and immunity, the underlying molecular mechanisms remain poorly defined. Multimodal analysis divulging differential transcriptional activity between distinct HSPC states indicates the presence of Fli-1 transcription factor binding motif in activated hematopoietic stem cells. We reveal that Fli-1 activity is essential during regenerative hematopoiesis in mice. Fli-1 directs activation programs while priming cellular sensory and output machineries, enabling HSPCs co-adoptability with a stimulated vascular niche through propagation of niche-derived angiocrine Notch1 signaling. Constitutively induced Notch1 signaling is sufficient to recuperate functional hematopoietic stem cells impairments in the absence of Fli-1, without leukemic transformation. Applying FLI-1 transient modified-mRNA transduction into latent adult human mobilized HSPCs, enables their niche-mediated expansion and superior engraftment capacities. Thus, decryption of stem cell activation programs offers valuable insights for immunological regenerative medicine.}, }
@article {pmid39999848, year = {2025}, author = {Ugalde-Morales, E and Wilf, R and Pluta, J and Ploner, A and Fan, M and Damra, M and Aben, KK and Anson-Cartwright, L and Chen, C and Cortessis, VK and Daneshmand, S and Ferlin, A and Gamulin, M and Gietema, JA and Gonzalez-Niera, A and Grotmol, T and Hamilton, RJ and Harland, M and Haugen, TB and Hauser, R and Hildebrandt, MAT and Karlsson, R and Kiemeney, LA and Kim, J and Lessel, D and Lothe, RA and Loveday, C and Chanock, SJ and McGlynn, KA and Meijer, C and Nead, KT and Nsengimana, J and Popovic, M and Rafnar, T and Richiardi, L and Rocca, MS and Schwartz, SM and Skotheim, RI and Stefansson, K and Stewart, DR and Turnbull, C and Vaughn, DJ and Winge, SB and Zheng, T and Monteiro, AN and Almstrup, K and Kanetsky, PA and Nathanson, KL and Wiklund, F and , }, title = {Identification of genes associated with testicular germ cell tumor susceptibility through a transcriptome-wide association study.}, journal = {American journal of human genetics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajhg.2025.01.022}, pmid = {39999848}, issn = {1537-6605}, abstract = {Transcriptome-wide association studies (TWASs) have the potential to identify susceptibility genes associated with testicular germ cell tumors (TGCTs). We conducted a comprehensive TGCT TWAS by integrating genome-wide association study (GWAS) summary data with predicted expression models from normal testis, TGCT tissues, and a cross-tissue panel that encompasses shared regulatory features across 22 normal tissues, including the testis. Gene associations were evaluated while accounting for variant-level effects from GWASs, followed by fine-mapping analyses in regions exhibiting multiple TWAS signals, and finally supplemented by colocalization analysis. Expression and protein patterns of identified TWAS genes were further examined in relevant tissues. Our analysis tested 19,805 gene-disease links, revealing 165 TGCT-associated genes with a false discovery rate of less than 0.01. We prioritized 46 candidate genes by considering GWAS-inflated signals, correlations between neighboring genes, and evidence of colocalization. Among these, 23 genes overlap with 22 GWAS loci, with 7 being associations not previously implicated in TGCT risk. Additionally, 23 genes located within 21 loci are at least 1 Mb away from published GWAS index variants. The 46 prioritized genes display expression levels consistent with expected expression levels in human gonadal cell types and precursor tumor cells and significant enrichment in TGCTs. Additionally, immunohistochemistry revealed protein-level accumulation of two candidate genes, ARID3B and GINM1, in both precursor and tumor cells. These findings enhance our understanding of the genetic predisposition to TGCTs and underscore the importance of further functional investigations into these candidate genes.}, }
@article {pmid39996762, year = {2025}, author = {Gang, M and Othus, M and Walter, RB}, title = {Significance of Measurable Residual Disease in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia.}, journal = {Cells}, volume = {14}, number = {4}, pages = {}, pmid = {39996762}, issn = {2073-4409}, support = {T32-HL007093//NIH/NHLBI/ ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/methods ; *Leukemia, Myeloid, Acute/therapy ; *Neoplasm, Residual ; *Transplantation, Homologous ; }, abstract = {Allogeneic hematopoietic cell transplantation (HCT) remains an important curative-intent treatment for many patients with acute myeloid leukemia (AML), but AML recurrence after allografting is common. Many factors associated with relapse after allogeneic HCT have been identified over the years. Central among these is measurable ("minimal") residual disease (MRD) as detected by multiparameter flow cytometry, quantitative polymerase chain reaction, and/or next-generation sequencing. Demonstration of a strong, independent prognostic role of pre- and early post-HCT MRD has raised hopes MRD could also serve as a predictive biomarker to inform treatment decision-making, with emerging data indicating the potential value to guide candidacy assessment for allografting as a post-remission treatment strategy, the selection of conditioning intensity, use of small molecule inhibitors as post-HCT maintenance therapy, and preemptive infusion of donor lymphocytes. Monitoring for leukemia recurrence after HCT and surrogacy for treatment response are other considerations for the clinical use of MRD data. In this review, we will outline the current landscape of MRD as a biomarker for patients with AML undergoing HCT and discuss areas of uncertainty and ongoing research.}, }
@article {pmid39996711, year = {2025}, author = {Morishita, T and Martin, PJ and Inamoto, Y}, title = {Treatment Response in Individual Organs Affected by Chronic Graft-Versus-Host Disease.}, journal = {Cells}, volume = {14}, number = {4}, pages = {}, pmid = {39996711}, issn = {2073-4409}, support = {22K08517//Japan Society for the Promotion of Science/ ; }, mesh = {*Graft vs Host Disease/therapy ; Humans ; Chronic Disease ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Treatment Outcome ; Organ Specificity ; }, abstract = {Chronic graft-versus-host disease (GVHD) occurs in 30-70% of patients after allogeneic hematopoietic cell transplantation (HCT) and increases the risks of morbidity and mortality. Systemic corticosteroids are the standard initial treatment, but one-third of patients require subsequent treatment with other systemic agents. Treatment decisions are often based on physicians' experience. The expected treatment response rates in specific organs affected by chronic GVHD may inform such decisions. In this review, we identify 20 studies reporting treatment response rates in individual organs according to objective criteria, summarize the results, discuss the caveats in data interpretation, identify the unmet needs, and suggest future directions in the field. For cutaneous sclerosis, we observed large discrepancies in organ response rates according to the current NIH criteria and patient-reported improvement, highlighting the need for better measurement tools. High response rates for lung involvement with certain novel drugs deserve further investigation.}, }
@article {pmid39994463, year = {2025}, author = {Banerjee, R and Fritz, AR and Akhtar, OS and Freeman, CL and Cowan, AJ and Shah, N and Landau, HJ and Kumar, SK and Vogl, DT and Efebera, YA and McCarthy, PL and Vesole, DH and Mendizabal, A and Krishnan, AY and Somlo, G and Stadtmauer, EA and Pasquini, MC}, title = {Urine-free response criteria predict progression-free survival in multiple myeloma: a post hoc analysis of BMT CTN 0702.}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, pmid = {39994463}, issn = {1476-5551}, }
@article {pmid39992626, year = {2025}, author = {Krishnamoorthy, GP and Glover, AR and Untch, BR and Sigcha-Coello, N and Xu, B and Vukel, D and Liu, Y and Tiedje, V and Pineda, JMB and Berman, K and Tamarapu, PP and Acuña-Ruiz, A and Saqcena, M and de Stanchina, E and Boucai, L and Ghossein, RA and Knauf, JA and Abdel-Wahab, O and Bradley, RK and Fagin, JA}, title = {RBM10 loss promotes metastases by aberrant splicing of cytoskeletal and extracellular matrix mRNAs.}, journal = {The Journal of experimental medicine}, volume = {222}, number = {5}, pages = {}, pmid = {39992626}, issn = {1540-9538}, support = {R01 CA50706-31/NH/NIH HHS/United States ; R01 CA255211/CA/NCI NIH HHS/United States ; RG183080//National Health and Medical Research Council/ ; //Marie-Jos&#xe9;e and Henry R. Kravis Center for Molecular Oncology/ ; R01 CA050706/CA/NCI NIH HHS/United States ; P30 CA008748-58/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; R01 CA249663/CA/NCI NIH HHS/United States ; //Cycle for Survival/ ; //Royal Australasian College of Surgeons Foundation/ ; }, mesh = {Animals ; Humans ; Mice ; *Extracellular Matrix/metabolism ; *RNA-Binding Proteins/metabolism/genetics ; *rac1 GTP-Binding Protein/metabolism/genetics ; *Neoplasm Metastasis ; *Hyaluronan Receptors/metabolism/genetics ; *RNA, Messenger/genetics/metabolism ; Cytoskeleton/metabolism ; Thyroid Neoplasms/genetics/pathology/metabolism ; Cell Line, Tumor ; RNA Splicing/genetics ; Exons/genetics ; Alternative Splicing/genetics ; Gene Expression Regulation, Neoplastic ; Proto-Oncogene Proteins p21(ras)/genetics/metabolism ; Cell Movement/genetics ; }, abstract = {RBM10 modulates transcriptome-wide cassette exon splicing. Loss-of-function RBM10 mutations are enriched in thyroid cancers with distant metastases. Analysis of transcriptomes and genes mis-spliced by RBM10 loss showed pro-migratory and RHO/RAC signaling signatures. RBM10 loss increases cell velocity. Cytoskeletal and ECM transcripts subject to exon inclusion events included vinculin (VCL), tenascin C (TNC), and CD44. Knockdown of the VCL exon inclusion transcript in RBM10-null cells reduced cell velocity, whereas knockdown of TNC and CD44 exon inclusion isoforms reduced invasiveness. RAC1-GTP levels were increased in RBM10-null cells. Mouse HrasG12V/Rbm1OKO thyrocytes develop metastases that are reversed by RBM10 expression or by combined knockdown of VCL, CD44, and TNC inclusion isoforms. Thus, RBM10 loss generates exon inclusion in transcripts regulating ECM-cytoskeletal interactions, leading to RAC1 activation and metastatic competency. Moreover, a CRISPR-Cas9 screen for synthetic lethality with RBM10 loss identified NFκB effectors as central to viability, providing a therapeutic target for these lethal thyroid cancers.}, }
@article {pmid39991196, year = {2025}, author = {Jefferson, JA and Chen, K and Hingorani, S and Malik, AB and Tykodi, SS and Keller, KH and Huang, Y and Smith, KD and Reed, RC and Weins, A and Akilesh, S}, title = {Genetic and Iatrogenic Defects in Peripheral Tolerance Associated with Anti-Nephrin Antibody-Associated Minimal Change Disease.}, journal = {Glomerular diseases}, volume = {5}, number = {1}, pages = {74-83}, pmid = {39991196}, issn = {2673-3633}, abstract = {INTRODUCTION: Minimal change disease (MCD) is a common cause of nephrotic syndrome in children and adults. Immune dysregulation is a contributor, but the relative roles of individual components of the immune system in MCD pathogenesis remain unclear.<br><br>CASE PRESENTATION: Here, we present 2 patients with defects in immune tolerance mechanisms that developed MCD associated with anti-nephrin antibodies. The first patient had a pathogenic deletion in FOXP3, leading to reduced regulatory T cells. Serum could not be obtained from this patient during the active phase of MCD to directly establish the presence of anti-nephrin antibodies. However, this patient demonstrated IgG dusting over podocyte cell bodies by immunofluorescence microscopy, as well as colocalization of IgG with nephrin in confocal microscopy. The second patient developed MCD in the context of immune checkpoint inhibitor treatment for metastatic carcinoma. Anti-nephrin antibodies were detected in this patient during active disease. The patient's kidney biopsy also showed evidence of binding of anti-nephrin antibodies within the glomeruli.<br><br>CONCLUSION: These cases demonstrate that genetic and iatrogenic mechanisms of breakdown in peripheral tolerance can lead to MCD.}, }
@article {pmid39990276, year = {2025}, author = {Goel, U and Zanwar, S and Cowan, AJ and Banerjee, R and Khouri, J and Dima, D}, title = {Ciltacabtagene Autoleucel for the Treatment of Relapsed/Refractory Multiple Myeloma: Efficacy, Safety, and Place in Therapy.}, journal = {Cancer management and research}, volume = {17}, number = {}, pages = {357-372}, pmid = {39990276}, issn = {1179-1322}, abstract = {Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) are two chimeric antigen receptor T cell (CAR T) therapies approved for use in patients with relapsed/refractory multiple myeloma (MM). Initially approved for late line MM (>4 prior lines), these were recently approved for use in MM with 1-2 prior lines of therapy in April 2024. As their use outside of the pivotal clinical trials continues to expand, it is important to critically evaluate the safety and efficacy of these therapies. Further, it is important to identify patients that would be most likely to benefit from the use of CAR T in earlier lines of therapy. Cilta-cel was initially studied in the phase-I LEGEND-2 study, followed by CARTITUDE-1 and CARTITUDE-4 trials, demonstrating remarkable efficacy. A recent large real-world study also demonstrated similar efficacy, in a mostly pivotal trial ineligible patient population. Based on these impressive results, cilta-cel is currently being studied in trials for newly diagnosed as well as smoldering multiple myeloma. Cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) are known toxicities of cilta-cel (and other CAR Ts), however movement and cognitive disorders (delayed neurotoxicity) and second primary malignancies are an evolving concern. In this article we discuss safety and efficacy data from existing cilta-cel studies. We propose that all patients with MM who have received ≥4 prior lines of therapy should be considered for CAR T. Earlier line use of CAR T should be restricted to patients with a high-risk disease phenotype (eg, functional high-risk disease). This disease phenotype has historically shown poor outcomes with standard triplet regimens and would be most likely to benefit from earlier use of CAR T: considering the availability of other safe and highly effective therapies, and potential high-risk toxicities of CAR T.}, }
@article {pmid39975072, year = {2025}, author = {Radford, CE and Bloom, JD}, title = {Comprehensive maps of escape mutations from antibodies 10-1074 and 3BNC117 for Envs from two divergent HIV strains.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39975072}, issn = {2692-8205}, support = {R01 AI140891/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; U01 AI169385/AI/NIAID NIH HHS/United States ; }, abstract = {Antibodies capable of neutralizing many strains of HIV are being explored as prophylactic and therapeutic agents, but viral escape mutations pose a major challenge. Efforts have been made to experimentally define the escape mutations from specific antibodies in specific viral strains, but it remains unclear how much the effects of mutations on neutralization differ among HIV strains. Here, we use pseudovirus deep mutational scanning to comprehensively map escape mutations from the V3 loop targeting antibody 10-1074 and the CD4-binding site targeting antibody 3BNC117 for both a clade A (BF520) and a clade B (TRO.11) HIV Envelope (Env). Mutations that escape neutralization by antibody 10-1074 are largely similar for the two Envs, but mutations that escape 3BNC117 differ greatly between Envs. Some differences in the effects of mutations on escape between Envs can be explained by strain-to-strain variation in mutational tolerance or glycosylation patterns, but other mutations have different effects on escape for unclear reasons. Overall, the extent that measurements of mutational effects on antibody neutralization can be generalized across HIV strains differs among antibodies.}, }
@article {pmid39974143, year = {2025}, author = {Park, MS and Kumar, RD and Ovadiuc, C and Folta, A and McEwen, AE and Snyder, A and Fowler, DM and Rubin, AF and Shirts, BH and Starita, LM and Stergachis, AB}, title = {Insights on improving accessibility and usability of functional data to unlock its potential for variant interpretation.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39974143}, support = {R01 HG013025/HG/NHGRI NIH HHS/United States ; UM1 HG011969/HG/NHGRI NIH HHS/United States ; }, abstract = {INTRODUCTION: Variant-level functional data is a core component of clinical variant classification and can aid in reinterpreting variants of uncertain significance (VUS). However, the usage of functional data by genetics professionals is currently unknown.<br><br>METHODS: An online survey was developed and distributed in spring of 2024 to individuals actively engaged in variant interpretation. Quantitative and qualitative methods were used to assess responses.<br><br>RESULTS: 190 eligible individuals responded, with 93% reporting interpreting 26 or more variants per year. The median respondent reported 11-20 years of experience. The most common professional roles were laboratory medical geneticists (23%) and variant review scientists (23%). 77% reported using functional data for variant interpretation in a clinical setting and overall respondents felt confident in assessing functional data. However, 67% indicated that functional data for variants of interest was rarely or never available, and 91% considered insufficient quality metrics or confidence in the accuracy of data as barriers to its use. 94% of respondents noted that better access to primary functional data and standardized interpretation of functional data would improve usage. Respondents also indicated that handling conflicting functional data is a common challenge in variant interpretation that is not performed in a systematic manner across institutions.<br><br>DISCUSSION: The results from this survey showed a demand for a comprehensive database with reliable quality metrics to support use of functional evidence in clinical variant interpretation. The results also highlight a need for guidelines regarding how putatively conflicting functional data should be used for variant classification.}, }
@article {pmid39990199, year = {2025}, author = {Meehan, KA and Waters, AR and Wangen, M and Odebunmi, OO and Ferrari, RM and Marciniak, MW and Brenner, AT and Wheeler, SB and Shah, PD}, title = {Not just about pills: Findings from a national survey of pharmacists to understand their views on addressing social determinants of health.}, journal = {Preventive medicine reports}, volume = {51}, number = {}, pages = {102991}, pmid = {39990199}, issn = {2211-3355}, abstract = {OBJECTIVE: We evaluated community pharmacists' perspectives on addressing social determinants of health for their patients in the United States.<br><br>METHODS: From 9/2022-1/2023, we conducted a national, online survey of 578 pharmacists to evaluate their perspectives on social barriers affecting their patients, their pharmacy staff's ability to address these social barriers, and resources available or needed to address barriers.<br><br>RESULTS: Healthcare access and quality was perceived as the most addressable social barrier (59&#xa0;%), while education (24&#xa0;%) and neighborhood/built environment were perceived as the least addressable (14&#xa0;%). Staff capacity to address social needs was significantly associated with increases in the pharmacy's ability to address social determinants of health across all five domains. Pharmacists were more likely to report adequate staff capacity if they practiced in independent community pharmacies.<br><br>CONCLUSIONS: Pharmacists commonly address social determinants of health of their patients, but most lack adequate staff capacity to address patient social barriers. Pharmacies with capacity can only address a portion of the social needs of their patient population. Greater access to resources and staffing support are needed to improve pharmacy's role in addressing patient unmet social needs.}, }
@article {pmid39989044, year = {2025}, author = {Unger, JM and Mazza, GL and Elsaid, MI and Duan, F and Dressler, EV and Snavely, AC and Enserro, DM and Pugh, SL}, title = {When to adjust for multiplicity in cancer clinical trials.}, journal = {Journal of the National Cancer Institute. Monographs}, volume = {2025}, number = {68}, pages = {3-9}, pmid = {39989044}, issn = {1745-6614}, support = {UG1 CA189974/CA/NCI NIH HHS/United States ; //ECOG/ ; UG1CA189961//University of Rochester/ ; UG1 CA189823/CA/NCI NIH HHS/United States ; UG1CA189974/NH/NIH HHS/United States ; UG1CA189824//Wake Forest University/ ; UG1CA189961//Alliance NCORP Research Base/ ; U10 CA180794/CA/NCI NIH HHS/United States ; UG1CA189828//ACRIN/ ; U10 CA180819/CA/NCI NIH HHS/United States ; UG1CA189828//NRG Oncology/ ; 5UG1CA189955-11//Children's Oncology Group/ ; UG1 CA189867/CA/NCI NIH HHS/United States ; P30 CA016058-47S1//ACRIN/ ; UG1CA189974//SWOG/ ; UG1 CA189828/CA/NCI NIH HHS/United States ; UG1 CA189955/CA/NCI NIH HHS/United States ; UG1CA189823//SWOG Cancer Research Network/ ; U10CA180822//Wake Fores NCORP Research Base/ ; P30 CA016058/CA/NCI NIH HHS/United States ; UG1 CA189961/CA/NCI NIH HHS/United States ; UG1CA189867//NCI Community Oncology Research Program/ ; UG1 CA189824/CA/NCI NIH HHS/United States ; UG1CA189824//URCC NCORP Research Base/ ; }, mesh = {Humans ; *Neoplasms/therapy ; *Clinical Trials as Topic ; Research Design ; United States ; National Cancer Institute (U.S.) ; Data Interpretation, Statistical ; False Positive Reactions ; }, abstract = {Interpreting cancer clinical trial results often depends on addressing issues of multiplicity. When testing multiple hypotheses, unreliable findings can occur by chance due to the inflation of the type I error rate, the probability of mistakenly rejecting the null hypothesis when the null hypothesis is true. In this setting, researchers may often set the type I error rate (or the alpha level) low to limit false positive findings and the interpretation of a causal relationship where none exists. Conversely, overly conservative type I error control may result in declaring findings, that do not meet multiplicity-adjusted alpha levels, as false when they are actually true, reducing opportunities for new discovery. This presentation focuses on multiplicity adjustment in the context of clinical trials conducted within the NCI's Community Oncology Research Program (NCORP). Because federally sponsored trials often require long-term participation from patients and represent a substantial investment by taxpayers, striking the right balance between optimizing what is learned from these trials, while avoiding false positive results, should be a priority.}, }
@article {pmid39989043, year = {2025}, author = {Mazza, GL and Culakova, E and Enserro, DM and Dignam, JJ and Unger, JM}, title = {Design and analysis considerations for investigating patient subgroups of interest within cancer clinical trials.}, journal = {Journal of the National Cancer Institute. Monographs}, volume = {2025}, number = {68}, pages = {22-29}, pmid = {39989043}, issn = {1745-6614}, support = {UG1CA189823/NH/NIH HHS/United States ; 5UG1CA189955-11//Children's Oncology Group/ ; //NCI Community Oncology Research Program/ ; UG1 CA189974/CA/NCI NIH HHS/United States ; //ECOG/ ; UG1CA189974//SWOG/ ; UG1CA189961//University of Rochester/ ; UG1 CA189823/CA/NCI NIH HHS/United States ; UG1 CA189961/CA/NCI NIH HHS/United States ; UG1 CA189824/CA/NCI NIH HHS/United States ; UG1CA189828//ACRIN/ ; U10 CA180822/CA/NCI NIH HHS/United States ; UG1 CA189828/CA/NCI NIH HHS/United States ; UG1 CA189955/CA/NCI NIH HHS/United States ; UG1CA189824//Wake Forest University/ ; UG1CA189867//NRG Oncology/ ; }, mesh = {Humans ; *Neoplasms/therapy ; *Clinical Trials as Topic ; *Research Design ; Precision Medicine/methods ; United States ; Patient Selection ; National Cancer Institute (U.S.) ; }, abstract = {Examining treatment effects in subgroups of patients defined by demographic, genetic, or clinical characteristics is increasingly of interest given the pursuit of personalized medicine and the importance of representation and equity in treatment decisions. The magnitude or even the direction of the treatment effect may vary across subgroups, and these differential treatment effects could have clinical implications. Subgroup analyses require caution in their interpretation, however, because of the high probability of a false-positive or false-negative conclusion. We outline study design and analysis considerations for responsibly investigating and reporting differential treatment effects across subgroups in oncology trials, with examples from the National Cancer Institute's National Clinical Trials Network and Community Oncology Research Program. Recommendations include ensuring appropriate representation of patients from subgroups of interest, recognizing power and multiplicity limitations, and treating exploratory subgroup analyses as hypothesis generating rather than practice changing.}, }
@article {pmid39989038, year = {2025}, author = {Bandos, H and Torres-Saavedra, PA and Culakova, E and Gunn, HJ and Lee, MK and Duan, F and Cecchini, RS and Unger, JM and Dueck, AC and Steingrimsson, JA}, title = {Best practices and pragmatic approaches for patient-reported outcomes and quality of life measures in cancer clinical trials.}, journal = {Journal of the National Cancer Institute. Monographs}, volume = {2025}, number = {68}, pages = {14-21}, pmid = {39989038}, issn = {1745-6614}, support = {5UG1CA189955-11//Children's Oncology Group/ ; //Community Oncology Research Program/ ; UG1 CA189974/CA/NCI NIH HHS/United States ; UG1CA189974//SWOG/ ; UG1CA189961//University of Rochester/ ; UG1 CA189823/CA/NCI NIH HHS/United States ; UG1 CA189824/CA/NCI NIH HHS/United States ; UG1CA189828//ACRIN/ ; U10 CA180819/CA/NCI NIH HHS/United States ; //ECOG/ ; U10CA180822/BC/NCI NIH HHS/United States ; UG1 CA189828/CA/NCI NIH HHS/United States ; UG1 CA189955/CA/NCI NIH HHS/United States ; UG1CA189824//Wake Forest University/ ; UG1CA189867//NRG Oncology/ ; /NH/NIH HHS/United States ; UG1 CA189961/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Quality of Life ; *Neoplasms/therapy/psychology ; *Patient Reported Outcome Measures ; *Clinical Trials as Topic ; Research Design ; }, abstract = {Patient-reported outcomes (PROs) are often collected in cancer clinical trials. Data obtained from trials with PROs are essential in evaluating participant experiences relating to symptoms, financial toxicity, or health-related quality of life. Although most features of clinical trial design, implementation, and analyses apply to trials with PROs, several considerations are unique. In this paper, we focus on specific issues such as selection of the tool, timing and frequency of assessments, and data collection methods. We discuss how the estimand framework can be used in connection with PROs, properties of common estimation methods, and handling of missing outcomes. With a plethora of literature available, we aim to summarize best practices and pragmatic approaches to the design and analysis of the studies incorporating PROs.}, }
@article {pmid39989035, year = {2025}, author = {Dressler, EV and Pugh, SL and Gunn, HJ and Unger, JM and Zahrieh, DM and Snavely, AC}, title = {Practical design considerations for cluster randomized controlled trials: lessons learned in community oncology research.}, journal = {Journal of the National Cancer Institute. Monographs}, volume = {2025}, number = {68}, pages = {56-64}, pmid = {39989035}, issn = {1745-6614}, support = {UG1 CA189974/CA/NCI NIH HHS/United States ; //ECOG/ ; R01CA207158/CA/NCI NIH HHS/United States ; UG1CA189824/CA/NCI NIH HHS/United States ; UG1CA189961//University of Rochester/ ; UG1 CA189823/CA/NCI NIH HHS/United States ; U10CA180822//Wake Forest NCORP/ ; //SWOG NCORP RB/ ; U10 CA180819/CA/NCI NIH HHS/United States ; 5UG1CA189955-11//Children's Oncology Group/ ; UG1 CA189867/CA/NCI NIH HHS/United States ; UG1 CA189828/CA/NCI NIH HHS/United States ; UG1 CA189955/CA/NCI NIH HHS/United States ; R01HS025194//Agency for Healthcare Research and Quality/ ; U10CA180882//NRG Oncology/ ; UG1CA189974//Alliance for Clinical Trials in Oncology/ ; UG1CA189824//Wake Forest University/ ; /NH/NIH HHS/United States ; UG1 CA189961/CA/NCI NIH HHS/United States ; UG1CA189867//NCI Community Oncology Research Program/ ; UG1 CA189824/CA/NCI NIH HHS/United States ; UG1CA189828//ACRIN/ ; R01 CA207158/CA/NCI NIH HHS/United States ; R01 HS025194/HS/AHRQ HHS/United States ; }, mesh = {Humans ; *Randomized Controlled Trials as Topic ; *Research Design ; *Medical Oncology/methods/standards ; *Neoplasms/therapy ; United States ; Cluster Analysis ; National Cancer Institute (U.S.) ; Sample Size ; Patient Selection ; }, abstract = {Cancer care delivery research trials conducted within the National Cancer Institute (NCI) Community Oncology Research Program (NCORP) routinely implement interventions at the practice or provider level, necessitating the use of cluster randomized controlled trials (cRCTs). The intervention delivery requires cluster-level randomization instead of participant-level, affecting sample size calculation and statistical analyses to incorporate correlation between participants within a practice. Practical challenges exist in the conduct of these cRCTs due to unique trial network infrastructures, including the possibility of unequal participant accrual totals and rates and staggered study initiation by clusters, potentially with differences between randomized arms. Execution of cRCT designs can be complex, ie, if some clusters do not accrue participants, unintended cluster-level crossover occurs, how best to identify appropriate cluster-level stratification, timing of randomization, and multilevel eligibility criteria considerations. This article shares lessons learned with potential mitigation strategies from 3 NCORP cRCTs.}, }
@article {pmid39988778, year = {2025}, author = {Stamatatos, L}, title = {The Germline Targeting Vaccine Concept: Overview and Updates from HIV Pre-Clinical and Clinical Trials.}, journal = {Current HIV research}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570162X358302250206074255}, pmid = {39988778}, issn = {1873-4251}, abstract = {An effective HIV-1 vaccine should elicit diverse immune responses, including broadly neutralizing antibodies (bNAbs). Such antibodies recognize regions of the viral envelope glyco-protein (Env) that are conserved among the diverse HIV-1 clades and strains. They are isolated from people living with HIV-1 to protect animals from experimental viral exposure and reduce HIV-1 acquisition in clinical settings. However, despite efforts spanning several decades, bNAbs have not been elicited through immunization. The HIV Env efficiently binds bNAbs, but not their unmutated (germline, gl) precursors. In contrast, Env readily engages the germline precursors of antibodies with no, or very narrow, cross-neutralizing activities (non-neutralizing antibodies, nnAbs). That, in part, explains why Env-based immunogens consistently elicit nnAbs, but not bNAbs. In the past decade, Env-derived proteins have been specifically designed to engage the germline precursors of diverse bNAbs. These 'germline-targeting' Env immunogens activate the corresponding naive B cells in vivo, but are unable to guide their proper maturation towards their broadly neutralizing forms. For this, immunizations with currently not well-defined heterologous Envs are required. Here, we discuss the development of germline-targeting Env immunogens, their in vivo evaluation, and the strategies currently under evaluation that aim to rapidly guide the mat-uration of germline-precursor BCRs into their broadly neutralizing forms.}, }
@article {pmid39975340, year = {2025}, author = {Jochim, BE and Topalidou, I and Lehrbach, NJ}, title = {Protein sequence editing defines distinct and overlapping functions of SKN-1A/Nrf1 and SKN-1C/Nrf2.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39975340}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P40 OD010440/OD/NIH HHS/United States ; R35 GM142728/GM/NIGMS NIH HHS/United States ; }, abstract = {The Nrf/NFE2L family of transcription factors regulates redox balance, xenobiotic detoxification, metabolism, proteostasis, and aging. Nrf1/NFE2L1 is primarily responsible for stress-responsive upregulation of proteasome subunit genes and is essential for adaptation to proteotoxic stress. Nrf2/NFE2L2 is mainly involved in activating oxidative stress responses and promoting xenobiotic detoxification. Nrf1 and Nrf2 contain very similar DNA binding domains and can drive similar transcriptional responses. In C. elegans, a single gene, skn-1, encodes distinct protein isoforms, SKN-1A and SKN-1C, that function analogously to mammalian Nrf1 and Nrf2, respectively, and share an identical DNA binding domain. Thus, the extent to which SKN-1A/Nrf1 and SKN-1C/Nrf2 functions are distinct or overlapping has been unclear. Regulation of the proteasome by SKN-1A/Nrf1 requires post-translational conversion of N-glycosylated asparagine residues to aspartate by the PNG-1/NGLY1 peptide:N-glycanase, a process we term 'sequence editing'. Here, we reveal the consequences of sequence editing for the transcriptomic output of activated SKN-1A. We confirm that activation of proteasome subunit genes is strictly dependent on sequence editing. In addition, we find that sequence edited SKN-1A can also activate genes linked to redox homeostasis and xenobiotic detoxification that are also regulated by SKN-1C, but the extent of these genes' activation is antagonized by sequence editing. Using mutant alleles that selectively inactivate either SKN-1A or SKN-1C, we show that both isoforms promote optimal oxidative stress resistance, acting as effectors for distinct signaling pathways. These findings suggest that sequence editing governs SKN-1/Nrf functions by tuning the SKN-1A/Nrf1 regulated transcriptome.}, }
@article {pmid39987960, year = {2025}, author = {Ross, WL and Santiago-Rivera, Y and Tan, MT and Roy, MM and Bryant, S and Appel, BE and Casillas, J and Demedis, J and Smitherman, AB and Horwitz, LI and Hurtado-de-Mendoza, A and Mendoza, JA and Santacroce, SJ and Kadan-Lottick, NS}, title = {Design and methods of a multi-level intervention to improve adherence to childhood cancer survivorship care by partnering with primary care providers: The BRIDGES randomized controlled trial.}, journal = {Contemporary clinical trials}, volume = {}, number = {}, pages = {107859}, doi = {10.1016/j.cct.2025.107859}, pmid = {39987960}, issn = {1559-2030}, abstract = {BACKGROUND: Despite heightened risk of chronic health conditions, <20 % of childhood cancer survivors (CCS) receive guideline-recommended surveillance for late effects. Barriers include avoidance of reminders, lack of knowledge, and costs. The goal of the BRIDGES Study is to evaluate the effects of a multi-level, remote intervention on adherence to guideline-recommended surveillance among CCS by partnering with primary care providers (PCPs).<br><br>METHODS: This ongoing study is a multi-site, two-arm, prospective, parallel design, 1:1 randomized controlled non-inferiority trial (N&#x202f;=&#x202f;240; n&#x202f;=&#x202f;120/group). Eligibility criteria are: cancer diagnosis at age&#x202f;<&#x202f;21&#x202f;years, 2.0-4.0&#x202f;years post-cancer therapy, and no previous specialty survivorship clinic care. The intervention includes: 1) patient survivorship education via telehealth with a cancer center nurse, including discussion of patient's individualized survivorship care plan (SCP), 2) ongoing patient-tailored health education within the electronic health record's patient portal, 3) a structured interactive phone call between the cancer center nurse and PCP, including discussion of patient's SCP, and 4) an in-person PCP visit for survivorship care. Patients randomized to the comparison group are contacted to schedule an in-person visit at their cancer center-based survivorship clinic. Adherence to guideline-recommended surveillance tests (primary outcome) is assessed at 1-year post-randomization (primary follow-up time point) and 2-years post-randomization (for durability). Patient knowledge, self-efficacy, and activation; PCP knowledge and self-efficacy; and process outcomes are also assessed.<br><br>CONCLUSION: Models of survivorship care that overcome existing barriers are needed. If efficacious, this scalable, remote intervention would be a valuable strategy to address barriers and bridge gaps in care to reach more CCS.<br><br>CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05448560.}, }
@article {pmid39986828, year = {2025}, author = {Lange, PH and Schellhammer, PF}, title = {Tribute to Michael Droller MD.}, journal = {Urologic oncology}, volume = {43}, number = {2}, pages = {94}, doi = {10.1016/j.urolonc.2024.05.008}, pmid = {39986828}, issn = {1873-2496}, }
@article {pmid39985691, year = {2025}, author = {Viskochil, RH and Lin, T and Gigic, B and Himbert, C and Bandera, VM and Skender, S and Holowatyj, AN and Schrotz-King, P and Steindorf, K and Strehli, I and Mutch, MG and Chao, D and Toriola, AT and Shibata, D and Siegel, EM and Li, CI and Hardikar, S and Peoples, AR and Figueiredo, JC and Schneider, M and Ulrich, CM and Ose, J}, title = {Sedentary behavior and physical activity one year after colorectal cancer diagnosis: results from the ColoCare Study.}, journal = {Journal of cancer survivorship : research and practice}, volume = {}, number = {}, pages = {}, pmid = {39985691}, issn = {1932-2267}, abstract = {PURPOSE: Physical activity plays key roles in colorectal cancer survivorship; however, the impact of different clinicodemographic outcomes on cross-sectional and longitudinal objectively measured physical activity 12 and 24 months post-diagnosis are unclear.<br><br>METHODS: ColoCare study participants (n&#x2009;=&#x2009;165) wore an Actigraph GT3x accelerometer for 4-10 consecutive days to objectively assess activity levels 12 and 24&#xa0;months after colorectal cancer diagnosis and resection. Associations between these clinical/demographic exposures and physical activity outcomes and longitudinal changes were determined using t-test, ANOVA F-test, and linear regression modeling, adjusting for common confounders (e.g., sex, age, stage).<br><br>RESULTS: Key physical activity and sedentary behavior variables significantly differed by demographic status, including minutes of weekly exercise by sex and age (age&#x2009;<&#x2009;50: 364&#xa0;min&#x2009;&#xb1;&#x2009;303&#xa0;min; age 50-70: 232&#xa0;min&#x2009;&#xb1;&#x2009;263&#xa0;min; age&#x2009;>&#x2009;70: 93&#xa0;min&#x2009;&#xb1;&#x2009;135&#xa0;min, p&#x2009;<&#x2009;0.001) and (%) daily sedentary time by age (age&#x2009;<&#x2009;50: 64&#x2009;&#xb1;&#x2009;10%; age 50-70: 67&#x2009;&#xb1;&#x2009;7%; age&#x2009;>&#x2009;70: 71&#x2009;&#xb1;&#x2009;7%, p&#x2009;=&#x2009;0.003). Within the multivariate model, age was the primary measure consistently associated with activity differences. Participants who wore accelerometers 12- and 24-month post-resection (n&#x2009;=&#x2009;52) significantly increased weekly exercise minutes (214&#xa0;min&#x2009;&#xb1;&#x2009;208&#xa0;min vs. 288&#xa0;min&#x2009;&#xb1;&#x2009;316&#xa0;min, p&#x2009;=&#x2009;0.04).<br><br>CONCLUSION: Age is the primary clinicodemographic determinant separating physical activity levels in colorectal cancer survivors, and increases in exercise from 12 to 24&#xa0;months are likely due to consolidation of sporadic daily physical activity into bouts of exercise.<br><br>Colorectal cancer survivors experience different volumes and changes in accelerometer-derived physical activity based on some (e.g., age) but not all (e.g., stage) clinicodemographic variables.}, }
@article {pmid39984572, year = {2025}, author = {Ahmed, SR and Befano, B and Egemen, D and Rodriguez, AC and Desai, KT and Jeronimo, J and Ajenifuja, KO and Clark, C and Perkins, R and Campos, NG and Inturrisi, F and Wentzensen, N and Han, P and Guillen, D and Norman, J and Goldstein, AT and Madeleine, MM and Donastorg, Y and Schiffman, M and de Sanjose, S and Kalpathy-Cramer, J and , }, title = {Generalizable deep neural networks for image quality classification of cervical images.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {6312}, pmid = {39984572}, issn = {2045-2322}, mesh = {Humans ; Female ; *Uterine Cervical Neoplasms/diagnostic imaging/diagnosis/pathology ; *Neural Networks, Computer ; *Cervix Uteri/diagnostic imaging/pathology ; Image Processing, Computer-Assisted/methods ; Image Interpretation, Computer-Assisted/methods ; Deep Learning ; Artificial Intelligence ; }, abstract = {Successful translation of artificial intelligence (AI) models into clinical practice, across clinical domains, is frequently hindered by the lack of image quality control. Diagnostic models are often trained on images with no denotation of image quality in the training data; this, in turn, can lead to misclassifications by these models when implemented in the clinical setting. In the case of cervical images, quality classification is a crucial task to ensure accurate detection of precancerous lesions or cancer; this is true for both gynecologic-oncologists' (manual) and diagnostic AI models' (automated) predictions. Factors that impact the quality of a cervical image include but are not limited to blur, poor focus, poor light, noise, obscured view of the cervix due to mucus and/or blood, improper position, and over- and/or under-exposure. Utilizing a multi-level image quality ground truth denoted by providers, we generated an image quality classifier following a multi-stage model selection process that investigated several key design choices on a multi-heterogenous "SEED" dataset of 40,534 images. We subsequently validated the best model on an external dataset ("EXT"), comprising 1,340 images captured using a different device and acquired in different geographies from "SEED". We assessed the relative impact of various axes of data heterogeneity, including device, geography, and ground-truth rater on model performance. Our best performing model achieved an area under the receiver operating characteristics curve (AUROC) of 0.92 (low quality, LQ vs. rest) and 0.93 (high quality, HQ vs. rest), and a minimal total %extreme misclassification (%EM) of 2.8% on the internal validation set. Our model also generalized well externally, achieving corresponding AUROCs of 0.83 and 0.82, and %EM of 3.9% when tested out-of-the-box on the external validation ("EXT") set. Additionally, our model was geography agnostic with no meaningful difference in performance across geographies, did not exhibit catastrophic forgetting upon retraining with new data, and mimicked the overall/average ground truth rater behavior well. Our work represents one of the first efforts at generating and externally validating an image quality classifier across multiple axes of data heterogeneity to aid in visual diagnosis of cervical precancer and cancer. We hope that this will motivate the accompaniment of adequate guardrails for AI-based pipelines to account for image quality and generalizability concerns.}, }
@article {pmid39983446, year = {2025}, author = {Ficarra, S and Kang, DW and Wilson, RL and Gonzalo-Encabo, P and Christopher, CN and Normann, AJ and Lopez, P and Lakićević, N and Dieli-Conwright, CM}, title = {Exercise medicine for individuals diagnosed with Lung Cancer: A systematic review and meta-analysis of health outcomes.}, journal = {Lung cancer (Amsterdam, Netherlands)}, volume = {201}, number = {}, pages = {108413}, doi = {10.1016/j.lungcan.2025.108413}, pmid = {39983446}, issn = {1872-8332}, abstract = {Consensus exists regarding the need to provide exercise interventions to individuals diagnosed with lung cancer (LC). Exercise interventions for this populations usually include multidisciplinary approaches, making the attempt to understand the effects of exercise a real challenge. Therefore, we designed a systematic review to identify the effects of exercise interventions among individuals with a LC diagnosis. Following the PRISMA guidelines, studies across 5 different databases were systematically screened. Eligible studies were randomised and non-randomised trials, including individuals with a LC diagnosis, administering exercise-only interventions. Three-level meta-analyses were performed for cardiorespiratory fitness, strength, physical function, anxiety, depression, and health-related quality of life. Differences between exercise types were also explored. The Cochrane Risk of Bias (RoB) II tool for randomised controlled trials and the RoB in non-randomised studies - of interventions were used to assess study quality. A total of 36,304 records were screened and 13 studies, including 547 LC survivors, were considered eligible. Randomised and non-randomised trials were mainly judged as "some concern" and at "serious" RoB, respectively. Meta-analyses reported significant improvements on physical function among exercise groups compared to control (ES = 0.62; 95 % CI: 0.10 to 1.15; p = 0.03), and no significant changes for all other variables. There is moderate evidence that exercise interventions appear to be an effective tool to improve physical function among individuals diagnosed with LC. Further studies are still needed to determine exercise prescription effectiveness on health outcomes, differences across exercise types and enhance individualized interventions.}, }
@article {pmid39982694, year = {2025}, author = {Alduhayh, S and Laskar, RS and Jiang, X and Zhu, Z and Vincent, EE and Constantinescu, AE and Buchanan, DD and Grant, RC and Phipps, AI and Brenner, H and Huang, WY and Kweon, SS and Li, L and Pearlman, R and Castellví-Bel, S and Gruber, SB and Li, CI and Pellatt, A and Platz, EA and Van Guelpen, B and Zheng, W and Chan, AT and Figueiredo, JC and Ogino, S and Ulrich, CM and Gunter, MJ and Haycock, P and Severi, G and Murphy, N and Dimou, N}, title = {Association of genetic liability to allergic diseases with overall and early-onset colorectal cancer risk: a Mendelian randomization study.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-24-0970}, pmid = {39982694}, issn = {1538-7755}, abstract = {BACKGROUND: Tumor immunosurveillance theory supports that allergic conditions could decrease cancer risk. However, observational evidence yielded inconsistent results for the association between allergic diseases and colorectal cancer risk. We used Mendelian randomization (MR) to examine potential causal associations of allergies with risk of overall and early-onset colorectal cancer.<br><br>METHODS: Genome-wide association study summary statistic data were used to identify genetic variants associated with allergic diseases (Nvariants=65) and individual allergic conditions (asthma, hay fever/allergic rhinitis, eczema). Using two-sample MR, we examined these variants in relation to incident overall (Ncases=52,775 cases) and early-onset colorectal cancer (Ncases=6,176). The mediating role of white blood cells was examined using multivariable MR.<br><br>RESULTS: In inverse-variance weighted models, genetic liability to allergic diseases was inversely associated with overall (ORper log(odds)= 0.90 [95% CI= 0.85-0.96]; P<&#x2009;0.01) and early-onset colorectal cancer (OR= 0.83 [95% CI= 0.73-0.95]; P=&#x2009;0.01). Similar inverse associations were found for hay fever/allergic rhinitis or eczema, while no evidence of association was found between liability to asthma-related phenotypes and colorectal cancer risk. Multivariable MR adjustment for eosinophils weakened the inverse associations for liability to allergic diseases for overall (OR= 0.96 [95% CI= 0.89-1.03]; P=&#x2009;0.26) and early-onset colorectal cancer (OR= 0.86 [95% CI= 0.73-1.01]; P=&#x2009;0.06).<br><br>CONCLUSIONS: Our study supports a potential causal association between liability to allergic diseases, specifically hay fever/allergic rhinitis or eczema, and colorectal cancer, possibly at least in part mediated via eosinophil counts.<br><br>IMPACT: Our results provide evidence that allergic responses may also have a role in immunosurveillance against colorectal cancer.}, }
@article {pmid39982410, year = {2025}, author = {Burfeind, KG and Funahashi, Y and Su, XT and Lackey, AE and Hagen, MW and Blanche, S and Emathinger, JM and Hebert, JF and McDonough, AA and Gurley, SB and Nelson, JW and Hutchens, MP}, title = {Kidney cell response to acute cardiorenal and isolated kidney ischemia-reperfusion injury.}, journal = {Physiological genomics}, volume = {}, number = {}, pages = {}, doi = {10.1152/physiolgenomics.00161.2024}, pmid = {39982410}, issn = {1531-2267}, support = {I01BX004288//U.S. Department of Veterans Affairs (VA)/ ; W81XWH2010196/PR191304//U.S. Department of Defense (DOD)/ ; 20CDA35320169//American Heart Association (AHA)/ ; K01DK121737//HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)/ ; //Collins Medical Trust (CMT)/ ; TL1TR002371//HHS | NIH | National Center for Advancing Translational Sciences (NCATS)/ ; KL2TR002370//HHS | NIH | National Center for Advancing Translational Sciences (NCATS)/ ; 24CDA1269598//American Heart Association (AHA)/ ; }, abstract = {Acute cardiorenal syndrome (CRS) represents a critical intersection of cardiac and renal dysfunction with profound clinical implications. Despite its significance, the molecular underpinnings that mediate cellular responses within the kidney during CRS remain inadequately understood. We employed single nucleus RNA sequencing (snRNAseq) to dissect the cellular transcriptomic landscape of the kidney following in a translational model of CRS, cardiac arrest/cardiopulmonary resuscitation (CA/PCR) in comparison to ischemia reperfusion injury (IRI). In each dataset, we found that proximal tubule (PT) cells of the kidney undergo significant gene expression changes, with decreased expression of genes critically important for cell identity and function, indicative of dedifferentiation. Based on this, we created a novel score to capture the dedifferentiation state of each kidney cell population and found that certain epithelial cell populations, such as the PT S1 and S2 segments, as well as the distal convoluted tubule, exhibited significant dedifferentiation response. Interestingly, the dedifferentiation response in the distal nephron differed in magnitude between IRI and CA/CPR. Gene set enrichment analysis (GSEA) of PT response to IRI and CA/CPR revealed similarities between the two models and key differences, including enrichment of immune system process genes. Transcriptional changes in both mouse models of AKI highly correlated with a dataset of human biopsies from patients diagnosed with acute kidney injury (AKI). This comprehensive single nucleus transcriptomic profiling provides valuable insights into the cellular mechanisms driving CRS.}, }
@article {pmid39981705, year = {2025}, author = {Taylor, MR and Bradford, MC and Zhou, C and Fladeboe, KM and Wittig, JF and Baker, KS and Yi-Frazier, JP and Rosenberg, AR}, title = {Heart Rate Variability as a Digital Biomarker in Adolescents and Young Adults Receiving Hematopoietic Cell Transplantation.}, journal = {Cancer medicine}, volume = {14}, number = {4}, pages = {e70609}, pmid = {39981705}, issn = {2045-7634}, support = {//American Cancer Society/ ; }, mesh = {Humans ; Adolescent ; *Hematopoietic Stem Cell Transplantation ; *Heart Rate ; Male ; Female ; Young Adult ; *Quality of Life ; *Patient Reported Outcome Measures ; Anxiety ; Biomarkers ; Child ; Prospective Studies ; Depression ; Adult ; Autonomic Nervous System/physiopathology ; }, abstract = {INTRODUCTION: Adolescents and young adults (AYAs) receiving hematopoietic cell transplantation (HCT) are at high risk for poor psychosocial outcomes. Heart rate variability (HRV), a surrogate for autonomic nervous system activity, is a promising digital biomarker that has been linked to important outcomes. The objectives of this study were to prospectively describe the trajectory of HRV among AYAs receiving HCT and explore the association between HRV and patient-reported outcomes (PROs).<br><br>METHODS: This was a multi-site study embedded in a randomized trial among AYAs receiving HCT (NCT03640325). We collected sequential 24-h HRV metrics, including the standard deviation of normal-to-normal beats (SDNN), root-mean-square of successive differences (RMSSD), as well as frequency domain measures. PRO surveys queried anxiety, depression, quality of life, hope, and resilience at baseline and 3&#x2009;months. We summarized outcomes using descriptive statistics, and Pearson correlation coefficients were used to examine the relationship between HRV and PROs.<br><br>RESULTS: Thirty-nine HRV recordings were collected from n&#x2009;=&#x2009;16 participants aged 12-21&#x2009;years. There was a moderately strong correlation between inferior baseline HRV and higher anxiety and depression (anxiety: r&#x2009;=&#x2009;-0.35 (p&#x2009;=&#x2009;0.18) for SDNN, r&#x2009;=&#x2009;-0.47 (p&#x2009;=&#x2009;0.07) for RMSSD; depression: r&#x2009;=&#x2009;-0.26 (p&#x2009;=&#x2009;0.34) for SDNN, r&#x2009;=&#x2009;-0.39 (p&#x2009;=&#x2009;0.14) for RMSSD). Among participants with elevated baseline anxiety, higher HRV suggested greater improvement in anxiety over time (r&#x2009;=&#x2009;-0.66 (p&#x2009;=&#x2009;0.08) for SDNN, r&#x2009;=&#x2009;-0.31 (p&#x2009;=&#x2009;0.45) for RMSSD).<br><br>CONCLUSIONS: There was a correlation between HRV and PROs in this study, and among those with elevated anxiety, HRV predicted improvement over time. Digital biomarkers may augment behavioral intervention design and implementation.}, }
@article {pmid39980037, year = {2025}, author = {Nikolaienko, O and Anderson, GL and Chlebowski, RT and Jung, SY and Harris, HR and Knappskog, S and Lønning, PE}, title = {MGMT epimutations and risk of incident cancer of the colon, glioblastoma multiforme, and diffuse large B cell lymphomas.}, journal = {Clinical epigenetics}, volume = {17}, number = {1}, pages = {28}, pmid = {39980037}, issn = {1868-7083}, mesh = {Humans ; *Glioblastoma/genetics/epidemiology ; Female ; *Lymphoma, Large B-Cell, Diffuse/genetics/epidemiology ; *Tumor Suppressor Proteins/genetics ; *DNA Repair Enzymes/genetics ; *DNA Modification Methylases/genetics ; Case-Control Studies ; *DNA Methylation/genetics ; Aged ; Middle Aged ; *Promoter Regions, Genetic/genetics ; *Colonic Neoplasms/genetics/epidemiology ; Mutation ; Genetic Predisposition to Disease/genetics ; Epigenesis, Genetic/genetics ; Incidence ; }, abstract = {BACKGROUND: Constitutional BRCA1 epimutations (promoter hypermethylation) are associated with an elevated risk of triple-negative breast cancer and high-grade serous ovarian cancer. While MGMT epimutations are frequent in colon cancer, glioblastoma, and B-cell lymphoma, it remains unknown whether constitutional MGMT epimutations are associated with risk of any of these malignancies.<br><br>METHODS: We designed a nested case-control study, assessing potential associations between MGMT epimutations in blood from healthy individuals and subsequent risk of incident cancer. The study cohort was drawn from postmenopausal women, participating in the Women's Health Initiative (WHI) study, who had not been diagnosed with either colon cancer, glioblastoma, or B-cell lymphoma prior to study entry. The protocol included n&#x2009;=&#x2009;400 women developing incident left-sided and n&#x2009;=&#x2009;400 women developing right-sided colon cancer, n&#x2009;=&#x2009;400 women developing diffuse large B-cell lymphomas, all matched on a 1:2 basis with cancer-free controls, and n&#x2009;=&#x2009;195 women developing incident glioblastoma multiforme, matched on a 1:4 basis. All cancers were confirmed in centralized medical record review. Blood samples, collected at entry, were analyzed for MGMT epimutations by massive parallel sequencing. Associations between MGMT methylation and incident cancers were analyzed by Cox proportional hazards regression.<br><br>RESULTS: Analyzing epimutations affecting the key regulatory area of the MGMT promoter, the hazard ratio (HR) was 1.07 (95% CI 0.79-1.45) and 0.80 (0.59-1.08) for right- and left-sided colon cancer, respectively, 1.13 (0.78-1.64) for glioblastoma, and 1.11 (0.83-1.48) for diffuse large B-cell lymphomas. Sensitivity analyses limited to subregions of the MGMT promoter and to individuals with different genotypes of a functional SNP in the MGMT promoter (rs16906252), revealed no significant effect on HR for any of the cancer forms.&#xa0;Neither did we observe any effect of rs16906252 status on HR for any of the cancer forms among individuals methylated or non-methylated at the MGMT promoter.<br><br>CONCLUSIONS: Constitutional MGMT promoter methylation in normal tissue is not associated with an increased risk of developing colon cancer, glioblastoma, or B-cell lymphoma.}, }
@article {pmid39979638, year = {2025}, author = {Toghani, D and Gupte, S and Zeng, S and Mahammadov, E and Crosse, EI and Seyedhassantehrani, N and Burns, C and Gravano, D and Radtke, S and Kiem, HP and Rodriguez, S and Carlesso, N and Pradeep, A and Georgiades, A and Lucas, F and Wilson, NK and Kinston, SJ and Göttgens, B and Zong, L and Beerman, I and Park, B and Janssens, DH and Jones, D and Toghani, A and Nerlov, C and Pietras, EM and Mesnieres, M and Maes, C and Kumanogoh, A and Worzfeld, T and Cheong, JG and Josefowicz, SZ and Kharchenko, P and Scadden, DT and Scialdone, A and Spencer, JA and Silberstein, L}, title = {Author Correction: Niche-derived Semaphorin 4A safeguards functional identity of myeloid-biased hematopoietic stem cells.}, journal = {Nature aging}, volume = {}, number = {}, pages = {}, doi = {10.1038/s43587-025-00837-x}, pmid = {39979638}, issn = {2662-8465}, }
@article {pmid39979464, year = {2025}, author = {Briney, CA and Henriksen, JC and Lin, C and Jones, LA and Benner, L and Rains, AB and Gutierrez, R and Gafken, PR and Rissland, OS}, title = {Muskelin is a substrate adaptor of the highly regulated Drosophila embryonic CTLH E3 ligase.}, journal = {EMBO reports}, volume = {}, number = {}, pages = {}, pmid = {39979464}, issn = {1469-3178}, support = {5T32GM136444//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; 5T32GM141742//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R35GM128680//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; 2P40OD010949//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; CAREER 2056136//National Science Foundation (NSF)/ ; P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD030225/CD/ODCDC CDC HHS/United States ; }, abstract = {The maternal-to-zygotic transition (MZT) is a conserved developmental process where the maternally-derived protein and mRNA cache is replaced with newly made zygotic gene products. We have previously shown that in Drosophila the deposited RNA-binding proteins ME31B, Cup, and Trailer Hitch are ubiquitylated by the CTLH E3 ligase and cleared. However, the organization and regulation of the CTLH complex remain poorly understood in flies because Drosophila lacks an identifiable substrate adaptor, and the mechanisms restricting the degradation of ME31B and its cofactors to the MZT are unknown. Here, we show that the developmental regulation of the CTLH complex is multi-pronged, including transcriptional control by OVO and autoinhibition of the E3 ligase. One major regulatory target is the subunit Muskelin, which we demonstrate is a substrate adaptor for the Drosophila CTLH complex. Finally, we find that Muskelin has few targets beyond the three known RNA-binding proteins, showing exquisite target specificity. Thus, multiple levels of integrated regulation restrict the activity of the embryonic CTLH complex to early embryogenesis, during which time it regulates three important RNA-binding proteins.}, }
@article {pmid38746305, year = {2025}, author = {Ni, X and Richardson, RB and Godoy, AS and Ferla, MP and Kikawa, C and Scheen, J and Hannon, WW and Capkin, E and Lahav, N and Balcomb, BH and Marples, PG and Fairhead, M and Wang, S and Williams, EP and Tomlinson, CWE and Aschenbrenner, JC and Lithgo, RM and Winokan, M and Giroud, C and Chandran, AV and Walsh, M and Thompson, W and Bloom, JD and Barr, H and Kirkegaard, K and Koekemoer, L and Fearon, D and Evans, MJ and von Delft, F}, title = {Crystallographic fragment screening and deep mutational scanning of Zika virus NS2B-NS3 protease enable development of resistance-resilient inhibitors.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38746305}, issn = {2692-8205}, support = {U19 AI171399/AI/NIAID NIH HHS/United States ; }, abstract = {The Zika viral protease NS2B-NS3 is essential for the cleavage of viral polyprotein precursor into individual structural and non-structural (NS) proteins and is therefore an attractive drug target. Generation of a robust crystal system of co-expressed NS2B-NS3 protease has enabled us to perform a crystallographic fragment screening campaign with 1076 fragments. 47 fragments with diverse scaffolds were identified to bind in the active site of the protease, with another 6 fragments observed in a potential allosteric site. To identify binding sites that are intolerant to mutation and thus suppress the outgrowth of viruses resistant to inhibitors developed from bound fragments, we performed deep mutational scanning of NS2B-NS3 protease. Merging fragment hits yields an extensive set of 'mergers', defined as synthetically accessible compounds that recapitulate constellations of observed fragment-protein interactions. In addition, the highly sociable fragment hits enable rapid exploration of chemical space via algorithmic calculation and thus yield diverse possible starting points that maximally explore the binding opportunities to NS2B-NS3 protease, facilitating its resistance-resilient antiviral development.}, }
@article {pmid39977705, year = {2025}, author = {Boiko, JR and Ensbey, KS and Waltner, OG and Jenkins, IC and Bhise, SS and MacDonald, KP and Blazar, BR and Hall, AM and Gooley, TA and Minnie, SA and Lee, SJ and Furlan, SN and Hill, GR}, title = {Defining pathogenic IL-17 and CSF-1 gene expression signatures in chronic graft-versus-host disease.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024025337}, pmid = {39977705}, issn = {1528-0020}, abstract = {Chronic graft-versus-host disease (cGVHD) remains the leading cause of non-relapse morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Effective therapeutics agents targeting dysregulated cytokines including IL-17 and CSF-1 have been defined in preclinical models of cGVHD, and efficacy in subsequent clinical trials has led to their recent FDA approval. Despite this, these agents are effective in only a subset of patients, expensive, difficult to access outside the US, and used in a trial-and-error fashion. The ability to readily discern druggable, dysregulated immunity in these patients is desperately needed to facilitate the selection of appropriate treatment and to potentially identify high-risk individuals for preemptive therapy. We used single cell sequencing-based approaches in our informative preclinical cGVHD models to "reverse engineer" temporal IL-17 and CSF-1 signatures in mouse blood that could be used to interrogate patients. We defined distinct, non-intuitive IL-17 and CSF-1 signatures in mouse blood monocytes that could be identified in relevant monocytes within 70% of patients at diagnosis of cGVHD and in half of patients at day +100 post-HCT who subsequently developed cGVHD. These signatures can now be evaluated prospectively in clinical studies to help delineate potential responder and non-responders to relevant therapeutics targeting these pathways.}, }
@article {pmid39976968, year = {2025}, author = {Umoren, RA and Ezeaka, C and Berkelhamer, SK and Hippe, DS and Asangansi, IE and Cook, MW and Fajolu, IB and Olawuyi, O and Adeboboye, C and Ekhalufoh, OO and Fashola, OS and Feltner, J and Fisher, JD and James, JM and Imoukhuede, OM and Park, N and Quach, V and Stiffler, AK and Engmann, CM}, title = {Essential Newborn Care Virtual Simulations for Skills Retention in Newborn Care.}, journal = {JAMA network open}, volume = {8}, number = {2}, pages = {e2460565}, pmid = {39976968}, issn = {2574-3805}, mesh = {Humans ; Infant, Newborn ; Female ; *Clinical Competence/statistics &amp; numerical data ; Nigeria ; *Simulation Training/methods ; Male ; Adult ; Infant Care/methods ; Cohort Studies ; Health Personnel/education ; }, abstract = {IMPORTANCE: Newborn mortality accounts for approximately 47% of all mortality of children under the age of 5 years. Virtual simulation may be a viable approach to support retention of essential newborn care knowledge and skills among health care professionals in low- and middle-income countries.<br><br>OBJECTIVE: To evaluate the association between mobile virtual simulation using Virtual Essential Newborn Care (vENC) and knowledge and skills retention in early newborn care in low-resource settings and to propose a frequency of virtual simulation use for among health care professionals who care for newborns in low-resource settings.<br><br>This cohort study was conducted at 23 primary, secondary, and tertiary health care facilities in Lagos, Nigeria, for 6 months between December 1, 2022, and June 30, 2023. Participants included nurses and midwives who participated in deliveries and provided newborn care. Potential participants who attended a Helping Babies Breathe or Essential Newborn Care (ENC) course within the past 1 year were excluded.<br><br>EXPOSURES: All participants received in-person training using the World Health Organization ENC 1 and ENC 2 curricula along with virtual simulation practice at variable recommended frequencies for 6 months after course completion.<br><br>MAIN OUTCOMES AND MEASURES: Primary outcomes included assessments of bag-valve-mask (BVM) ventilation skills, and performance on ENC 1 and ENC 2 case A and B scenarios conducted by trained research assistants before, immediately after, and 6 months after the in-person course. All scores ranged from 0% to 100%, with higher scores indicating better performance.<br><br>RESULTS: Of 70 enrolled participants (67 of 69 [97%] female), 62 (89%) completed the 6-month follow-up. Immediate posttraining performance (median [IQR] scores: BVM ventilation skills, 93% [86%-100%]; ENC 1 case scenario A, 72% [61%-78%]; ENC 1 case scenario B, 76% [68%-88%]; ENC 2 case scenario A, 80% [73%-87%]; and ENC 2 case scenario B, 88% [70%-95%]) improved compared with pretraining performance for all skill assessments (median [IQR] scores: BVM ventilation skills, 57% [29%-64%]; ENC 1 case scenario A, 39% [28%-50%]); ENC 2 case scenario A, 33% [20%-45%]) (all P&#x2009;<&#x2009;.001). There were further gains in performance at the 6-month follow-up assessment for BVM ventilation (median [IQR], 100% [86%-100%]; P&#x2009;=&#x2009;.04) and the ENC1 and ENC2 assessments by case scenario (case scenario A: ENC 1 median [IQR] score, 78% [72%-83%]; P&#x2009;=&#x2009;.001 and ENC 2 median [IQR] score, 87% [80%-93%]; P&#x2009;=&#x2009;.008; and case scenario B: ENC 1 median [IQR] score, 88% [76%-92%]; P&#x2009;=&#x2009;.009 and ENC 2 median [IQR] score, 93% [80%-100%]; P&#x2009;=&#x2009;.004) relative to the immediate postcourse assessment scores.<br><br>CONCLUSIONS AND RELEVANCE: Findings of this cohort study suggest that the app-based simulations may be effective in supporting the retention of knowledge and skills following ENC training and may contribute to further performance gains for health care professionals in low- and middle-income countries. More clinical and implementation research is needed to explore the impact of virtual simulations on health professionals' clinical practices and neonatal outcomes.}, }
@article {pmid39976936, year = {2025}, author = {DeVine, A and Landier, W and Hudson, MM and Constine, LS and Bhatia, S and Armenian, SH and Gramatges, MM and Chow, EJ and Friedman, DN and Ehrhardt, MJ}, title = {The Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers: A Review.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaoncol.2024.6812}, pmid = {39976936}, issn = {2374-2445}, abstract = {IMPORTANCE: Since 2003, the Children's Oncology Group (COG) has developed and disseminated the Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. These guidelines have benchmarked the standard of care for long-term survivors of childhood cancer in North America and beyond. Since their inception, they have evolved in depth, scope, and contributors to maintain fidelity toward continually emerging evidence related to cancer survivorship. They are intended to inform care for individuals who survived 2 or more years from completion of childhood, adolescent, and young adult cancer-directed therapy and receiving care in either specialty or primary care environments. The guidelines are updated on a 5-year cycle, during which comprehensive literature searches pertaining to guideline-specific questions are performed, evidence abstracted from pertinent publications, and recommendations determined and scored following expert deliberation.<br><br>OBSERVATIONS: Version 6.0 of the guidelines, released in October 2023, comprised 165 sections and 45 health links and represents the cooperative efforts of 220 individuals. Major changes include the addition of recommendations regarding surveillance for genetic cancer predisposition, surveillance following the use of novel cancer treatment modalities, and routine vaccination practices during long-term follow-up. In addition, surveillance echocardiograms were omitted for those at low risk of cardiomyopathy.<br><br>CONCLUSIONS AND RELEVANCE: This narrative review outlines the historical evolution of the COG Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers, current methods guiding their development, and key recommendations from version 6.0. The guidelines are publicly available in their entirety online. The COG guidelines continue to set the standard for surveillance practices for long-term survivors of childhood, adolescent, and young adult cancer. The growing body of evidence supporting these recommendations will continue to guide their evolution to inform optimal survivorship care practices.}, }
@article {pmid39976415, year = {2025}, author = {Dumm, W and Ralph, D and DeWitt, W and Vora, A and Araki, T and Victora, GD and Matsen Iv, FA}, title = {Leveraging DAGs to improve context-sensitive and abundance-aware tree estimation.}, journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences}, volume = {380}, number = {1919}, pages = {20230315}, doi = {10.1098/rstb.2023.0315}, pmid = {39976415}, issn = {1471-2970}, support = {/NH/NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; //James S. McDonnell Foundation/ ; /RI/ORIP NIH HHS/United States ; }, mesh = {*Phylogeny ; Models, Genetic ; Receptors, Antigen, B-Cell/genetics ; Software ; Likelihood Functions ; }, abstract = {The phylogenetic inference package GCtree uses abundance of sampled sequences to improve the performance of parsimony-based inference, using a branching process model. Our previous work showed that GCtree performs competitively on B-cell receptor data, compared with other similar tools. In this article, we describe recent enhancements to GCtree, including an efficient tree storage data structure that discovers additional diversity of parsimonious trees with negligible additional computational cost. We also describe a suite of new objective functions that can be used to rank these trees, including a Poisson context likelihood function that models sequence evolution in a context-sensitive way. We validate these additions to GCtree with simulated B-cell receptor data, and benchmark performance against other phylogenetic inference tools.This article is part of the theme issue '"A mathematical theory of evolution": phylogenetic models dating back 100 years'.}, }
@article {pmid39974149, year = {2025}, author = {Bhardwaj, S and Galanter, N and Berenbrok, LA and Shah, PD and Bacci, JL}, title = {Pediatric vaccination in pharmacies is not associated with delayed well-child visits among commercially insured children.}, journal = {Health affairs scholar}, volume = {3}, number = {2}, pages = {qxaf028}, pmid = {39974149}, issn = {2976-5390}, abstract = {Pediatric vaccination rates in the United States lag national goals. Policies that expand pharmacy-based vaccinations among children could help improve vaccination rates. Opponents argue, however, that such policies will result in delayed or missed well-child visits as most children receive routine vaccinations in primary care settings. We evaluated the likelihood of having a timely well-child visit following a routine vaccination in pharmacies and primary care settings among children aged 4-17 years. We conducted a retrospective cohort analysis with commercial claims data from 2016-2019, using conditional logistic regression models. A timely well-child visit was defined as one within 12 months after a preceding well-child visit for primary analysis and 15 months for secondary analysis. Approximately 95% of the sample consisted of children with influenza among their index vaccine(s). The odds of having a timely well-child visit were similar between children who received vaccines in pharmacies and those who received them in primary care settings. Findings suggest that guardians or parents who choose pharmacy-based pediatric vaccinations for their commercially insured children do not forgo well-child visits and may actually be more likely to obtain a timely well-child visit. Extending pharmacy-based vaccinations to patients of all ages can help improve pediatric vaccination rates.}, }
@article {pmid39973814, year = {2025}, author = {Landi, D and Navai, SA and Brock, RM and Fousek, K and Nawas, Z and Sanber, K and Chauvin-Fleurence, C and Bhat, RR and Xu, S and Krishnamurthy, P and Choe, M and Campbell, M and Morris, JS and Gad, AZ and Shree, A and Echeandia, A and Saadeldin, A and Matthew, PR and Mullikin, D and Bielamowicz, K and Kurenbekova, L and Major, AM and Salsman, VS and Byrd, TT and Hicks, MJ and Zhang, YJ and Yustein, J and Carisey, AF and Joseph, SK and Ahmed, N and Hegde, M}, title = {A checkpoint reversal receptor mediates bipartite activation and enhances CAR T-cell function.}, journal = {Cancer research communications}, volume = {}, number = {}, pages = {}, doi = {10.1158/2767-9764.CRC-24-0125}, pmid = {39973814}, issn = {2767-9764}, abstract = {The efficacy of CAR T-cells (CART) in solid tumors is limited by immune inhibition. In our study, we observed that effector cytokines mediated the upregulation of the PD-L1 immune-checkpoint in primary glioblastoma (GBM). To offset the PD-L1 inhibitory signal, we engineered PD-1 checkpoint reversal receptors (CPR) with a CD28 or 41BB co-stimulatory endodomain and co-expressed them with a first-generation or a CD28-containing second-generation HER2-specific CAR (CPR/CART) using bicistronic vectors. We found that bipartite T-cell activation, by CAR-generated signal 1 and CPR co-stimulation (signal 2), fine-tuned pro-inflammatory cytokine release and sustained antitumor activity. While both CPR28 and CPR41BB effectively counteracted the PD-1 signal in vitro, CPR41BB, when co-expressed with a first-generation CAR (CARζ/CPR41BB), promoted central memory differentiation following repeat antigenic stimulation. CARζ/CPR41BB T-cells formed a robust immune synapse with tumor targets, similar to a 4-1BB-containing second-generation CART, maintained the favorable metabolic parameters associated with 4-1BB co-stimulation, and demonstrated superior antitumor function after adoptive transfer in xenograft models of GBM and metastatic osteosarcoma. Thus, a CPR molecule with 4-1BB co-stimulation that curtails PD-1 inhibition and complements CAR signaling to optimize T-cell activation could enhance CART efficacy against solid tumors.}, }
@article {pmid39973220, year = {2025}, author = {Meanley, S and Rodriguez Garcia, L and Lisha, NE and Ahmed, A and Korolkova, A and Figueroa, T and Nguyen, E and J Peluso, M and Cohn, LB and Deeks, S and Dubé, K and Sauceda, J}, title = {Exploring Stigma and Self-Image: Mixed-Methods Insights from HIV Cure-Related Research Participants Undergoing Analytical Treatment Interruptions.}, journal = {AIDS patient care and STDs}, volume = {}, number = {}, pages = {}, doi = {10.1089/apc.2024.0254}, pmid = {39973220}, issn = {1557-7449}, abstract = {This mixed-methods study explored self-image among people with HIV participating in an HIV cure-related study involving analytical treatment interruptions (ATIs). Using both quantitative and qualitative approaches, we described how self-image emerged across study participation, focusing on internalized stigma, emotional strengths, and the psychosocial dimensions of study participation. Data come from the SCOPE-ATI substudy (NCT00187512) of the University of California San Francisco SCOPE cohort (NCT04359186). Quantitative data were collected at three timepoints: pre-ATI (n = 15), post-ATI (n = 12), and end of the study (n = 14). We observed a general decline in self-image scores over time. However, participants maintained a moderately high agreement with statements about contributing to reducing HIV stigma through their involvement in the study. Qualitative interviews were collected pre-ATI (n = 11), during ATI (n = 8), and post-ATI (n = 6). Qualitative findings revealed two major themes shaping self-image: (1) experiencing and reconciling internalized HIV stigma and (2) self-evaluations in relation to life purpose. Many participants expressed disappointment at having to resume antiretroviral therapy, viewing it as a reminder of their HIV status and its associated stigma. Nevertheless, some found purpose and pride in their participation, motivated by altruistic contributions to improving future HIV control options. The findings highlight the emotional complexities of participating in HIV cure research and underscore the need for psychosocial support throughout ATI studies. While most participants experienced a decline in self-image, some derived meaning and empowerment from their involvement. This study suggests that addressing emotional well-being and reinforcing participants' contributions to science can enhance their experience in future research.}, }
@article {pmid39970314, year = {2025}, author = {Theodore, DA and Neradilek, M and Gillespie, K and Edupuganti, S and Hinojosa, JC and Lama, JR and De La Grecca, R and Wu, YH and Davis, A and Mangini, D and Andrew, P and Marovich, MA and Zwerski, S and Broder, G and Andrasik, MP and Castor, D and Roxby, AC and Cohen, M and Huang, Y and Karuna, ST and Sobieszczyk, ME}, title = {Brief Report: Associations Between Gender and Solicited Adverse Events After Passive Infusion of VRC01 or Placebo in HVTN 704/HPTN 085.}, journal = {Journal of acquired immune deficiency syndromes (1999)}, volume = {98}, number = {4}, pages = {340-345}, doi = {10.1097/QAI.0000000000003582}, pmid = {39970314}, issn = {1944-7884}, support = {//HIV Vaccine Trials Network/ ; }, mesh = {Humans ; Male ; Female ; *HIV Infections/drug therapy ; Adult ; *Broadly Neutralizing Antibodies/therapeutic use/administration &amp; dosage ; Transgender Persons ; Peru ; Young Adult ; Brazil ; Sexual and Gender Minorities ; Sex Factors ; Middle Aged ; United States ; Adolescent ; Antibodies, Monoclonal ; HIV Antibodies ; }, abstract = {BACKGROUND: Realizing the potential of HIV prevention options requires understanding product tolerability across diverse groups vulnerable to HIV acquisition. Gender minority (GM) individuals are understudied in clinical trials.<br><br>SETTING: HVTN 704/HIV Prevention Trials Network 085, a phase 2b randomized HIV prevention trial, enrolled MSM and transgender participants from Brazil, Peru, Switzerland, and the United States to receive an infusion every 8 weeks (10 total) of VRC01 30 mg/kg, VRC01 10 mg/kg, or placebo. Solicited adverse events (AEs) were recorded for 3 days after each infusion.<br><br>METHODS: Gender was defined by self-report and sex assigned-at-birth. Multivariate mixed logistic models were used to estimate the association between gender (cisgender men [CM] vs. GM participants [transgender women, transgender men, or another gender]) and solicited AE frequency and severity.<br><br>RESULTS: GM participants reported more solicited AEs than CM among all participants (adjusted OR 1.59, 95% CI: 1.20 to 2.10, P = 0.001) and among placebo recipients (1.72, 1.05 to 2.81, P = 0.031). The severity of solicited AEs (occurrence of grade 2 and higher event) did not significantly differ overall (1.83, 0.79 to 4.20, P = 0.174) or among placebo recipients (3.05, 0.76 to 12.32, P = 0.112). Grade 2 events were reported after 1% and 2% of total infusions among CM and GM participants, respectively. Grade 3-4 events were rare overall (<0.1%). Completion of 10 infusions was high (78.6%) and slightly higher in CM (79.2%) than GM participants (73%).<br><br>CONCLUSIONS: This is the first report of associations between gender and solicited AEs after monoclonal antibody infusion. GM participants reported more events; severity was low. HIV prevention trials must engage and support GM individuals to best evaluate tolerability of novel agents.}, }
@article {pmid39970310, year = {2025}, author = {Sommers, J and Dizon, DS and Lewis, MA and Stone, E and Andreoli, R and Henderson, V}, title = {Assessing health information seeking behaviors among targeted social media users using an infotainment video about a cancer clinical trial: a Population-based Descriptive Study.}, journal = {JMIR cancer}, volume = {}, number = {}, pages = {}, doi = {10.2196/56098}, pmid = {39970310}, issn = {2369-1999}, abstract = {BACKGROUND: Lack of information, awareness, and misconceptions about clinical trials are major barriers to cancer clinical trial participation. Digital and social media are dominant sources of health information and offer optimal opportunities to improve public medical awareness and education by providing accurate and trust-worthy sources of health information from reliable sources. Infotainment, material intended to both entertain and inform, is an effective strategy for engaging and educating audiences that can be easily disseminated using social media and may be a novel way to improve awareness of and recruitment in clinical trials.<br><br>OBJECTIVE: The purpose of this study was to evaluate whether an infotainment video promoting a clinical trial, disseminated using social media, could drive health information seeking behaviors.<br><br>METHODS: As part of a video series, we created an infotainment video focused on promotion of a specific cancer clinical trial. We instituted a dissemination and marketing process on Facebook to measure video engagement and health information seeking behaviors among targeted audiences who expressed interest in breast cancer research and organizations. To evaluate video engagement, we measured reach, retention, outbound clicks, and outbound click-through rate. Frequencies and descriptive statistics were used to summarize each measure.<br><br>RESULTS: The video substantially increased health information seeking behavior by increasing viewership from 1 visitor one month prior to launch to 414 outbound clicks from the video to the clinical trial webpage during the 21-day social media campaign period.<br><br>CONCLUSIONS: Our study shows that digital and social media tools can be tailored for specific target audiences, are scalable, and can be disseminated at low cost, making it an accessible educational, recruitment, and retention strategy focused on improving awareness of clinical trials.<br><br>CLINICALTRIAL: ClinicalTrials.gov NCT03418961.}, }
@article {pmid39896663, year = {2025}, author = {Dadonaite, B and Burrell, AR and Logue, J and Chu, HY and Payne, DC and Haslam, DB and Staat, MA and Bloom, JD}, title = {SARS-CoV-2 neutralizing antibody specificities differ dramatically between recently infected infants and immune-imprinted individuals.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39896663}, issn = {2692-8205}, abstract = {The immune response to viral infection is shaped by past exposures to related virus strains, a phenomenon known as imprinting. For SARS-CoV-2, much of the population has been imprinted by a viral spike from an early strain, either through vaccination or infection during the early stages of the COVID-19 pandemic. As a consequence of this imprinting, infection with more recent SARS-CoV-2 strains primarily boosts cross-reactive antibodies elicited by the imprinting strain. Here we compare the neutralizing antibody specificities of imprinted individuals versus infants infected with a recent strain. Specifically, we use pseudovirus-based deep mutational scanning to measure how spike mutations affect neutralization by the serum antibodies of adults and children imprinted by the original vaccine versus infants with a primary infection by a XBB* variant. While the serum neutralizing activity of the imprinted individuals primarily targets the spike receptor-binding domain (RBD), serum neutralizing activity of infants only infected with XBB* mostly targets the spike N-terminal domain (NTD). In these infants, secondary exposure to the XBB* spike via vaccination shifts more of the neutralizing activity towards the RBD, although the specific RBD sites targeted are different than for imprinted adults. The dramatic differences in neutralization specificities among individuals with different exposure histories likely impact SARS-CoV-2 evolution.}, }
@article {pmid39896535, year = {2025}, author = {Verwimp, S and Wagoner, J and Arenas, EG and De Coninck, L and Abdelnabi, R and Hyde, JL and Schiffer, JT and White, JM and Matthijnssens, J and Neyts, J and Polyak, SJ and Delang, L}, title = {Combinations of approved oral nucleoside analogues confer potent suppression of alphaviruses in vitro and in vivo.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39896535}, issn = {2692-8205}, abstract = {Alphaviruses such as chikungunya virus (CHIKV) pose a significant threat to global health, yet specific antiviral therapies remain unavailable. In this study, we evaluated combinations of three approved oral directly acting antiviral (DAA) drugs (sofosbuvir (SOF), molnupiravir (MPV) and favipiravir (FAV)) against CHIKV, Semliki Forest virus (SFV), Sindbis virus (SINV), and Venezuelan Equine Encephalitis virus (VEEV) in vitro and in vivo. In human skin fibroblasts, synergistic antiviral effects were observed for the drug combinations MPV + SOF and FAV + SOF against CHIKV, and for FAV + SOF against SFV. In human liver Huh7 cells, the combinations of FAV + MPV conferred additive to synergistic activity against VEEV and SINV strains, while SOF synergized with FAV against SINV strains. In a mouse model of CHIKV arthritis, MPV improved CHIKV-induced foot swelling and reduced systemic infectious virus titers. Combination treatment with suboptimal doses of MPV and SOF significantly reduced foot swelling and decreased infectious virus titers in serum as compared to single doses of each drug. Sequencing of CHIKV RNA from mouse joint tissue revealed that MPV caused dose-dependent increases in mutations in the CHIKV genome. Upon combination therapy of MPV with SOF, the number of mutations was significantly lower compared to single treatment with several higher doses of MPV. In summary, combining approved oral nucleoside analogs confers potent suppression of multiple alphaviruses in vitro and in vivo with enhanced control of viral genetic evolution in the face of antiviral drug pressure. These drug combinations may ultimately lead to the development of potent combinations of pan-family alphavirus inhibitors.}, }
@article {pmid39868184, year = {2025}, author = {Gen, R and Addetia, A and Asarnow, D and Park, YJ and Quispe, J and Chan, MC and Brown, JT and Lee, J and Campbell, MG and Lapointe, CP and Veesler, D}, title = {SARS-CoV-2 nsp1 mediates broad inhibition of translation in mammals.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39868184}, issn = {2692-8205}, abstract = {SARS-CoV-2 nonstructural protein 1 (nsp1) promotes innate immune evasion by inhibiting host translation in human cells. However, the role of nsp1 in other host species remains elusive, especially in bats which are natural reservoirs of sarbecoviruses and possess a markedly different innate immune system than humans. Here, we reveal that SARS-CoV-2 nsp1 potently inhibits translation in bat cells from Rhinolophus lepidus, belonging to the same genus as known sarbecovirus reservoirs hosts. We determined a cryo-electron microscopy structure of SARS-CoV-2 nsp1 bound to the Rhinolophus lepidus 40S ribosome and show that it blocks the mRNA entry channel via targeting a highly conserved site among mammals. Accordingly, we found that nsp1 blocked protein translation in mammalian cell lines from several species, underscoring its broadly inhibitory activity and conserved role in numerous SARS-CoV-2 hosts. Our findings illuminate the arms race between coronaviruses and mammalian host immunity (including bats), providing a foundation for understanding the determinants of viral maintenance in bat hosts and spillovers.}, }
@article {pmid39969870, year = {2025}, author = {Chen, J and Raymundo, C and Martinez, A and Lee, SJ and Stevenson, PA and Shinohara, MM}, title = {Histopathologic Grading of Acute Cutaneous Graft-vs-Host Disease and Nonrelapse Mortality.}, journal = {JAMA dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamadermatol.2024.6147}, pmid = {39969870}, issn = {2168-6084}, }
@article {pmid39969427, year = {2025}, author = {Levy, C and Naik, H and Overbey, J and Hedstrom, K and Wang, K and McDonough, C and Freeman, M and Keel, SB and Erwin, AL and Dickey, AK and Leaf, RK and Quigley, J and Mazepa, M and Wang, B and Phillips, J and Parker, C and McGuire, B and Kazamel, M and Bonkovsky, H and Rudnick, S and Anderson, KE and Moghe, A and Thapar, M and Saberi, B and Wheeden, K and Desnick, R and Balwani, M and , }, title = {Liver involvement in a large cohort of patients with erythropoietic protoporphyria or X-linked protoporphyria.}, journal = {Hepatology communications}, volume = {9}, number = {3}, pages = {}, doi = {10.1097/HC9.0000000000000657}, pmid = {39969427}, issn = {2471-254X}, mesh = {Humans ; Female ; *Protoporphyria, Erythropoietic/complications ; Male ; Adult ; Middle Aged ; *Liver/pathology ; Young Adult ; Adolescent ; Protoporphyrins/blood ; Genetic Diseases, X-Linked/complications ; Liver Diseases/etiology ; Child ; Longitudinal Studies ; Aged ; 5-Aminolevulinate Synthetase/deficiency ; }, abstract = {BACKGROUND: Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are characterized by the accumulation of protoporphyrin in the marrow, erythrocytes, plasma, skin, and liver, and present clinically with painful cutaneous phototoxicity. Liver abnormalities have been reported in over 25% of patients with EPP. Further characterization of liver involvement in protoporphyria is needed.<br><br>METHODS: Patients with EPP or XLP enrolled in the longitudinal studies of the NIH-supported Porphyrias Consortium were included. Medical history, laboratory, and liver histology data were abstracted and described.<br><br>RESULTS: A total of 322 patients were enrolled; 28 (8.7%) had XLP, 52% were female, and the median age at enrollment was 33.3 years. Liver chemistries were available for 235 patients, and 132 (56.2%) had abnormalities, mostly mild. Abnormal liver enzymes were associated with higher erythrocyte protoporphyrin levels. Eleven patients had advanced protoporphyric hepatopathy. In total, 54 (16.8%) underwent cholecystectomy, 8 (2.5%) had a liver transplant, 4 (1.2%) had a bone marrow transplant, and 8 (2.5%) died. At least 4 deaths were caused by liver failure due to protoporphyric hepatopathy, 2 were complications of bone marrow transplant, and 1 from HCC, which developed in a patient with EPP without cirrhosis. Patients with XLP were more likely to develop liver-related complications compared to EPP.<br><br>CONCLUSIONS: Liver abnormalities are common in patients with EPP and XLP. In this national registry, only 3.4% had protoporphyric hepatopathy, with most requiring a transplant. Of the deaths, 62.5% were attributable to liver disease. Further observations are needed for guiding hepatic evaluation and management of patients with protoporphyria with or without initial hepatic abnormalities.}, }
@article {pmid39969207, year = {2025}, author = {Mehta, RS and Lee, SJ and Gooley, TA and Thur, L and Dahlberg, A and Delaney, C and Gyurkocza, B and Vo, PT and Deeg, HJ and Milano, F}, title = {Long-Term Outcomes and Quality of Life with Treosulfan-Based Conditioning in Hematological Malignancies.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024015392}, pmid = {39969207}, issn = {2473-9537}, }
@article {pmid39966732, year = {2025}, author = {Chawana, TD and Walsh, SR and Stranix-Chibanda, L and Chirenje, ZM and Yu, C and Zhang, L and Seaton, KE and Heptinstall, J and Zhang, L and Paez, CA and Gamble, T and Karuna, ST and Andrew, P and Hanscom, B and Sobieszczyk, ME and Edupuganti, S and Gay, CL and Mannheimer, SB and Hurt, CB and Stephenson, KE and Polakowski, LL and Spiegel, H and Yacovone, M and Regenold, S and Yen, C and Baumblatt, JA and Gama, L and Barouch, DH and Piwowar-Manning, E and Koup, RA and Tomaras, GD and Hyrien, O and Roxby, AC and Huang, Y and , }, title = {Pharmacokinetic interaction assessment of an HIV broadly neutralizing monoclonal antibody VRC07-523LS: a cross-protocol analysis of three phase 1 trials in people without HIV.}, journal = {BMC immunology}, volume = {26}, number = {1}, pages = {8}, pmid = {39966732}, issn = {1471-2172}, support = {UM1 AI068614/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Adult ; *HIV Antibodies/immunology ; Female ; Male ; *Antibodies, Monoclonal/pharmacokinetics ; *HIV Infections/drug therapy/immunology ; Middle Aged ; Broadly Neutralizing Antibodies ; HIV-1/immunology ; Antibodies, Neutralizing/immunology ; Young Adult ; }, abstract = {VRC07-523LS is a safe and well-tolerated monoclonal antibody (mAb) targeting the CD4 binding site on the HIV envelope (Env) trimer. Efficacy of VRC07-523LS, in combination with mAbs targeting other HIV epitopes, will be evaluated in upcoming trials to prevent HIV acquisition in adults. However, differences in the pharmacokinetics (PK) of VRC07-523LS when administered alone vs. in combination with other mAbs have not been formally assessed. We performed a cross-protocol analysis of three clinical trials and included data from a total of 146 adults without HIV who received intravenous (n = 95) or subcutaneous (n = 51) VRC07-523LS, either alone ('single'; n = 100) or in combination with 1 or 2 other mAbs ('combined'; n = 46). We used an open, two-compartment population PK model to describe serum concentrations of VRC07-523LS over time, accounting for inter-individual variabilities. We compared individual-level PK parameters between the combined vs. single groups using the targeted maximum likelihood estimation method to adjust for participant characteristics. No significant differences were observed in clearance rate, inter-compartmental clearance, distribution half-life, or total VRC07-523LS exposure over time. However, for the combined group, mean central volume of distribution, peripheral volume of distribution, and elimination half-life were slightly greater, corresponding to slightly lower predicted concentrations early post-administration with high levels being maintained in both groups. These results suggest potential PK interactions between VRC07-523LS and other mAbs, but with small clinical impact in the context of HIV prevention. Our findings support coadministration of VRC07-523LS with other mAbs, and the use of the developed PK models to design future trials for HIV prevention.}, }
@article {pmid39966627, year = {2025}, author = {Bock, TJ and Colonne, CK and Fiorenza, S and Turtle, CJ}, title = {Outcome correlates of approved CD19-targeted CAR T cells for large B cell lymphoma.}, journal = {Nature reviews. Clinical oncology}, volume = {}, number = {}, pages = {}, pmid = {39966627}, issn = {1759-4782}, abstract = {CD19-targeted chimeric antigen receptor (CAR) T cells have provided a breakthrough in the treatment of patients with relapsed and/or refractory large B cell lymphoma (LBCL). Currently, three CD19-targeted CAR T cell products are approved by the FDA and various other regulators for the treatment of patients with LBCL: axicabtagene ciloleucel, tisagenlecleucel and lisocabtagene maraleucel. Response rates following infusion of these CD19-targeted CAR T cells have been promising; however, approximately half of treated patients show relapse within 2 years. Furthermore, receiving these agents can be associated with serious toxicities, including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. In this Review, we summarize the factors associated with the efficacy, including response and survival outcomes, and toxicity of CD19-targeted CAR T cells in pivotal clinical trials and large real-world datasets describing the outcomes of patients with LBCL who received treatment with these products.}, }
@article {pmid39965886, year = {2025}, author = {Attygalle, AD and Karube, K and Jeon, YK and Cheuk, W and Bhagat, G and Chan, JKC and Naresh, KN}, title = {The fifth edition of the WHO classification of mature T cell, NK cell and stroma-derived neoplasms.}, journal = {Journal of clinical pathology}, volume = {}, number = {}, pages = {}, doi = {10.1136/jcp-2025-210074}, pmid = {39965886}, issn = {1472-4146}, abstract = {The fifth edition of the WHO Classification of Haematolymphoid Tumors (WHO-HAEM5) introduces significant advancements in the understanding and diagnosis of mature T cell and NK cell, and stroma-derived neoplasms, and incorporates molecular and genetic data/findings accrued over the past years. The classification has been reorganised using a hierarchical system, employed across the fifth edition of the WHO classification of tumours of all organ systems. This review highlights recent developments, evolving concepts, and key updates since the revised fourth edition (WHO-HAEM4R). It enumerates the minimal/essential criteria necessary for diagnosis and classification, constituting not only the importance of clonality analysis in the workup of certain T cell neoplasms and the detection of infectious agents and specific genetic alterations in a subset of entities but also the applicability of these criteria in resource-constrained settings. 'Stroma-derived neoplasms of lymphoid tissues discussed in this review is a new category introduced in HAEM5 that encompasses mesenchymal tumours occurring exclusively in lymph nodes and spleen and mesenchymal dendritic cell neoplasms previously classified as 'histiocytic/dendritic cell neoplasms'.}, }
@article {pmid39965175, year = {2025}, author = {Hansen, DK and Peres, LC and Dima, D and Richards, A and Shune, L and Afrough, A and Midha, S and Dhakal, B and Kocoglu, MH and Atrash, S and Ferreri, C and Castaneda, O and Davis, JA and Bhurtel, E and McGuirk, J and Wagner, C and Bansal, R and Costello, P and Smith, K and Lieberman-Cribbin, A and De Avila, G and Purvey, S and Hosoya, H and Mikkilineni, L and Oswald, LB and Kaur, G and Pasvolsky, O and Gaballa, M and Herr, MM and Forsberg, P and Janakiram, M and Htut, M and Asoori Maringanti, S and Kalariya, N and Hashmi, H and Reshef, R and Sborov, DW and Nadeem, O and Anwer, F and Khouri, J and Raza, S and Atanackovic, D and Alsina, M and Freeman, CL and Locke, FL and Voorhees, P and Anderson, LD and Richard, S and Martin, T and Lin, Y and Patel, KK and Sidana, S and , }, title = {Comparison of Standard-of-Care Idecabtagene Vicleucel and Ciltacabtagene Autoleucel in Relapsed/Refractory Multiple Myeloma.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2401730}, doi = {10.1200/JCO-24-01730}, pmid = {39965175}, issn = {1527-7755}, abstract = {PURPOSE: Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), two B-cell maturation antigen-directed chimeric antigen receptor (CAR) T-cell therapies have demonstrated remarkable efficacy in relapsed/refractory multiple myeloma (RRMM). We compare safety, efficacy, and survival among patients with RRMM treated with standard-of-care (SOC) ide-cel or cilta-cel.<br><br>METHODS: Data were from a retrospective chart review of patients with RRMM leukapheresed by December 31, 2022, with the intent to receive SOC ide-cel or cilta-cel at 19 institutions. An inverse probability of treatment weighting (IPTW) approach was used to compare outcomes by therapy type.<br><br>RESULTS: A total of 641 patients were leukapheresed by December 31, 2022, with ide-cel (n = 386) and cilta-cel (n = 255). Five hundred eighty-six patients were infused (n = 350 for ide-cel; n = 236 for cilta-cel) with a median follow-up of 12.6 and 13.0 months for ide-cel and cilta-cel, respectively. After IPTW, patient characteristics were well balanced. Cilta-cel was associated with higher likelihood of grade &#x2265;3 cytokine release syndrome (CRS; odds ratio [OR], 6.80 [95% CI, 2.28 to 20.33]), infections (OR, 2.03 [95% CI, 1.41 to 2.92]), second primary malignancies (OR, 1.77 [95% CI, 0.89 to 3.56]), and delayed neurotoxicity (OR, 20.07 [95% CI, 4.46 to 90.20]). Cilta-cel was also associated with better treatment responses (&#x2265;complete response: OR, 2.42 [95% CI, 1.63 to 3.60]), longer progression-free survival (hazard ratio [HR], 0.48 [95% CI, 0.36 to 0.63]), and longer overall survival (HR, 0.67 [95% CI, 0.46 to 0.97]). No associations were observed between therapy type and immune effector cell-associated neurotoxicity syndrome, any CRS, severe cytopenia at days 30 and 90, or nonrelapse mortality. We observed consistent findings when repeating the analyses restricting the ide-cel cohort to patients infused during the same time period as Food and Drug Administration approval for cilta-cel (&#x2265;March 2022).<br><br>CONCLUSION: Cilta-cel demonstrated superior efficacy and survival, with higher incidence of certain toxicities, compared with ide-cel.}, }
@article {pmid39964269, year = {2025}, author = {Lawson, MB and Zhu, W and Miglioretti, DL and Onega, T and Henderson, LM and Rauscher, GH and Kerlikowske, K and Sprague, BL and Bowles, EJA and O'Meara, ES and Tosteson, ANA and diFlorio-Alexander, RM and Hubbard, RA and Lee, JM and Lee, CI}, title = {Disparities in Standard-of-Care, Advanced, and Same-Day Diagnostic Services among Patients with Abnormal Screening Mammography.}, journal = {Radiology}, volume = {314}, number = {2}, pages = {e241673}, doi = {10.1148/radiol.241673}, pmid = {39964269}, issn = {1527-1315}, mesh = {Humans ; Female ; *Mammography/statistics &amp; numerical data/methods ; Middle Aged ; Aged ; Retrospective Studies ; *Breast Neoplasms/diagnostic imaging ; Adult ; *Healthcare Disparities/ethnology ; Aged, 80 and over ; *Early Detection of Cancer/methods ; United States ; Health Services Accessibility ; Biopsy/statistics &amp; numerical data ; }, abstract = {Background Diagnostic imaging and biopsy are used to evaluate abnormal screening mammography. Differences in on-site availability and receipt of these diagnostic services may contribute to disparities in breast cancer outcomes across sociodemographic groups. Purpose To identify multilevel factors associated with on-site availability and receipt of diagnostic imaging and biopsy after screening mammography. Materials and Methods This retrospective study included female patients (age range, 40-89 years) who underwent screening mammography at 136 facilities in the United States from January 2010 to December 2020. The primary exposure variables were race and ethnicity and neighborhood-level educational attainment, household income, and rurality. The adjustment variables were age, breast density, breast biopsy history, personal and family history of breast cancer, time from prior mammographic examination to screening mammography, screening modality, facility academic affiliation, and screening examination year. The relative risk (RR) of factors for on-site availability at screening facilities and undergoing standard-of-care imaging (ie, mammography and/or US) and advanced diagnostic imaging (ie, digital breast tomosynthesis, MRI) and biopsy, and undergoing any same-day diagnostic service and biopsy were estimated using modified Poisson regression. Results In total, 1 123 177 female patients (median age, 59 years; IQR, 51-67 years) underwent 3 519 502 screening mammographic examinations: 10.3% Asian patients (362 440 of 3 519 502), 12.7% Black patients (447 777 of 3 519 502), 6.5% Hispanic patients (227 177 of 3 519 502), 68.3% White patients (2 403 159 of 3 519 502), and 2.2% all other races and ethnicities (78 949 of 3 519 502). In most fully adjusted models, race or ethnicity and neighborhood-level socioeconomic status were not associated with on-site diagnostic service availability. However, compared with White patients, patients belonging to racial and ethnic minority groups were less likely to undergo same-day diagnostic services after abnormal screening mammography (Asian patients: RR, 0.74 [95% CI: 0.64, 0.85]; Black patients: RR, 0.56 [95% CI: 0.49, 0.63]; Hispanic patients: RR, 0.61 [95% CI: 0.52, 0.71]). Black patients were less likely to undergo same-day biopsies after an abnormal diagnostic workup (RR, 0.46; 95% CI: 0.33, 0.65). Conclusion Although no evidence existed that on-site diagnostic service availability varied by race and ethnicity in most models, patients in racial and ethnic minority groups were less likely to be provided same-day diagnostic services and Black patients were less likely to undergo same-day biopsy. © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Mullen in this issue.}, }
@article {pmid39963309, year = {2025}, author = {Wadden, E and Lai, C and Grivas, P and Bhatia, S and Portuguese, AJ and Salem, JE and Moslehi, JJ and Cheng, RK}, title = {Successful treatment of immune checkpoint inhibitor-associated fulminant myocarditis with abatacept and ruxolitinib: a case report.}, journal = {European heart journal. Case reports}, volume = {9}, number = {2}, pages = {ytaf019}, pmid = {39963309}, issn = {2514-2119}, abstract = {BACKGROUND: Immune checkpoint inhibitors (ICIs) are a class of cancer immunotherapy with growing indications for treatment of various malignancies. Immune checkpoint inhibitors are monoclonal antibodies that block inhibitory pathways in immune cells, including cytotoxic T lymphocyte antigen-4 (CTLA4), programmed death 1 receptor (PD1), and programmed cell death ligand-1 (PDL1), to activate the immune system. However, these agents can disrupt self-tolerance and lead to immune-related adverse events. Fulminant myocarditis, a feared complication of ICIs, can be highly fatal, and there is a need for effective treatment options.<br><br>CASE SUMMARY: A 70-year-old patient with recurrent metastatic disease of urothelial carcinoma subsequently developed fulminant myocarditis after receiving eight cycles of pembrolizumab. He developed cardiogenic shock and required inotropes and a percutaneous microaxial flow pump placement for temporary mechanical circulatory support. He received methylprednisolone initially and then was started on second-line immunosuppression agents, ruxolitinib and abatacept, for steroid-refractory myocarditis. Abatacept is thought to inhibit activation of T-cell CTLA4 and PD1/PDL1 pathways and reverse ICI-activated pathways. Ruxolitinib is a Janus kinase inhibitor that impairs immune activation through suppressing cytokine sensing and production and T-cell activation. After these treatments, the patient subsequently clinically improved and his myocarditis resolved.<br><br>DISCUSSION: This case highlights ICI myocarditis refractory to corticosteroids leading to treatment with second-line immunosuppression. As immunotherapies are increasingly applied to a broader range of cancers, further research is needed to evaluate the optimal treatment strategy for ICI-related myocarditis and other immune-related adverse events.}, }
@article {pmid39962532, year = {2025}, author = {Hunter, NB and Peterson, LM and Specht, JM and Mankoff, DA and Muzi, M and Chen, DL and Gwin, WR and Vinayak, S and Davidson, NE and Linden, HM}, title = {Fluoroestradiol (FES) and Fluorodeoxyglucose (FDG) PET imaging in patients with ER+, HER2-positive or HER2-negative metastatic breast cancer.}, journal = {Breast cancer research : BCR}, volume = {27}, number = {1}, pages = {23}, pmid = {39962532}, issn = {1465-542X}, support = {CA72064/NH/NIH HHS/United States ; CA42045/NH/NIH HHS/United States ; }, mesh = {Humans ; Female ; *Fluorodeoxyglucose F18 ; *Breast Neoplasms/pathology/metabolism/diagnostic imaging/drug therapy/mortality ; *Receptor, ErbB-2/metabolism ; *Receptors, Estrogen/metabolism ; Middle Aged ; *Positron-Emission Tomography/methods ; Retrospective Studies ; Aged ; Adult ; *Estradiol/analogs &amp; derivatives ; Neoplasm Metastasis ; Radiopharmaceuticals ; Aged, 80 and over ; }, abstract = {BACKGROUND: [18]F-Fluorodeoxyglucose (FDG) and [18]F-Fluorestradiol (FES) have been FDA approved for measuring tumor glycolytic activity and estrogen receptor (ER) uptake, respectively, in clinical positron emission tomography (PET) imaging for patients with hormone-receptor (HR) positive metastatic breast cancer (MBC), but little is known about its utility in patients with breast tumors that overexpress human epidermal growth factor 2 (HER2). We hypothesize that comparing patterns of FDG and FES uptake in patients with HER2-positive versus HER2-negative MBC can guide further biologic and clinical studies into the HR/HER2-positive phenotype.<br><br>METHODS: We conducted a retrospective study examining uptake in matched lesions for FES and FDG-PET scans, assessing these parameters in 213 patients with ER-positive/HER2-positive (n&#x2009;=&#x2009;33) versus ER-positive/HER2-negative MBC (n&#x2009;=&#x2009;180). We employed log-rank and t-tests to assess the association of HER2 status with outcome variables and the hypotheses that patients expressing HER2-positive disease lived longer than patient with HER2-negative disease.<br><br>RESULTS: No difference in FES or FDG avidity was observed between patients with HER2-negative or HER2-positive tumor status. Limited data also suggests that patients with HER2-positive disease had better overall survival (p&#x2009;=&#x2009;0.024), than those with HER2-negative disease, but not time-to-progression between the same patient cohorts.<br><br>CONCLUSION: This retrospective analysis suggests that there is a possible role for future trials using FES-PET in helping to select patients with ER+/HER2-positive primary tumors who retain ER expression at all sites of disease and may benefit from endocrine therapy.}, }
@article {pmid39962220, year = {2025}, author = {Gang, M and Othus, M and Sandmaier, BM and Davis, C and Basom, RS and Walter, RB}, title = {Modulators of relapse risk in adults allografted for acute myeloid leukemia in measurable residual disease-positive remission.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, pmid = {39962220}, issn = {1476-5365}, support = {T32-HL007093//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; P01-CA078902//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P01-CA018029//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P30-CA015704//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; }, }
@article {pmid39961473, year = {2025}, author = {Munshi, PN and Olin, RL and Wall, S and McCurdy, SR and Al-Juhaishi, T and Baker, J and Bhatt, VR and Chokr, N and Dahi, P and DeFilipp, Z and Espinoza-Gutarra, M and Farhan, S and Gowda, L and Hamilton, BK and Inamoto, Y and Jayani, R and Kharfan-Dabaja, MA and Lin, R and Meyers, G and Mishra, A and Murthy, HS and Nawas, M and Rosko, AE and Ruiz, M and Sorror, ML and Sung, AD and Carpenter, PA and Hamadani, M and Artz, AS}, title = {US Geriatric Assessment Practices for Older Adults Undergoing Hematopoietic Cell Transplantation or CAR T- cell therapy: An ASTCT Physician Survey from the Aging Special Interest Group and Committee on Practice Guidelines.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.02.014}, pmid = {39961473}, issn = {2666-6367}, abstract = {Geriatric assessment (GA) may identify vulnerabilities and promote risk-stratification in older adults predisposed to toxicities after autologous (auto), allogeneic (allo) hematopoietic cell transplantation (HCT) and chimeric antigen T-cell therapies (CAR T). With increased utilization cellular therapies for older adults the American Society for Transplantation and Cellular Therapy (ASTCT) Committee on Practice Guidelines and its Special Interest Group for Aging (SIG) conducted an online cross-sectional survey between April 2023 and August 2023 to determine transplantation and cellular therapy physicians' practice patterns regarding GA in older patients receiving HCT and CAR T-cell therapies. E-mail surveys were sent to 1168 ASTCT physician members and only 96 (8.2%) respondents completed the survey. Most (86%) were affiliated with university/teaching centers and 70% had a combined HCT and cellular therapy practice. More than 50% of respondents were interested in pursuing GA but 68% described barriers. The top two recognized barriers to GA were lack of time (96%) and clinical support staff (90%). Despite interest, only 15% respondents reported to know the domains of GA 'well'. Among those using GA, the minimum age used for routine GA was 65 years for allo-HCT and CAR T in over 91% respondents. Taken together, we recommend the HCT community leadership and GA experts combine efforts to address the gap in GA uptake and implementation.}, }
@article {pmid39960754, year = {2025}, author = {Estevam, GO and Linossi, E and Rao, J and Macdonald, CB and Ravikumar, A and Chrispens, KM and Capra, JA and Coyote-Maestas, W and Pimentel, H and Collisson, EA and Jura, N and Fraser, JS}, title = {Mapping kinase domain resistance mechanisms for the MET receptor tyrosine kinase via deep mutational scanning.}, journal = {eLife}, volume = {13}, number = {}, pages = {}, pmid = {39960754}, issn = {2050-084X}, support = {GM145238/GM/NIGMS NIH HHS/United States ; R01 CA239604/CA/NCI NIH HHS/United States ; LM013434/NH/NIH HHS/United States ; S10 OD028511/OD/NIH HHS/United States ; R35 GM145238/GM/NIGMS NIH HHS/United States ; CA239604/CA/NCI NIH HHS/United States ; R01 LM013434/LM/NLM NIH HHS/United States ; }, mesh = {*Proto-Oncogene Proteins c-met/genetics/metabolism ; Humans ; *Protein Kinase Inhibitors/pharmacology ; *Mutation ; *Drug Resistance, Neoplasm/genetics ; Protein Domains ; DNA Mutational Analysis/methods ; }, abstract = {Mutations in the kinase and juxtamembrane domains of the MET Receptor Tyrosine Kinase are responsible for oncogenesis in various cancers and can drive resistance to MET-directed treatments. Determining the most effective inhibitor for each mutational profile is a major challenge for MET-driven cancer treatment in precision medicine. Here, we used a deep mutational scan (DMS) of ~5764 MET kinase domain variants to profile the growth of each mutation against a panel of 11 inhibitors that are reported to target the MET kinase domain. We validate previously identified resistance mutations, pinpoint common resistance sites across type I, type II, and type I ½ inhibitors, unveil unique resistance and sensitizing mutations for each inhibitor, and verify non-cross-resistant sensitivities for type I and type II inhibitor pairs. We augment a protein language model with biophysical and chemical features to improve the predictive performance for inhibitor-treated datasets. Together, our study demonstrates a pooled experimental pipeline for identifying resistance mutations, provides a reference dictionary for mutations that are sensitized to specific therapies, and offers insights for future drug development.}, }
@article {pmid39959858, year = {2025}, author = {Ninga, X and Sun, Y and Pan, Y and Gilbert, PB}, title = {Regression analysis of semiparametric Cox-Aalen transformation models with partly interval-censored data.}, journal = {Electronic journal of statistics}, volume = {19}, number = {1}, pages = {240-290}, pmid = {39959858}, issn = {1935-7524}, support = {R37 AI054165/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; }, abstract = {Partly interval-censored data, comprising exact and intervalcensored observations, are prevalent in biomedical, clinical, and epidemiological studies. This paper studies a flexible class of the semiparametric Cox-Aalen transformation models for regression analysis of such data. These models offer a versatile framework by accommodating both multiplicative and additive covariate effects and both constant and time-varying effects within a transformation, while also allowing for potentially time-dependent covariates. Moreover, this class of models includes many popular models such as the semiparametric transformation model, the Cox-Aalen model, the stratified Cox model, and the stratified proportional odds model as special cases. To facilitate efficient computation, we formulate a set of estimating equations and propose an Expectation-Solving (ES) algorithm that guarantees stability and rapid convergence. Under mild regularity assumptions, the resulting estimator is shown to be consistent and asymptotically normal. The validity of the weighted bootstrap is also established. A supremum test is proposed to test the time-varying covariate effects. Finally, the proposed method is evaluated through comprehensive simulations and applied to analyze data from a randomized HIV/AIDS trial.}, }
@article {pmid39956433, year = {2025}, author = {Wilson, MH and Harrington, J and Suh, J and Fearon, C and Reavis, M and Srisatidnarakul, S and Swetky, M and Warren, N and Badalucco, A and Adams Barker, CM and Nandakumar, S and Pergam, SA}, title = {Isolation Precautions Associated with COVID-19 Infections Among Immunocompromised Populations: A Multi-Center Study of Nine National Cancer Institute-Designated Comprehensive Cancer Centers.}, journal = {American journal of infection control}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajic.2025.02.002}, pmid = {39956433}, issn = {1527-3296}, abstract = {BACKGROUND: Nine Comprehensive Cancer Centers sought to understand COVID-19 infection management experiences through the pandemic to improve future immunocompromised host guideline development.<br><br>METHODS: Volunteers from Comprehensive Cancer Center Infection Prevention and Control (C3IC) completed two surveys on COVID-19 practices from March 2020 to December 2023. Three reviewers independently validated qualitative analysis of findings. Virtual meetings were leveraged to review information gathered, discuss findings, and identify themes among respondents.<br><br>RESULTS: 100% (9/9) of respondents changed in COVID-19-associated isolation discontinuation guidance at least once. All (9/9) included patient immune status as criterion. All (9/9) required PCR clearance testing at some point in the pandemic, 6 of 9 (66%) continued to require clearance testing at the time of the survey; Only 1 of 9 (11%) allowed antigen testing to meet criteria. Cycle threshold (CT) values were inconsistently referenced and considered related to isolation management. Seven isolation titles were noted across 9 institutions, despite near agreement on measures employed.<br><br>DISCUSSION: Variability existed in COVID-19 management among study participants despite serving similar populations, which may stem from limited data supporting understanding of viral transmissibility in immunocompromised hosts.<br><br>CONCLUSIONS: Guideline development for immunocompromised hosts, potential drivers for viral evolution, can lack clarity for consistent management of the population. Engaging subject matters in these populations in future guideline development will improve infection prevention in healthcare settings.}, }
@article {pmid39955465, year = {2025}, author = {Chow, EJ and Blythe, NA and Cushing-Haugen, KL and Duggan, C and Baker, KS and Cole, AM and Green, S and Guiterrez, AI and Lee, E and Linden, HM and Mendoza, JA and Ohlsen, TJD and Ortblad, KF and Schwartz, SM and Yung, RL and Ceballos, RM}, title = {Enhancing survivorship care among Hispanic/Latino cancer survivors via lay health educators: results of a pilot randomized trial.}, journal = {Journal of cancer survivorship : research and practice}, volume = {}, number = {}, pages = {}, pmid = {39955465}, issn = {1932-2267}, support = {CA015704/NH/NIH HHS/United States ; CA258105/NH/NIH HHS/United States ; CA258105/NH/NIH HHS/United States ; CA015704/NH/NIH HHS/United States ; CA015704/NH/NIH HHS/United States ; 75N91020C00005/NH/NIH HHS/United States ; CA258105/NH/NIH HHS/United States ; CA015704/NH/NIH HHS/United States ; HHSN261201800004I/NH/NIH HHS/United States ; CA258105/NH/NIH HHS/United States ; }, abstract = {PURPOSE: Assess the feasibility, acceptability, and preliminary efficacy of lay health educators to enhance Hispanic/Latino survivors' knowledge of their cancer history, screening needs, and health-related self-efficacy.<br><br>METHODS: Hispanic/Latino survivors diagnosed within 5&#xa0;years were recruited from three clinics and a regional cancer registry. Survivors were randomized to receive a personalized survivorship care plan (SCP; control) or SCP plus telephone session with a bilingual-bicultural lay health educator (intervention). Survivors were reassessed after 3&#xa0;months. Primary outcomes were feasibility (meeting accrual, n&#x2009;=&#x2009;60-100) and acceptability of the SCP and education session. Secondary outcomes were changes in survivors' knowledge of their cancer history, screening needs, and health-related self-efficacy.<br><br>RESULTS: Ninety-fine survivors (median age 55&#xa0;years, 78% female, 56% low/marginal health literacy) were randomized (n&#x2009;=&#x2009;48 intervention). Seventy-nine completed the study; most found the SCP useful (82% intervention; 68% control); 84% of the intervention group rated the education session useful. Over time, both groups had improved knowledge of their cancer history (accuracy increased from 71.5&#x2009;&#xb1;&#x2009;16.4% to 73.8&#x2009;&#xb1;&#x2009;15.0%; p&#x2009;=&#x2009;0.19) although differences over time and between groups were not statistically significant. At follow-up compared with baseline, participants were more likely to report plans for future screening: cervical (57% versus 31%, p&#x2009;=&#x2009;0.002); colorectal (39% versus 26%, p&#x2009;=&#x2009;0.10). Although the change in self-efficacy did not differ between study groups, self-efficacy significantly improved within the control group over time (0.3; 95% CI 0.1, 0.5).<br><br>CONCLUSIONS: Hispanic/Latino survivors found the SCP and education session acceptable. SCPs alone may improve knowledge and adherence to cancer screening.<br><br>Provision of a SCP may benefit Hispanic/Latino survivors.<br><br>CLINICAL TRIAL REGISTRATION: clinicaltrials.gov NCT04081779.}, }
@article {pmid39954698, year = {2025}, author = {Ortblad, KF and Ngure, K}, title = {Safety of dapivirine vaginal rings during breastfeeding.}, journal = {The lancet. HIV}, volume = {}, number = {}, pages = {}, doi = {10.1016/S2352-3018(24)00342-4}, pmid = {39954698}, issn = {2352-3018}, }
@article {pmid39954697, year = {2025}, author = {Noguchi, LM and Owor, M and Mgodi, NM and Gati Mirembe, B and Dadabhai, S and Horne, E and Gundacker, H and Richardson, BA and Bunge, K and Scheckter, R and Song, M and Marzinke, MA and Anderson, PL and Livant, E and Jacobson, C and Piper, JM and Chakhtoura, N and Hillier, SL and Balkus, JE and , }, title = {Safety and drug quantification of the dapivirine vaginal ring and oral pre-exposure prophylaxis in breastfeeding mother-infant pairs (MTN-043): a phase 3B, open-label, randomised trial.}, journal = {The lancet. HIV}, volume = {}, number = {}, pages = {}, doi = {10.1016/S2352-3018(24)00306-0}, pmid = {39954697}, issn = {2352-3018}, abstract = {BACKGROUND: In 2021, WHO recommended dapivirine vaginal rings (DVRs) for HIV prevention, but noted evidence gaps for breastfeeding populations. This trial aimed to describe safety profiles associated with DVRs and oral pre-exposure prophylaxis (PrEP) use during breastfeeding and to summarise study-drug quantification and concentrations for mothers and infants.<br><br>METHODS: Microbicide Trials Network (MTN)-043 was a phase 3b, open-label, randomised trial in which mother-infant pairs were recruited from local health facilities and enrolled at four HIV clinical trial sites in Malawi, South Africa, Uganda, and Zimbabwe. Eligible mothers (aged &#x2265;18 years) were HIV-negative, exclusively breastfeeding one infant (aged 6-12 weeks, birthweight &#x2265;2000 g), and had not been exposed to HIV post-exposure prophylaxis in the previous 6 months. Mother-infant pairs were randomly assigned (3:1) via a computer-generated sequence to 12 weeks of 25 mg monthly DVR or daily oral PrEP (200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate), with stratification by site using a permuted block design. Participants and staff were aware of study product assignment. Primary outcomes were maternal and infant safety (all serious adverse events and grade 3 or worse adverse events) and drug concentrations, which were measured in maternal plasma, maternal blood, breastmilk, infant plasma, and infant blood. All mother-infant pairs who received at least one dose of study product were included in the primary safety analysis, and those with at least one post-enrolment drug concentration result were included in the drug quantification analysis. The trial was registered at ClinicalTrials.gov (NCT04140266).<br><br>FINDINGS: Between Sept 24, 2020, and July 29, 2021, 197 mother-infant pairs enrolled (148 on DVR and 49 on PrEP), all of whom received at least one dose of study product and were included in the primary safety analysis. Two (1%) of 148 mothers in the DVR group had serious adverse events, and three (2%) in the DVR group and two (4%) in the oral PrEP group had a grade 3 or worse adverse event; four (3%) of 148 infants in the DVR group had a serious adverse event, and ten (7%) in the DVR group and one (2%) in the oral PrEP group had a grade 3 or worse adverse event. No mother or infant in the oral PrEP group had a serious adverse event. No HIV infections were detected. 144 participants in the DVR group and 48 in the oral PrEP group had at least one post-enrolment drug concentration result. Quantifiable median dapivirine concentrations ranged from 656&#xb7;0 (IQR 407&#xb7;0-878&#xb7;0) pg/mL at week 1 to 558&#xb7;5 (282&#xb7;0-778&#xb7;0) pg/mL at month 3, but were observed infrequently (5-15%) in specimens from infants, with median concentrations below the limit of quantification at all visits. Median tenofovir diphosphate concentrations ranged from 263&#xb7;0 (193&#xb7;0-363&#xb7;0) fmol/punch at week 1 to 777&#xb7;0 (381&#xb7;0-1241&#xb7;0) fmol/punch at month 3, but were not observed in specimens from infants, with all concentrations below the limit of quantification at all visits.<br><br>INTERPRETATION: Increased risk of HIV acquisition in the postnatal period, favourable product safety profile, and low drug exposures among infants support the recommendation for DVRs as an additional HIV prevention choice during breastfeeding.<br><br>FUNDING: US National Institutes of Health.}, }
@article {pmid39953849, year = {2025}, author = {Dontchos, BN and Phelps, MD and Rahbar, H and Lam, DL}, title = {Pre-Treatment Breast MRI: Clinical Indications, Outcomes, and Future Directions.}, journal = {Journal of magnetic resonance imaging : JMRI}, volume = {}, number = {}, pages = {}, doi = {10.1002/jmri.29741}, pmid = {39953849}, issn = {1522-2586}, abstract = {Breast MRI is the most sensitive modality for assessing the extent of disease in patients with newly-diagnosed breast cancer because it identifies clinically- and mammographically-occult breast cancers. Though highly sensitive, breast MRI has lower specificity that may result in false positive findings and potential overestimation of disease if additional MRI findings are not biopsied prior to surgery. It had been anticipated that the superior cancer detection rate of pre-treatment MRI would translate to improved immediate (surgical re-excision) and long-term patient outcomes such as breast cancer recurrence and survival rates, but studies have not necessarily supported this assumption. In this review, current recommendations and utilization of breast MRI for pre-treatment local staging of breast cancer will be presented, with an emphasis on specific clinical scenarios for patient selection and its impact on short- and long-term patient clinical outcomes. We will also present new evidence that pre-treatment MRI may support de-escalation of treatment and discuss emerging advanced MRI techniques that may improve diagnostic performance.}, }
@article {pmid39953405, year = {2025}, author = {Soussand, F and Abdou, AY and Sanchez, M and Huynh, BT and Giese, C and Tran-Kiem, C and Béraud, G and Guillemot, D and Cauchemez, S and Opatowski, L and Bosetti, P}, title = {Evolution of social contacts patterns in France over the SARS-CoV-2 pandemic: results from the SocialCov survey.}, journal = {BMC infectious diseases}, volume = {25}, number = {1}, pages = {224}, pmid = {39953405}, issn = {1471-2334}, mesh = {Humans ; *COVID-19/epidemiology/transmission/prevention &amp; control ; France/epidemiology ; Adult ; Middle Aged ; Male ; Female ; Surveys and Questionnaires ; Aged ; Adolescent ; *SARS-CoV-2 ; Young Adult ; *Contact Tracing ; Child ; Pandemics ; Child, Preschool ; Infant ; Aged, 80 and over ; Quarantine ; }, abstract = {BACKGROUND: Non-pharmaceutical measures such as lockdowns, curfews and place closures were implemented in France during 2020-2022 to reduce contacts in the population, to limit the spread of SARS-CoV-2 and reduce COVID-19 healthcare burden. Individuals also changed their behaviours as a response to the pandemic. Here, we present the results of the SocialCov survey that characterise the evolution of contacts in France between December 2020 and May 2022 to better understand the short and long term impact of these interventions on social mixing.<br><br>METHODS: A questionnaire was advertised over six independent communication campaigns through the governmental application TousAntiCovid between December 2020 and June 2022. Participants were asked to detail social contacts in the previous day, including contact age, location, duration and type (physical/conversational).<br><br>RESULTS: Over the six distinct campaigns, 44,396 individuals participated in the survey, declaring 300,735 contacts in total. The patterns of contacts strongly evolved over time, along with the progressive easing of national mitigation measures. The number of contacts in the French population increased from 5.3 contacts per day on average in December 2020 to 9.7 in May 2022. Mixing patterns were affected by age of participants, holidays and weekends. Healthcare workers declared 18.4 contacts on average during working days, roughly twice more than other workers. Reported risk perception changed throughout the two year period.<br><br>CONCLUSIONS: Results provide a detailed picture of contact evolution over the years 2020-2022 in France. In addition to a major evolution of contact density over time, this study highlights strong heterogeneities in contact patterns according to age, employment and weekend/vacation periods. The contact matrices provided here can be used to inform age-stratified transmission models of respiratory pathogens in the context of implementation of multiple non-pharmaceutical measures.}, }
@article {pmid39951468, year = {2025}, author = {Chen, KY and Toro-Moreno, M and Subramaniam, AR}, title = {GitHub enables collaborative and reproducible laboratory research.}, journal = {PLoS biology}, volume = {23}, number = {2}, pages = {e3003029}, pmid = {39951468}, issn = {1545-7885}, mesh = {*Software ; Laboratories ; Reproducibility of Results ; Humans ; Cooperative Behavior ; Workflow ; }, abstract = {GitHub, a platform widely used in software development, offers a robust framework for documenting all activities of laboratory research projects. This Community Page highlights the benefits of, and provides guidance for, incorporating the GitHub ecosystem into "wet" lab workflows.}, }
@article {pmid39951264, year = {2025}, author = {Chung, DH and Caverly, TJ and Schipper, MJ and Hofer, TP and Gulati, R and Rose, BS and Caram, MEV and Tsao, PA and Stensland, KD and Elliott, D and Saini, SD and Bryant, AK}, title = {Prostate Cancer Mortality in Men Aged 70 Years Who Recently Underwent Prostate-Specific Antigen Screening.}, journal = {JAMA network open}, volume = {8}, number = {2}, pages = {e2459766}, pmid = {39951264}, issn = {2574-3805}, mesh = {Humans ; Male ; *Prostatic Neoplasms/mortality/diagnosis/blood ; *Prostate-Specific Antigen/blood ; Aged ; *Early Detection of Cancer/methods/statistics &amp; numerical data ; Cohort Studies ; United States/epidemiology ; Risk Assessment/methods ; Mass Screening/methods/statistics &amp; numerical data ; }, abstract = {IMPORTANCE: Continuing prostate-specific antigen (PSA) screening after age 70 years might benefit men at high risk of prostate cancer-specific mortality (PCSM) or metastatic prostate cancer (mPCa), but the relative value of clinical factors (race and ethnicity, competing mortality, and PSA history) in identifying men at higher vs lower risk is unknown.<br><br>OBJECTIVE: To examine the value of PSA levels, race and ethnicity, and competing mortality in risk stratification for PCSM and mPCa in men after age 70 years.<br><br>In this cohort study, clinical data of all men receiving health care through the Veterans Health Administration who turned age 70 years between 2008 and 2020 and had a normal screening PSA value between age 65 and 69 years (<4 ng/mL [baseline PSA]) and no prior history of prostate cancer or biopsy were examined. The data cutoff date was December 26, 2023.<br><br>EXPOSURE: The most recent screening PSA value from age 65 to 69 years, self-reported race and ethnicity, and competing mortality risk derived from a machine learning model.<br><br>MAIN OUTCOME AND MEASURES: The 10-year absolute risk of PCSM and mPCa were determined using regression modeling.<br><br>RESULTS: The cohort included 921&#x202f;609 men who turned 70 years between 2008 and 2020; 11% of whom self-reported as Black and 82% as White race. Between age 65 and 70 years, 45% of patients had a baseline PSA of less than 1.00 ng/mL, and 32% had a baseline PSA of 1.00 to 1.99 ng/mL. Most patients (87%) continued to undergo screening past age 70 years, with little variation by competing mortality risk or race and ethnicity. The 10-year cumulative incidence of PCSM was 0.26% overall, and 95% of men had a 10-year risk less than 0.73%. Higher baseline PSA level between age 65 and 69 years was associated with 10-year PCSM risk (0.79% for 3.00-3.99 ng/mL vs 0.10% for 0.20-0.99 ng/mL), race and ethnicity (0.36% for Black vs 0.25% for White), and competing mortality (0.24% for the highest quintile vs 0.21% for the lowest quintile). Similar results were found for mPCa. Low PSA (0.20-0.99 ng/mL) was associated with very low PCSM and mPCa risk, even among Black men in the healthiest quintile of competing mortality risk (10-year PCSM risk, 0.08% [95% CI, 0.01%-0.44%]; 10-year mPCa risk 0.24% [95% CI, 0.10%-0.52%]).<br><br>CONCLUSIONS AND RELEVANCE: In this cohort study, the findings suggest that most men receiving care through the VHA continue PSA screening after age 70 years despite low absolute 10-year PCSM risks. The PSA values from age 65 to 69 years may be highly informative for adverse prostate cancer outcomes after age 70 years, with a PSA less than 1 ng/mL associated with a very low risk of long-term PCSM and mPCa.}, }
@article {pmid39951243, year = {2025}, author = {Javid, SH and Kazerouni, AS and Hippe, DS and Hirano, M and Schnuck-Olapo, J and Biswas, D and Bryant, ML and Li, I and Xiao, J and Kim, AG and Guo, A and Dontchos, B and Kilgore, M and Kim, J and Partridge, SC and Rahbar, H}, title = {ASO Visual Abstract: Preoperative MRI to Predict Upstaging of DCIS to Invasive Cancer at Surgery.}, journal = {Annals of surgical oncology}, volume = {}, number = {}, pages = {}, doi = {10.1245/s10434-025-16994-7}, pmid = {39951243}, issn = {1534-4681}, }
@article {pmid39950338, year = {2025}, author = {Iyer, KR and Clarke, SL and Guarischi-Sousa, R and Gjoni, K and Heath, AS and Young, EP and Stitziel, NO and Laurie, C and Broome, JG and Khan, AT and Lewis, JP and Xu, H and Montasser, ME and Ashley, KE and Hasbani, NR and Boerwinkle, E and Morrison, AC and Chami, N and Do, R and Rocheleau, G and Lloyd-Jones, DM and Lemaitre, RN and Bis, JC and Floyd, JS and Kinney, GL and Bowden, DW and Palmer, ND and Benjamin, EJ and Nayor, M and Yanek, LR and Kral, BG and Becker, LC and Kardia, SLR and Smith, JA and Bielak, LF and Norwood, AF and Min, YI and Carson, AP and Post, WS and Rich, SS and Herrington, D and Guo, X and Taylor, KD and Manson, JE and Franceschini, N and Pollard, KS and Mitchell, BD and Loos, RJF and Fornage, M and Hou, L and Psaty, BM and Young, KA and Regan, EA and Freedman, BI and Vasan, RS and Levy, D and Mathias, RA and Peyser, PA and Raffield, LM and Kooperberg, C and Reiner, AP and Rotter, JI and Jun, G and de Vries, PS and Assimes, TL}, title = {Unveiling the Genetic Landscape of Coronary Artery Disease Through Common and Rare Structural Variants.}, journal = {Journal of the American Heart Association}, volume = {}, number = {}, pages = {e036499}, doi = {10.1161/JAHA.124.036499}, pmid = {39950338}, issn = {2047-9980}, support = {K26 DK138425/DK/NIDDK NIH HHS/United States ; R01 DK117445/DK/NIDDK NIH HHS/United States ; R01 HL163972/HL/NHLBI NIH HHS/United States ; R01 HL175681/HL/NHLBI NIH HHS/United States ; }, abstract = {BACKGROUND: Genome-wide association studies have identified several hundred susceptibility single nucleotide variants for coronary artery disease (CAD). Despite single nucleotide variant-based genome-wide association studies improving our understanding of the genetics of CAD, the contribution of structural variants (SVs) to the risk of CAD remains largely unclear.<br><br>METHOD AND RESULTS: We leveraged SVs detected from high-coverage whole genome sequencing data in a diverse group of participants from the National Heart Lung and Blood Institute's Trans-Omics for Precision Medicine program. Single variant tests were performed on 58&#x2009;706 SVs in a study sample of 11&#x2009;556 CAD cases and 42&#x2009;907 controls. Additionally, aggregate tests using sliding windows were performed to examine rare SVs. One genome-wide significant association was identified for a common biallelic intergenic duplication on chromosome 6q21 (P=1.54E-09, odds ratio=1.34). The sliding window-based aggregate tests found 1 region on chromosome 17q25.3, overlapping USP36, to be significantly associated with coronary artery disease (P=1.03E-10). USP36 is highly expressed in arterial and adipose tissues while broadly affecting several cardiometabolic traits.<br><br>CONCLUSIONS: Our results suggest that SVs, both common and rare, may influence the risk of coronary artery disease.}, }
@article {pmid39660994, year = {2025}, author = {Livingston, JA and Blay, JY and Trent, J and Valverde, C and Agulnik, M and Gounder, M and Le Cesne, A and McKean, M and Wagner, MJ and Stacchiotti, S and Agresta, S and Quintás-Cardama, A and Reilly, SA and Healy, K and Hickman, D and Zhao, T and Ballesteros-Perez, A and Khalil, A and Collins, MP and Piel, J and Horrigan, K and Lefkovith, A and Innis, S and Lazar, AJ and Cote, GM and Wagner, AJ}, title = {A Phase I Study of FHD-609, a Heterobifunctional Degrader of Bromodomain-Containing Protein 9, in Patients with Advanced Synovial Sarcoma or SMARCB1-Deficient Tumors.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {31}, number = {4}, pages = {628-638}, doi = {10.1158/1078-0432.CCR-24-2583}, pmid = {39660994}, issn = {1557-3265}, support = {//Foghorn Therapeutics Inc. (Foghorn)/ ; }, mesh = {Humans ; Male ; Female ; *Sarcoma, Synovial/drug therapy/genetics/pathology ; Middle Aged ; Adult ; Aged ; *Transcription Factors/genetics ; *Maximum Tolerated Dose ; *SMARCB1 Protein/genetics/deficiency ; Young Adult ; Treatment Outcome ; Antineoplastic Agents/adverse effects/administration &amp; dosage/pharmacokinetics ; Bromodomain Containing Proteins ; }, abstract = {PURPOSE: FHD-609, a potent, selective, heterobifunctional degrader of bromodomain-containing protein 9 (BRD9), was evaluated for treating patients with advanced synovial sarcoma or SMARCB1-deficient tumors.<br><br>PATIENTS AND METHODS: In this multinational, open-label, phase I study (NCT04965753), patients received FHD-609 intravenously at escalating doses either twice weekly (5-80 mg; n = 40) or once weekly (40-120 mg; n = 15).<br><br>RESULTS: Fifty-five patients received FHD-609 for a median of 43 days. The maximum tolerated doses were 40 mg twice weekly and the equivalent weekly dose, 80 mg once weekly. Dose-limiting toxicities of QTc (heart rate-corrected QT interval) prolongation and syncope were observed at 40 and 60 mg twice weekly. Treatment-related adverse events were predominantly grades 1 to 2 in severity, most commonly dysgeusia (40%), dry mouth (29.1%), fatigue (27.3%), and anemia (25.5%). Eleven (20%) patients had treatment-emergent QTc (Fridericia formula) prolongation preceded by T-wave inversions; 21 (38.2%) patients had T-wave inversions without further cardiac events or ECG abnormalities. FHD-609 showed dose-dependent increases in pharmacokinetic exposure, with no substantial accumulation. Extensive BRD9 degradation in tumor tissue corresponded to the downregulation of cancer cell proliferation gene sets. One (2%) patient achieved a partial response; eight (15%) patients achieved stable disease, which lasted longer than 6 months in two patients.<br><br>CONCLUSIONS: FHD-609 showed dose-dependent increases in systemic FHD-609 exposure and pharmacodynamic response profiles. The maximum tolerated doses were identified (40 mg twice weekly/80 mg once weekly) and preliminary clinical activity was observed. Future studies of BRD9 degraders will require strict cardiac monitoring given the QTc prolongation observed in this study.}, }
@article {pmid39947884, year = {2025}, author = {Chen, X and Patkar, N and Tembhare, P and Papagudi, S and Yeung, C and Kanagal Shamanna, R and Gujral, S and Wood, B and Naresh, KN}, title = {Fifth edition WHO classification: myeloid neoplasms.}, journal = {Journal of clinical pathology}, volume = {}, number = {}, pages = {}, doi = {10.1136/jcp-2024-210022}, pmid = {39947884}, issn = {1472-4146}, abstract = {The fifth edition of the WHO classification of haematolymphoid tumours (WHO-HEM5) introduces significant advancements in the understanding and diagnosis of myeloid neoplasms, emphasising molecular and genetic insights. This review highlights key updates from the revised fourth edition (WHO-HEM4R), particularly the integration of genetic criteria for disease classification. Many entities are now defined by specific genetic abnormalities, enhancing diagnostic precision and prognostic assessment. Notably, the elimination of the 20% blast threshold for acute myeloid leukaemia (AML) with specific defining genetic alterations reflects a shift towards genomic-driven diagnostics. Additional updates include the refined subclassification of myelodysplastic neoplasms (MDS) and MDS/myeloproliferative neoplasms, as well as the recognition of novel entities such as clonal haematopoiesis and MDS with biallelic TP53 inactivation, further expanding the spectrum of myeloid neoplasms. WHO-HEM5 illustrates the diagnostic utility of morphology, flow cytometry, immunohistochemistry and next-generation sequencing in resource-rich settings. However, its implementation in low-income and middle-income countries (LMICs) remains challenging due to limited access to advanced diagnostic tools. This review explores strategies to optimise diagnosis in resource-constrained environments, where morphology and immunophenotyping remain fundamental. By integrating molecular diagnostics with traditional methods, WHO-HEM5 aims to refine classification and facilitate risk stratification in the era of personalised medicine, providing haematopathologists and clinicians with an essential framework to navigate the complexities of myeloid neoplasms. The emphasis on advancing haematopathology practices worldwide, including in LMICs, demonstrates the ongoing commitment to improving global outcomes in haematological malignancies.}, }
@article {pmid39946483, year = {2025}, author = {Henikoff, S and Zheng, Y and Paranal, RM and Xu, Y and Greene, JE and Henikoff, JG and Russell, ZR and Szulzewsky, F and Thirimanne, HN and Kugel, S and Holland, EC and Ahmad, K}, title = {RNA polymerase II at histone genes predicts outcome in human cancer.}, journal = {Science (New York, N.Y.)}, volume = {387}, number = {6735}, pages = {737-743}, doi = {10.1126/science.ads2169}, pmid = {39946483}, issn = {1095-9203}, mesh = {*RNA Polymerase II/metabolism ; Humans ; Animals ; Mice ; *Histones/metabolism ; Glioma/genetics ; Receptor, ErbB-2/genetics/metabolism ; Meningioma/genetics ; Breast Neoplasms/genetics ; Female ; S Phase ; Prognosis ; Chromatin/metabolism ; Aneuploidy ; Neoplasms/genetics ; Gene Expression Regulation, Neoplastic ; }, abstract = {Genome-wide hypertranscription is common in human cancer and predicts poor prognosis. To understand how hypertranscription might drive cancer, we applied our formalin-fixed paraffin-embedded (FFPE)-cleavage under targeted accessible chromatin method for mapping RNA polymerase II (RNAPII) genome-wide in FFPE sections. We demonstrate global RNAPII elevations in mouse gliomas and assorted human tumors in small clinical samples and discover regional elevations corresponding to de novo HER2 amplifications punctuated by likely selective sweeps. RNAPII occupancy at S-phase-dependent histone genes correlated with WHO grade in meningiomas, accurately predicted rapid recurrence, and corresponded to whole-arm chromosome losses. Elevated RNAPII at histone genes in meningiomas and diverse breast cancers is consistent with histone production being rate-limiting for S-phase progression and histone gene hypertranscription driving overproliferation and aneuploidy in cancer, with general implications for precision oncology.}, }
@article {pmid39943310, year = {2025}, author = {Jyoti, D and Reeves, D and Gordon-Wylie, S and Eskey, C and Weaver, J}, title = {Improving Stroke Treatment Using Magnetic Nanoparticle Sensors to Monitor Brain Thrombus Extraction.}, journal = {Sensors (Basel, Switzerland)}, volume = {25}, number = {3}, pages = {}, pmid = {39943310}, issn = {1424-8220}, support = {1R43NS129419//1R43NS129419 and AI155224/ ; }, mesh = {Humans ; *Magnetite Nanoparticles/chemistry/therapeutic use ; *Thrombosis ; *Thrombectomy/methods/instrumentation ; *Stroke/therapy ; }, abstract = {(1) Background: Mechanical thrombectomy (MT) successfully treats ischemic strokes by extracting the thrombus, or clot, using a stent retriever to pull it through the blood vessel. However, clot slippage and/or fragmentation can occur. Real-time feedback to a clinician about attachment between the stent and clot could enable more complete removal. We propose a system whereby antibody-targeted magnetic nanoparticles (NPs) are injected via a microcatheter to coat the clot, oscillating magnetic fields excite the particles, and a small coil attached to the catheter picks up a signal that determines the proximity of the clot to the stent. (2) Methods: We used existing simulation code to model the signal from NPs distributed on a hemispherical clot with three orthogonally applied magnetic fields. An in vitro apparatus was built that applied fields and read out signals from a 1.5 mm pickup coil at a variable distance and orientation angle from a sample of 100 nm iron oxide core/shell NPs. (3) Results: Our simulations suggest that the sum of the voltages induced in the pickup coil from three orthogonal applied fields could localize a clot to within 180 µm, regardless of the exact orientation of the pickup coil, with further precision added via rotation-correction formulae. Our experimental system validated simulations; we estimated an in vitro distance recovery precision of 41 µm with a pickup coil 1 mm from the clot. (4) Conclusions: Magnetic NP sensing could be a safe and real-time method to estimate whether a clot is attached to the stent retriever during MT.}, }
@article {pmid39939790, year = {2025}, author = {Adli, M and Przybyla, L and Burdett, T and Burridge, PW and Cacheiro, P and Chang, HY and Engreitz, JM and Gilbert, LA and Greenleaf, WJ and Hsu, L and Huangfu, D and Hung, LH and Kundaje, A and Li, S and Parkinson, H and Qiu, X and Robson, P and Schürer, SC and Shojaie, A and Skarnes, WC and Smedley, D and Studer, L and Sun, W and Vidović, D and Vierbuchen, T and White, BS and Yeung, KY and Yue, F and Zhou, T and , }, title = {MorPhiC Consortium: towards functional characterization of all human genes.}, journal = {Nature}, volume = {638}, number = {8050}, pages = {351-359}, pmid = {39939790}, issn = {1476-4687}, support = {U24 HG012674/HG/NHGRI NIH HHS/United States ; }, mesh = {Humans ; *Phenotype ; *Alleles ; *Genome, Human/genetics ; Genomics ; }, abstract = {Recent advances in functional genomics and human cellular models have substantially enhanced our understanding of the structure and regulation of the human genome. However, our grasp of the molecular functions of human genes remains incomplete and biased towards specific gene classes. The Molecular Phenotypes of Null Alleles in Cells (MorPhiC) Consortium aims to address this gap by creating a comprehensive catalogue of the molecular and cellular phenotypes associated with null alleles of all human genes using in vitro multicellular systems. In this Perspective, we present the strategic vision of the MorPhiC Consortium and discuss various strategies for generating null alleles, as well as the challenges involved. We describe the cellular models and scalable phenotypic readouts that will be used in the consortium's initial phase, focusing on 1,000 protein-coding genes. The resulting molecular and cellular data will be compiled into a catalogue of null-allele phenotypes. The methodologies developed in this phase will establish best practices for extending these approaches to all human protein-coding genes. The resources generated-including engineered cell lines, plasmids, phenotypic data, genomic information and computational tools-will be made available to the broader research community to facilitate deeper insights into human gene functions.}, }
@article {pmid39939524, year = {2025}, author = {Adil, M and Kolarova, TR and Doebley, AL and Chen, LA and Tobey, CL and Galipeau, P and Rosen, S and Yang, M and Colbert, B and Patton, RD and Persse, TW and Kawelo, E and Reichel, JB and Pritchard, CC and Akilesh, S and Lockwood, CM and Ha, G and Shree, R}, title = {Preeclampsia risk prediction from prenatal cell-free DNA screening.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {39939524}, issn = {1546-170X}, support = {HL150169//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; HD086620//U.S. Department of Health &amp; Human Services | NIH | NICHD | National Center for Medical Rehabilitation Research (NCMRR)/ ; T32GM007454//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; CA237746//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; CA280624//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; }, abstract = {Preeclampsia is characterized by placental dysfunction and results in significant morbidity, but reliable early prediction remains challenging. We investigated whether clinically obtained prenatal cell-free DNA (cfDNA) screening (PDNAS) using whole-genome sequencing (WGS) data can be leveraged to predict preeclampsia risk early in pregnancy (≤16 weeks). Using 1,854 routinely collected clinical PDNAS samples (median, 12.1 weeks) with low-coverage (0.5×) WGS data, we developed a framework to quantify maternal and fetal tissue signatures using nucleosome accessibility, revealing early placental and endothelial dysfunction. These signatures informed a prediction model for preeclampsia risk, which achieved a validation performance of 0.85 area under the receiver operating characteristic curve (AUC) (81% sensitivity at 80% specificity) for preterm phenotypes several months prior to disease onset in a separate cohort of 831 consecutively collected samples, and subsequently confirmed in an external cohort of 141 samples (AUC 0.84, 79% sensitivity). We demonstrate that assessment of cfDNA nucleosome accessibility from early-pregnancy cfDNA sequence data enables the detection of early placental and endothelial-tissue aberrations and may aid in the determination of preeclampsia risk.}, }
@article {pmid39939078, year = {2025}, author = {Hsieh, RW and Symonds, LK and Siu, J and Cohen, SA}, title = {Identification of circulating tumor DNA as a biomarker for diagnosis and response to therapies in cancer patients.}, journal = {International review of cell and molecular biology}, volume = {391}, number = {}, pages = {43-93}, doi = {10.1016/bs.ircmb.2024.08.006}, pmid = {39939078}, issn = {1937-6448}, mesh = {Humans ; *Circulating Tumor DNA/blood ; *Biomarkers, Tumor/blood ; *Neoplasms/diagnosis/blood/therapy/genetics ; Treatment Outcome ; }, abstract = {The sampling of circulating biomarkers provides an opportunity for non-invasive evaluation and monitoring of cancer activity. In modern day practice, this has typically been in the form of circulating tumor DNA (ctDNA) detected in plasma. The field of ctDNA has been a burgeoning technology, with prominent applications for blood-based cancer screening and in disease status assessment, especially after curative-intent surgery to evaluate for minimal residual disease (MRD). Clinical applications for the latter show an incredibly high sensitivity in certain cancer types with a need for additional studies to determine how much clinical decision-making should be adapted based on ctDNA results and which cancer types, stages, and treatments are best informed by ctDNA results. This chapter provides an overview of ctDNA detection as tool for cancer screening, detecting MRD, and/or molecularly characterizing a cancer, highlighting the rapidly amassing research as a prognostic biomarker and emerging data on ctDNA as a predictive biomarker.}, }
@article {pmid39938471, year = {2025}, author = {Colevas, AD and Cmelak, AJ and Pfister, DG and Spencer, S and Adkins, D and Birkeland, AC and Brizel, DM and Busse, PM and Caudell, JJ and Durm, G and Fakhry, C and Galloway, T and Geiger, JL and Gillison, ML and Glastonbury, C and Haddad, RI and Hicks, WL and Hitchcock, YJ and Jimeno, A and Juloori, A and Kase, M and Leizman, D and Maghami, E and Mell, LK and Mittal, BB and Pinto, HA and Price, K and Rocco, JW and Rodriguez, CP and Schwartz, D and Shah, JP and Sher, D and John, MS and Wang, H and Weinstein, G and Worden, F and Bruce, JY and Yom, SS and Zhen, W and Montgomery, S and Darlow, SD}, title = {NCCN Guidelines® Insights: Head and Neck Cancers, Version 2.2025.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {23}, number = {2}, pages = {2-11}, doi = {10.6004/jnccn.2025.0007}, pmid = {39938471}, issn = {1540-1413}, mesh = {Humans ; *Head and Neck Neoplasms/therapy/diagnosis/pathology ; Practice Guidelines as Topic ; Education, Medical, Continuing ; }, abstract = {The NCCN Guidelines for Head and Neck Cancers address tumors arising in the oral cavity (including mucosal lip), pharynx, larynx, and paranasal sinuses, as well as occult primary cancer, salivary gland cancer, and mucosal melanoma (MM). The specific site of disease, stage, and pathologic findings guide treatment (eg, the appropriate surgical procedure, radiation targets, dose and fractionation of radiation, indications for systemic therapy). The NCCN Head and Neck Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding management of nasopharynx cancer and ongoing research in this area.}, }
@article {pmid39938467, year = {2025}, author = {Inaba, H and Teachey, D and Annesley, C and Batra, S and Beck, J and Colace, S and Cooper, S and Dallas, M and Oliveira, S and Kelly, K and Kitko, C and Kohorst, M and Kutny, M and Lacayo, N and Lee-Miller, C and Ludwig, K and Madden, L and Maloney, K and Mangum, D and Massaro, S and McCall, D and Morocco, P and Muller, B and Murphy, L and Nardi, V and Rossoff, J and Schuettpelz, L and Shah, B and Sun, J and Wong, V and Yanik, G and Awotiwon, A and Stehman, K}, title = {Pediatric Acute Lymphoblastic Leukemia, Version 2.2025, NCCN Clinical Practice Guidelines In Oncology.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {23}, number = {2}, pages = {41-62}, doi = {10.6004/jnccn.2025.0006}, pmid = {39938467}, issn = {1540-1413}, mesh = {Humans ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy/diagnosis/genetics ; Child ; Medical Oncology/standards/methods ; Infant ; }, abstract = {The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pediatric Acute Lymphoblastic Leukemia (ALL) were developed as a result of meetings convened by a multidisciplinary panel of pediatric ALL experts, with the goal of providing recommendations on standard treatment approaches based on current evidence. The NCCN Guidelines for pediatric ALL focus on risk assessment and stratification of risk-adapted therapy; treatment strategies for BCR::ABL1 (Philadelphia chromosome [Ph])-negative and BCR::ABL1-positive B-cell lineage, T-cell lineage, and infant ALL; and supportive care considerations. This selection from the NCCN Guidelines for pediatric ALL focuses on the diagnosis of and management of pediatric T-ALL.}, }
@article {pmid39938019, year = {2025}, author = {Chavez, JC and Dickinson, M and Munoz, J and Ulrickson, ML and Thieblemont, C and Oluwole, OO and Herrera, AF and Ujjani, C and Lin, Y and Riedell, PA and Kekre, N and de Vos, S and Wullf, J and Williams, CM and Winters, J and Kloos, IM and Xu, H and Neelapu, SS}, title = {Three-year follow-up analysis of first-line axicabtagene ciloleucel in high-risk large B-cell lymphoma (ZUMA-12).}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024027347}, pmid = {39938019}, issn = {1528-0020}, abstract = {ZUMA-12 is a multicenter phase 2 study that evaluated axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, as part of first-line treatment in patients with high-risk large B-cell lymphoma (LBCL). In the primary efficacy analysis (n=37; 15.9 months median follow-up), axi-cel demonstrated a high rate of complete responses (CR; 78%) and a safety profile consistent with prior experience. Here, we assessed updated outcomes from ZUMA-12 in 40 treated patients after ≥3 years of follow-up. Eligible adults underwent leukapheresis, followed by lymphodepleting chemotherapy and a single axi-cel infusion of 2×106 CAR T cells/kg. Investigator-assessed CR, objective response, survival, safety, and CAR T-cell expansion were assessed. The CR rate among response-evaluable patients (n=37) increased after the primary analysis to 86% (95% CI, 71-95), with a 92% objective response rate. After a median follow-up of 47.0 months (range, 37.1-57.8), 36-month estimates (95% CI) of duration of response and event-free, progression-free, and overall survival in response-evaluable patients were 81.8% (63.9-91.4), 73.0% (55.6-84.4), 75.1% (57.5-86.2), and 81.1% (64.4-90.5), respectively. In total, 4 patients had new malignancies, 2 occurring after the data cutoff of the primary analysis, none were related to axi-cel. Eight patients died on study, 2 of whom died from non-relapse mortality causes. After ≥3 years of follow-up, axi-cel demonstrated a high cure rate in first-line high-risk LBCL, with no new safety signals after the primary analysis. Further assessments are needed to determine its benefit versus first-line standard-of-care. This trial was registered at clinicaltrials.gov, as #NCT03761056.}, }
@article {pmid39938007, year = {2025}, author = {Samples, L and Sadrzadeh, H and Frigault, MJ and Jacobson, CA and Hamadani, M and Gurumurthi, A and Strati, P and Shouval, R and Noy, A and Riedell, PA and Dahiya, S and Maloney, DG and Till, BG and Hirayama, AV and Gauthier, J and Gopal, AK and Smith, SD and Poh, C and Lynch, RC and Ujjani, C and Di, M and Raghunathan, V and Shakib-Azar, M and Naresh, KN and Gooley, TA and Yared, JA and Jain, MD and Locke, FL and Leslie, LA and Epperla, N and Ghosh, M and Skarbnik, AP and Hill, BT and Kamdar, M and Ortiz-Maldonado, V and Martínez-Cibrian, N and Shune, L and Shadman, M}, title = {Outcomes Among Adult Recipients of CAR T-cell Therapy for Burkitt Lymphoma.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024026831}, pmid = {39938007}, issn = {1528-0020}, abstract = {Burkitt lymphoma (BL) is an aggressive B-cell lymphoma associated with poor outcomes in patients with relapsed/refractory disease. This multicenter, retrospective study evaluated real-world CD19 CAR T-cell therapy outcomes in patients with relapsed/refractory BL using data abstracted from the medical records. In total, 31 patients received CAR T-cells after a median of 3 prior therapies (range 1-6). Patients received axi-cel (n = 19), liso-cel (n = 4), tisa-cel (n = 4) or other agents (n = 4). Grade 1-2 CRS occurred in 83.9% of patients (grade ≥3 6.5%), and grade 1-2 ICANS occurred in 29% of patients (grade ≥3 19.4%). Twenty-eight-day mortality was 16.1%, including one patient who died from grade 5 ICANS. The overall response rate at 1 month was 58.0% with a complete response (CR) rate of 41.9%, however the 6-month CR rate was only 25.8%. Median progression-free survival was 2.3 months (95% CI 1.0 - 9.0), and median overall survival was 6.0 months (95% CI 1.9 - 11.5). Three patients (9.7%) received consolidative allogeneic stem cell transplants, but all subsequently relapsed. In conclusion, CD19 CAR T-cell therapy infrequently delivers long term disease control in BL. Further investigation is needed to determine the most effective alternative management of these patients.}, }
@article {pmid39935960, year = {2025}, author = {Zane, GK and Barbee, LA and Duerr, A and Golden, MR and Manhart, LE and Dimitrov, D and Khosropour, C}, title = {High Incidence and Duration of Antibiotic Use Among a Cohort of Men Who Have Sex With Men in Seattle, Washington.}, journal = {Open forum infectious diseases}, volume = {12}, number = {2}, pages = {ofaf051}, pmid = {39935960}, issn = {2328-8957}, support = {K23 AI113185/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: Doxycycline postexposure prophylaxis (doxy-PEP) effectively prevents bacterial sexually transmitted infections (STIs) but may increase antibiotic pressure. Little is known about longitudinal antibiotic use among men who have sex with men (MSM), a key population for doxy-PEP.<br><br>METHODS: We analyzed data from a prospective cohort of MSM in Seattle, Washington, from 2016 to 2018, prior to the introduction of doxy-PEP. Antibiotic use and reason for prescription were self-reported in weekly surveys and extracted from medical records. We characterized antibiotic use across 49 weeks of follow-up, stratified by specific antibiotics of interest and reasons for prescription. Incidence rates (IRs) were calculated for the number of incident events of antibiotic initiation per 100 person-years (PY) at risk. We assessed factors associated with antibiotic initiation using negative binomial regression to estimate adjusted incidence rate ratios (IRRs).<br><br>RESULTS: Among 140 participants, 68.6% (n = 96) received at least 1 antibiotic during follow-up, resulting in an overall IR of 264.5 events of antibiotic initiation per 100 PY and 1696 total days of antibiotic use. STI treatment was the most common reason for antibiotic initiation (IR, 153.5 events per 100 PY; 462 days); however, treatment for other conditions contributed most to overall days of antibiotic use (IR, 42.6 events per 100 PY; 947 days). An age of 25-39 years (IRR, 1.54 [95% confidence interval {CI}, 1.02-2.32]) and a history of bacterial STIs <12 months prior to enrollment (IRR, 1.81 [95% CI, 1.12-2.93]) were significantly associated with higher incidence of antibiotic initiation.<br><br>CONCLUSIONS: Antibiotic consumption among this population was very high. Our analysis provides a necessary foundation for assessing the potential impacts of doxy-PEP.}, }
@article {pmid39934055, year = {2025}, author = {Powles, T and Tagawa, S and Vulsteke, C and Gross-Goupil, M and Park, SH and Necchi, A and De Santis, M and Duran, I and Morales-Barrera, R and Guo, J and Sternberg, CN and Bellmunt, J and Goebell, PJ and Kovalenko, M and Boateng, F and Sierecki, M and Wang, L and Sima, CS and Waldes, J and Loriot, Y and Grivas, P}, title = {Sacituzumab govitecan in advanced urothelial carcinoma: TROPiCS-04, a phase III randomized trial.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.annonc.2025.01.011}, pmid = {39934055}, issn = {1569-8041}, abstract = {BACKGROUND: Sacituzumab govitecan (SG), a Trop-2-directed antibody-drug conjugate, demonstrated efficacy and manageable toxicity in the phase II TROPHY-U-01 study in pretreated advanced urothelial carcinoma (aUC). We report the results from final analysis of the global open-label randomized phase III TROPiCS-04 study (NCT04527991) in pretreated aUC.<br><br>PATIENTS AND METHODS: Patients with aUC whose disease had progressed on prior platinum-based chemotherapy and checkpoint inhibitor therapy were randomized 1 : 1 to receive SG or treatment of physician's choice (TPC; paclitaxel, docetaxel, or vinflunine). The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS) and objective response rate (ORR) by investigator and blinded independent committee review, as well as safety.<br><br>RESULTS: Overall, 711 patients were randomized. After a median follow-up of 9.2 months, the primary endpoint was not met [median OS for SG versus TPC: 10.3 months versus 9.0 months, hazard ratio (HR) 0.86, 95% confidence interval (CI)&#xa0;0.73-1.02, P&#xa0;= 0.087]. Median PFS with SG and TPC was 4.2 months and 3.6 months, respectively (HR 0.86, 95% CI 0.72-1.03); ORR (95% CI) was 23% (18% to 27%) and 14% (10% to 18%). The most common grade &#x2265;3 treatment-related adverse event (TRAE) with SG was neutropenia (35%, including 12% with febrile neutropenia). Incidence of grade &#x2265;3 TRAEs (67% versus 35%) and grade 5 treatment-emergent adverse events (TEAEs; 7% versus 2%) was higher with SG versus TPC. In the SG group, 16/25 grade 5 TEAEs were infections with neutropenia mostly occurring early in the treatment course of patients with multiple risk factors for febrile neutropenia. Primary prophylactic granulocyte colony-stimulating factor (G-CSF) usage with SG and TPC was 21% and 22%, respectively.<br><br>CONCLUSIONS: SG did not result in a significant improvement in OS or PFS compared with TPC in pretreated aUC, although SG activity was demonstrated by a higher ORR. Early toxicity-related complications with SG may have impacted efficacy outcomes.}, }
@article {pmid39932777, year = {2025}, author = {Patel, SH and Colby, S and Sohal, D and Guthrie, KA and Kachnic, LA and Chiorean, EG and Lowy, AM and Rocha, FG and Hochster, HS and Philip, PA and Ahmad, SA}, title = {Chemotherapy dose density is prognostic for overall survival in patients with resectable pancreas cancer: A landmark analysis of SWOG 1505.}, journal = {Cancer}, volume = {131}, number = {4}, pages = {e35759}, pmid = {39932777}, issn = {1097-0142}, support = {U10 CA180819/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; U10CA180888/NH/NIH HHS/United States ; U10CA180819/NH/NIH HHS/United States ; }, mesh = {Humans ; *Pancreatic Neoplasms/surgery/mortality/drug therapy/pathology ; Male ; Female ; Aged ; Middle Aged ; *Carcinoma, Pancreatic Ductal/surgery/mortality/drug therapy/pathology ; Prognosis ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Deoxycytidine/analogs &amp; derivatives/administration &amp; dosage/therapeutic use ; Gemcitabine ; Fluorouracil/administration &amp; dosage/therapeutic use ; Adult ; Oxaliplatin/administration &amp; dosage/therapeutic use ; Pancreatectomy ; Leucovorin/administration &amp; dosage/therapeutic use ; }, abstract = {BACKGROUND: Chemotherapy is required to improve the overall survival (OS) of patients with resectable pancreatic ductal adenocarcinoma (PDAC). Assessing the impact of chemotherapy dose density (DD) on survival is difficult as a result of confounding. The objective of this study was to determine the impact of chemotherapy DD on OS in patients with resectable PDAC.<br><br>METHODS: This was a secondary analysis of SWOG 1505, a randomized phase 2 trial of perioperative chemotherapy in resectable PDAC. DD was defined as the percentage of chemotherapy dose received of the total planned. Two landmark time points for OS were used: after surgery and at 40 weeks (which encompassed the entire treatment period).<br><br>RESULTS: Of the 102 eligible patients enrolled, 73 (71%) underwent surgery, and median preoperative chemotherapy DD was 89%. Patients with &#x2265;85% DD had higher OS compared to those with <85% DD (median, 38.1 vs. 17.2 months; p&#xa0;=&#xa0;.039). Of the 82 patients who survived to 40 weeks postrandomization, 67 underwent surgery, and median DD for all perioperative chemotherapy was 67%. In this cohort, DD&#xa0;&#x2265;70% was associated with better OS (median, 32.2 vs. 14.0 months; p&#xa0;=&#xa0;.017). Perioperative DD was not significantly associated with pathologic response, margin status, or lymph node negativity.<br><br>CONCLUSIONS: This is the first study to identify a prognostic association of chemotherapy DD with OS in patients undergoing perioperative chemotherapy and surgery for resectable PDAC. Patients who received &#x2265;85% DD preoperatively and/or &#x2265;70% DD perioperatively survived longer than those receiving a smaller proportion of protocol therapy.}, }
@article {pmid39930085, year = {2025}, author = {Hoffmann, TJ and Graff, RE and Madduri, RK and Rodriguez, AA and Cario, CL and Feng, K and Jiang, Y and Wang, A and Klein, RJ and Pierce, BL and Eggener, S and Tong, L and Blot, W and Long, J and Goss, LB and Darst, BF and Rebbeck, T and Lachance, J and Andrews, C and Adebiyi, AO and Adusei, B and Aisuodionoe-Shadrach, OI and Fernandez, PW and Jalloh, M and Janivara, R and Chen, WC and Mensah, JE and Agalliu, I and Berndt, SI and Shelley, JP and Schaffer, K and Machiela, MJ and Freedman, ND and Huang, WY and Li, SA and Goodman, PJ and Till, C and Thompson, I and Lilja, H and Ranatunga, DK and Presti, J and Van Den Eeden, SK and Chanock, SJ and Mosley, JD and Conti, DV and Haiman, CA and Justice, AC and Kachuri, L and Witte, JS}, title = {Genome-wide association study of prostate-specific antigen levels in 392,522 men identifies new loci and improves prediction across ancestry groups.}, journal = {Nature genetics}, volume = {57}, number = {2}, pages = {334-344}, pmid = {39930085}, issn = {1546-1718}, mesh = {Humans ; Male ; *Genome-Wide Association Study ; *Prostate-Specific Antigen/blood/genetics ; *Prostatic Neoplasms/genetics/ethnology ; *Polymorphism, Single Nucleotide ; Middle Aged ; Aged ; Hispanic or Latino/genetics ; White People/genetics ; Genetic Predisposition to Disease ; Cohort Studies ; }, abstract = {We conducted a multiancestry genome-wide association study of prostate-specific antigen (PSA) levels in 296,754 men (211,342 European ancestry, 58,236 African ancestry, 23,546 Hispanic/Latino and 3,630 Asian ancestry; 96.5% of participants were from the Million Veteran Program). We identified 318 independent genome-wide significant (P ≤ 5 × 10[-8]) variants, 184 of which were novel. Most demonstrated evidence of replication in an independent cohort (n = 95,768). Meta-analyzing discovery and replication (n = 392,522) identified 447 variants, of which a further 111 were novel. Out-of-sample variance in PSA explained by our genome-wide polygenic risk scores ranged from 11.6% to 16.6% for European ancestry, 5.5% to 9.5% for African ancestry, 13.5% to 18.2% for Hispanic/Latino and 8.6% to 15.3% for Asian ancestry and decreased with increasing age. Midlife genetically adjusted PSA levels were more strongly associated with overall and aggressive prostate cancer than unadjusted PSA levels. Our study highlights how including proportionally more participants from underrepresented populations improves genetic prediction of PSA levels, offering potential to personalize prostate cancer screening.}, }
@article {pmid39929823, year = {2025}, author = {Raeisi Dehkordi, S and Wong, IT and Ni, J and Luebeck, J and Zhu, K and Prasad, G and Krockenberger, L and Xu, G and Chowdhury, B and Rajkumar, U and Caplin, A and Muliaditan, D and Gnanasekar, A and Coruh, C and Jin, Q and Turner, K and Teo, SX and Pang, AWC and Alexandrov, LB and Chua, CEL and Furnari, FB and Maciejowski, J and Paulson, TG and Law, JA and Chang, HY and Yue, F and DasGupta, R and Zhao, J and Mischel, PS and Bafna, V}, title = {Breakage fusion bridge cycles drive high oncogene number with moderate intratumoural heterogeneity.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {1497}, pmid = {39929823}, issn = {2041-1723}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; U24 CA264379/CA/NCI NIH HHS/United States ; P50 CA168504/CA/NCI NIH HHS/United States ; R35 CA210057/CA/NCI NIH HHS/United States ; OT2 CA278635/CA/NCI NIH HHS/United States ; R01 GM114362/GM/NIGMS NIH HHS/United States ; OT2 CA278688/CA/NCI NIH HHS/United States ; P01 CA091955/CA/NCI NIH HHS/United States ; CGCATF-2021/100025//Cancer Research UK (CRUK)/ ; }, mesh = {Humans ; *Oncogenes/genetics ; Cell Line, Tumor ; *Gene Amplification ; *Neoplasms/genetics ; Animals ; Mice ; Algorithms ; Genetic Heterogeneity ; Whole Genome Sequencing ; }, abstract = {Oncogene amplification is a key driver of cancer pathogenesis. Both breakage fusion bridge (BFB) cycles and extrachromosomal DNA (ecDNA) can lead to high oncogene copy numbers, but the impact of BFB amplifications on intratumoral heterogeneity, treatment response, and patient survival remains poorly understood due to detection challenges with DNA sequencing. We introduce an algorithm, OM2BFB, designed to detect and reconstruct BFB amplifications using optical genome mapping (OGM). OM2BFB demonstrates high precision (>93%) and recall (92%) in identifying BFB amplifications across cancer cell lines, patient-derived xenograft models, and primary tumors. Comparisons using OGM reveal that BFB detection with our AmpliconSuite toolkit for short-read sequencing also achieves high precision, though with reduced sensitivity. We identify 371 BFB events through whole genome sequencing of 2557 primary tumors and cancer cell lines. BFB amplifications are prevalent in cervical, head and neck, lung, and esophageal cancers, but rare in brain cancers. Genes amplified through BFB exhibit lower expression variance, with limited potential for regulatory adaptation compared to ecDNA-amplified genes. Tumors with BFB amplifications (BFB(+)) show reduced structural heterogeneity in amplicons and delayed resistance onset relative to ecDNA(+) tumors. These findings highlight ecDNA and BFB amplifications as distinct oncogene amplification mechanisms with differing biological characteristics, suggesting distinct avenues for therapeutic intervention.}, }
@article {pmid39928955, year = {2025}, author = {Petty, NE and Radtke, S and Kanestrom, G and Fields, E and Humbert, O and Fiorenza, S and Llewellyn, MJ and Laszlo, GS and Thomas, J and Burger, Z and Swing, K and Zhu, H and Jerome, KR and Turtle, CJ and Walter, RB and Kiem, HP}, title = {Protection of CD33-modified hematopoietic stem cell progeny from CD33-directed CAR T cells in nonhuman primates.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024015016}, pmid = {39928955}, issn = {2473-9537}, abstract = {The treatment of monogenetic disorders, such as hemoglobinopathies and lysosomal storage diseases, has markedly improved with the advent of cell and gene therapies, particularly allogeneic or gene-modified autologous stem cell transplantations. However, therapeutic efficacy is reliant on maintaining engraftment above a critical threshold. To maintain such engraftment levels, we and others have pursued approaches to shield edited cells from antibody or CAR T-cell mediated selection. Here we focused on CD33, which is expressed early on hematopoietic stem and progenitor cells (HSPC) as well as on myeloid progenitors. Rhesus macaques were engrafted with HSPCs edited to ablate CD33 utilizing either CRISPR/Cas9 or adenine base editor. Both editing strategies showed similar post-transplant recovery kinetics and yielded equivalent levels of engraftment. We then created a V-set domain specific chimeric antigen receptor construct (CAR33), validated its functionality in vitro, and treated both animals with autologous CAR33 T cells. CAR33 T cells expanded after infusion and caused specific depletion of CD33WT but not CD33null progeny - leading to a transient enrichment for gene-edited cells in the blood. No depletion was seen in the bone marrow stem cell compartment with CD34+CD90+ HSCs expressing lower levels of CD33 in comparison to monocytes. Thus, we show proof of concept and safety of an epitope editing based enrichment/protection strategy in macaques.}, }
@article {pmid39928329, year = {2025}, author = {Henderson, LM and Kim, RY and Tanner, NT and Tsai, EB and Begnaud, A and Dako, F and Gieske, M and Kallianos, K and Richman, I and Sakoda, LC and Schwartz, RG and Yeboah, J and Fong, KM and Lam, S and Lee, P and Pasquinelli, M and Smith, RA and Triplette, M and Tanoue, LT and Rivera, MP}, title = {Lung Cancer Screening and Incidental Findings: A Research Agenda. An Official American Thoracic Society Research Statement.}, journal = {American journal of respiratory and critical care medicine}, volume = {}, number = {}, pages = {}, doi = {10.1164/rccm.202501-0011ST}, pmid = {39928329}, issn = {1535-4970}, support = {K08 CA279881/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Lung cancer screening with low-dose computed tomography (LDCT) may uncover incidental findings (IFs) unrelated to lung cancer. There may be potential benefits from identifying clinically significant IFs that warrant intervention and potential harms related to identifying IFs that are not clinically significant but may result in additional evaluation, clinician effort, patient anxiety, complications, and excess cost.<br><br>OBJECTIVES: To identify knowledge and research gaps and develop and prioritize research questions to address the approach to and management of IFs.<br><br>METHODS: We convened a multidisciplinary panel to review the available literature on IFs detected in lung cancer screening LDCT exams, focusing on variability and standardizing reporting, management of IFs, and evaluation of the benefits and harms of IFs, particularly cardiovascular-related IFs. We used a three-round modified Delphi process to prioritize research questions.<br><br>RESULTS: This statement identifies knowledge gaps in (1) reporting of IFs, (2) management of IFs, and (3) identifying and reporting coronary artery calcification found on lung cancer screening LDCT. Finally, we present the panel's initial 36 research questions and the final 20 prioritized questions.<br><br>CONCLUSIONS: This statement provides a prioritized research agenda to further efforts focused on evaluating, managing, and increasing awareness of IFs in lung cancer screening.}, }
@article {pmid39928141, year = {2025}, author = {Papadopoulos, A and Kyriakou, I and Matsuya, Y and Cortés-Giraldo, MA and Galocha-Oliva, M and Plante, I and Stewart, RD and Tran, NH and Li, W and Daglis, IA and Santin, G and Nieminen, P and Incerti, S and Emfietzoglou, D}, title = {Analytic and Monte Carlo calculations of dose-mean lineal energy for 1 MeV-1 GeV protons with application to radiation protection quality factor.}, journal = {Radiation and environmental biophysics}, volume = {}, number = {}, pages = {}, pmid = {39928141}, issn = {1432-2099}, support = {4000132935/21/NL/CRS//European Space Agency (ESA)/ ; 4000132935/21/NL/CRS//European Space Agency (ESA)/ ; 4000132935/21/NL/CRS//European Space Agency (ESA)/ ; 4000132935/21/NL/CRS//European Space Agency (ESA)/ ; 4000132935/21/NL/CRS//European Space Agency (ESA)/ ; }, abstract = {Radiation quality for determining biological effects is commonly linked to the microdosimetric quantity lineal energy (y) and to the dose-mean lineal energy (y D). Calculations of y D are typically performed by specialised Monte Carlo track-structure (MCTS) codes, which can be time-intensive. Thus, microdosimetry-based analytic models are potentially useful for practical calculations. Analytic model calculations of proton y D and radiation protection quality factor (Q) values in sub-micron liquid water spheres (diameter 10-1000 nm) over a broad energy range (1 MeV-1 GeV) are compared against MCTS simulations by PHITS, RITRACKS, and Geant4-DNA. Additionally, an improved analytic microdosimetry model is proposed. The original analytic model of Xapsos is refined and model parameters are updated based on Geant4-DNA physics model. Direct proton energy deposition is described by an alternative energy-loss straggling distribution and the contribution of secondary electrons is calculated using the dielectric formulation of the relativistic Born approximation. MCTS simulations of proton y D values using the latest versions of the PHITS, RITRACKS, and Geant4-DNA are reported along with the Monte Carlo Damage Simulation (MCDS) algorithm. The y D datasets are then used within the Theory of Dual Radiation Action (TDRA) to illustrate variations in Q with proton energy. By a careful selection of parameters, overall differences at the ~ 10% level between the proposed analytic model and the MCTS codes can be attained, significantly improving upon existing models. MCDS estimates of y D are generally much lower than estimates from MCTS simulations. The differences of Q among the examined methods are somewhat smaller than those of y D . Still, estimates of proton Q values by the present model are in better agreement with MCTS-based estimates than the existing analytic models. An improved microdosimetry-based analytic model is presented for calculating proton y D values over a broad range of proton energies (1 MeV-1 GeV) and target sizes (10-1000 nm) in very good agreement with state-of-the-art MCTS simulations. It is envisioned that the proposed model might be used as an alternative to CPU-intensive MCTS simulations and advance practical microdosimetry and quality factor calculations in medical, accelerator, and space radiation applications.}, }
@article {pmid39927451, year = {2025}, author = {Sears, E and Dahlquist, J and Stayman, S and Ko, C and Konnick, EQ and Cole, A and Zhang, Y and Kohn, M and Henderson, V and Knerr, S}, title = {Feasibility of Using Patient Navigation to Improve Identification of Hereditary Cancer Syndromes in Newly Diagnosed Colorectal Cancer Patients.}, journal = {Genetics in medicine : official journal of the American College of Medical Genetics}, volume = {}, number = {}, pages = {101372}, doi = {10.1016/j.gim.2025.101372}, pmid = {39927451}, issn = {1530-0366}, abstract = {PURPOSE: Using germline genetic testing to identify hereditary cancer syndromes in patients newly diagnosed with colorectal cancer (CRC) carries substantial benefits. We examined the feasibility of using patient navigation, an evidence-based approach to reducing structural barriers to recommended care, to improve test completion by increasing pre-test counseling attendance.<br><br>METHODS: We conducted key informant interviews with representatives from organizations providing cancer care to CRC patients. Interviews included questions derived from the Consolidated Framework for Implementation Research, which delineates barriers and facilitators to implementing evidence-based practices. We used an inductive-deductive coding approach to identify themes related to program feasibility.<br><br>RESULTS: We interviewed nineteen participants across thirteen organizations. Key feasibility barriers included: funding to implement and sustain a navigation program; staffing and supervising the navigator role; health information technology needs; gaining administrators' buy-in; and evolving genetic service delivery models. Participants suggested multiple strategies to address implementation barriers, but most would prefer other approaches to improve genetic test completion over implementing a genomics-focused patient navigation program.<br><br>CONCLUSION: Stakeholders across a range of health care organizations saw limited value in improving identification of hereditary CRC syndromes by implementing a program designed to increase pre-test genetic counseling attendance. The need to scale up genetic testing has shifted interest towards delivery models better integrated in established care pathways, requiring fewer resources, and providing broader reach.}, }
@article {pmid39926260, year = {2025}, author = {Wu, X and Lazris, D and Wong, R and Tykodi, SS}, title = {Belzutifan for the treatment of renal cell carcinoma.}, journal = {Therapeutic advances in medical oncology}, volume = {17}, number = {}, pages = {17588359251317846}, pmid = {39926260}, issn = {1758-8340}, abstract = {Belzutifan received its first FDA approval in 2021 for treating clinical manifestations of von Hippel-Lindau (VHL) disease including renal cell carcinoma (RCC) followed by approval in 2023 for treating advanced sporadic RCC that has progressed through multiple lines of treatment. It is the first FDA-approved drug to target hypoxia-inducible factor 2 alpha (HIF-2α). By inhibiting the HIF-2α transcription factor, belzutifan prevents HIF-2α from dimerizing with HIF-1β, thereby preventing the transcription of downstream oncogenes. Most clear cell renal cell carcinoma (ccRCC) tumors are associated with VHL deletion or inactivation resulting in HIF-2α overexpression that represents a key contributor to tumorigenesis, thereby making belzutifan a uniquely optimal drug for targeting ccRCC. Belzutifan has demonstrated activity in clinical trials as a front- and later-line therapy, and in combination with tyrosine kinase inhibitors. It has been largely well tolerated, although anemia represents a common on-target side effect and, along with hypoxia, requires monitoring during treatment. Ongoing phase III trials are investigating belzutifan in combination regimens in the relapsed/refractory, front-line, and adjuvant settings. Future studies will focus on identifying predictive biomarkers and resistance pathways.}, }
@article {pmid39925467, year = {2025}, author = {Mediano, MFF and Mok, Y and Ballew, SH and Gonzalez, F and Sotres-Alvarez, D and Mossavar-Rahmani, Y and Kaplan, R and Carlson, JA and Alver, SK and Daviglus, M and Garcia-Bedoya, O and Evenson, KR and Schrack, JA and Matsushita, K}, title = {The association of physical activity fragmentation with all-cause mortality in Hispanics: a prospective cohort study.}, journal = {Lancet regional health. Americas}, volume = {42}, number = {}, pages = {100996}, pmid = {39925467}, issn = {2667-193X}, support = {R01 HL146132/HL/NHLBI NIH HHS/United States ; HHSN268201300003I/HL/NHLBI NIH HHS/United States ; N01HC65236/HL/NHLBI NIH HHS/United States ; N01HC65235/HL/NHLBI NIH HHS/United States ; N01HC65234/HL/NHLBI NIH HHS/United States ; N01HC65233/HL/NHLBI NIH HHS/United States ; N01HC65237/HL/NHLBI NIH HHS/United States ; HHSN268201300003C/HL/NHLBI NIH HHS/United States ; }, abstract = {BACKGROUND: Physical activity fragmentation represents the frequency of transitioning from an active to sedentary state. The prognostic information of physical activity fragmentation is unclear in Hispanics/Latinos. This study examined the association of PA fragmentation with all-cause mortality in Hispanic/Latino adults.<br><br>METHODS: We investigated 11,992 participants from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) (18-74&#xa0;yr; 52.2% women), from four United States urban communities (Bronx, New York; Chicago, Illinois; Miami, Florida; San Diego, California), that wore an accelerometer for one week. Physical activity fragmentation was calculated using the active-to-sedentary transition probability (ASTP) as the reciprocal of the average active bout duration. Daily total log-transformed activity count (TLAC) was used as a measure of total physical activity. The residual of ASTP regressed on TLAC (TLAC-adjusted ASTP) was explored to investigate the association of ASTP independent of total physical activity. Deaths were identified from annual follow-up interviews, obituary searches, or matches to the National Death Index through December 31, 2021. Cox regression models were fitted according to physical activity fragmentation.<br><br>FINDINGS: There were 745 deaths (6.2%) over a mean follow-up of 11.2 (SD 2.2) years. The highest compared to the lowest tertile of ASTP showed a HR of 1.45 (95% CI 1.10-1.92) of all-cause mortality after accounting for confounders. The mortality risk also increased for each 0.10-unit increase of ASTP, as a continuous variable, by 22% (HR 1.22; 95% CI 1.07-1.39). The results were similar considering TLAC-adjusted ASTP.<br><br>INTERPRETATION: Among Hispanic/Latino adults, more fragmented physical activity was associated with elevated all-cause mortality, independent of total physical activity volume.<br><br>FUNDING: HCHS/SOL was supported by the National Institutes of Health.}, }
@article {pmid39925094, year = {2025}, author = {Bovee, LB and Gooley, TA and Perlman, JE and Hirsch, IB}, title = {The Role of a Continuous Glucose Monitoring-Derived Glycation Ratio in the Development of Microvascular Complications.}, journal = {Diabetes technology &amp; therapeutics}, volume = {}, number = {}, pages = {}, doi = {10.1089/dia.2024.0580}, pmid = {39925094}, issn = {1557-8593}, abstract = {Background: Previous studies have evaluated the associations between HbA1c discordance and diabetes complications using indices of glycation. The ideal index would allow for identification of those at increased risk for microvascular complications. This analysis evaluates the association of a newly published index, the glycation ratio (GR), with diabetic retinopathy (DR) and diabetic kidney disease (DKD). Methods: This is a retrospective review of 661 patients with diabetes seen at the University of Washington. All patients used continuous glucose monitoring (CGM) before the study. Diabetes duration was greater than 20 years in 59%. Median age was 45 years. GR was defined as the ratio of the glucose management indicator (GMI) to the HbA1c. The associations of GR with microvascular complications were each assessed using logistic regression. Results: Modeling GR as a continuous linear variable, each increase in GR of 0.20 units was associated with a 38% relative reduction in the odds of DR (adjusted odds ratio [OR] = 0.62; 95% confidence interval [CI]: 0.45-0.86, P = 0.004] and a similar reduction in the odds of DKD (OR = 0.61; 95% CI: 0.41-0.93, P = 0.02). Conclusions: GR may be a useful marker for risk of diabetic microvascular complications. Longitudinal assessment will be required to see how well GR compares with GMI or HbA1c alone.}, }
@article {pmid39924630, year = {2025}, author = {Daniel, LC and Lubas, MM and Wang, H and Szklo-Coxe, M and Ness, KK and Williams, AM and Mulrooney, DA and Howell, R and Leisenring, W and Yasui, Y and Robison, LL and Armstrong, GT and Chow, EJ and Krull, KR and Brinkman, TM}, title = {Frailty and Sleep in Adult Survivors of Childhood Cancer: A Childhood Cancer Survivor Study Report.}, journal = {Psycho-oncology}, volume = {34}, number = {2}, pages = {e70098}, pmid = {39924630}, issn = {1099-1611}, support = {//American Lebanese Syrian Associated Charities/ ; /CA/NCI NIH HHS/United States ; //St. Jude Children's Research Hospital/ ; }, mesh = {Humans ; Male ; *Cancer Survivors/psychology/statistics &amp; numerical data ; Female ; Adult ; *Frailty/epidemiology ; *Neoplasms/psychology/epidemiology ; *Sleep Wake Disorders/epidemiology ; Middle Aged ; Sleep Quality ; Young Adult ; Child ; Adolescent ; Chronic Disease ; }, abstract = {BACKGROUND: Young adult survivors of childhood cancer exhibit rates of frailty similar to adults several decades older without a cancer history. Frailty has been associated with sleep disturbances in non-cancer populations, but the relationship has not been examined in childhood cancer survivors who are known to exhibit elevated rates of sleep problems.<br><br>AIMS: Examine associations between frailty and poor sleep quality in long-term survivors of childhood cancer.<br><br>METHODS: This study utilized data from 9044 participants (> 5&#xa0;years from diagnosis, Mage&#xa0;=&#xa0;40.8&#xa0;years [SD&#xa0;=&#xa0;9.5]) in the Childhood Cancer Survivor Study. Survivors' frailty status, chronic health conditions (CHC), health behaviors, mental health, and pain were collected in 2014-2016, and self-reported sleep quality in 2017-2019. Multivariable logistic regression models examined frailty status as a predictor of clinically significant poor sleep. All models were adjusted for age at diagnosis, age at survey, sex, race/ethnicity, smoking, risky/heavy alcohol use, and physical inactivity. Separate models included treatment-related variables, CHC burden (number/severity), and emotional health/pain as co-variates.<br><br>RESULTS: Frail survivors had 6-fold (95% CI 4.48-7.96) increased odds of future poor sleep quality. Little attenuation of this association was observed when accounting for cancer diagnosis (Odds Ratio [OR] 5.80, 95% CI 4.47-7.52), treatment exposures (OR 5.80, 95% CI 4.43-7.71), or chronic health condition burden (OR 5.12, 95% CI 3.98-6.59), but adjustment for emotional health/pain (OR 2.88, 95% CI 2.18-3.82) attenuated the association appreciably.<br><br>CONCLUSIONS: Frail childhood cancer survivors have a higher prevalence of clinically significant poor sleep quality. Addressing poor physiologic reserve may impact sleep in frail childhood cancer survivors.}, }
@article {pmid39924174, year = {2025}, author = {Landsburg, DJ and Frigault, MJ and Heim, M and Foley, SR and Hill, B and Schofield, G and Jacobson, CA and Jaglowski, S and Locke, FL and Ram, R and Riedell, PA and Shah, G and Popplewell, LL and Tiwari, R and Lim, S and Majdan, M and Masood, A and Pasquini, M and Turtle, CJ}, title = {Real-world outcomes with tisagenlecleucel in aggressive B-cell lymphoma: subgroup analyses from the CIBMTR registry.}, journal = {Journal for immunotherapy of cancer}, volume = {13}, number = {2}, pages = {}, doi = {10.1136/jitc-2024-009890}, pmid = {39924174}, issn = {2051-1426}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Registries ; Aged ; Adult ; Lymphoma, Large B-Cell, Diffuse/drug therapy/mortality ; Receptors, Antigen, T-Cell/therapeutic use ; Treatment Outcome ; Immunotherapy, Adoptive/methods ; Lymphoma, B-Cell/drug therapy/mortality/therapy ; Young Adult ; }, abstract = {BACKGROUND: Tisagenlecleucel, a CD19 chimeric antigen receptor T-cell therapy, is approved for adults with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBCL) after ≥2 lines of therapy. When used in real-world settings, tisagenlecleucel has shown similar efficacy and improved safety compared with previous clinical trials. However, long-term data on real-world outcomes are lacking.<br><br>METHODS: Clinical data from a cohort of patients treated with tisagenlecleucel in a real-world setting were captured in the Center for International Blood and Marrow Transplant Research registry. The main clinical outcomes analysed included response rate, duration of response, survival, adverse events and clinicopathologic and treatment characteristics that may affect those outcomes.<br><br>RESULTS: As of May 2022, 1159 patients with R/R DLBCL/HGBCL received tisagenlecleucel. The overall response rate was 59.5%, and the complete response rate was 44.5%. With a median follow-up of 23.2 months in the efficacy set (n=968), the 24&#x2009;month rates of progression-free survival, ongoing response and overall survival were 28.4%, 52.6% and 43.6%, respectively. Grade &#x2265;3 cytokine release syndrome and neurotoxicity were reported in 6% and 7.4% of patients, respectively. Patients with DLBCL (vs HGBCL), complete response before infusion, prior autologous or allogeneic haematopoietic stem cell transplant and lactate dehydrogenase (LDH) within normal limits experienced more favourable efficacy outcomes, and those with Eastern Cooperative Oncology Group performance status of &#x2265;2, &#x2265;3 prior lines of therapy, elevated LDH and fludarabine-based lymphodepleting chemotherapy experienced less favourable safety outcomes.<br><br>CONCLUSIONS: This real-world study of tisagenlecleucel for patients with R/R DLBCL/HGBCL shows consistent efficacy and better safety outcomes than the pivotal trial. This study also identifies baseline disease characteristics and prior or concurrent treatments that may affect clinical outcomes.Tisagenlecleucel, a CD19 chimeric antigen receptor T-cell therapy, is approved for adults with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBCL) after &#x2265;2 lines of therapy. When used in real-world settings, tisagenlecleucel has shown similar efficacy and improved safety compared with previous clinical trials. However, long-term data on real-world outcomes are lacking.Clinical data from a cohort of patients treated with tisagenlecleucel in a real-world setting were captured in the Center for International Blood and Marrow Transplant Research registry. The main clinical outcomes analysed included response rate, duration of response, survival, adverse events, and clinicopathologic and treatment characteristics that may affect those outcomes.As of May 2022, 1159 patients with R/R DLBCL/HGBCL received tisagenlecleucel. The overall response rate was 59.5%, and the complete response rate was 44.5%. With a median follow-up of 23.2 months in the efficacy set (n=968), the 24 month rates of progression-free survival, ongoing response, and overall survival were 28.4%, 52.6%, and 43.6%, respectively. Grade &#x2265;3 cytokine release syndrome and neurotoxicity were reported in 6% and 7.4% of patients, respectively. Patients with DLBCL (vs HGBCL), complete response before infusion, prior autologous or allogeneic haematopoietic stem cell transplant, and lactate dehydrogenase (LDH) within normal limits experienced more favourable efficacy outcomes, and those with Eastern Cooperative Oncology Group performance status &#x2265;2, &#x2265;3 prior lines of therapy, elevated LDH, and fludarabine-based lymphodepleting chemotherapy experienced less favourable safety outcomes.In conclusion, this real-world study of tisagenlecleucel for patients with R/R DLBCL/HGBCL shows consistent efficacy and better safety outcomes than the pivotal trial. This study also identifies baseline disease characteristics and prior or concurrent treatments that may affect clinical outcomes.}, }
@article {pmid39923937, year = {2025}, author = {Jurdi, NE and Hamilton, BK and Pidala, JA and Onstad, L and Mun, C and Jain, S and Lee, SJ}, title = {Longitudinal tear cytokine biomarkers: an analysis from the Close Assessment and Testing for Chronic Graft-vs.-Host disease (CATCH) protocol: Predictive tear cytokine biomarkers for ocular GVHD.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.02.004}, pmid = {39923937}, issn = {2666-6367}, abstract = {BACKGROUND: Ocular graft-versus-host disease (oGVHD) is one of the most common initial manifestations of chronic GVHD (cGVHD) leading to significant morbidity and reduced quality of life. Early detection of oGVHD using susceptibility/risk biomarkers is urgently needed to enable preemptive therapy.<br><br>OBJECTIVES: In this subset analysis of patients enrolled on the CATCH Study (NCT04188912), we tested whether changes in tear film cytokines or ocular symptoms, as assessed by the Lee symptom scale (LSS) eye subscale, can predict oGVHD onset.<br><br>STUDY DESIGN: LSS eye subscores, Inflammadry (MMP9) and conjunctival washing samples were collected before hematopoietic cell transplantation (HCT) and every 2 months (mos) until 12 mos. A custom-designed 13-plex human cytokine magnetic bead panel was used to measure: IL-10, IL-17A, IL-1Ra, IL-1&#x3b1;, ELA2, IL-1&#x3b2;, LIGHT/TNFSF14, NGAL, OSM, IL-8, IP-10, TNF-&#x3b1;, and VEGF-A. Cytokine levels at the pre-HCT visit were compared across the groups using the Kruskal-Wallis test. Fold change (FC) of the cytokines, defined as post-HCT value divided by pre-HCT value, was calculated and FC&#x2265;2 was used in further analyses. oGVHD diagnosis was based on the NIH diagnostic criteria and having an eye score &#x2265;1. Cox regression models were used to examine the longitudinal relationships between potential predictors and oGVHD development.<br><br>RESULTS: Of the 44 patients included, 18 developed oGVHD, 11 had cGVHD without oGVHD, and 15 did not have any cGVHD. Median age was 64.5 years, median time from HCT to cGVHD was 6.4 mos and to oGVHD was 8.3 mos. There were no significant differences in baseline cytokine levels among groups. None of the tear cytokines or the InflammaDry MMP9 test predicted oGVHD onset. Clinically meaningful change in LSS eye score was associated with subsequent oGVHD development when compared to cGVHD without eye involvement (HR 2.5, 95% CI 1.2-5.1, p=0.01); and when compared to controls (HR 3.0, 95%CI 1.4-6.0, p=0.004) but the PPV of LSS change &#x2265;15 points was low (27.6%), with a higher NPV (89.4%).<br><br>CONCLUSIONS: This is the first prospective longitudinal study of tear cytokines and symptoms in a cohort of patients observed closely through HCT for development of cGVHD. We were not able to identify any biological susceptibility/risk markers for oGVHD. Patient-reported symptoms as measured by the LSS are associated with oGVHD development but the low PPV and overlap with diagnostic criteria limit its usefulness as a biomarker to guide preemptive treatment studies.}, }
@article {pmid39923936, year = {2025}, author = {Douglas, AP and Lamoth, F and John, TM and Groll, AH and Shigle, TL and Papanicolaou, GA and Chemaly, RF and Carpenter, PA and Dadwal, SS and Walsh, TJ and Kontoyiannis, DP}, title = {American Society of Transplantation and Cellular Therapy Series: #8- Management and Prevention of Non-Aspergillus Molds in Hematopoietic Cell Transplantation Recipients.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.01.892}, pmid = {39923936}, issn = {2666-6367}, abstract = {The Practice Guidelines Committee of the American Society of Transplantation and Cellular Therapy partnered with its Transplant Infectious Disease Special Interest Group to create a guideline focusing on non-Aspergillus invasive molds, which are uncommon yet lethal invasive fungal diseases in the peri-HCT period. We used a compendium-style approach by dissecting this broad, heterogeneous and highly complex topic into a series of standalone frequently asked questions (FAQs) and tables. Adult and pediatric infectious diseases and HCT content experts developed, then answered FAQs, and finalized topics with harmonized recommendations. All the evidence for NAIMI is non-RCT and mostly level III, therefore there are no recommendation grades and instead key references are provided. Through this format, this "8th" topic in the series focuses on the relevant risk factors, diagnostic considerations, prophylaxis and treatment approaches relevant to rare mold infections in the pre- and post-transplant periods.}, }
@article {pmid39921591, year = {2025}, author = {Schleicher, TK and Cohen, M and Graf, SA}, title = {The preclinical discovery and development of zanubrutinib for the treatment of chronic lymphocytic leukemia.}, journal = {Expert opinion on drug discovery}, volume = {}, number = {}, pages = {}, doi = {10.1080/17460441.2025.2465365}, pmid = {39921591}, issn = {1746-045X}, abstract = {INTRODUCTION: The history of treating chronic lymphocytic leukemia (CLL) inflected in 2014 with the Food and Drug Administration's (FDA) approval of ibrutinib, the first-in-class small molecule inhibitor of the Bruton's tyrosine kinase (BTK). Zanubrutinib is a 2[nd] generation covalent BTK inhibitor developed and manufactured by BeiGene.<br><br>AREAS COVERED: In this review, the authors trace the arc of zanubrutinib development from the preclinical phase through the two landmark phase 3 studies in the CLL space, ALPINE and SEQUOIA. The authors cover contemporary management strategies in CLL and highlight the areas of need that zanubrutinib was designed to mitigate.<br><br>EXPERT OPINION: Zanubrutinib entered a fray of novel, exciting therapies for CLL. As the second of two 2[nd] generation covalent BTK inhibitors its path to prominence in CLL management was narrow. Emphasis during development on kinase selectivity and enhanced bioavailability identified a molecule with superior efficacy and tolerability; hierarchical endpoints in trial design allowed for efficient acquisition of comparative data. Zanubrutinib is endorsed by the National Comprehensive Cancer Network as a preferred, category 1 recommended treatment choice for CLL. Future efforts in combination therapies and response-directed treatment breaks will hopefully lead to still further improvements in use.}, }
@article {pmid39921375, year = {2025}, author = {Olivieri, DJ and Gopal, AK and Uldrick, TS and Menon, MP}, title = {Exclusion of People Living with HIV in Aggressive B-Cell Non-Hodgkin Lymphoma Studies: A Cross-Sectional Analysis of Clinical Trials from 2014 to 2024.}, journal = {Cancer investigation}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/07357907.2025.2462568}, pmid = {39921375}, issn = {1532-4192}, abstract = {BACKGROUND: Human immunodeficiency virus is associated with the development of various aggressive non-Hodgkin B-cell lymphomas (NHL). Despite this, people living with HIV (PLWH) are often excluded from clinical trials. Here we analyze the change in clinical trial exclusion among PLWH resulting from multilateral advocacy efforts since 2017.<br><br>METHODS: We identified all US-based clinical trials with the keyword "lymphoma" with start dates between January 01, 2014 and January 04, 2025 using the publicly available NIH Clinical Trial Database (https://www.clinicaltrials.gov/). All studies with aggressive B-cell NHL subtypes were included. Regression models were performed to analyze descriptive factors.<br><br>RESULTS: 1,973&#x2009;US-based clinical trials were captured, of which 945 met criteria for further analysis. PLWH were excluded from 59% pre-2018 versus 48% post-2018. After multivariate adjustment, NIH-funded trials (24% exclusion rate, p&#x2009;<&#x2009;0.001), other funders (64% exclusion rate), and studies initiated post-2018 (48% exclusion rate, p&#x2009;<&#x2009;0.001) were associated with inclusion, while CAR-T-related studies (62% exclusion rate, p&#x2009;<&#x2009;0.05) were associated with exclusion.<br><br>CONCLUSIONS: Likely partly due to advocacy from ASCO, NCI, and NCCN, there was a significant decrease in exclusion among PLWH in US-based NHL clinical trials. Future research should analyze the safety and efficacy of immunotherapy in PLWH to foster inclusion and reduce stigma among physicians and researchers.}, }
@article {pmid39921208, year = {2025}, author = {Alkhunaizi, M and Soto, F and Leung, CH and Bhan, N and Bashoura, L and Dickey, BF and Sharifi, H and Cheng, GS and Yanik, G and Rondon, G and Saliba, R and Chen, G and Al-Atrash, G and Hosing, C and Kebriaei, P and Popat, UR and Shpall, EJ and Champlin, RE and Li, L and Alousi, AM and Sheshadri, A}, title = {Restrictive Ventilatory Defect Following Hematopoietic Stem Cell Transplant Is Associated With Increased Mortality.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.02.001}, pmid = {39921208}, issn = {2666-6367}, abstract = {INTRODUCTION: Hematopoietic cell transplantation (HCT) can potentially cure hematologic malignancies, but despite advancements in HCT regimens and graft-versus-host disease (GVHD) management, post-HCT complications, remain a major challenge. The epidemiology of post-HCT pulmonary impairment causing restrictive ventilatory defect (RVD) has not been examined. This study investigates the incidence, etiology, and impact of new-onset RVD following HCT on overall survival (OS) and non-relapse mortality (NRM).<br><br>METHODS: We conducted a retrospective review of adult patients who underwent their first allogeneic HCT for primary hematologic malignancies at The University of Texas MD Anderson Cancer Center between February 1999 and March 2018. RVD was defined by a total lung capacity (TLC) <5th percentile of the lower limit of normal. Patient data were analyzed using the Kaplan-Meier method, log-rank tests, and Cox regression models.<br><br>RESULTS: Among 3030 patients, 50 had pre-HCT RVD and 1275 developed new pulmonary impairment post-HCT, of which, we found 270 cases of new-onset RVD. The most common causes of post-HCT RVD were respiratory tract infections (23%), interstitial lung disease (15%) and truncal sclerosis (11%). Multivariate analysis indicated increased age (HR 1.03 per year, 95% CI 1.03-1.04, p<0.001), matched unrelated donor transplant (HR 1.29, 95% CI 1.04-1.60, p=0.02), mismatched related transplant (HR 2.04, 95% CI 1.33-3.14, p=0.001), cord blood stem cell source (HR 3.02, 95% CI 2.26-4.05, p<0.001), RVD (HR 2.27, 95% CI 1.77-2.90, p<0.001) and cGVHD (HR 1.72, 95% CI 1.44-2.05, p<0.001) were associated with higher mortality. More severe restriction (HR 4.04, 95% CI 2.83-5.77, p<0.001), progressive RVD (5.04, 95% CI 1.88-13.52, p=0.001), and RVD onset within 1 year of HCT (HR 2.61, 95% CI 1.72-3.98, p<0.001) were associated with higher mortality.<br><br>CONCLUSION: New-onset RVD post-HCT is associated with increased mortality. These findings emphasize the importance of identifying RVD through proactive pulmonary function monitoring to improve post-HCT outcomes.}, }
@article {pmid39921094, year = {2025}, author = {Nagle, CM and Ibiebele, TI and Na, R and Bandera, EV and Cramer, D and Doherty, JA and Giles, GG and Goodman, MT and Hanley, GE and Harris, HR and Jensen, A and Kjaer, SK and Lee, A and McGuire, V and Milne, RL and Qin, B and Richardson, J and Sasamoto, N and Schildkraut, JM and Sieh, W and Terry, KL and Titus, L and Trabert, B and Wentzensen, N and Wu, AH and Berchuck, A and Pike, MC and Pearce, CL and Webb, PM and , }, title = {Diet and survival after a diagnosis of ovarian cancer: a pooled analysis from the Ovarian Cancer Association Consortium.}, journal = {The American journal of clinical nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajcnut.2025.02.004}, pmid = {39921094}, issn = {1938-3207}, abstract = {BACKGROUND: Prognosis following a diagnosis of invasive epithelial ovarian cancer is poor. Some studies have suggested modifiable behaviors, like diet, are associated with survival but the evidence is inconsistent.<br><br>OBJECTIVE: To pool data from studies conducted around the world to evaluate the relation between dietary indices, foods, and nutrients from food sources and survival after a diagnosis of ovarian cancer.<br><br>METHODS: This analysis from the Multidisciplinary Ovarian Cancer Outcomes Group within the Ovarian Cancer Association Consortium included 13 studies with 7,700 individuals with ovarian cancer, who completed food-frequency questionnaires regarding their pre-diagnosis diet. Adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for associations with overall survival were estimated using Cox proportional hazards models.<br><br>RESULTS: Overall, there was no association between any of the seven dietary indices (representing pre-diagnosis diet) evaluated and survival; however, associations differed by tumor stage. While there were no consistent associations among those with advanced disease, among those with earlier stage (local/regional) disease, higher scores on the alternate Healthy Eating Index (aHR Quartile 4 versus 1 = 0.66, 95% CI=0.50, 0.87), Healthy Eating Index-2015 (aHR 0.75; 95% CI=0.59, 0.97) and alternate Mediterranean diet (aHR 0.76; 95% CI=0.60, 0.98) were associated with better survival. Better survival was also observed for individuals with early-stage disease who reported higher intakes of dietary components that contribute to the healthy diet indices (aHR for Q4 versus Q1: vegetables 0.71; 95% CI=0.56, 0.91), tomatoes (aHR 0.72; 95% CI=0.57, 0.91) and nuts and seeds (aHR 0.71; 95% CI=0.55, 0.92). In contrast, there were suggestions of worse survival with higher scores on two of the three inflammatory indices and higher intake of trans-fatty acids.<br><br>CONCLUSIONS: Adherence to a more heathy, less inflammatory diet may confer a survival benefit for individuals with early-stage ovarian cancer.}, }
@article {pmid39920506, year = {2025}, author = {Li, X and Chen, H and Selvaraj, MS and Van Buren, E and Zhou, H and Wang, Y and Sun, R and McCaw, ZR and Yu, Z and Jiang, MZ and DiCorpo, D and Gaynor, SM and Dey, R and Arnett, DK and Benjamin, EJ and Bis, JC and Blangero, J and Boerwinkle, E and Bowden, DW and Brody, JA and Cade, BE and Carson, AP and Carlson, JC and Chami, N and Chen, YI and Curran, JE and de Vries, PS and Fornage, M and Franceschini, N and Freedman, BI and Gu, C and Heard-Costa, NL and He, J and Hou, L and Hung, YJ and Irvin, MR and Kaplan, RC and Kardia, SLR and Kelly, TN and Konigsberg, I and Kooperberg, C and Kral, BG and Li, C and Li, Y and Lin, H and Liu, CT and Loos, RJF and Mahaney, MC and Martin, LW and Mathias, RA and Mitchell, BD and Montasser, ME and Morrison, AC and Naseri, T and North, KE and Palmer, ND and Peyser, PA and Psaty, BM and Redline, S and Reiner, AP and Rich, SS and Sitlani, CM and Smith, JA and Taylor, KD and Tiwari, HK and Vasan, RS and Viali, S and Wang, Z and Wessel, J and Yanek, LR and Yu, B and ,  and Dupuis, J and Meigs, JB and Auer, PL and Raffield, LM and Manning, AK and Rice, KM and Rotter, JI and Peloso, GM and Natarajan, P and Li, Z and Liu, Z and Lin, X}, title = {A statistical framework for multi-trait rare variant analysis in large-scale whole-genome sequencing studies.}, journal = {Nature computational science}, volume = {}, number = {}, pages = {}, pmid = {39920506}, issn = {2662-8457}, support = {R35-CA197449//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; U19-CA203654//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; U01-HG012064//U.S. Department of Health &amp; Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; U01-HG009088//U.S. Department of Health &amp; Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; R00HG012956-02//U.S. Department of Health &amp; Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; NHLBI TOPMed Fellowship 75N92021F00229//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; NHLBI TOPMed Fellowship 75N92021F00229//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; U01-HL072524//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01-HL104135-04S1//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; U01-HL054472//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; U01-HL054473//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; U01-HL054495//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; U01-HL054509//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01-HL055673-18S1//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01-HL153805//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R03-HL154284//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; HL105756//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; 1R35-HL135818//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01-HL113338//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; HL046389//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; U01-HL137162//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01-HL142711//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01-HL127564//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01-HL142711//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01-HL127564//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; HL151855//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; HHSN268201700001I/HL/NHLBI NIH HHS/United States ; HHSN268201700002I/HL/NHLBI NIH HHS/United States ; HHSN268201700003I/HL/NHLBI NIH HHS/United States ; HHSN268201700005I/HL/NHLBI NIH HHS/United States ; HHSN268201700004I/HL/NHLBI NIH HHS/United States ; R01-MD012765//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01-DK117445//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; HHSN268201600002C/HL/NHLBI NIH HHS/United States ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; HHSN268201800001I//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; 75N92020D00001/HL/NHLBI NIH HHS/United States ; HHSN268201500003I/HL/NHLBI NIH HHS/United States ; N01-HC-95159//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; 75N92020D00005/HL/NHLBI NIH HHS/United States ; N01-HC-95160//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; 75N92020D00002/HL/NHLBI NIH HHS/United States ; N01-HC-95161//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; 75N92020D00003/HL/NHLBI NIH HHS/United States ; N01-HC-95162//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; 75N92020D00006/HL/NHLBI NIH HHS/United States ; N01-HC-95163//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; 75N92020D00004/HL/NHLBI NIH HHS/United States ; N01-HC-95164//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; 75N92020D00007/HL/NHLBI NIH HHS/United States ; N01-HC-95165//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; N01-HC-95166//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; N01-HC-95167//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; N01-HC-95168//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; N01-HC-95169//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; UL1-TR-000040//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; UL1-TR-001079//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; UL1-TR-001420//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; UL1-TR001881//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; DK063491//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01-HL071051//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01-HL071205//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01-HL071250//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01-HL071251//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01-HL071258//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01-HL071259//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; UL1-RR033176//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; 1R01AG086379-01//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; DK078616//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; }, abstract = {Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally scalable analytical pipeline for functionally informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple traits, and further empowers rare variant association analysis by incorporating multiple functional annotations. We applied MultiSTAAR to jointly analyze three lipid traits in 61,838 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered and replicated new associations with lipid traits missed by single-trait analysis.}, }
@article {pmid39920014, year = {2025}, author = {Raychaudhuri, R and Tuchayi, AM and Low, SK and Arafa, AT and Graham, LS and Gulati, R and Pritchard, CC and Montgomery, RB and Haffner, MC and Nelson, PS and Yu, EY and Hawley, JE and Cheng, HH and Mo, G and Chen, DL and Antonarakis, ES and Kilari, D and Hope, TA and Iravani, A and Schweizer, MT}, title = {Association of Prior PARP Inhibitor Exposure with Clinical Outcomes after [177]Lu-PSMA-617 in Men with Castration-resistant Prostate Cancer and Mutations in DNA Homologous Recombination Repair Genes.}, journal = {European urology oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.euo.2025.01.002}, pmid = {39920014}, issn = {2588-9311}, abstract = {BACKGROUND AND OBJECTIVE: The prostate-specific membrane antigen (PSMA) radioligand [177]Lu-PSMA-617 (LuPSMA) is approved for treatment of metastatic castration-resistant prostate cancer (mCRPC). PARP inhibitors (PARPi) are approved for patients with mCRPC and mutations in homologous recombination repair (HRR) pathway genes. Both modalities induce DNA damage and therefore may share mechanisms of resistance. We investigated whether PARPi exposure would reduce the subsequent efficacy of LuPSMA.<br><br>METHODS: This retrospective study included 100 patients with a PARPi-qualifying HRR alteration treated with LuPSMA. Clinical outcomes on LuPSMA, including PSA50 response, PSA progression-free survival (PFS), and overall survival (OS), were compared between those who had not previously received PARPi (PARPi-N) and those who had (PARPi-T). Subgroup analyses were performed for the most frequent HRR alterations (BRCA2 and ATM).<br><br>KEY FINDINGS AND LIMITATIONS: PSA50 responses on LuPSMA were similar between PARPi-N (n&#xa0;=&#xa0;47) and PARPi-T (n&#xa0;=&#xa0;53), although PSA PFS was longer in the PARPi-N group (9.1 vs 4.8 mo; p&#xa0;=&#xa0;0.037). Among patients with BRCA2 alterations, the PARPi-N group had a better PSA50 response rate (89% vs 35%; p&#xa0;=&#xa0;0.009), PSA PFS (14 vs 2.9 mo; p&#xa0;=&#xa0;0.026), and OS (19 vs 5.3 mo; p&#xa0;=&#xa0;0.10). PARPi exposure did not influence LuPSMA outcomes among patients with ATM alterations. Limitations include the retrospective design and differences in prior lines of therapy between the groups.<br><br>PARPi exposure is associated with inferior LuPSMA outcomes, particularly for patients with BRCA2 alterations. These findings suggest potential cross-resistance and underscore the need for prospective studies assessing the optimal sequencing of these agents.}, }
@article {pmid39919997, year = {2025}, author = {Danilov, AV and Sauter, C and Phillips, T and Coombs, CC and Ip, A and Wang, Y and Rhodes, J and Leslie, L and Barrientos, J and Saeed, H and Strati, P and Barta, SK and Shadman, M}, title = {Perspectives on Current Challenges and Emerging Approaches for Lymphoma Management From the First Bridging the Gaps in Leukemia, Lymphoma, and Multiple Myeloma Conference.}, journal = {Clinical lymphoma, myeloma &amp; leukemia}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.clml.2025.01.005}, pmid = {39919997}, issn = {2152-2669}, abstract = {Recent years have brought a much-needed paradigm shift to the management and treatment of mature B-cell lymphomas. Pathophysiologic and clinical heterogeneity within the various subtypes have historically contributed to treatment challenges and differences in outcomes. Novel genomic tools and therapeutic modalities give promise for improved patient outcomes, but are also making treatment planning increasingly complex. To bridge the gaps between therapeutic advancements and clinical practice, an assembly of multidisciplinary hematologic oncology faculty convened to deliberate on the prevailing challenges, knowledge gaps, and controversies in B-cell lymphoma and chronic lymphocytic leukemia management. Many controversies and questions were identified regarding treatment selection, sequencing, and high-risk subtypes. There is a need for head-to-head trials in this therapeutic area to help answer some of these questions. The insights explored and the gaps in knowledge identified by this panel will inform a follow-up conference in 2025 that will employ the modified Delphi method to develop and publish formal consensus recommendations that can provide actionable guidance to practicing clinicians.}, }
@article {pmid39919043, year = {2025}, author = {Bender Ignacio, R and Kitahata, M and Montaño, M and Shapiro, A}, title = {Mpox in People with HIV: Prioritizing Interventions for those without HIV Viral Suppression.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciaf059}, pmid = {39919043}, issn = {1537-6591}, }
@article {pmid39916630, year = {2025}, author = {Wilechansky, RM and Challa, PK and Han, X and Hua, X and Manning, AK and Corey, KE and Chung, RT and Zheng, W and Chan, AT and Simon, TG}, title = {Pre-Diagnostic Plasma Metabolites are Associated with Incident Hepatocellular Carcinoma: A Prospective Analysis.}, journal = {Cancer prevention research (Philadelphia, Pa.)}, volume = {}, number = {}, pages = {}, doi = {10.1158/1940-6207.CAPR-24-0440}, pmid = {39916630}, issn = {1940-6215}, abstract = {Despite increasing incidence of hepatocellular carcinoma (HCC) in vulnerable populations, accurate early detection tools are lacking. We aimed to investigate the associations between pre-diagnostic plasma metabolites and incident HCC in a diverse population. In a prospective, nested case-control study within the Southern Community Cohort Study (SCCS), we conducted pre-diagnostic liquid chromatography-mass spectrometry metabolomics profiling in 150 incident HCC cases (median time to diagnosis 7.9 years) and 100 controls with cirrhosis. Logistic regression assessed metabolite associations with HCC risk. Metabolite set enrichment analysis identified enriched pathways, and random forest classifier was used for risk classification models. Candidate metabolites were validated in the UK Biobank (N=12 incident HCC cases and 24 cirrhosis controls). In logistic regression analysis, seven metabolites were associated with incident HCC (Meff p<0.0004), including N-acetylmethionine (OR=0.46, 95% CI=0.31-0.66). Multiple pathways were enriched in HCC, including histidine and coenzyme A metabolism (FDR p<0.001). Random forest classifier identified ten metabolites for inclusion in HCC risk classification models, which improved HCC risk classification compared to clinical covariates alone (AUC=0.66 for covariates vs. 0.88 for 10 metabolites plus covariates; p<0.0001). Findings were consistent in the UK Biobank (AUC=0.72 for covariates vs. 0.88 for four analogous metabolites plus covariates; p=0.04), assessed via nuclear magnetic resonance spectroscopy. Pre-diagnostic metabolites, primarily amino acid and sphingolipid derivatives, are associated with HCC risk and improve HCC risk classification beyond clinical covariates. These metabolite profiles, detectable years before diagnosis, could serve as early biomarkers for HCC detection and risk stratification if validated in larger studies.}, }
@article {pmid39916525, year = {2025}, author = {Brzezinski, JJ and Malkin, D}, title = {Knudson's "Two-Hit" Hypothesis and Cancer Predisposition: A Bit More Complicated but Still Going Strong.}, journal = {Cancer discovery}, volume = {15}, number = {2}, pages = {258-260}, doi = {10.1158/2159-8290.CD-24-1662}, pmid = {39916525}, issn = {2159-8290}, mesh = {Humans ; *Genetic Predisposition to Disease ; *Wilms Tumor/genetics/pathology ; Neoplasms/genetics ; Kidney Neoplasms/genetics ; Child ; }, abstract = {This study by Treger and colleagues is a comprehensive evaluation of the genome and epigenome of tumors and constitutional tissue from children with Wilms tumor predisposition syndromes that demonstrates that the molecular features of Wilms tumors are dependent on the constitutional milieu of the patient in which they develop. See related article by Treger et al., p. 286.}, }
@article {pmid39916421, year = {2025}, author = {Unger, JM}, title = {Financial toxicity: A ubiquitous condition in patients with cancer.}, journal = {Cancer}, volume = {131}, number = {4}, pages = {e35748}, doi = {10.1002/cncr.35748}, pmid = {39916421}, issn = {1097-0142}, }
@article {pmid39916344, year = {2024}, author = {Meisner, A and Xia, F and Chan, KCG and Mayer, K and Wheeler, D and Zangeneh, S and Donnell, D}, title = {Estimating the effect of pre-exposure prophylaxis in Black men who have sex with men.}, journal = {International journal of epidemiology}, volume = {54}, number = {1}, pages = {}, pmid = {39916344}, issn = {1464-3685}, support = {NIH U01 HL146242/NH/NIH HHS/United States ; }, mesh = {Humans ; Male ; *Pre-Exposure Prophylaxis/methods ; *Homosexuality, Male/statistics &amp; numerical data ; *HIV Infections/prevention &amp; control ; *Black or African American/statistics &amp; numerical data ; Adult ; United States/epidemiology ; *Anti-HIV Agents/therapeutic use/administration &amp; dosage ; Medication Adherence/ethnology ; Young Adult ; Middle Aged ; White ; }, abstract = {BACKGROUND: Black men who have sex with men (MSM) are disproportionately burdened by the HIV epidemic in the USA. The effectiveness of pre-exposure prophylaxis (PrEP) in preventing HIV infection has been demonstrated through randomized placebo-controlled clinical trials in several populations. Importantly, no such trial has been conducted exclusively among Black MSM in the USA, and it would be unethical and infeasible to do so now.<br><br>METHODS: To estimate the causal effects of PrEP access, initiation, and adherence on HIV risk, we utilized causal inference methods to combine data from two non-randomized studies that exclusively enrolled Black MSM.<br><br>RESULTS: The estimated relative risks of HIV were: (i) 0.52 (95% confidence interval: 0.21, 1.22) for individuals with versus without PrEP access, (ii) 0.48 (0.12, 0.89) for individuals who initiated PrEP but were not adherent versus those who did not initiate, and (iii) 0.23 (0.02, 0.80) for individuals who were adherent to PrEP versus those who did not initiate.<br><br>CONCLUSION: Beyond addressing the knowledge gap around the effect of PrEP in Black MSM in the USA, which may have ramifications for public health, we have provided a framework to combine data from multiple non-randomized studies to estimate causal effects, which has broad utility.}, }
@article {pmid39915487, year = {2025}, author = {Xie, J and Chen, DG and Chour, W and Ng, RH and Zhang, R and Yuan, D and Choi, J and McKasson, M and Troisch, P and Smith, B and Jones, L and Webster, A and Rasheed, Y and Li, S and Edmark, R and Hong, S and Murray, KM and Logue, JK and Franko, NM and Lausted, CG and Piening, B and Algren, H and Wallick, J and Magis, AT and Watanabe, K and Mease, P and Greenberg, PD and Chu, H and Goldman, JD and Su, Y and Heath, JR}, title = {APMAT analysis reveals the association between CD8 T cell receptors, cognate antigen, and T cell phenotype and persistence.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {1402}, pmid = {39915487}, issn = {2041-1723}, support = {HHSO10201600031C//U.S. Department of Health &amp; Human Services | Biomedical Advanced Research and Development Authority (BARDA)/ ; }, mesh = {Humans ; *CD8-Positive T-Lymphocytes/immunology ; *COVID-19/immunology/virology ; *Receptors, Antigen, T-Cell/immunology/metabolism ; *SARS-CoV-2/immunology ; *Single-Cell Analysis/methods ; *Phenotype ; HLA-A2 Antigen/immunology/metabolism ; Antigens, Viral/immunology ; Peptides/immunology ; Male ; Transcriptome ; Female ; }, abstract = {Elucidating the relationships between a class I peptide antigen, a CD8 T cell receptor (TCR) specific to that antigen, and the T cell phenotype that emerges following antigen stimulation, remains a mostly unsolved problem, largely due to the lack of large data sets that can be mined to resolve such relationships. Here, we describe Antigen-TCR Pairing and Multiomic Analysis of T-cells (APMAT), an integrated experimental-computational framework designed for the high-throughput capture and analysis of CD8 T cells, with paired antigen, TCR sequence, and single-cell transcriptome. Starting with 951 putative antigens representing a comprehensive survey of the SARS-CoV-2 viral proteome, we utilize APMAT for the capture and single cell analysis of CD8 T cells from 62 HLA A*02:01 COVID-19 participants. We leverage this comprehensive dataset to integrate with peptide antigen properties, TCR CDR3 sequences, and T cell phenotypes to show that distinct physicochemical features of the antigen-TCR pairs strongly associate with both T cell phenotype and T cell persistence. This analysis suggests that CD8 T cell phenotype following antigen stimulation is at least partially deterministic, rather than the result of stochastic biological properties.}, }
@article {pmid39915263, year = {2025}, author = {Ramaswami, R and Kask, AS and D'Amico, L and Menon, MP and Lurain, K and Yarchoan, R and Ekwede, I and Couey, P and Burnham, E and Angeldekao, A and Ha Lee, B and Kaiser, JC and Cheever, M and Uldrick, TS and Kwok, LL and Wright, A and Fling, SP and Wang, CJ}, title = {Phase I study of efineptakin alfa (NT-I7) for the treatment of Kaposi sarcoma.}, journal = {Journal for immunotherapy of cancer}, volume = {13}, number = {2}, pages = {}, pmid = {39915263}, issn = {2051-1426}, mesh = {Humans ; Male ; *Sarcoma, Kaposi/drug therapy ; Middle Aged ; Female ; Adult ; Aged ; HIV Infections/drug therapy/complications ; CD4-Positive T-Lymphocytes/immunology/drug effects/metabolism ; Interleukin-7 ; }, abstract = {BACKGROUND: CD4[+] T-cell lymphocytopenia and immune dysfunction are factors that drive the onset and persistence of Kaposi sarcoma (KS) in people with (PWH) and without HIV. Standard chemotherapy agents for KS can contribute to increasing CD4[+] T cell lymphocytopenia. IL-7 is a cytokine that is essential in T-cell development, proliferation and homeostasis. In PWH, IL-7 administration leads to increased numbers of circulating central memory and naïve T-cell phenotypes.<br><br>METHODS: In this multicenter phase I study with a 3+3&#x2009;dose escalation design, participants with KS with or without HIV received up to four intramuscular injections of IL-7 (NT-I7) every 9 weeks. The primary endpoint of the study was to evaluate safety over three escalating dose levels (DL) of NT-I7 (DL1:480&#x2009;&#xb5;g/kg, DL2: 960&#x2009;&#xb5;g/kg and DL3: 1200&#x2009;&#xb5;g/kg) and identify a maximum tolerated dose. Secondary endpoints included evaluation of antitumor activity per the modified AIDS Clinical Trials Group Criteria and assessment of the effect of NT-I7 on the kinetics of CD4[+] and CD8[+] T-cells.<br><br>RESULTS: Eight cisgender male participants (five with HIV infection) were enrolled. Six participants were treated at DL1, and two were treated at DL2. The study was closed to accrual after enrolment of the second participant on DL2 due to termination of study funding. Four of the eight participants (three in DL1 and one in DL2) completed all four doses of the NT-I7. With regard to treatment-emergent adverse events (AEs), all participants had <grade 2 AEs, which included injection site reaction and alanine aminotransferase increase. Injection site reaction was a dose-limiting toxicity in one participant at DL1. The overall KS objective response rate to NT-I7 was 42.9% (95% CI 9.9%, 81.6%) and all three responders were PWH. Absolute lymphocyte counts, CD4[+] and CD8[+] T-cell counts increased among all participants following administration of NT-I7. Participants who experienced a response had HIV and lower CD4/CD8 ratio at baseline and throughout the study as compared with those who did not have KS response to NT-I7.<br><br>CONCLUSIONS: Preliminary data demonstrate safety and activity of IL-7 in patients with KS and activity specifically among individuals HIV-associated KS.<br><br>TRIAL REGISTRATION NUMBER: NCT04893018.}, }
@article {pmid39914257, year = {2025}, author = {Carter, JJ and Smith, RA and Scherer, EM and Skibinski, DAG and Sankaranarayanan, S and Luxembourg, A and Kollmann, T and Marty, KD and Sadarangani, M and Dobson, S and Galloway, DA}, title = {Term immune memory responses to human papillomavirus (HPV) vaccination following 2 versus 3 doses of HPV vaccine.}, journal = {Vaccine}, volume = {50}, number = {}, pages = {126817}, doi = {10.1016/j.vaccine.2025.126817}, pmid = {39914257}, issn = {1873-2518}, abstract = {Human papillomavirus (HPV) vaccines provide excellent protection from infection and disease. The minimum number of doses needed for long-term protection and the potential need for boosters are areas of continuing interest. Studies on the durability of vaccines have focused on antibodies, fewer have analyzed memory immune cells that could provide protection even when antibody levels are low. In this study, subjects who had participated in one of two trials comparing two and three doses (2D, 3D), were given an additional vaccine dose (Gardasil®9, 9vHPV) several years after the initial vaccine doses, and the magnitude of immune responses were compared. Both trials had 2D children who received doses at 0 and 6 months (G1a), 3D children 9-13 (08-001) or 9-14 (V503-010) years old at enrollment in the original trial (G2) and 3D women (age 16-26) (G3). Trial V503-010 had a second 2D group of children vaccinated at 0 and 12 months (G1b). Changes in numbers of HPV specific memory B cells (Bmem) (N = 6 per group, both studies) at 1 month and plasmablasts (PB) (08-001: N = 6 per group, V503-010: G1a N = 12, G1b N = 8, G2 N = 6, G3 N = 28) at 1 week, relative to baseline at the additional dose, were compared among groups. Changes in the geometric mean titers (GMTs) of HPV specific antibodies relative to baseline were compared (N = same as PB). Statistically significant (p < 0.05) increases in the numbers of PB, Bmem and antibody levels (GMT) were seen among subjects receiving an extra vaccine dose relative to baseline. Increases in the number of PB and Bmem were not significantly different among subjects receiving two or three doses. Thus, robust immune responses were observed and did not differ significantly among subjects vaccinated with two or three doses.}, }
@article {pmid39913928, year = {2025}, author = {Venditti, A and Palmieri, R and Maurillo, L and Röllig, C and Wierzbowska, A and de Leeuw, DC and Efficace, F and Curti, A and Ngai, LL and Tettero, JM and Adès, L and Almeida, AM and Bullinger, L and Dennis, M and Esteve, J and Ferrara, F and Heuser, M and Huls, GA and Lübbert, M and Mehta, P and Montesinos, P and Pabst, T and Récher, C and Rossi, G and Russell, NH and Sierra, J and Stauder, R and Vey, N and Walter, RB and Wang, ES and Nier, S and Martins, CG and Ossenkoppele, GJ}, title = {FITNESS ASSESSMENT IN ACUTE MYELOID LEUKEMIA: RECOMMENDATIONS FROM AN EXPERT PANEL ON BEHALF OF EUROPEAN LEUKEMIA NET.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024013744}, pmid = {39913928}, issn = {2473-9537}, abstract = {Fitness assessment in patients with acute myeloid leukemia (AML) is critical to deliver the right therapy to the right patient. While several scoring systems are available to aid in determining fitness, the absence of validation studies has resulted in the lack of universally accepted assessment procedures. This limitation, combined with the increasing availability of novel agents expanding the spectrum of less-intensive options, has introduced additional complexity to the fitness assessment process. In this evolving context, fitness should reflect eligibility for a specific treatment among the several available, rather than a generic binary classification of eligibility for intensive chemotherapy. Moreover, the growing emphasis on patient-centered care, further highlights the importance of integrating quality of life, patients' preferences, patients' self-reported physical and social functioning status, social support, and early integration of palliative care into the assessment framework. A modern interpretation of fitness assessment should incorporate a comprehensive evaluation that extends beyond traditional clinical and biological disease characteristics. Thus, fitness assessment in patients with AML represents only one piece of a larger puzzle, encompassing the patient's overall capacity to sustain and benefit from a specific therapeutic program.}, }
@article {pmid39913208, year = {2025}, author = {Pitzen, SP and Rudenick, AN and Qiu, Y and Zhang, W and Munro, SA and McCluskey, BM and Forster, C and Bergom, HE and Ali, A and Boytim, E and Lafin, JT and Linder, S and Ismail, M and Devlies, W and Sessions, CJ and Claessens, F and Joniau, S and Attard, G and Zwart, W and Nelson, PS and Corey, E and Wang, Y and Lang, JM and Beltran, H and Strand, D and Antonarakis, ES and Hwang, J and Murugan, P and Huang, RS and Dehm, SM}, title = {Comparative transcriptomics reveals a mixed basal, club, and hillock epithelial cell identity in castration-resistant prostate cancer.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {6}, pages = {e2415308122}, doi = {10.1073/pnas.2415308122}, pmid = {39913208}, issn = {1091-6490}, support = {R01CA174777//HHS | NIH | National Cancer Institute (NCI)/ ; R01CA270539//HHS | NIH | National Cancer Institute (NCI)/ ; R01CA276269//HHS | NIH | National Cancer Institute (NCI)/ ; }, mesh = {Male ; *Prostatic Neoplasms, Castration-Resistant/genetics/metabolism/pathology ; Humans ; *Epithelial Cells/metabolism ; *Receptors, Androgen/metabolism/genetics ; *Transcriptome ; *Kruppel-Like Transcription Factors/metabolism/genetics ; *Gene Expression Regulation, Neoplastic ; Cell Line, Tumor ; Receptors, Retinoic Acid/metabolism/genetics ; Signal Transduction ; Prostate/metabolism/pathology ; }, abstract = {Inhibiting the androgen receptor (AR) is effective for treatment of advanced prostate cancers because of their AR-dependent luminal epithelial cell identity. Tumors progress during therapy to castration-resistant prostate cancer (CRPC) by restoring AR signaling and maintaining luminal identity or by converting through lineage plasticity to a neuroendocrine (NE) identity or double-negative CRPC (DNPC) lacking luminal or NE identities. Here, we show that DNPC cells express genes defining basal, club, and hillock epithelial cells from benign prostate. We identified KLF5 as a regulator of genes defining this mixed basal, club, and hillock cell identity in DNPC models. KLF5-mediated upregulation of RARG uncovered a DNPC sensitivity to growth inhibition by retinoic acid receptor agonists, which down-regulated KLF5 and up-regulated AR. These findings offer CRPC classifications based on prostate epithelial cell identities and nominate KLF5 and RARG as therapeutic targets for CRPC displaying a mixed basal, club, and hillock identity.}, }
@article {pmid39912912, year = {2025}, author = {Sharifi, MN and Sperger, JM and Taylor, AK and Tippins, KE and Reese, SR and Carreno, V and Kaufmann, KR and Chang, AH and Nunamaker, LA and Linebarger, C and Mora-Rodriguez, L and Schehr, JL and Krause, HM and Helzer, KT and Bootsma, ML and Blitzer, GC and Floberg, JM and Kyriakopoulos, CE and Emamekhoo, H and Heath, EI and Wells, M and Tagawa, ST and Sjöström, M and Choudhury, AD and Yu, M and Armstrong, AJ and Rathkopf, DE and Beltran, H and Nelson, PS and Feng, FY and Dehm, SM and Kosoff, D and Wei, XX and McKay, RR and Zhao, SG and Lang, JM}, title = {High-purity CTC RNA sequencing identifies prostate cancer lineage phenotypes prognostic for clinical outcomes.}, journal = {Cancer discovery}, volume = {}, number = {}, pages = {}, doi = {10.1158/2159-8290.CD-24-1509}, pmid = {39912912}, issn = {2159-8290}, abstract = {The development of treatment resistance remains universal for patients with metastatic prostate cancer, driven by AR alterations and lineage state transitions. Identifying the evolution of lineage transitions in treatment resistance has been limited by the challenges of collecting serial tissue biopsies on treatment, which can be overcome using blood-based liquid biopsies. Utilizing a novel circulating tumor cell (CTC) isolation approach, we collected 273 CTC samples from 117 patients with metastatic prostate cancer for RNA sequencing. 146 samples from 70 patients had tumor purity comparable to tissue biopsies. We identified four CTC transcriptional phenotypes, mirroring lineage states identified in tissue. Patients with a luminal-B-like CTC phenotype defined by persistent AR signaling and high proliferation, as well as those with a neuroendocrine CTC phenotype, had significantly shorter survival than patients with luminal-A-like and low proliferation phenotypes. In a prospective substudy, pre-treatment CTC luminal-B-like phenotype was associated with early progression on 177Lu-PSMA-617.}, }
@article {pmid39912719, year = {2025}, author = {Mongiovi, JM and Townsend, MK and Vitonis, AF and Harris, HR and Doherty, JA and Babic, A and Hecht, JL and Soong, TR and Titus, L and Conejo-Garcia, JR and Fridley, BL and Tworoger, SS and Terry, KL and Sasamoto, N}, title = {Associations between parity, history of breastfeeding, and T cell profile of ovarian tumors.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-24-1414}, pmid = {39912719}, issn = {1538-7755}, abstract = {BACKGROUND: Parity and breastfeeding are associated with systemic changes in maternal inflammation and reduced risk of ovarian cancer, but little is known about their impact on the ovarian tumor immune microenvironment.<br><br>METHODS: We evaluated the associations of self-reported parity and history of breastfeeding with tumor-infiltrating T cells among 1,706 ovarian carcinoma cases with tumor tissue collected across four studies. The abundance of tumor-infiltrating T cells was measured by multiplex immunofluorescence in tumor tissue microarrays. Odds ratios (OR) and 95% confidence intervals (CIs) for the positivity of tumor immune cells were calculated using beta-binomial models and stratified by histotype.<br><br>RESULTS: Compared to ovarian tumors in nulliparous women, there was no association between parity and ovarian tumor T cell abundance among all histotypes combined, but suggestion of increased cytotoxic T cells and T cell exhaustion among parous women with clear cell tumors. When restricted to parous women, history of breastfeeding was associated with increased odds for all T cell types (i.e., total, cytotoxic, helper, regulatory, and exhausted T cells), with ORs ranging from 1.11-1.42. For every 6 months of breastfeeding, we observed increased odds of activated helper T cell infiltration (CD3+CD4+CD69+, OR:1.13, 95% CI: 0.99-1.29), with a similar association for high-grade serous tumors, but lower odds in clear cell tumors (OR:0.43, 95% CI:0.21-0.87).<br><br>CONCLUSIONS: History of breastfeeding may alter the ovarian tumor immune microenvironment by modulating the abundance of tumor-infiltrating T cells.<br><br>IMPACT: While replication is required, history of breastfeeding may play a role in activation of the ovarian tumor immune response.}, }
@article {pmid39909144, year = {2025}, author = {Ehret, F and Bhandarkar, AR and Chisam, M and Goulenko, V and Kumar, R and Fekrmandi, F and Skalina, KA and Kresl, J and Lo, SS and Gibbs, IC and Soltys, SG and Sheehan, JP and Fürweger, C and Slotman, BJ and Shih, HA and Chao, ST}, title = {Stereotactic Radiosurgery for Vestibular Schwannoma - A Case-Based Practice Guide from the Radiosurgery Society.}, journal = {Practical radiation oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.prro.2025.01.010}, pmid = {39909144}, issn = {1879-8519}, abstract = {PURPOSE: Vestibular schwannomas (VS) are the most common benign intracranial nerve sheath tumors. Surgery and radiotherapy - particularly stereotactic radiosurgery (SRS) - are the primary treatment options. SRS is the dominant treatment for small- and medium-sized VS and selected larger tumors due to its excellent local control rates and favorable safety profile compared to surgery. However, careful treatment planning is essential, taking into account patient preferences, tumor location and size, symptoms, and anticipated treatment-related toxicity.<br><br>METHODS AND MATERIALS: Four clinical VS scenarios have been selected to illustrate the use of SRS, including a unilateral, small intracanalicular VS, a large VS with cystic components, reirradiation with SRS after local tumor recurrence, and bilateral VS in the setting of neurofibromatosis type 2-related schwannomatosis.<br><br>RESULTS: SRS is an effective and safe treatment modality for the majority of VS cases, requiring careful treatment planning and a thorough understanding of potential limitations and challenges.<br><br>CONCLUSIONS: This case-based practice guide aims to provide a concise overview of the treatment of VS with SRS. We present and discuss four different clinical scenarios of VS to illustrate the pitfalls and best practice recommendations.}, }
@article {pmid39909038, year = {2025}, author = {Hesselman, MC and Zeeb, M and Rusert, P and Pasin, C and Mamrosh, J and Kariuki, S and Pichler, I and Sickmann, M and Kaufmann, MM and Schmidt, D and Friedrich, N and Metzner, KJ and Rindler, A and Kuster, H and Adams, C and Thebus, R and Huber, M and Yerly, S and Leuzinger, K and Perreau, M and Koller, R and Dollenmaier, G and Frigerio, S and Westfall, DH and Deng, W and deCamp, AC and Juraska, M and Edupuganti, S and Mgodi, N and Murrell, H and Garrett, N and Wagh, K and Mullins, JI and Williamson, C and Moore, PL and Günthard, HF and Kouyos, RD and Trkola, A}, title = {Rare twin cysteine residues in the HIV-1 envelope variable region 1 link to neutralization escape and breadth development.}, journal = {Cell host &amp; microbe}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.chom.2025.01.004}, pmid = {39909038}, issn = {1934-6069}, abstract = {Identifying HIV-1 envelope (Env) traits associated with neutralization cross-reactivity is crucial for vaccine design. Variable loops 1 and 2 (V1V2), positioned at the Env trimer apex, are key regions linked to neutralization. We describe non-canonical cysteine (Cys) residues in V1 that are enriched in individuals with elite neutralization breadth. Analyzing over 65,000 V1 sequences from the CATNAP database, AMP trials, and longitudinal HIV-1 cohorts (SHCS, ZPHI, and CAPRISA), we found that Env variants with extra V1 Cys are present at low levels and fluctuate over time. Extra V1 Cys associate with elite plasma neutralization, and two additional Cys are preferred, suggesting stabilization through disulfide bonds. Among 34 broadly neutralizing antibody (bnAb)-inducer Envs, 17.6% had elongated V1 regions with extra Cys. These extra Cys moderately increased neutralization resistance and altered bnAb epitope accessibility. Collectively, altering epitope exposure alongside Env stabilization renders the V1 twin Cys motif a promising feature for HIV-1 bnAb immunogens.}, }
@article {pmid39908783, year = {2025}, author = {Urselli, F and Gomez, A and Gray, MD and Cameron, CE and Taylor, JJ}, title = {Identification of antibodies induced by immunization with the syphilis vaccine candidate Tp0751.}, journal = {Vaccine}, volume = {50}, number = {}, pages = {126804}, doi = {10.1016/j.vaccine.2025.126804}, pmid = {39908783}, issn = {1873-2518}, abstract = {The continued and increasing prevalence of syphilis worldwide highlights the need for an effective syphilis vaccine to complement public health measures. Previous work demonstrated that immunization of the rabbit animal model with vaccine candidates derived from the T. pallidum endothelial cell adhesin Tp0751 could reduce dissemination of T. pallidum to lymph nodes. In those studies, a proportion of animals exhibited complete inhibition of treponemal dissemination and others exhibited partial or no inhibition of treponemal dissemination, consistent with results expected from an outbred animal model. In the current study we further characterized the Tp0751-specific antibody response in immunized animals that showed inhibition of T. pallidum dissemination. To do this, we generated Tp0751 tetramers to identify Tp0751-specific B cells before and after immunization. Using this approach, we found a robust expansion of Tp0751-specific B cells in the blood and spleens of immunized animals compared to unimmunized control animals. Ten antibodies from Tp0751-immunized rabbits were cloned and binding to specific structural regions of the Tp0751 protein was assessed using epitope mapping assays and structural modeling. Importantly, nine out of the ten antibodies cloned from Tp0751 tetramer-binding B cells were able to significantly inhibit T. pallidum attachment to human endothelial cells in vitro, including antibodies exhibiting weaker binding to Tp0751. Combined, our results provide a proof-of-principle that Tp0751-based subunit vaccines can stimulate strong B cell responses resulting in the production of antibodies able to inhibit T. pallidum attachment to endothelial cells.}, }
@article {pmid39908568, year = {2025}, author = {Newcomb, RA and Amonoo, HL and Kavanaugh, AR and Wharton, KC and Rowland, M and Fausto, J and Webb, JA and Jackson, V and Greer, JA and Temel, JS and Lark, P and Rabideau, DJ and O'Brien, K and LeBlanc, TW and Lee, SJ and El-Jawahri, A}, title = {Factors associated with early quality of life response to palliative care during hematopoietic cell transplantation.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024014574}, pmid = {39908568}, issn = {2473-9537}, abstract = {Limited data exist on factors associated with early quality of life (QOL) response to palliative care (PC) in patients undergoing hematopoietic cell transplantation (HCT). We conducted a secondary analysis from two randomized clinical trials of PC versus usual care in adults with hematologic malignancies undergoing HCT. We measured patient-reported QOL, physical and psychological symptoms, and coping (categorized as approach-oriented and avoidant) at time of HCT admission, 2-weeks, 3- and 6- months post-HCT. PC clinicians completed weekly surveys documenting PC domains addressed. We defined early QOL response to PC as change in FACT-BMT Total score from HCT admission to week 2 and used the median split to define "high" responders. 252 participants were included in analyses. The median change in QOL from HCT admission to week 2 was -10.7 (range: -77.0, +52.0). Minoritized race (OR=3.2, CI=[1.7,6.3], p<0.001), lower baseline QOL (OR=0.97, CI=[0.96,0.99], p<0.001), higher physical (OR=1.02, CI=[1.0,1.04], p=0.004) and PTSD symptoms (OR=1.04, CI=[1.01,1.07], p=0.008) were associated with being a high PC responder. High PC responders reported greater use of approach-oriented coping at week 2 (D=2.5, CI=[0.9,4.1], p=0.002), 3 months (D=1.7, CI=[0.1,3.3], p=0.04), and 6 months post-HCT (D=2.6, CI=[0.8,4.4], p=0.003). Based on PC clinician surveys during HCT, high responders' PC visits focused on coping, illness/HCT education, and symptom education, compared to low responders' visits which focused on symptom management. These findings provide insights into factors associated with early QOL response to PC in HCT and help identify those most likely to benefit in real world practice. The clinical trial were registered at clinicaltrials.gov (NCT02207322, NCT03641378).}, }
@article {pmid39905680, year = {2025}, author = {Johnson, ACM and Zager, RA}, title = {RBT-1, a "preconditioning" agent, mitigates syndecan-1 shedding in patients undergoing "on pump" cardiac surgery and following experimental AKI.}, journal = {Physiological reports}, volume = {13}, number = {3}, pages = {e70218}, pmid = {39905680}, issn = {2051-817X}, support = {//Renibus Therapeutics/ ; }, mesh = {Animals ; *Syndecan-1/blood/metabolism ; Male ; Humans ; *Acute Kidney Injury/metabolism/prevention &amp; control/etiology ; Mice ; *Hepatitis A Virus Cellular Receptor 1/metabolism ; Middle Aged ; *Cardiac Surgical Procedures/adverse effects ; Female ; Aged ; Lipocalin-2/blood/metabolism ; Interleukin-6/blood/metabolism ; NF-E2-Related Factor 2/metabolism/genetics ; }, abstract = {During systemic stress, syndecan-1 (SDC-1) shedding into plasma results, implying endothelial damage. RBT-1, a "preconditioning" agent, has been shown to mitigate postoperative complications following cardiac surgeries. This study assessed whether RBT-1 preconditioning attenuated SDC-1 shedding in these patients, implying a vascular protective effect. Patients (n, 112) were randomized to receive low-dose RBT-1, high-dose RBT-1, or placebo 24-48 h prior to surgery. Plasma samples were obtained before and 2 days postsurgery and assayed for SDC-1 (ELISA). To gain further insights, male CD-1 mice were subjected to acute renal injuries, and RBT-1's impact on plasma SDC-1 increases, vascular/aortic stress responses (NGAL/KIM-1/IL-6 gene induction), and two vascular cytoprotective pathways (Nrf2; ferritin) were assessed. Baseline plasma SDC-1 levels did not differ between patient groups. The placebo group developed an approximate 50% plasma SDC-1 (ng/mL) increase (p, 0.012). Conversely, no significant SDC-1 increases were seen in the RBT-1 treatment groups. Experimental injury markedly increased plasma SDC-1 concentrations, and these were significantly blunted by RBT-1 preconditioning. RBT-1 also mitigated AKI-induced aortic NGAL/KIM-1/IL-6 mRNA increases, activated aortic Nrf2, and increased vascular ferritin levels. RBT-1 preconditioning diminishes SDC-1 release and upregulates vascular ferritin and Nrf2. Hence, RBT-1 preconditioning can confer select vasoprotective effects.}, }
@article {pmid39903606, year = {2025}, author = {Cameli, M and Pieroni, M and Pastore, MC and Brucato, A and Castelletti, S and Crotti, L and Dweck, M and Frustaci, A and Gimelli, A and Klingel, K and Kuchynka, P and Kuusisto, J and Lazaros, G and Mandoli, GE and Merlo, M and Moon, J and Muraru, D and Pantazis, A and Rigopoulos, AG and Ristic, A and Elif Sade, L and Sheppard, MN and Tschoepe, C and Petersen, SE and Imazio, M}, title = {The role of cardiovascular multimodality imaging in the evaluation of Anderson-Fabry disease: from early diagnosis to therapy monitoring A clinical consensus statement of the ESC Working Group on Myocardial &amp; Pericardial Diseases and the European Association of Cardiovascular Imaging of the ESC.}, journal = {European heart journal. Cardiovascular Imaging}, volume = {}, number = {}, pages = {}, doi = {10.1093/ehjci/jeaf038}, pmid = {39903606}, issn = {2047-2412}, abstract = {Anderson-Fabry disease (AFD) is a rare genetic disease with X-linked transmission characterized by a defect in the enzyme alpha-galactosidase A (alpha-GAL), which impairs glycosphingolipid metabolism and leads to an excessive storage of globotriaosylceramide (Gb3) within lysosomes. AFD involves renal, cardiac, vascular, and nervous systems and is mainly observed in male patients with onset in childhood, although cardiac manifestation is often shown in adults. AFD cardiomyopathy is caused by the accumulation of Gb3 within myocytes first showed by left ventricular (LV) hypertrophy and diastolic dysfunction, leading to restrictive cardiomyopathy and systolic heart failure with biventricular involvement. The diagnosis of AFD cardiomyopathy may be insidious in the first stages and requires accurate differential diagnosis with other cardiomyopathies with hypertrophic phenotype. However, it is fundamental to promptly initiate specific therapies that have shown promising results, particularly for early treatment. A careful integration between clinical evaluation, genetic tests, and cardiac imaging is required to diagnose AFD with cardiac involvement. Basic and advanced echocardiography, cardiac magnetic resonance, and nuclear imaging may offer pivotal information for early diagnosis (Central illustration) and the management of these patients is often limited to centres with high expertise in the field. This clinical consensus statement, developed by experts from the European Society of Cardiology (ESC) Working Group on Myocardial &amp; Pericardial Diseases and the European Association of Cardiovascular Imaging of the ESC, aims to provide practical advice for all clinicians regarding the use of multimodality imaging to simplify the diagnostic evaluation, prognostic stratification, and management of cardiac involvement in AFD.}, }
@article {pmid39902315, year = {2025}, author = {Garrett, N and Tapley, A and Hudson, A and Dadabhai, S and Zhang, B and Mgodi, NM and Andriesen, J and Takalani, A and Fisher, LH and Kee, JJ and Magaret, CA and Villaran, M and Hural, J and Andersen-Nissen, E and Ferarri, G and Miner, MD and Le Roux, B and Wilkinson, E and Lessells, R and de Oliveira, T and Odhiambo, J and Shah, P and Polakowski, L and Yacovone, M and Samandari, T and Chirenje, Z and Elyanu, PJ and Makhema, J and Kamuti, E and Nuwagaba-Biribonwoha, H and Badal-Faesen, S and Brumskine, W and Coetzer, S and Dawson, R and Delany-Moretlwe, S and Diacon, AH and Fry, S and Gill, KM and Ebrahim Hoosain, ZA and Hosseinipour, MC and Inambao, M and Innes, C and Innes, S and Kalonji, D and Kasaro, M and Kassim, P and Kayange, N and Kilembe, W and Laher, F and Malahleha, M and Maluleke, VL and Mboya, G and McHarry, K and Mitha, E and Mngadi, K and Mda, P and Moloantoa, T and Mutuluuza, CK and Naicker, N and Naicker, V and Nana, A and Nanvubya, A and Nchabeleng, M and Otieno, W and Potgieter, EL and Potloane, D and Punt, Z and Said, J and Singh, Y and Tayob, MS and Vahed, Y and Wabwire, DO and McElrath, MJ and Kublin, JG and Bekker, LG and Gilbert, PB and Corey, L and Gray, GE and Huang, Y and Kotze, P and , }, title = {Hybrid versus vaccine immunity of mRNA-1273 among people living with HIV in East and Southern Africa: a prospective cohort analysis from the multicentre CoVPN 3008 (Ubuntu) study.}, journal = {EClinicalMedicine}, volume = {80}, number = {}, pages = {103054}, pmid = {39902315}, issn = {2589-5370}, support = {T32 AI007044/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: With limited access to mRNA COVID-19 vaccines in lower income countries, and people living with HIV (PLWH) largely excluded from clinical trials, Part A of the multicentre CoVPN 3008 (Ubuntu) study aimed to assess the safety of mRNA-1273, the relative effectiveness of hybrid versus vaccine immunity, and SARS-CoV-2 viral persistence among PLWH in East and Southern Africa during the omicron outbreak.<br><br>METHODS: Previously unvaccinated adults with HIV and/or other comorbidities associated with severe COVID-19 received either one (hybrid immunity) or two (vaccine immunity) 100-mcg doses of ancestral strain mRNA-1273 in the first month, depending on baseline evidence of prior SARS-CoV-2 infection. In a prospective cohort study design, we used covariate-adjusted Cox regression and counterfactual cumulative incidence methods to determine the hazard ratio and relative risk of COVID-19 and severe COVID-19 with hybrid versus vaccine immunity within six months. The ongoing Ubuntu study is registered on ClinicalTrials.gov (NCT05168813) and this work was conducted from December 2021 to March&#xa0;2023.<br><br>FINDINGS: Between December 2021 and September 2022, 14,237 participants enrolled, and 14,002 (83% PLWH, 69% SARS-CoV-2 seropositive) were included in the analyses. Vaccinations were safe and well tolerated. Common adverse events were pain or tenderness at the injection site (26.7%), headache (20.4%), and malaise (20.3%). Severe adverse events were rare (0.8% of participants after the first and 1.1% after the second vaccination), and none were life-threatening or fatal. Among PLWH, the median CD4 count was 635&#xa0;cells/&#x3bc;l and 18.5% had HIV viraemia. The six-month cumulative incidences in the hybrid immunity and vaccine immunity groups were 2.02% (95% confidence interval [CI] 1.61-2.44) and 3.40% (95% CI 2.30-4.49) for COVID-19, and 0.048% (95% CI 0.00-0.10) and 0.32% (95% CI 0.59-0.63) for severe COVID-19. Among all PLWH the hybrid immunity group had a 42% lower hazard rate of COVID-19 (hazard ratio [HR] 0.58; 95% CI 0.44-0.77; p&#xa0;<&#xa0;0.001) and a 73% lower hazard rate of severe COVID-19 (HR 0.27; 95% CI 0.07-1.04; p&#xa0;=&#xa0;0.056) than the vaccine immunity group, but this effect was not seen among PLWH with CD4 counts <350&#xa0;cells/&#x3bc;l or HIV viraemia. Twenty PLWH had persistent SARS-CoV-2 virus at least 50 days.<br><br>INTERPRETATION: Hybrid immunity was associated with superior protection from COVID-19 compared to vaccine immunity with the ancestral mRNA-1273 vaccine. Persistent infections among immunocompromised PLWH may provide reservoirs for emerging variants.<br><br>FUNDING: National Institute of Allergy and Infectious Diseases.}, }
@article {pmid39901049, year = {2025}, author = {Kachuri, L and Hoffmann, TJ and Jiang, Y and Berndt, SI and Shelley, JP and Schaffer, KR and Machiela, MJ and Freedman, ND and Huang, WY and Li, SA and Easterlin, R and Goodman, PJ and Till, C and Thompson, I and Lilja, H and Van Den Eeden, SK and Chanock, SJ and Haiman, CA and Conti, DV and Klein, RJ and Mosley, JD and Graff, RE and Witte, JS}, title = {Author Correction: Genetically adjusted PSA levels for prostate cancer screening.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41591-025-03539-4}, pmid = {39901049}, issn = {1546-170X}, }
@article {pmid39900920, year = {2025}, author = {Musalgaonkar, S and Yelland, JN and Chitale, R and Rao, S and Ozadam, H and Taylor, DW and Cenik, C and Johnson, AW}, title = {The assembly factor Reh1 is released from the ribosome during its initial round of translation.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {1278}, pmid = {39900920}, issn = {2041-1723}, support = {R35 GM127127/GM/NIGMS NIH HHS/United States ; R35 GM138348/GM/NIGMS NIH HHS/United States ; R35 GM150667/GM/NIGMS NIH HHS/United States ; R35GM138348//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; }, mesh = {*Saccharomyces cerevisiae/metabolism/genetics ; *Saccharomyces cerevisiae Proteins/metabolism/genetics ; *Protein Biosynthesis ; *Cryoelectron Microscopy ; *Ribosomes/metabolism ; Ribosome Subunits, Large, Eukaryotic/metabolism ; Ribosomal Proteins/metabolism ; Open Reading Frames/genetics ; Codon, Initiator ; Peptide Chain Elongation, Translational ; Protein Binding ; }, abstract = {Assembly of functional ribosomal subunits and successfully delivering them to the translating pool is a prerequisite for protein synthesis and cell growth. In S. cerevisiae, the ribosome assembly factor Reh1 binds to pre-60S subunits at a late stage during their cytoplasmic maturation. Previous work shows that the C-terminus of Reh1 inserts into the polypeptide exit tunnel of the pre-60S subunit. Here, we show that Reh1-bound nascent 60S subunits associate with 40S subunits to form actively translating ribosomes. Using selective ribosome profiling, we found that Reh1-bound ribosomes populate open reading frames near start codons. Reh1-bound ribosomes are also strongly enriched for initiator tRNA, indicating they are associated with early elongation. Using cryo-electron microscopy to image Reh1-bound 80S ribosomes, we found they contain A site peptidyl tRNA, P site tRNA and eIF5A, indicating that Reh1 does not dissociate from 60S until translation elongation. We propose that Reh1 is displaced by the elongating peptide chain, making it the last assembly factor released from the nascent 60S subunit during its initial round of translation.}, }
@article {pmid39900903, year = {2025}, author = {Zeng, Z and Zhang, T and Zhang, J and Li, S and Connor, S and Zhang, B and Zhao, Y and Wilson, J and Singh, D and Kulikauskas, R and Church, CD and Pulliam, TH and Jani, S and Nghiem, P and Topalian, SL and Forde, PM and Pardoll, DM and Ji, H and Smith, KN}, title = {A minimal gene set characterizes TIL specific for diverse tumor antigens across different cancer types.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {1070}, pmid = {39900903}, issn = {2041-1723}, support = {R01 HG009518/HG/NHGRI NIH HHS/United States ; R01 HG013409/HG/NHGRI NIH HHS/United States ; R01HG013409//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; T32CA080416//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R37 CA251447/CA/NCI NIH HHS/United States ; R37CA251447//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P01 CA225517/CA/NCI NIH HHS/United States ; P01CA255517//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01HG010889//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01 HG010889/HG/NHGRI NIH HHS/United States ; T32 CA080416/CA/NCI NIH HHS/United States ; P30CA006973//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; P30 CA006973/CA/NCI NIH HHS/United States ; R01HG009518//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; CRI4946//Cancer Research Institute (CRI)/ ; }, mesh = {Humans ; *Antigens, Neoplasm/immunology/genetics ; *Lymphocytes, Tumor-Infiltrating/immunology ; *Melanoma/genetics/immunology ; *CD8-Positive T-Lymphocytes/immunology ; *Lung Neoplasms/genetics/immunology ; Neoplasms/immunology/genetics ; Mutation ; Algorithms ; Gene Expression Regulation, Neoplastic ; Immunotherapy/methods ; Single-Cell Analysis/methods ; }, abstract = {Identifying tumor-specific T cell clones that mediate immunotherapy responses remains challenging. Mutation-associated neoantigen (MANA) -specific CD8+ tumor-infiltrating lymphocytes (TIL) have been shown to express high levels of CXCL13 and CD39 (ENTPD1), and low IL-7 receptor (IL7R) levels in many cancer types, but their collective relevance to T cell functionality has not been established. Here we present an integrative tool to identify MANA-specific TIL using weighted expression levels of these three genes in lung cancer and melanoma single-cell RNAseq datasets. Our three-gene "MANAscore" algorithm outperforms other RNAseq-based algorithms in identifying validated neoantigen-specific CD8+ clones, and accurately identifies TILs that recognize other classes of tumor antigens, including cancer testis antigens, endogenous retroviruses and viral oncogenes. Most of these TIL are characterized by a tissue resident memory gene expression program. Putative tumor-reactive cells (pTRC) identified via MANAscore in anti-PD-1-treated lung tumors had higher expression of checkpoint and cytotoxicity-related genes relative to putative non-tumor-reactive cells. pTRC in pathologically responding tumors showed distinguished gene expression patterns and trajectories. Collectively, we show that MANAscore is a robust tool that can greatly enrich candidate tumor-specific T cells and be used to understand the functional programming of tumor-reactive TIL.}, }
@article {pmid39699563, year = {2024}, author = {Singal, AG and Quirk, L and Boike, J and Chernyak, V and Feng, Z and Giamarqo, G and Kanwal, F and Ioannou, GN and Manes, S and Marrero, JA and Mehta, N and Pillai, A and Shaheen, NJ and Shaukat, A and Sirlin, CB and Verna, E and Wani, S and Wilson Woods, A and Yang, JD and Parikh, ND}, title = {Value of HCC surveillance in a landscape of emerging surveillance options: Perspectives of a multi-stakeholder modified Delphi panel.}, journal = {Hepatology (Baltimore, Md.)}, volume = {}, number = {}, pages = {}, pmid = {39699563}, issn = {1527-3350}, support = {U01 CA283935/CA/NCI NIH HHS/United States ; U01 CA288375/CA/NCI NIH HHS/United States ; R01 CA255621/CA/NCI NIH HHS/United States ; R01 CA233794/CA/NCI NIH HHS/United States ; R01 CA256977/CA/NCI NIH HHS/United States ; R01 CA282178/CA/NCI NIH HHS/United States ; U01 CA271887/CA/NCI NIH HHS/United States ; }, abstract = {HCC surveillance is recommended by liver professional societies but lacks broad acceptance by several primary care and cancer societies due to limitations in the existing data. We convened a diverse multidisciplinary group of cancer screening experts to evaluate current and future paradigms of HCC prevention and early detection using a rigorous Delphi panel approach. The experts had high agreement on 21 statements about primary prevention, HCC surveillance benefits, HCC surveillance harms, and the evaluation of emerging surveillance modalities. The experts agreed that current data have methodologic limitations as well as unclear generalizability to Western populations. Although a randomized clinical trial of surveillance versus no surveillance is unlikely feasible, they concurred that alternative designs, such as a comparison of 2 surveillance modalities, could provide indirect evidence of surveillance efficacy. The panel acknowledged the presence of surveillance harms, but concurred the overall value of surveillance appears high, particularly given a greater emphasis on benefits over harms by both patients and clinicians. The experts underscored the importance of a framework for measuring both benefits and harms when evaluating emerging surveillance strategies. The panel acknowledged performance metrics of emerging methods may differ from other cancer screening programs given differences in populations, including higher risk of cancer development and competing risk of morality, and differences in diagnostic workflow in patients at risk of HCC. These data provide insights into the perceived value of HCC surveillance in an era of emerging blood- and imaging-based surveillance strategies.}, }
@article {pmid39899881, year = {2025}, author = {Zaiken, MC and Jin, S and McDonald-Hyman, C and Hartigan, C and Sage, P and Hippen, KL and Koehn, BH and Panoskaltsis-Mortari, A and Riddle, MJ and Eide, C and Tolar, J and Hill, GR and Luznik, L and Cutler, CS and Ritz, J and Kean, LS and Tsagaratou, A and Rao, A and Blazar, BR}, title = {Deficiency of T follicular helper cell Tet3 DNA demethylation inhibits pathogenic IgG2c class switching and chronic GVHD.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024025036}, pmid = {39899881}, issn = {1528-0020}, abstract = {Chronic graft-versus-host disease (cGVHD) is the leading cause of morbidity and non-relapse associated mortality following allogeneic hematopoietic cell transplantation (aHSCT). Treating steroid resistant/refractory cGVHD remains challenging. Epigenetic regulators can have global transcriptional effects that control donor T-cell responses. We previously showed that inhibiting histone lysine motifs by chromatin-modifying enzymes can ameliorate murine cGVHD. Targeting donor T-cell DNA methyltransferases reduce acute GVHD. Here, we sought to investigate the DNA demethylase Tet (ten-eleven translocase) methylcytosine dioxygenases 2 (Tet2) and Tet3 in T follicular helper cell (TFH) dependent cGVHD. In a clinically relevant model of cGVHD that recapitulates pulmonary fibrosis from bronchiolitis obliterans, recipients of Tet2 deleted donor T-cells did not have improved pulmonary function tests in contrast to the markedly improved pulmonary function in Tet3 deleted donor T-cells. Tet3 deleted donor T-cells did not impair TFH-dependent germinal center (GC) formation. Unexpectedly, TET3 deficiency resulted in elevated GATA3 expression in and IL-4 production by TFH cells. TET3 deficient TFH cells supported GC B-cell immunoglobulin (Ig) class switching to nonpathogenic IgG1 but not pathogenic IgG2c allowing mice to escape cGVHD pulmonary fibrosis. Elevated GATA3 expression and disruption of IgG2c class switching was recapitulated in an in-vitro human GC culture system. These studies provide new insights into the function of Tet3 in TFH driven Ig class switching and suggest a new approach to mitigate cGVHD.}, }
@article {pmid39898809, year = {2025}, author = {Salerno, S and Miao, J and Afiaz, A and Hoffman, K and Neufeld, A and Lu, Q and McCormick, TH and Leek, JT}, title = {ipd: An R Package for Conducting Inference on Predicted Data.}, journal = {Bioinformatics (Oxford, England)}, volume = {}, number = {}, pages = {}, doi = {10.1093/bioinformatics/btaf055}, pmid = {39898809}, issn = {1367-4811}, abstract = {SUMMARY: ipd is an open-source R software package for the downstream modeling of an outcome and its associated features where a potentially sizable portion of the outcome data has been imputed by an artificial intelligence or machine learning (AI/ML) prediction algorithm. The package implements several recent proposed methods for inference on predicted data (IPD) with a single, user-friendly wrapper function, ipd. The package also provides custom print, summary, tidy, glance, and augment methods to facilitate easy model inspection. This document introduces the ipd software package and provides a demonstration of its basic usage.<br><br>AVAILABILITY: ipd is freely available on CRAN or as a developer version at our GitHub page: github.com/ipd-tools/ipd. Full documentation, including detailed instructions and a usage 'vignette' are available at github.com/ipd-tools/ipd.}, }
@article {pmid39898780, year = {2025}, author = {Chalitsios, CV and Markozannes, G and Papagiannopoulos, C and Aglago, EK and Berndt, SI and Buchanan, DD and Campbell, PT and Cao, Y and Chan, AT and Dimou, N and Drew, DA and French, AJ and Georgeson, P and Giannakis, M and Gruber, SB and Gunter, MJ and Harrison, TA and Hoffmeister, M and Hsu, L and Huang, WY and Hullar, MA and Huyghe, JR and Lynch, BM and Moreno, V and Newton, CC and Nowak, JA and Obón-Santacana, M and Ogino, S and Qu, C and Schmit, SL and Steinfelder, RS and Sun, W and Thomas, CE and Toland, AE and Trinh, QM and Ugai, T and Um, CY and Van Guelpen, B and Zaidi, SH and Murphy, N and Peters, U and Phipps, AI and Tsilidis, KK}, title = {Waist circumference, a body shape index, and molecular subtypes of colorectal cancer: A pooled analysis of four cohort studies.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-24-1534}, pmid = {39898780}, issn = {1538-7755}, abstract = {Background Waist circumference (WC) and its allometric counterpart, "a body shape index" (ABSI), are risk factors for colorectal cancer (CRC); however, it is uncertain whether associations with these body measurements are limited to specific molecular subtypes of the disease. Methods Data from 2,772 CRC cases and 3,521 controls were pooled from four cohort studies within the Genetics and Epidemiology of Colorectal Cancer Consortium. Four molecular markers (BRAF mutation, KRAS mutation, CpG island methylator phenotype, and microsatellite instability) were analysed individually and in combination (Jass-types). Multivariable logistic and multinomial logistic models were used to assess the associations of WC and ABSI with overall CRC risk and in case-only analyses evaluating heterogeneity by molecular subtype, respectively. Results Higher WC (ORper 5cm=1.06, 95%CI:1.04-1.09) and ABSI (ORper 1-SD=1.07, 95%CI:1.00-1.14) were associated with elevated CRC risk. There was no evidence of heterogeneity between the molecular subtypes. No difference was observed regarding the influence of WC and ABSI on the four major molecular markers in proximal colon, distal colon, and rectal cancer, as well as in early and later onset CRC. Associations did not differ in the Jass-type analysis. Conclusions Higher WC and ABSI were associated with elevated CRC risk; however, they do not differentially influence all four major molecular mutations involved in colorectal carcinogenesis but underscore the importance of maintaining a healthy body weight in CRC prevention. Impact The proposed results have potential utility in colorectal cancer prevention.}, }
@article {pmid39894975, year = {2025}, author = {Yay Donderici, E and Forbes, SP and Zhang, NJ and Schafer, G and Raymond, VM and Das, AK and Eagle, C and Talasaz, A and Grady, WM}, title = {Cost-effectiveness of blood-based colorectal cancer screening - a simulation model incorporating real-world longitudinal adherence.}, journal = {Expert review of pharmacoeconomics &amp; outcomes research}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/14737167.2025.2458044}, pmid = {39894975}, issn = {1744-8379}, abstract = {OBJECTIVES: Although U.S. Preventive Services Task Force (USPSTF) recommended CRC screenings are effective; patient reluctance reduces adherence. Most cost-effectiveness models assume perfect adherence, yet one-third of eligible individuals aren't current with CRC screening. Our study assesses the cost-effectiveness of Shield, an FDA-approved blood-based CRC screening test, using real-world adherence.<br><br>METHODS: The CAN-SCREEN (Colorectal cANcer SCReening Economics and adherENce) model, a validated discrete-event simulation, evaluated clinical and economic outcomes of CRC screening under real-world adherence scenarios. We compared the Shield blood-based test administered every 3 years to no screening, considering it cost-effective if the incremental cost-effectiveness ratio (ICER) was under $100,000 per quality-adjusted life-year (QALY) gained.<br><br>RESULTS: Shield increased QALYs by 154 and raised costs by $7.5 million per 1,000 individuals, with an ICER of $48,662 per QALY, meeting the $100,000/QALY threshold. Shield remained cost-effective up to a unit cost of $3,241 (at $100,000/QALY) and $4,942 (at $150,000/QALY). Sensitivity analyses confirmed cost-effectiveness with lower adherence to diagnostic colonoscopy (56.1%) and annual screenings.<br><br>CONCLUSION: The CAN-SCREEN model shows that Shield is cost-effective compared to no screening. Including real-world adherence improves accuracy in assessing screening strategies. Shield's noninvasive approach offers a promising, cost-effective way to increase adherence and reduce CRC mortality.}, }
@article {pmid39892391, year = {2025}, author = {Lemarquis, AL and Kousa, AI and Argyropoulos, KV and Jahn, L and Gipson, B and Pierce, J and Serrano-Marin, L and Victor, K and Kanno, Y and Girotra, NN and Andrlova, H and Tsai, J and Velardi, E and Sharma, R and Grassmann, S and Ekwall, O and Goldstone, AB and Dudakov, JA and DeWolf, S and van den Brink, MRM}, title = {Recirculating regulatory T cells mediate thymic regeneration through amphiregulin following damage.}, journal = {Immunity}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.immuni.2025.01.006}, pmid = {39892391}, issn = {1097-4180}, abstract = {Thymic injury associated with disease or cancer treatment reduces T cell production and makes patients more vulnerable to infections and cancers. Here, we examined the role of regulatory T (Treg) cells on thymic regeneration. Treg cell frequencies increased in the thymus in various acute injury models. Depletion of Treg cells impaired thymic regeneration, impacting both the thymocyte compartment and the stromal cell compartment; adoptive transfer of Treg cells enhanced regeneration. Expansion of circulating Treg cells, as opposed to that of tissue resident or recent thymic emigrants, explained this increase, as seen using parabiotic and adoptive transfer models. Single-cell analyses of recirculating Treg cells revealed expression of various regenerative factors, including the cytokine amphiregulin. Deletion of amphiregulin in these Treg cells impaired regeneration in the injured thymus. We identified an analogous population of CD39[+]ICOS[+] Treg cells in the human thymus. Our findings point to potential therapeutic avenues to address aging- and treatment-induced immunosuppression.}, }
@article {pmid39892390, year = {2025}, author = {Zhang, Y and Luo, K and Peters, BA and Mossavar-Rahmani, Y and Moon, JY and Wang, Y and Daviglus, ML and Van Horn, L and McClain, AC and Cordero, C and Floyd, JS and Yu, B and Walker, RW and Burk, RD and Kaplan, RC and Qi, Q}, title = {Sugar-sweetened beverage intake, gut microbiota, circulating metabolites, and diabetes risk in Hispanic Community Health Study/Study of Latinos.}, journal = {Cell metabolism}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cmet.2024.12.004}, pmid = {39892390}, issn = {1932-7420}, abstract = {No population-based studies examined gut microbiota and related metabolites associated with sugar-sweetened beverage (SSB) intake among US adults. In this cohort of US Hispanic/Latino adults, higher SSB intake was associated with nine gut bacterial species, including lower abundances of several short-chain-fatty-acid producers, previously shown to be altered by fructose and glucose in animal studies, and higher abundances of fructose- and glucose-utilizing Clostridium bolteae and Anaerostipes caccae. Fifty-six serum metabolites were correlated with SSB intake and a gut microbiota score based on these SSB-related species in consistent directions. These metabolites were clustered into several modules, including a glycerophospholipid module, two modules comprising branched-chain amino acid (BCAA) and aromatic amino acid (AAA) derivatives from microbial metabolism, etc. Higher glycerophospholipid and BCAA derivative levels and lower AAA derivative levels were associated with higher incident diabetes risk during follow-up. These findings suggest a potential role of gut microbiota in the association between SSB intake and diabetes.}, }
@article {pmid39890673, year = {2025}, author = {Ergas, IJ and Cheng, RK and Roh, JM and Kresovich, JK and Iribarren, C and Nguyen-Huynh, M and Rana, JS and Rillamas-Sun, E and Laurent, CA and Lee, VS and Quesenberry, CP and Bhatt, A and Yao, S and Kushi, LH and Greenlee, H and Kwan, ML}, title = {Diet quality and cardiometabolic health in breast cancer survivors: the Pathways Study.}, journal = {Breast cancer research and treatment}, volume = {}, number = {}, pages = {}, pmid = {39890673}, issn = {1573-7217}, support = {R01CA105274/CA/NCI NIH HHS/United States ; R01CA214057/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: Breast cancer (BC) survivors experience higher rates of cardiometabolic conditions, partly due to treatment. While healthy eating decreases the risk of these conditions in the general population, its association in BC survivors is unclear.<br><br>METHODS: We included 3415 participants from the Pathways Study, a prospective cohort of women diagnosed with invasive BC between 2005 and 2013 and followed through 2021. Concordance of food intakes from food frequency questionnaires was estimated for five healthy eating patterns at BC diagnosis: Dietary Approaches to Stop Hypertension (DASH), healthy Plant-based Dietary Index (hPDI), 2020 Healthy Eating Index (HEI), American Cancer Society nutrition guidelines (ACS), and the alternate Mediterranean Diet Index (aMED). Incident hypertension, diabetes, and dyslipidemia were identified through electronic health records. Cumulative incidence rates (CIRs) were estimated accounting for the competing risk of death. Covariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Fine and Gray regression models, stratified by BC treatment status.<br><br>RESULTS: Over an average 11.5&#xa0;years (range&#x2009;=&#x2009;0.3-16.3) of follow-up, 554 (16.2%) participants developed hypertension, 362 (10.6%) developed diabetes, and 652 (19.1%) developed dyslipidemia. CIRs for any cardiometabolic condition 15&#xa0;years after BC diagnosis were 39.2% for women in the highest HEI quartile compared to 49.3% in the lowest. After adjustment, women in the highest HEI quartile had lower risks of any cardiometabolic condition (HR&#x2009;=&#x2009;0.70, 95% CI 0.54-0.91,&#xa0;Ptrend&#x2009;=&#x2009;0.006), including hypertension (HR&#x2009;=&#x2009;0.71, 95% CI 0.54-0.94,&#xa0;Ptrend&#x2009;=&#x2009;0.007), diabetes (HR&#x2009;=&#x2009;0.57, 95% CI 0.41-0.79,&#xa0;Ptrend&#x2009;<&#x2009;0.001), and dyslipidemia (HR&#x2009;=&#x2009;0.77, 95% CI 0.59-0.99,&#xa0;Ptrend&#x2009;=&#x2009;0.04). Similar associations were observed for DASH, hPDI, and ACS with diabetes incidence.<br><br>CONCLUSION: Healthier diets at BC diagnosis, particularly those aligned with the HEI, were associated with lower cardiometabolic risks.}, }
@article {pmid39788211, year = {2025}, author = {Walker, R and Joo, JE and Mahmood, K and Georgeson, P and ,  and Winship, IM and Buchanan, DD}, title = {DNA Mismatch Repair Gene Mosaicism Is Rare in People With Mismatch Repair-Deficient Cancers.}, journal = {Gastroenterology}, volume = {}, number = {}, pages = {}, doi = {10.1053/j.gastro.2024.12.027}, pmid = {39788211}, issn = {1528-0012}, }
@article {pmid39890520, year = {2025}, author = {Baker, SG and Etzioni, R}, title = {Letter to the editor regarding "Early detection of pancreatic cancer: Study design and analytical considerations in biomarker discovery and early phase validation studies".}, journal = {Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.pan.2025.01.009}, pmid = {39890520}, issn = {1424-3911}, }
@article {pmid39890296, year = {2025}, author = {Cheng, GS and Ramirez, JA and Staitieh, BS and Evans, SE}, title = {Challenges of Managing Pulmonary Disease in the Immunocompromised Host.}, journal = {Clinics in chest medicine}, volume = {46}, number = {1}, pages = {xiii-xvii}, doi = {10.1016/j.ccm.2024.12.001}, pmid = {39890296}, issn = {1557-8216}, }
@article {pmid39889280, year = {2025}, author = {Santiago-Torres, M and Mull, KE and Sullivan, BM and Cupertino, AP and Salloum, RG and Triplette, M and Zvolensky, MJ and Bricker, JB}, title = {Evaluating the Impact of Pharmacotherapy in Augmenting Quit Rates Among Hispanic Adults in an App-Delivered Smoking Cessation Intervention: Secondary Analysis of a Randomized Controlled Trial.}, journal = {JMIR formative research}, volume = {9}, number = {}, pages = {e69311}, doi = {10.2196/69311}, pmid = {39889280}, issn = {2561-326X}, mesh = {Humans ; *Smoking Cessation/methods ; Female ; Male ; Adult ; *Hispanic or Latino ; *Mobile Applications ; Middle Aged ; *Varenicline/therapeutic use ; *Tobacco Use Cessation Devices ; Smoking Cessation Agents/therapeutic use ; Bupropion/therapeutic use ; White ; }, abstract = {BACKGROUND: Hispanic adults receive less advice to quit smoking and use fewer evidence-based smoking cessation treatments compared to their non-Hispanic counterparts. Digital smoking cessation interventions, such as those delivered via smartphone apps, provide a feasible and within-reach treatment option for Hispanic adults who smoke and want to quit smoking. While the combination of pharmacotherapy and behavioral interventions are considered best practices for smoking cessation, its efficacy among Hispanic adults, especially alongside smartphone app-based interventions, is uncertain.<br><br>OBJECTIVE: This secondary analysis used data from a randomized controlled trial that compared the efficacy of 2 smoking cessation apps, iCanQuit (based on acceptance and commitment therapy) and QuitGuide (following US clinical practice guidelines), to explore the association between pharmacotherapy use and smoking cessation outcomes among the subsample of 173 Hispanic participants who reported on pharmacotherapy use. Given the randomized design, we first tested the potential interaction of pharmacotherapy use and intervention arm on 12-month cigarette smoking abstinence. We then examined whether the use of any pharmacotherapy (ie, nicotine replacement therapy [NRT], varenicline, or bupropion) and NRT alone augmented each app-based intervention efficacy.<br><br>METHODS: Participants reported using pharmacotherapy on their own during the 3-month follow-up and cigarette smoking abstinence at the 12-month follow-up via web-based surveys. These data were used (1) to test the interaction effect of using pharmacotherapy to aid smoking cessation and intervention arm (iCanQuit vs QuitGuide) on smoking cessation at 12 months and (2) to test whether the use of pharmacotherapy to aid smoking cessation augmented the efficacy of each intervention arm to help participants successfully quit smoking.<br><br>RESULTS: The subsample of Hispanic participants was recruited from 30 US states. They were on average 34.5 (SD 9.3) years of age, 50.9% (88/173) were female, and 56.1% (97/173) reported smoking at least 10 cigarettes daily. Approximately 22% (38/173) of participants reported using pharmacotherapy to aid smoking cessation at the 3-month follow-up, including NRT, varenicline, or bupropion, with no difference between intervention arms. There was an interaction between pharmacotherapy use and intervention arm that marginally influenced 12-month quit rates at 12 months (P for interaction=.053). In the iCanQuit arm, 12-month missing-as-smoking quit rates were 43.8% (7/16) for pharmacotherapy users versus 28.8% (19/16) for nonusers (odds ratio 2.21, 95% CI 0.66-7.48; P=.20). In the QuitGuide arm, quit rates were 9.1% (2/22) for pharmacotherapy users versus 21.7% (15/69) for nonusers (odds ratio 0.36, 95% CI 0.07-1.72; P=.20). Results were similar for the use of NRT only.<br><br>CONCLUSIONS: Combining pharmacotherapy to aid smoking cessation with a smartphone app-based behavioral intervention that teaches acceptance of cravings to smoke (iCanQuit) shows promise in improving quit rates among Hispanic adults. However, this combined approach was not effective with the US clinical guideline-based app (QuitGuide).<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT02724462; https://clinicaltrials.gov/study/NCT02724462.<br><br>RR2-10.1001/jamainternmed.2020.4055.}, }
@article {pmid39889250, year = {2025}, author = {Bhatia, S and Topalian, SL and Sharfman, W and Meyer, T and Steven, N and Lao, CD and Fariñas-Madrid, L and Devriese, LA and Moore, K and Ferris, RL and Honma, Y and Elias, I and Srirangam, A and Garnett-Benson, C and Lee, M and Nghiem, P}, title = {Nivolumab With or Without Ipilimumab in Patients With Recurrent or Metastatic Merkel Cell Carcinoma: A Nonrandomized, Open-Label, International, Multicenter Phase I/II Study.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2402138}, doi = {10.1200/JCO-24-02138}, pmid = {39889250}, issn = {1527-7755}, abstract = {PURPOSE: Approximately 50% of patients with advanced Merkel cell carcinoma (MCC) have primary or acquired resistance to PD-(L)1 blockade, which may be overcome using combination immune checkpoint inhibition (ICI) with anti-cytotoxic T lymphocyte antigen-4 antibody. We present results from the recurrent/metastatic MCC cohort in CheckMate 358, a nonrandomized, multicohort, phase I/II study of nivolumab (NIVO) with or without ipilimumab (IPI) in virus-associated cancers (ClinicalTrials.gov identifier: NCT02488759).<br><br>METHODS: ICI-na&#xef;ve patients with recurrent/metastatic MCC and 0-2 previous systemic therapies were administered NIVO monotherapy at 240 mg once every 2 weeks or combination therapy with NIVO 3 mg/kg once every 2 weeks + IPI 1 mg/kg once every 6 weeks. The primary end point was objective response. Secondary end points included duration of response (DOR), progression-free survival (PFS), and overall survival (OS).<br><br>RESULTS: Sixty-eight patients received NIVO (n = 25) or NIVO + IPI (n = 43). The objective response rate (95% CI) and median DOR (95% CI), respectively, were 60% (38.7 to 78.9) and 60.6 months (16.7 to not applicable [NA]) with NIVO and 58% (42.1 to 73) and 25.9 months (10.4 to NA) with NIVO + IPI. The median PFS (95% CI) and OS (95% CI), respectively, were 21.3 (9.2 to 62.5) and 80.7 (23.3 to NA) months with NIVO and 8.4 (3.7 to 24.3) and 29.8 (8.5 to 48.3) months with NIVO + IPI. The incidence of grade 3/4 treatment-related adverse events was 28% with NIVO and 47% with the combination.<br><br>CONCLUSION: This nonrandomized study showed frequent and durable responses with both NIVO and NIVO + IPI in patients with ICI-na&#xef;ve advanced MCC. However, it did not show improvement in efficacy with the combination, thus contradicting previous study reports that had suggested clinical benefit with combination ICI. A randomized trial of NIVO + IPI versus NIVO monotherapy is warranted.}, }
@article {pmid39888950, year = {2025}, author = {Montaño, MA and Sindelo, S and Fata, A and Rousseau, E and Bekker, LG and Katz, IT and Drain, PK}, title = {Urine tenofovir adherence testing: Perspectives of recently diagnosed South African adolescents and young adults with HIV accessing care via mobile HIV clinics.}, journal = {PloS one}, volume = {20}, number = {1}, pages = {e0318308}, pmid = {39888950}, issn = {1932-6203}, mesh = {Humans ; *HIV Infections/drug therapy/diagnosis/psychology/urine ; Adolescent ; Male ; Female ; Young Adult ; *Tenofovir/therapeutic use ; South Africa ; *Medication Adherence ; *Anti-HIV Agents/therapeutic use ; Adult ; Focus Groups ; Ambulatory Care Facilities ; }, abstract = {BACKGROUND: Adolescents and young adults (AYA) living with HIV face several challenges to engaging in HIV care, which can impact adherence to antiretroviral therapy (ART). Point-of-care (POC) diagnostics that detect tenofovir in urine may be a useful tool to support ART adherence, but perspectives from AYA in South Africa have not been explored.<br><br>METHODS: We conducted in-depth interviews (IDIs) among young people (age 18-24) newly diagnosed with HIV in Cape Town, and a focus group discussion (FGD) with HIV care providers to understand their perspectives regarding the use of POC urine tenofovir testing to support ART adherence. Transcripts were analyzed using Dedoose, with an iterative thematic approach.<br><br>RESULTS: Transcripts from 8 IDI participants and 8 FGD participants were included in the analysis. Major themes identified during analysis related to beliefs about POC urine adherence testing and recommendations for future clinical implementation. Most IDI participants indicated they would want to use the tests if clinically available, and both IDI and FGD participants believed the tests would be helpful to clinicians. Participants believed the tests could motivate people to take their ART regularly, either by reassuring them ART was present in their bodies, or to avoid the negative consequences of being found to be non-adherent. Drawbacks of POC adherence testing identified by respondents included not wanting to be caught skipping ART doses, concerns about privacy, how the test results would be explained, and adding to the amount of testing required for HIV clinical care.<br><br>CONCLUSIONS: AYA living with HIV in South Africa had favorable views toward POC tenofovir adherence testing and felt utilizing these tests in HIV clinical care would motivate people to remain adherent to ART.}, }
@article {pmid39887373, year = {2025}, author = {Byrd, DA and Damerell, V and Gomez Morales, MF and Hogue, SR and Lin, T and Ose, J and Himbert, C and Ilozumba, MN and Kahlert, C and Shibata, D and Toriola, AT and Li, CI and Figueiredo, J and Stephens, WZ and Warby, CA and Hardikar, S and Siegel, EM and Round, J and Ulrich, CM and Gigic, B}, title = {The gut microbiome is associated with disease-free survival in stage I-III colorectal cancer patients.}, journal = {International journal of cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijc.35342}, pmid = {39887373}, issn = {1097-0215}, support = {//ERA-NET on Translational Cancer Research (TRANSCAN)/ ; //Heidelberger Stiftung Chirurgie, Heidelberg University Hospital/ ; //Medizinische Fakult&#xe4;t Heidelberg, Universit&#xe4;t Heidelberg/ ; //Matthias-Lackas Foundations/ ; //Stiftung LebensBlicke/ ; R01 CA189184/NH/NIH HHS/United States ; U01 CA206110/NH/NIH HHS/United States ; //Rahel Goitein-Straus-Program/ ; 01KD2101D//German Federal Ministry of Education and Research/ ; 01KT1503//German Federal Ministry of Education and Research/ ; }, abstract = {Colorectal cancer (CRC) is the second overall leading cause of cancer death in the United States, with recurrence being a frequent cause of mortality. Approaches to improve disease-free survival (DFS) are urgently needed. The gut microbiome, reflected in fecal samples, is likely mechanistically linked to CRC progression and may serve as a non-invasive biomarker. Accordingly, we leveraged baseline fecal samples from N = 166 stage I-III CRC patients in the ColoCare Study, a prospective cohort of newly diagnosed CRC patients. We sequenced the V3 and V4 regions of the 16S rRNA gene to characterize fecal bacteria. We calculated estimates of alpha diversity, beta diversity, and a priori- and exploratory-selected bacterial presence/absence and relative abundance. Associations of microbial metrics with DFS were estimated using multivariable Cox proportional hazards models. We found that alpha diversity was strongly associated with improved DFS, most strongly among rectal cancer patients (Shannon HRrectum = 0.40 95% CI = 0.19, 0.87; p = .02). Overall microbiome composition differences (beta diversity), as characterized by principal coordinate axes, were statistically significantly associated with DFS. Peptostreptococcus was statistically significantly associated with worse DFS (HR = 1.62, 95% CI = 1.13, 2.31; p = .01 per 1-SD) and Order Clostridiales was associated with improved DFS (HR = 0.62, 95% CI = 0.43-0.88; p = .01 per 1-SD). In exploratory analyses, Coprococcus and Roseburia were strongly associated with improved DFS. Overall, higher bacterial diversity and multiple bacteria were strongly associated with DFS. Metagenomic sequencing to elucidate species, gene, and functional level details among larger, diverse patient populations are critically needed to support the microbiome as a biomarker of CRC outcomes.}, }
@article {pmid39885116, year = {2025}, author = {Edwards, ER and Geraci, JC and Gildea, SM and Houtsma, C and Holdcraft, JA and Kennedy, CJ and King, AJ and Luedtke, A and Marx, BP and Naifeh, JA and Sampson, NA and Stein, MB and Ursano, RJ and Kessler, RC}, title = {Improving explainability of post-separation suicide attempt prediction models for transitioning service members: insights from the Army Study to Assess Risk and Resilience in Servicemembers - Longitudinal Study.}, journal = {Translational psychiatry}, volume = {15}, number = {1}, pages = {37}, pmid = {39885116}, issn = {2158-3188}, support = {HU0001-15-2-0004//U.S. Department of Defense (United States Department of Defense)/ ; Project SPR-002-24F//U.S. Department of Veterans Affairs (Department of Veterans Affairs)/ ; }, mesh = {Humans ; *Military Personnel/psychology ; *Suicide, Attempted/psychology/statistics &amp; numerical data ; Male ; Female ; Adult ; Longitudinal Studies ; *Resilience, Psychological ; Young Adult ; United States ; Machine Learning ; Risk Assessment ; Risk Factors ; }, abstract = {Risk of U.S. Army soldier suicide-related behaviors increases substantially after separation from service. As universal prevention programs have been unable to resolve this problem, a previously reported machine learning model was developed using pre-separation predictors to target high-risk transitioning service members (TSMs) for more intensive interventions. This model is currently being used in a demonstration project. The model is limited, though, in two ways. First, the model was developed and trained in a relatively small cross-validation sample (n = 4044) and would likely be improved if a larger sample was available. Second, the model provides no guidance on subtyping high-risk TSMs. This report presents results of an attempt to refine the model to address these limitations by re-estimating the model in a larger sample (n = 5909) and attempting to develop embedded models for differential risk of post-separation stressful life events (SLEs) known to mediate the association of model predictions with post-separation nonfatal suicide attempts (SAs; n = 4957). Analysis used data from the Army STARRS Longitudinal Surveys. The revised model improved prediction of post-separation SAs in the first year (AUC = 0.85) and second-third years (AUC = 0.77) after separation, but embedded models could not predict post-separation SLEs with enough accuracy to support intervention targeting.}, }
@article {pmid39885052, year = {2025}, author = {Grady, WM}, title = {Are Non-invasive Multi-cancer Early Cancer Detection Tests the Future?.}, journal = {Digestive diseases and sciences}, volume = {}, number = {}, pages = {}, pmid = {39885052}, issn = {1573-2568}, support = {U2CCA271902/CA/NCI NIH HHS/United States ; }, abstract = {Current cancer screening methods are effective for detecting early stage cancers and even preventing some cancers, but their effectiveness has only been demonstrated for a handful of cancers, and for many cancers, there are no screening tests clinically available. In addition, the majority of the screening methods are not ideal, resulting in suboptimal compliance and the occurrence of preventable cancers. A screening test that is convenient, safe, accurate and that can screen for multiple cancers is an ideal screening test that would address many of the shortcomings of the current tests. Multi-cancer detection tests (MCD) have the potential to meet these challenges and have engendered substantial enthusiasm in light of this. Using advances in DNA sequencing technology, cancer epigenetics and artificial intelligence, they are able to detect a large number of cancers predominantly via the patterns of methylated DNA alterations, DNA sequence alterations, and DNA fragment patterns of cell free DNA in the plasma and can accurately distinguish the cancer site of origin. Of note, some of the tests also combine circulating free DNA (cfDNA) with protein-based markers. However, for the majority of early stage cancers, the sensitivity is modest and below that of most of the current standard of care cancer screening tests. Furthermore, the clinical utility of screening for many of the cancers detectable by MCD tests remains to be proven. Here we describe the features of MCD tests, review the current data supporting their potential to be used in the clinic for cancer screening, and discuss the knowledge gaps surrounding understanding their clinical utility, with a focus on GI cancer screening.}, }
@article {pmid39884302, year = {2025}, author = {Deming, ME and Brown, ER and McArthur, MA and Schrag, SJ and Arvay, M and Humphrys, M and Ravel, J and Adelglass, J and Essink, B and Musante, DB and Maguire, R and Gorman, R and Formentini, E and Mason, R and Robb, ML and Neuzil, KM and Rapaka, RR and Wolff, P and Kotloff, KL and , }, title = {Vaccine efficacy of NVX-CoV2373 against SARS-CoV-2 infection in adolescents in the USA: an ancillary study to a phase 3, observer-blinded, randomised, placebo-controlled trial.}, journal = {The Lancet. Microbe}, volume = {}, number = {}, pages = {100984}, doi = {10.1016/j.lanmic.2024.100984}, pmid = {39884302}, issn = {2666-5247}, abstract = {BACKGROUND: Although existing COVID-19 vaccines are known to be highly effective against severe disease and death, data are needed to assess their ability to reduce SARS-CoV-2 infection. We aimed to estimate the efficacy of the NVX-CoV2373 protein subunit vaccine against SARS-CoV-2 infection, regardless of symptoms, among adolescents.<br><br>METHODS: We performed an ancillary observational study (SNIFF) to the phase 3, observer-blinded, randomised, placebo-controlled PREVENT-19 trial that assessed vaccine efficacy against symptomatic COVID-19 in the USA. Participants in the PREVENT-19 trial included healthy adolescents aged 12-17&#xa0;years and with no history of laboratory-confirmed SARS-CoV-2 infection. They were randomly assigned (2:1) to receive either the NVX-CoV2373 (Novavax, Gaithersburg, MD, USA) vaccine (immediate NVX-CoV2373 group) or placebo (delayed NVX-CoV2373 group) on days 0&#xa0;and 21 (initial series). After 2&#xa0;months, in a crossover series, participants received two doses, 21&#xa0;days apart, of the intervention that they did not receive in their initial series. Participants at 47 of the PREVENT-19&#xa0;sites were invited to participate in the SNIFF study and self-collect nasal swabs at home twice weekly for SARS-CoV-2 testing to assess vaccine efficacy against SARS-CoV-2 infection. This primary outcome was defined as the first identification of SARS-CoV-2 detected by RT-PCR, regardless of symptoms, with onset within 4&#xa0;weeks after the second dose of the initial vaccination series until the second dose of the crossover series. Secondary outcomes were vaccine efficacy against asymptomatic and minimally symptomatic SARS-CoV-2 infection, durability of vaccine efficacy against SARS-CoV-2 infection, and durability of vaccine efficacy against asymptomatic and minimally symptomatic infections. Outcomes were analysed in the modified intention-to-treat population, which included all participants without previous SARS-CoV-2 infection and was restricted to participants enrolled within 4&#xa0;weeks of the second dose of the primary (primary analysis population) or crossover (post-crossover analysis population) series. This&#xa0;study is registered with ClinicalTrials.gov (NCT04611802).<br><br>FINDINGS: Between June 1 and Dec 17, 2021, 1196 (53&#xb7;2%) of the 2247&#xa0;adolescent participants recruited in the PREVENT-19 trial enrolled in the SNIFF study. The primary analysis population included 471&#xa0;participants in the immediate NVX-CoV2373 group and 220&#xa0;in the delayed NVX-CoV2373 group. Incidence of SARS-CoV-2 infection was 14&#xb7;9&#xa0;cases per 100 person-years (95% CI 7&#xb7;9-25&#xb7;5) in the immediate group and 54&#xb7;2&#xa0;cases per 100 person-years (33&#xb7;6-82&#xb7;9) in the delayed group; vaccine efficacy was 73&#xb7;5% (95% CI 47&#xb7;1-86&#xb7;7; p=0&#xb7;0002). Incidence of minimally symptomatic or asymptomatic SARS-CoV-2 infection was 10&#xb7;3&#xa0;cases per 100 person-years (95% CI 4&#xb7;7-19&#xb7;6) in the&#xa0;immediate group and 36&#xb7;1&#xa0;cases per 100 person-years (19&#xb7;8-60&#xb7;7) in the delayed group; vaccine efficacy was 72&#xb7;8% (95% CI 37&#xb7;1-88&#xb7;2; p=0&#xb7;0023). After the second crossover dose, incidence of SARS-CoV-2 was 14&#xb7;6&#xa0;cases per 100 person-years (95% CI 8&#xb7;6-23&#xb7;0) in the immediate group (receiving placebo at crossover) and 9&#xb7;1&#xa0;cases per 100&#xa0;person-years (3&#xb7;0-21&#xb7;3) in the delayed group, with a durability ratio of 160&#xb7;3 (95% CI 59&#xb7;5-431&#xb7;6; p=0&#xb7;35). Almost all infections after crossover were minimally symptomatic or asymptomatic, with a durability ratio of 151&#xb7;4&#xa0;(55&#xb7;9-410&#xb7;4; p=0&#xb7;41).<br><br>INTERPRETATION: Among adolescents participating in the PREVENT-19 trial during the delta (B.1.617.2) variant wave of the COVID-19 pandemic, the NVX-CoV2373 vaccine was highly efficacious against SARS-CoV-2 infection regardless of symptoms, indicating its potential to reduce the reservoir of infections that contribute to community transmission.<br><br>FUNDING: US Department of Health and Human Services, Administration for Strategic Preparedness and Response, Biomedical Advanced Research and Development Authority, National Institute of Allergy and Infectious Diseases, and National Institutes of Health.}, }
@article {pmid39868296, year = {2025}, author = {Guccione, C and Sfiligoi, I and Gonzalez, A and Shaffer, JP and Kazachkova, M and Weng, Y and McDonald, D and Shah, SC and Minot, SS and Paulson, T and Grady, WM and Alexandrov, LB and Knight, R and Curtius, K}, title = {Community assembly modeling of microbial evolution within Barrett's esophagus and esophageal adenocarcinoma.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39868296}, issn = {2692-8205}, support = {K12 GM068524/GM/NIGMS NIH HHS/United States ; R01 CA241728/CA/NCI NIH HHS/United States ; P30 DK120515/DK/NIDDK NIH HHS/United States ; R01 CA140657/CA/NCI NIH HHS/United States ; IK2 CX002027/CX/CSRD VA/United States ; T32 GM007198/GM/NIGMS NIH HHS/United States ; R21 CA259687/CA/NCI NIH HHS/United States ; R01 CA270235/CA/NCI NIH HHS/United States ; P30 CA023100/CA/NCI NIH HHS/United States ; U24 CA248454/CA/NCI NIH HHS/United States ; }, abstract = {Mathematical modeling of somatic evolution, a process impacting both host cells and microbial communities in the human body, can capture important dynamics driving carcinogenesis. Here we considered models for esophageal adenocarcinoma (EAC), a cancer that has dramatically increased in incidence over the past few decades in Western populations, with high case fatality rates due to late-stage diagnoses. Despite advancements in genomic analyses of the precursor Barrett's esophagus (BE), prevention of late-stage EAC remains a significant clinical challenge. Previous microbiome studies in BE and EAC have focused on quantifying static microbial abundance differences rather than evolutionary dynamics. Using whole genome sequencing data from esophageal tissues, we first applied a robust bioinformatics pipeline to extract non-host DNA reads, mapped these putative reads to microbial taxa, and retained those taxa with high genomic coverage. When applying mathematical models of microbial evolution to sequential stages of progression to EAC, we observed evidence of neutral dynamics in community assembly within normal esophageal tissue and BE, but not EAC. In a case-control study of BE patients who progressed to EAC cancer outcomes (CO) versus those who had non-cancer outcomes (NCO) during follow-up (mean=10.5 years), we found that Helicobacter pylori deviated significantly from the neutral expectation in BE NCO, suggesting that factors related to H. pylori or H. pylori infection itself may influence EAC risk. Additionally, simulations incorporating selection recapitulated non-neutral behaviors observed in the datasets. Formally modeling dynamics during progression holds promise in clinical applications by offering a deeper understanding of microbial involvement in cancer development.}, }
@article {pmid39883890, year = {2025}, author = {Bellmunt, J and Russell, BM and Szabados, B and Valderrama, BP and Nadal, R}, title = {Current and Future Role of Circulating DNA in the Diagnosis and Management of Urothelial Carcinoma.}, journal = {American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting}, volume = {45}, number = {2}, pages = {e471912}, doi = {10.1200/EDBK-25-471912}, pmid = {39883890}, issn = {1548-8756}, mesh = {Humans ; *Circulating Tumor DNA/blood ; Liquid Biopsy/methods ; *Biomarkers, Tumor/blood ; Urinary Bladder Neoplasms/therapy/blood/diagnosis/genetics/pathology ; Disease Management ; Prognosis ; Cell-Free Nucleic Acids/blood ; Carcinoma, Transitional Cell/therapy/blood/genetics/diagnosis ; Urologic Neoplasms/diagnosis/therapy/genetics/blood/pathology ; }, abstract = {The growing sophistication of tumor molecular profiling has helped to slowly transition oncologic care toward a more personalized approach in different tumor types, including in bladder cancer. The National Comprehensive Cancer Network recommends that all patients with stage IVA and stage IVB urothelial carcinoma have molecular analysis that integrates at least FGFR3 testing to help facilitate the selection of future therapeutic options. Sequencing of tumor-derived tissue is the mainstay to obtain this genomic testing, but as in other cancers, there has been extensive research into the integration of liquid biopsies in longitudinal management. Liquid biopsies broadly refer to the isolation of both cellular and noncellular tumor components including proteins and nucleic acids such as mRNA and circulating free DNA within a liquid sample. Although protein-based testing and testing of circulating tumor cells are options, the bulk of promising research in bladder cancer is investigating the role of plasma-based circulating tumor DNA (ctDNA). Currently, a universal consensus on optimal preanalytic and analytic approaches has not been fully defined, and the exact role that liquid biopsies should have in screening, diagnosis, prognostication, treatment selection, and monitoring is not yet known. Still, it can be expected that ctDNA testing will be a part of appropriate management of muscle-invasive bladder cancer and metastatic bladder cancer in the near future. In this review, the goal is to provide a practical overview of the current and future role of ctDNA in bladder cancer including ongoing trials.}, }
@article {pmid39883451, year = {2025}, author = {Hunter, N and Hurvitz, S}, title = {Where Did the Passion Go?-Rethinking Adjuvant Immune Therapy for Triple-Negative Breast Cancer.}, journal = {JAMA}, volume = {}, number = {}, pages = {}, doi = {10.1001/jama.2024.26811}, pmid = {39883451}, issn = {1538-3598}, }
@article {pmid39883059, year = {2025}, author = {Phipps, W and Bhinder, B and Towlerton, A and Mooka, P and Kafeero, J and Fitzgibbon, M and Elemento, O and Cesarman, E}, title = {Exome sequencing reveals a sparse genomic landscape in Kaposi sarcoma.}, journal = {Molecular cancer research : MCR}, volume = {}, number = {}, pages = {}, doi = {10.1158/1541-7786.MCR-24-0373}, pmid = {39883059}, issn = {1557-3125}, abstract = {Kaposi Sarcoma (KS) is a frequently aggressive malignancy caused by Kaposi sarcoma herpesvirus (KSHV/HHV-8). People with immunodeficiencies, including HIV, are at increased risk for developing KS, but our understanding of the contributions of the cellular genome to KS pathogenesis remains limited. To determine if there are cellular genetic alterations in KS that might provide biological or therapeutic insights, we performed whole exome sequencing on 78 KS tumors and matched normal control skin from 59 adults with KS (46 with HIV-associated KS and 13 with HIV-negative KS) receiving treatment at the Uganda Cancer Institute in Kampala, Uganda. We found a very low mutational burden in all but one specimen (median=11 mutations), which is the lowest number of mutations among all 33 tumor types in The Cancer Genome Atlas (TCGA). No recurrent mutations were seen and the most commonly affected oncogenic pathway was RTK/RAS. Mutational signatures included defective DNA mismatch repair and smoking. There was no evidence suggesting that multiple tumors from the same patient originated from the same original clone. The number of genome copy alterations per genome were higher in tumors from those without HIV infection and in tumors from participants with advanced stage disease, suggesting that lesions that take longer to develop may accumulate more alterations, although the number of alterations remain low compared to other cancers. Implications: Our findings indicate that the pathogenesis of KS differs from other malignancies, and that the primary driver of carcinogenesis is KSHV viral infection and expression of viral oncogenes, rather than clonal oncogenic transformation.}, }
@article {pmid39882642, year = {2025}, author = {Özcan, M and Cassaday, RD and Zarzycka, E and Vandendries, E and Zhang, F and Chen, Y and Nieto, A and Demirkan, F and Montesinos, P and Altuntas, F}, title = {Efficacy and safety of currently approved and lower starting doses of inotuzumab ozogamicin in adult patients with relapsed or refractory acute lymphoblastic leukemia: a phase IV study.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2024.286091}, pmid = {39882642}, issn = {1592-8721}, abstract = {Inotuzumab ozogamicin (InO) is approved for treatment of relapsed/refractory acute lymphoblastic leukemia (R/R ALL). Previous studies reported higher rates of post- hematopoietic stem cell transplant (HSCT) hepatic sinusoidal obstruction syndrome (SOS) in patients receiving InO versus chemotherapy prior to HSCT. It is unknown if a lower InO dose would reduce risk of post-HSCT SOS or if it would impact efficacy. This study evaluated efficacy and safety of the currently approved InO starting dose and a lower dose in adults with R/R ALL who were eligible for HSCT and were identified as being at higher risk of post- HSCT SOS. This open-label, phase 4 study (NCT03677596) had 2 phases: in the run-in phase patients received InO at 1.2 mg/m2/cycle (n=22); in the randomized phase patients received InO starting at dose levels of 1.8 mg/m2/cycle (n=38) or 1.2 mg/m2/cycle (n=42). Primary endpoints were rate of SOS and rate of hematologic remission. Overall, SOS was reported in 10 patients (9.8%); all were post-HSCT SOS. In patients who proceeded to HSCT, post-HSCT SOS rates were 20%, 28.6%, 25.8%, and 16.7% in 1.2 mg/m2/cycle (run-in), 1.2 mg/m2/cycle (randomized), 1.2 mg/m2/cycle (run-in and randomized), and 1.8 mg/m2/cycle (randomized), respectively. The CR/CRi rates were 50.0%, 83.3%, 71.9%, and 68.4% in the respective subgroups. The study found that a starting dose of 1.2mg/m2/cycle demonstrated consistent efficacy and safety to the recommended 1.8 mg/m2/cycle dose in adults with R/R ALL who were eligible for HSCT and had a higher risk of post-HSCT SOS.}, }
@article {pmid39881206, year = {2025}, author = {Vo, PT and Sandmaier, BM and Othus, M and Ali, N and Rodríguez-Arbolí, E and Orvain, C and Davis, C and Basom, RS and Storb, R and Walter, RB}, title = {Relationship between age, conditioning intensity, and outcome after allografting in adults age ≥60 years with AML.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, pmid = {39881206}, issn = {1476-5365}, abstract = {Methodological advancements now allow older adults with AML to receive allografts although conflicting data exist regarding relative outcomes across age groups and benefits of different conditioning intensities. We retrospectively analyzed 495 adults aged 60-64 (n = 184), 65-69 (n = 189), or ≥70 (n = 122) allografted for AML in remission at our institution from 2006 to 2023. There were no significant differences in relapse or relapse-free survival (RFS) among the 3 age cohorts after multivariable adjustment. Patients aged ≥70 years had higher non-relapse mortality (NRM) than those aged ≥60-64 (P = 0.022) but their overall survival (OS) was only statistically non-significantly shorter (P = 0.11). There was an important interplay between age, conditioning intensity, and outcomes. Relative to age 60-64, age ≥70 years was associated with a higher risk of relapse (hazard ratio [HR] = 3.47; P = 0.012) and NRM (HR = 3.88; P = 0.001) with reduced intensity conditioning (RIC), leading to shorter RFS (HR = 3.79; P < 0.001) and OS (HR = 3.46; P < 0.001), while no such associations were found with nonmyeloablative (NMA) conditioning. Underlying, patients aged 60-64 and 65-69, but not those aged ≥70, had a significantly lower relapse risk with RIC relative to NMA conditioning, whereas NRM risks increased across all age cohorts. Our findings support allografting for adults ≥70 with AML in remission, especially with NMA conditioning.}, }
@article {pmid39881190, year = {2025}, author = {Toghani, D and Gupte, S and Zeng, S and Mahammadov, E and Crosse, EI and Seyedhassantehrani, N and Burns, C and Gravano, D and Radtke, S and Kiem, HP and Rodriguez, S and Carlesso, N and Pradeep, A and Georgiades, A and Lucas, F and Wilson, NK and Kinston, SJ and Göttgens, B and Zong, L and Beerman, I and Park, B and Janssens, DH and Jones, D and Toghani, A and Nerlov, C and Pietras, EM and Mesnieres, M and Maes, C and Kumanogoh, A and Worzfeld, T and Cheong, JG and Josefowicz, SZ and Kharchenko, P and Scadden, DT and Scialdone, A and Spencer, JA and Silberstein, L}, title = {Niche-derived Semaphorin 4A safeguards functional identity of myeloid-biased hematopoietic stem cells.}, journal = {Nature aging}, volume = {}, number = {}, pages = {}, pmid = {39881190}, issn = {2662-8465}, support = {HL148189//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; HL148189//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; HL148189//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; HL148189//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; }, abstract = {Somatic stem cell pools comprise diverse, highly specialized subsets whose individual contribution is critical for the overall regenerative function. In the bone marrow, myeloid-biased hematopoietic stem cells (myHSCs) are indispensable for replenishment of myeloid cells and platelets during inflammatory response but, at the same time, become irreversibly damaged during inflammation and aging. Here we identify an extrinsic factor, semaphorin 4A (Sema4A), which non-cell-autonomously confers myHSC resilience to inflammatory stress. We show that, in the absence of Sema4A, myHSC inflammatory hyper-responsiveness in young mice drives excessive myHSC expansion, myeloid bias and profound loss of regenerative function with age. Mechanistically, Sema4A is mainly produced by neutrophils, signals via a cell surface receptor, plexin D1, and safeguards the myHSC epigenetic state. Our study shows that, by selectively protecting a distinct stem cell subset, an extrinsic factor preserves functional diversity of somatic stem cell pool throughout organismal lifespan.}, }
@article {pmid39875703, year = {2025}, author = {Harris, HR and Lind, K and Fest, S and Thomson, CA and Saquib, N and Shadyab, AH and Schnatz, PF and Robles-Morales, R and Qi, L and Strickler, HD and Roe, DJ and Farland, LV}, title = {Infertility and risk of ovarian cancer in the women's health initiative.}, journal = {Cancer causes &amp; control : CCC}, volume = {}, number = {}, pages = {}, pmid = {39875703}, issn = {1573-7225}, support = {R03 HD102403/HD/NICHD NIH HHS/United States ; }, abstract = {PURPOSE: There is a consistent relationship with greater ovulation frequency and increased risk of ovarian cancer. However, prior research on infertility, which may be associated with ovulation frequency through multiple mechanisms, and ovarian cancer has yielded conflicting results, possibly due to prior research conflating fertility treatment with infertility and restricting follow-up to premenopausal cases. Our objective was to determine the association between infertility and risk of postmenopausal ovarian cancer, overall and by histotype, in a population that had not received treatment with IVF.<br><br>METHODS: We utilized data from the Women's Health Initiative (n&#x2009;=&#x2009;112,925 postmenopausal participants) with over 25&#xa0;years of follow-up. At baseline, participants were asked whether they had ever tried to become pregnant for more than one year without becoming pregnant and whether a reason was found. Cox proportional hazards models were used to calculate hazard ratios (HRs) of incident adjudicated ovarian cancer comparing participants with a history of infertility to fertile participants overall and by histotype.<br><br>RESULTS: 17% of participants reported a history of infertility at baseline and 1,109 ovarian cancer cases were diagnosed during follow-up. No statistically significant association was observed between infertility and risk of any ovarian cancer (HR: 1.09, 95% CI 0.92-1.29), but those reporting infertility had a 90% higher risk of endometrioid and clear cell ovarian cancers (HR: 1.90 95% CI 1.09-3.34) compared to fertile participants. The reported reason(s) for infertility had no discernable impact on these associations.<br><br>CONCLUSIONS: Infertility may be associated with clear cell and endometrioid ovarian cancer but not other ovarian tumor histotypes.}, }
@article {pmid39874304, year = {2025}, author = {Sabo, MC and Mustafa, S and Saha, A and Oyaro, B and Fiedler, TL and Krueger, M and Fuchs, E and Mureithi, M and Mandaliya, K and Jaoko, W and Richardson, BA and Gharib, SA and Fredricks, DN and Shah, JA and McClelland, RS}, title = {Bacterial vaginosis is associated with transcriptomic changes but not higher concentrations of cervical leukocytes in a study of women at high risk for HIV acquisition.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiaf049}, pmid = {39874304}, issn = {1537-6613}, abstract = {BACKGROUND: The association between bacterial vaginosis (BV) and increased HIV acquisition risk may be related to concentrations of HIV-susceptible immune cells in the cervix.<br><br>METHODS: Participants (31 with BV and 30 with normal microbiota) underwent cervical biopsy at a single visit. Immune cells were quantified and sorted using flow cytometry (N=55), localization assessed by immunofluorescence (N=16), and function determined by bulk RNA sequencing (RNA-seq) of live CD45+ cells (N=21).<br><br>RESULTS: Linear regression analyses demonstrated no differences in mean log2 [cells/mg tissue] between women with BV vs normal microbiota for antigen presenting cell (APC) subtypes linked to HIV risk (including CD1a+HLA-DR+ Langerhans cells, CD11c+CD14+ dendritic cells [DCs], and CD11c+HLA-DR+ DCs) and CD4+ T cells. Women with BV had a higher median proportion of CD11c+HLA-DR+ APCs (out of total cells) in cervical epithelium (0.1% vs 0.0%; p=0.03 using Mann-Whitney testing). RNA-seq identified 1,032 differentially expressed genes (adjusted p-value <0.05) in CD45+ cells between women with BV vs normal microbiota. Women with BV demonstrated downregulation of pathways linked to translation, metabolism, cell stress, and immune signaling.<br><br>CONCLUSIONS: BV alters immune cell localization and function; future studies are needed to address how these changes may mediate HIV acquisition risk.}, }
@article {pmid39763728, year = {2024}, author = {Gauderman, WJ and Fu, Y and Queme, B and Kawaguchi, E and Wang, Y and Morrison, J and Brenner, H and Chan, A and Gruber, SB and Keku, T and Li, L and Moreno, V and Pellatt, AJ and Peters, U and Samadder, NJ and Schmit, SL and Ulrich, CM and Um, C and Wu, A and Lewinger, JP and Drew, DA and Mi, H}, title = {Pathway Polygenic Risk Scores (pPRS) for the Analysis of Gene-environment Interaction.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39763728}, issn = {2692-8205}, support = {U01 HG004438/HG/NHGRI NIH HHS/United States ; U01 HG004446/HG/NHGRI NIH HHS/United States ; P30 DK034987/DK/NIDDK NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; R01 CA081488/CA/NCI NIH HHS/United States ; R01 CA042182/CA/NCI NIH HHS/United States ; UM1 CA167552/CA/NCI NIH HHS/United States ; R01 CA059045/CA/NCI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; R01 CA197350/CA/NCI NIH HHS/United States ; R01 CA076366/CA/NCI NIH HHS/United States ; R35 CA197735/CA/NCI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; U10 CA037429/CA/NCI NIH HHS/United States ; R01 CA072520/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P30 CA006973/CA/NCI NIH HHS/United States ; R01 CA273198/CA/NCI NIH HHS/United States ; K05 CA154337/CA/NCI NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; R01 CA151993/CA/NCI NIH HHS/United States ; U01 CA152753/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R01 CA048998/CA/NCI NIH HHS/United States ; R01 CA189184/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; Z01 CP010200/ImNIH/Intramural NIH HHS/United States ; U24 CA074794/CA/NCI NIH HHS/United States ; R01 CA066635/CA/NCI NIH HHS/United States ; U01 CA206110/CA/NCI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; R01 CA137178/CA/NCI NIH HHS/United States ; U01 CA074794/CA/NCI NIH HHS/United States ; HHSN268201200008C/HL/NHLBI NIH HHS/United States ; R01 CA242218/CA/NCI NIH HHS/United States ; R01 CA143237/CA/NCI NIH HHS/United States ; R01 CA201407/CA/NCI NIH HHS/United States ; R01 CA063464/CA/NCI NIH HHS/United States ; P01 CA033619/CA/NCI NIH HHS/United States ; U01 CA093326/CA/NCI NIH HHS/United States ; U01 CA086308/CA/NCI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; R01 CA207371/CA/NCI NIH HHS/United States ; R03 CA153323/CA/NCI NIH HHS/United States ; R01 CA060987/CA/NCI NIH HHS/United States ; R01 CA136726/CA/NCI NIH HHS/United States ; K05 CA152715/CA/NCI NIH HHS/United States ; U01 CA122839/CA/NCI NIH HHS/United States ; KL2 TR000421/TR/NCATS NIH HHS/United States ; U01 CA074783/CA/NCI NIH HHS/United States ; R35 CA253185/CA/NCI NIH HHS/United States ; UM1 CA182883/CA/NCI NIH HHS/United States ; HHSN268201200008I/HL/NHLBI NIH HHS/United States ; R37 CA054281/CA/NCI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; R01 CA097325/CA/NCI NIH HHS/United States ; HHSN268201700006C/HL/NHLBI NIH HHS/United States ; U19 CA148107/CA/NCI NIH HHS/United States ; U01 AG018033/AG/NIA NIH HHS/United States ; }, abstract = {A polygenic risk score (PRS) is used to quantify the combined disease risk of many genetic variants. For complex human traits there is interest in determining whether the PRS modifies, i.e. interacts with, important environmental (E) risk factors. Detection of a PRS by environment (PRS × E) interaction may provide clues to underlying biology and can be useful in developing targeted prevention strategies for modifiable risk factors. The standard PRS may include a subset of variants that interact with E but a much larger subset of variants that affect disease without regard to E. This latter subset will 'water down' the underlying signal in former subset, leading to reduced power to detect PRS × E interaction. We explore the use of pathway-defined PRS (pPRS) scores, using state of the art tools to annotate subsets of variants to genomic pathways. We demonstrate via simulation that testing targeted pPRS × E interaction can yield substantially greater power than testing overall PRS × E interaction. We also analyze a large study (N=78,253) of colorectal cancer (CRC) where E = non-steroidal anti-inflammatory drugs (NSAIDs), a well-established protective exposure. While no evidence of overall PRS × NSAIDs interaction (p=0.41) is observed, a significant pPRS × NSAIDs interaction (p=0.0003) is identified based on SNPs within the TGF-β / gonadotropin releasing hormone receptor (GRHR) pathway. NSAIDS is protective (OR=0.84) for those at the 5[th] percentile of the TGF-β/GRHR pPRS (low genetic risk, OR), but significantly more protective (OR=0.70) for those at the 95[th] percentile (high genetic risk). From a biological perspective, this suggests that NSAIDs may act to reduce CRC risk specifically through genes in these pathways. From a population health perspective, our result suggests that focusing on genes within these pathways may be effective at identifying those for whom NSAIDs-based CRC-prevention efforts may be most effective.}, }
@article {pmid39873851, year = {2025}, author = {Javid, SH and Kazerouni, AS and Hippe, DS and Hirano, M and Schnuck-Olapo, J and Biswas, D and Bryant, ML and Li, I and Xiao, J and Kim, AG and Guo, A and Dontchos, B and Kilgore, M and Kim, J and Partridge, SC and Rahbar, H}, title = {Preoperative MRI to Predict Upstaging of DCIS to Invasive Cancer at Surgery.}, journal = {Annals of surgical oncology}, volume = {}, number = {}, pages = {}, pmid = {39873851}, issn = {1534-4681}, support = {ROI CA203883 (Rahbar)/GF/NIH HHS/United States ; }, abstract = {BACKGROUND: Ductal carcinoma in situ (DCIS) is overtreated, in part because of inability to predict which DCIS cases diagnosed at core needle biopsy (CNB) will be upstaged at excision. This study aimed to determine whether quantitative magnetic resonance imaging (MRI) features can identify DCIS at risk of upstaging to invasive cancer.<br><br>METHODS: This prospective observational clinical trial analyzed women with a diagnosis of DCIS on CNB. All the participants&#xa0;underwent preoperative 3T MRI. Quantitative MRI features from routine dynamic contrast-enhanced (DCE) MR images (e.g., peak percent enhancement [PE]) and from advanced high temporal-resolution DCE MR images (e.g., Ktrans) were measured. Clinical, pathologic, and mammographic features were reviewed. Associations with upstaging were summarized using the area under the receiver operating characteristic curve (AUC).<br><br>RESULTS: Of 58 DCIS lesions at CNB, 15 (26%) were upstaged to invasive cancer at surgery. Of the 58 lesions, 46 (79%) enhanced on MRI, although enhancement alone was not significantly associated with upstaging (p = 0.71). Among the DCIS lesions that enhanced, higher PE was most strongly associated with upstaging (AUC, 0.81; adjusted p = 0.009) and outperformed MRI features acquired via high temporal resolution DCE-MRI (AUC, 0.50-0.73). Lesion span on MRI was not significantly associated with upstaging risk (AUC, 0.55; adjusted p = 0.61), nor were any clinical, pathologic, or mammographic features (p > 0.24).<br><br>CONCLUSIONS: Quantitative features acquired from routine clinical breast MRI and advanced DCE-MRI demonstrated good performance in identifying which DCIS lesions were upstaged to invasive cancer at excision. These features may prove valuable for appropriate selection of active surveillance in future DCIS de-escalation trials.}, }
@article {pmid39873699, year = {2025}, author = {Huang, Y and Kwan, ML and Heckbert, SR and Smith, NL and Othus, M and Laurent, CA and Roh, JM and Rillamas-Sun, E and Lee, VS and Kolevska, T and Cheng, RK and Irribarren, C and Nguyen-Huynh, M and Hershman, DL and Kushi, LH and Greenlee, H}, title = {Duration of aromatase inhibitor use and long-term cardiovascular risk in breast cancer survivors.}, journal = {JNCI cancer spectrum}, volume = {}, number = {}, pages = {}, doi = {10.1093/jncics/pkaf009}, pmid = {39873699}, issn = {2515-5091}, abstract = {BACKGROUND: There are limited data on duration of aromatase inhibitor (AI) and cardiovascular disease (CVD) risk in breast cancer (BC) survivors. We examined risk of CVD and mortality associated with duration of AI use in postmenopausal women with early-stage hormone receptor-positive BC.<br><br>METHODS: Postmenopausal women diagnosed with hormone receptor-positive BC (n&#x2009;=&#x2009;5,853) who used an AI were included. Cause-specific hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between AI use duration (short-term: >0 and <2&#x2009;years; intermediate-term: &#x2265;2 and <5&#x2009;years; long-term: &#x2265;5&#x2009;years) and CVD and mortality outcomes. The landmark method was used to avoid immortal time bias; the selected landmark was 6&#x2009;years after BC diagnosis.<br><br>RESULTS: Anastrozole was the AI predominantly prescribed (95.4%). Over a median follow-up of 3&#x2009;years for women who survived 6&#x2009;years after BC diagnosis, a lower risk of stroke was observed in intermediate-term AI users (HR&#x2009;=&#x2009;0.60, 95% CI: 0.37-0.96) and long-term AI users (HR&#x2009;=&#x2009;0.51, 95% CI: 0.30-0.85), than in short-term AI users. The longer duration of AI use was also associated with lower risk of all-cause mortality and non-CVD-related mortality. In addition, long-term AI users were at 37% lower risk of CVD-related mortality than short-term AI users. No significant differences were observed in risks of major adverse cardiovascular events, ischemic heart disease, and heart failure across the three groups.<br><br>CONCLUSION: Among postmenopausal women with early-stage hormone receptor-positive BC who survived to 6&#x2009;years after BC diagnosis, longer duration of AI use was not associated with elevated CVD risk.}, }
@article {pmid39871186, year = {2025}, author = {Pinto-Santini, D and Jalil, EM and Fernandes, GT and Hilaire, G and Kolevic, L and Cabello, R and Grinsztejn, B and Pape, W and Deschamps, MM and House, MG and Brofsky, E and Sahasrabuddhe, VV and Dasgupta, S and Pasalar, S and Madeleine, MM and Carter, J and Prabhu, PR and Galloway, D and Duerr, A}, title = {ULACNet-301, OPTIMO protocol: optimizing HPV vaccination regimen for cancer prevention in children and adolescents living with HIV.}, journal = {BMC cancer}, volume = {25}, number = {1}, pages = {151}, pmid = {39871186}, issn = {1471-2407}, support = {U54 CA242977/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Child ; Adolescent ; *HIV Infections/prevention &amp; control/immunology/complications ; *Papillomavirus Infections/prevention &amp; control/immunology/virology/complications ; Female ; *Papillomavirus Vaccines/administration &amp; dosage/immunology ; Male ; Uterine Cervical Neoplasms/prevention &amp; control/virology/immunology ; Immunization Schedule ; Vaccination/methods ; Human Papillomavirus Recombinant Vaccine Quadrivalent, Types 6, 11, 16, 18/administration &amp; dosage/immunology ; }, abstract = {BACKGROUND: Persistent infection with human papillomavirus (HPV) is associated with most cervical and anal cancer cases and a large fraction of other anogenital and oropharyngeal cancers. The prophylactic HPV vaccines are known to prevent HPV infections and HPV-associated disease, although there is evidence of reduced response to the HPV vaccination among individuals living with HIV. Prior studies among individuals without HIV suggest that a single HPV vaccine dose induces humoral immune responses that, while lower than those induced by two or three doses, still confer protection against HPV infection. Current recommendations for HPV vaccine include a single-dose schedule for children 9-14-years-olds without HIV. Although two to three doses are recommended for children living with HIV (CLWH), there is very limited data comparing responses to one vs. 2-3 doses in CLWH.<br><br>METHODS: The OPTIMO study will compare immune responses to HPV vaccination in CLWH by measuring antibody and memory B cell (Bmem) responses after 1, 2, or 3 doses of the 9-valent HPV (9vHPV) vaccine, Gardasil-9. A comparison group of children without HIV will receive one dose of the vaccine. The durability of the response will be assessed at 24 months after the last dose of a given regimen. The OPTIMO trial will take place among CLWH from low and middle-income country (LMIC) settings in Peru, Brazil, and Haiti.<br><br>DISCUSSION: Previous studies of single-dose regimens in individuals without HIV raise questions about whether one dose would suffice for CLWH and, if not, whether two or three doses are needed to provide protection against HPV-related cancers. These questions have operational consequences in LMICs given the barriers to delivering multiple doses, uneven availability, and intermittent shortages of HPV vaccines. In addition, information on HIV status for children and adolescents is rarely available during vaccination campaigns based in schools or public health clinics, so CLWH may receive a single dose despite policy recommendations that they receive two or three. This study will provide evidence on the optimal number of doses needed for CLWH that can inform HPV vaccination campaigns in LMICs, especially those with a higher burden of HIV infection and higher incidence of HPV-related cancers.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT04265950.}, }
@article {pmid39870767, year = {2025}, author = {Costa, LJ and Banerjee, R and Mian, H and Weisel, K and Bal, S and Derman, BA and Htut, MM and Nagarajan, C and Rodriguez, C and Richter, J and Frigault, MJ and Ye, JC and van de Donk, NWCJ and Voorhees, PM and Puliafito, B and Bahlis, N and Popat, R and Chng, WJ and Ho, PJ and Kaur, G and Kapoor, P and Du, J and Schjesvold, F and Berdeja, J and Einsele, H and Cohen, AD and Mikhael, J and Biru, Y and Rajkumar, SV and Lin, Y and Martin, TG and Chari, A}, title = {International myeloma working group immunotherapy committee recommendation on sequencing immunotherapy for treatment of multiple myeloma.}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, pmid = {39870767}, issn = {1476-5551}, abstract = {T-cell redirecting therapy (TCRT), specifically chimeric antigen receptor T-cell therapy (CAR T-cells) and bispecific T-cell engagers (TCEs) represent a remarkable advance in the treatment of multiple myeloma (MM). There are several products available around the world and several more in development targeting primarily B-cell maturation antigen (BCMA) and G protein-coupled receptor class C group 5 member D (GRPC5D). The relatively rapid availability of multiple immunotherapies brings the necessity to understand how a certain agent may affect the safety and efficacy of a subsequent immunotherapy so MM physicians and patients can aim at optimal sequential use of these therapies. The International Myeloma Working Group conveyed panel of experts to review patient and disease-related factors affecting efficacy and safety of immunotherapy, summarize existing information on sequencing therapy and provide a series of core recommendations.}, }
@article {pmid39870766, year = {2025}, author = {Othus, M and Garcia-Manero, G and Appelbaum, FR and Erba, HP and Dietrich, E and Raychaudhuri, S and Appelbaum, J and Estey, E and Percival, ME}, title = {Probability of remission with reinduction with 7+3 versus high-dose cytarabine: analysis of SWOG trial S1203.}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, pmid = {39870766}, issn = {1476-5551}, support = {CA180819//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; }, }
@article {pmid39869930, year = {2025}, author = {Cardle, II and Scherer, DR and Jensen, MC and Pun, SH and Sellers, DL}, title = {In Situ Bioconjugation of Synthetic Peptides onto Universal Chimeric Antigen Receptor T Cells for Targeted Cancer Immunotherapies.}, journal = {ACS nano}, volume = {}, number = {}, pages = {}, doi = {10.1021/acsnano.4c16824}, pmid = {39869930}, issn = {1936-086X}, abstract = {The recent development of modular universal chimeric antigen receptor (CAR) T-cell platforms that use bifunctional adaptor intermediates to redirect engineered T-cell effector function has greatly expanded the capabilities of adoptive T-cell therapy, enabling safer and more comprehensive cancer treatment. However, universal CAR receptor systems rely on unstable transient recognition of tag-coupled intermediates for T-cell activation, and the array of targeting intermediates has been limited to antibodies and small molecules. Addressing these shortcomings, we engineered universal CAR T-cell receptors that can be covalently modified with synthetic biomaterials in vivo by accelerated SpyCatcher003-SpyTag003 chemistry for cancer-cell targeting. SpyCatcher003-modified CARs, nicknamed DB5 CARs, displayed fast, low-nanomolar reaction kinetics with a synthetic αvβ6-binding peptide that incorporates a SpyTag003 peptide via branched peptide synthesis to comprise a bifunctional intermediate. Prearming DB5 CAR T cells or prelabeling target cells with the bifunctional peptide produced selective CD4[+] and CD8[+] CAR T-cell responses against αvβ6[+] cancer cells in vitro. Furthermore, the synthetic targeting intermediate showed robust DB5 CAR T-cell arming in vivo and selectively reduced αvβ6[+] tumor progression in a dual flank xenograft model. We demonstrate the versatility and therapeutic potential of "Cyborg" CAR T-cell therapies that utilize synthetic biomaterials to direct CAR T-cell activity via highly selective bioconjugation that occurs in vivo.}, }
@article {pmid39866881, year = {2025}, author = {Vo, P and Ng, K and Schoch, HG and Cooper, J and Vupalanchi, A and Flowers, M and Sandmaier, B and Gooley, T and Storb, R}, title = {Subsequent Cancers following Non-myeloablative Conditioning for Allogeneic Hematopoietic Cell Transplantation.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39866881}, issn = {2693-5015}, support = {P01 CA078902/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {We examined the risk of subsequent malignant neoplasms (SMNs) in 1720 patients with hematologic cancers given allogeneic hematopoietic grafts from 03/1998 to 08/2023 after nonmyeloablative conditioning regimens. With a median follow-up of 12 years, the cumulative incidence of SMNs was 17% (95% CI, [15%, 19%]). Most SMNs (n = 543) were non-melanoma skin cancers seen in 208 patients; unfortunately, information on these cancers was not available in the Surveillance, Epidemiology, and End Results (SEER) database for comparison with such tumors in the general population. However, developing non-melanoma skin cancers was statistically significantly associated with chronic GVHD and, thus, unlikely to be conditioning regimen related. Eighty-six patients (5%) developed 93 other SMNs. This number (93 SNMs) significantly exceeded the expected 73.4 cases in the comparison group (p = 0.03). This increase was driven exclusively by increases in uterine adenocarcinoma (n = 2), squamous lip cancer (n = 5), and squamous penile cancer (n = 2); the latter two cancers were, again, associated with chronic GVHD. Apart from these three tumor types, there were no observed increases in the risk of other tumors compared to those in the general population.}, }
@article {pmid39871876, year = {2024}, author = {Sokolov, D and Sullivan, LB}, title = {A metabolic signalling role for arginine in liver cancer.}, journal = {Life metabolism}, volume = {3}, number = {1}, pages = {load046}, pmid = {39871876}, issn = {2755-0230}, }
@article {pmid39869835, year = {2025}, author = {Mascarenhas, L and DuBois, SG and Albert, CM and Bielack, S and Orbach, D and Federman, N and Geoerger, B and Nagasubramanian, R and Zhang, Y and Chisholm, J and Gallego Melcon, S and Goto, H and Morgenstern, DA and Owens, C and Pappo, AS and Perreault, S and Schulte, JH and Shukla, N and Zwaan, CM and Neu, N and Bernard-Gauthier, V and De La Cuesta, E and van Tilburg, CM and Laetsch, TW}, title = {Elective Discontinuation of Larotrectinib in Pediatric Patients With TRK Fusion Sarcomas and Related Mesenchymal Tumors.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2400848}, doi = {10.1200/JCO.24.00848}, pmid = {39869835}, issn = {1527-7755}, abstract = {Larotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor with efficacy in children with TRK fusion tumors. We evaluated patient outcomes after elective discontinuation of larotrectinib in the absence of disease progression in a protocol-defined wait-and-see subset analysis of eligible patients where treatment resumption with larotrectinib was allowed if disease progressed. We also assessed the safety and efficacy of larotrectinib in all pediatric patients with sarcoma. This cohort included 91 patients (younger than 18 years) from two clinical trials: infantile fibrosarcoma (49), other soft tissue sarcomas or related mesenchymal tumors (41), and bone sarcoma (1). Treatment-related adverse events were of maximum grade 1 or 2 in 25% and 25% of patients, respectively. The overall response rate was 87% (95% CI, 78 to 93). In the wait-and-see analysis, 47 patients discontinued larotrectinib. Median time from discontinuation to disease progression was not reached. Sixteen patients had tumor progression during the wait-and-see period. All 16 patients resumed larotrectinib, and 15 (94%) achieved disease control, with 11 objective responses. Larotrectinib continues to demonstrate durable responses with favorable safety in children with TRK fusion sarcomas. Treatment discontinuation is feasible in select patients with objective response and clinical benefit noted in those who have disease progression after elective treatment discontinuation.}, }
@article {pmid39869680, year = {2025}, author = {Lum, MA and Jonas, KA and Parmar, S and Black, AR and O'Connor, CM and Dobersch, S and Yamamoto, N and Robertson, TM and Schutter, A and Giambi, M and Avelar, RA and DiFeo, A and Woods, NT and Kugel, S and Narla, G and Black, JD}, title = {Small molecule modulators of B56-PP2A restore 4E-BP function to suppress eIF4E-dependent translation in cancer cells.}, journal = {The Journal of clinical investigation}, volume = {}, number = {}, pages = {}, doi = {10.1172/JCI176093}, pmid = {39869680}, issn = {1558-8238}, abstract = {Dysregulated eIF4E-dependent translation is a central driver of tumorigenesis and therapy resistance. eIF4E binding proteins (4E-BP1/2/3) are major negative regulators of eIF4E-dependent translation that are inactivated in tumors through inhibitory phosphorylation or downregulation. Previous studies have linked PP2A phosphatase(s) to activation of 4E-BP1. Here, we leveraged biased small molecule activators of PP2A (SMAPs) to explore the role of B56-PP2A(s) in 4E-BP regulation and the potential of B56-PP2A activation for restoring translational control in tumors. SMAP treatment promoted PP2A-dependent hypophosphorylation of 4E-BP1/2, supporting a role for B56-PP2As (e.g., B56α-PP2A) as 4E-BP phosphatases. Unexpectedly, SMAPs induced transcriptional upregulation of 4E-BP1 through a B56 PP2A→TFE3/TFEB→ATF4 axis. Cap-binding and co-immunoprecipitation assays showed that B56-PP2A(s) activation blocks assembly of the eIF4F translation initiation complex, and cap-dependent translation assays confirmed the translation inhibitory effects of SMAPs. Thus, B56-PP2A(s) orchestrate a translation repressive program involving transcriptional induction and activation of 4E-BP1. Notably, SMAPs promoted 4E-BP1-dependent apoptosis in tumor cells and potentiated 4E-BP1 function in the presence of ERK or mTOR inhibitors, agents that rely on inhibition of eIF4E-dependent translation for antitumor activity. These findings, combined with the ability of SMAPs to regulate 4E-BP1 in vivo, highlight the potential of PP2A activators for cancer therapy and overcoming therapy resistance.}, }
@article {pmid39868116, year = {2025}, author = {Gupta, A and Morella, N and Sutormin, D and Li, N and Gaisser, K and Robertson, A and Ispolatov, Y and Seelig, G and Dey, N and Kuchina, A}, title = {Combinatorial phenotypic landscape enables bacterial resistance to phage infection.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39868116}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R21 DE032890/DE/NIDCR NIH HHS/United States ; R35 GM150994/GM/NIGMS NIH HHS/United States ; }, abstract = {Success of phage therapies is limited by bacterial defenses against phages. While a large variety of anti-phage defense mechanisms has been characterized, how expression of these systems is distributed across individual cells and how their combined activities translate into protection from phages has not been studied. Using bacterial single-cell RNA sequencing, we profiled the transcriptomes of ~50,000 cells from cultures of a human pathobiont, Bacteroides fragilis, infected with a lytic bacteriophage. We quantified the asynchronous progression of phage infection in single bacterial cells and reconstructed the infection timeline, characterizing both host and phage transcriptomic changes as infection unfolded. We discovered a subpopulation of bacteria that remained uninfected and determined the heterogeneously expressed host factors associated with protection. Each cell's vulnerability to phage infection was defined by combinatorial phase-variable expression of multiple genetic loci, including capsular polysaccharide (CPS) biosynthesis pathways, restriction-modification systems (RM), and a previously uncharacterized operon likely encoding fimbrial genes. By acting together, these heterogeneously expressed phase-variable systems and anti-phage defense mechanisms create a phenotypic landscape where distinct protective combinations enable the survival and re-growth of bacteria expressing these phenotypes without acquiring additional mutations. The emerging model of complementary action of multiple protective mechanisms heterogeneously expressed across an isogenic bacterial population showcases the potent role of phase variation and stochasticity in bacterial anti-phage defenses.}, }
@article {pmid39869261, year = {2025}, author = {Stearns, V and Chen, R and Blackford, AL and Saylor, E and Mull, J and Folmer, A and Jelinek, J and Hodgdon, C and Bacon, J and Engle, J and Shah, M and Sheinberg, R and Pedraza-Cardozo, S and Wilkinson, M and Alvendia, M and Snyder, C and Smith, KL}, title = {The Johns Hopkins Hope at Hopkins Clinic: supporting the comprehensive needs of individuals with metastatic breast cancer.}, journal = {Breast cancer research and treatment}, volume = {}, number = {}, pages = {}, pmid = {39869261}, issn = {1573-7217}, support = {5 NU58DP006673//Centers for Disease Control and Prevention Foundation/ ; 5 NU58DP006673//Centers for Disease Control and Prevention Foundation/ ; 5 NU58DP006673//Centers for Disease Control and Prevention Foundation/ ; 5 NU58DP006673//Centers for Disease Control and Prevention Foundation/ ; 5 NU58DP006673//Centers for Disease Control and Prevention Foundation/ ; 5 NU58DP006673//Centers for Disease Control and Prevention Foundation/ ; 5 NU58DP006673//Centers for Disease Control and Prevention Foundation/ ; 5 NU58DP006673//Centers for Disease Control and Prevention Foundation/ ; 5 NU58DP006673//Centers for Disease Control and Prevention Foundation/ ; P30CA006973//Johns Hopkins Cancer Center Support Grant/ ; P30CA006973//Johns Hopkins Cancer Center Support Grant/ ; P30CA006973//Johns Hopkins Cancer Center Support Grant/ ; }, abstract = {PURPOSE: Individuals with metastatic breast cancer (MBC) may live with their disease for many years. We initiated the Johns Hopkins Hope at Hopkins Clinic to assess the needs and optimize the care of these patients.<br><br>PATIENTS AND METHODS: Patients with MBC who agreed to participate in the Clinic in addition to usual care completed patient-reported outcome (PRO) surveys. They met with a navigator and underwent core consults (cancer rehabilitation, integrative medicine, supportive and palliative care, social work, and nutrition), clinical trial eligibility assessment, and optional services based on PRO responses and selection from a Clinic Menu. A medical oncologist provided a Care Plan during a final consult. Participants were asked to complete 3- and 6-month follow-up PRO surveys. We report on initial Clinic implementation, participant characteristics, and baseline PROs.<br><br>RESULTS: From 11/2020 to 6/2022, 45 patients completed baseline surveys and participated in the Clinic. Median age was 58 (32-86); the majority (71%) were white and had estrogen receptor-positive (84%) tumors. Baseline physical and mental health were not good for&#x2009;&#x2265;&#x2009;14&#xa0;days of the past month for 22 and 10%, respectively. PROMIS measure scores were&#x2009;>&#x2009;1 standard deviation worse than average for 32% for Physical Health, 16% for Mental Health, and 23% for Physical Function. PHQ-8 and GAD-7 scores suggested depression and anxiety for 22 and 7%, respectively. More than 80% of participants received specific recommendations from the core consultants. Only 20% of participants completed follow-up surveys.<br><br>CONCLUSION: Patients living with MBC have multiple needs. We used our results to implement routine PRO assessments and to expand services for patients with MBC. Our experience can serve as a model for coordinated care in other systems.}, }
@article {pmid39868844, year = {2025}, author = {Elyaman, W and Stern, LJ and Jiang, N and Dressman, D and Bradley, P and Klatzmann, D and Bradshaw, EM and Farber, DL and Kent, SC and Chizari, S and Funk, K and Devanand, D and Thakur, KT and Raj, T and Dalahmah, OA and Sarkis, RA and Weiner, HL and Shneider, NA and Przedborski, S}, title = {Exploring the role of T cells in Alzheimer's and other neurodegenerative diseases: Emerging therapeutic insights from the T Cells in the Brain symposium.}, journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association}, volume = {}, number = {}, pages = {e14548}, doi = {10.1002/alz.14548}, pmid = {39868844}, issn = {1552-5279}, support = {AG R01AG055422/NH/NIH HHS/United States ; R35GM141457/NH/NIH HHS/United States ; R01AI137198/NH/NIH HHS/United States ; R01AG076018/NH/NIH HHS/United States ; AI106697/NH/NIH HHS/United States ; R01AG067581/NH/NIH HHS/United States ; R13AG090018-01/NH/NIH HHS/United States ; T32AI148099-4/NH/NIH HHS/United States ; }, abstract = {This proceedings article summarizes the inaugural "T Cells in the Brain" symposium held at Columbia University. Experts gathered to explore the role of T cells in neurodegenerative diseases. Key topics included characterization of antigen-specific immune responses, T cell receptor (TCR) repertoire, microbial etiology in Alzheimer's disease (AD), and microglia-T cell crosstalk, with a focus on how T cells affect neuroinflammation and AD biomarkers like amyloid beta and tau. The symposium also examined immunotherapies for AD, including the Valacyclovir Treatment of Alzheimer's Disease (VALAD) trial, and two clinical trials leveraging regulatory T cell approaches for multiple sclerosis and amyotrophic lateral sclerosis therapy. Additionally, single-cell RNA/TCR sequencing of T cells and other immune cells provided insights into immune dynamics in neurodegenerative diseases. This article highlights key findings from the symposium and outlines future research directions to further understand the role of T cells in neurodegeneration, offering innovative therapeutic approaches for AD and other neurodegenerative diseases. HIGHLIGHTS: Researchers gathered to discuss approaches to study T cells in brain disorders. New technologies allow high-throughput screening of antigen-specific T cells. Microbial infections can precede several serious and chronic neurological diseases. Central and peripheral T cell responses shape neurological disease pathology. Immunotherapy can induce regulatory T cell responses in neuroinflammatory disorders.}, }
@article {pmid39866245, year = {2025}, author = {Knäusl, B and Vestergaard, A and Schwarz, M and Muren, LP}, title = {New guidelines and recommendations to advance treatment planning in proton therapy.}, journal = {Physics and imaging in radiation oncology}, volume = {33}, number = {}, pages = {100695}, pmid = {39866245}, issn = {2405-6316}, }
@article {pmid39866161, year = {2025}, author = {Goldberg, SR and Ko, LK and Hsu, L and Yin, H and Kooperberg, C and Peters, U and Burnett-Hartman, AN}, title = {Patient Perspectives on Personalized Risk Communication Using Polygenic Risk Scores to Inform Colorectal Cancer Screening Decisions.}, journal = {AJPM focus}, volume = {4}, number = {1}, pages = {100308}, pmid = {39866161}, issn = {2773-0654}, support = {R01 CA244588/CA/NCI NIH HHS/United States ; }, abstract = {INTRODUCTION: Colorectal cancer is increasingly diagnosed in people aged <50 years. New U.S. guidelines recommend screening initiation at age 45 years. Providing personalized risk for colorectal cancer using polygenic risk scores may be an opportunity to engage this younger population in colorectal cancer screening. There is limited research on patient understanding of polygenic risk scores results and use of polygenic risk scores to inform colorectal cancer screening decisions.<br><br>METHODS: From May 2022 to June 2023, 20 Kaiser Permanente Colorado members aged 46-51 years who had been offered colorectal cancer screening but had never completed it signed consent to provide a saliva sample for colorectal cancer polygenic risk score analysis. After receiving personalized polygenic risk scores for colorectal cancer, participants completed a semistructured interview regarding the understanding of their polygenic risk scores, perceived colorectal cancer risk, and intention to screen. Thematic analysis was conducted using Atlas.ti, Version 8.<br><br>RESULTS: Of the 19 participants who successfully completed polygenic risk score-related testing and a semistructured interview, 13 were female, 14 never smoked cigarettes, 6 were Hispanic, and 13 were non-Hispanic White. One participant had high risk for colorectal cancer on the basis of polygenic risk score results. Qualitative interviews showed participants' understanding of their results, trust in polygenic risk scores, perception of risk for colorectal cancer, plans to complete colorectal cancer screening, intent to share polygenic risk scores with healthcare providers, and concerns about genetic results impacting health care.<br><br>CONCLUSIONS: Qualitative analyses suggest that participants were interested in and understood their polygenic risk score results. Further study is needed to develop guidelines, effective calls to action, provider engagement, and health education materials on use of polygenic risk scores for health decision making.}, }
@article {pmid39866156, year = {2025}, author = {Marcotte, LM and Khor, S and Wong, ES and Akinsoto, N and Lee, ES and Onstad, S and Issaka, RB}, title = {A Pilot Analysis of Patient Portal Use and Breast Cancer Screening Among Black Patients in a Large Academic Health System.}, journal = {AJPM focus}, volume = {4}, number = {1}, pages = {100305}, pmid = {39866156}, issn = {2773-0654}, abstract = {INTRODUCTION: Patient portals may facilitate breast cancer screening and could be an important factor to address inequities; however, this association is not well characterized. The authors sought to examine this association in a large academic health system to inform interventions to address breast cancer screening inequities.<br><br>METHODS: The authors conducted a cross-sectional study among Black patients in a large academic health system using logistic regression to examine the association between breast cancer screening and portal use, adjusting for multilevel covariates and interactions. The authors estimated average marginal effects to examine the additive probability of breast cancer screening completion given portal use in the prior 12 months.<br><br>RESULTS: In the unadjusted model, portal use was associated with an estimated mean 24.8 percentage points (95% CI=20.7, 29.0) increased likelihood of completing breast cancer screening. In the adjusted model, portal use was associated with an estimated mean 16.2 percentage points (95% CI=11.2, 21.3) increased likelihood for completing breast cancer screening.<br><br>CONCLUSIONS: Improving portal access and use among racialized groups who face both portal and breast cancer screening inequities could be one strategy to address inequities. These pilot data will inform subsequent community-engaged research to better understand this association and develop and test a portal intervention to facilitate breast cancer screening access among Black patients eligible for screening.}, }
@article {pmid39866001, year = {2025}, author = {Karvonen, KA and Doody, DR and Barry, D and Bona, K and Winestone, LE and Rosenberg, AR and Mendoza, JA and Schwartz, SM and Chow, EJ}, title = {Historical redlining and survival among children, adolescents, and young adults with cancer diagnosed between 2000-2019 in Seattle and Tacoma, Washington.}, journal = {Cancer}, volume = {131}, number = {3}, pages = {e35677}, doi = {10.1002/cncr.35677}, pmid = {39866001}, issn = {1097-0142}, support = {T32CA009351/NH/NIH HHS/United States ; 2023YIA-6719883013//Conquer Cancer Foundation/ ; HE-FY24-MS-07-Karvonen//Mentored Scholars Grant by Seattle Children's Hospital Center for Diversity and Health/ ; N01-CN-67009//Cancer Surveillance System of the Fred Hutchinson Cancer Center/ ; N01-PC-35142//Cancer Surveillance System of the Fred Hutchinson Cancer Center/ ; N01-PC-2010-00029//Cancer Surveillance System of the Fred Hutchinson Cancer Center/ ; HHSN261201800004I//Cancer Surveillance System of the Fred Hutchinson Cancer Center/ ; }, mesh = {Humans ; Adolescent ; Washington/epidemiology ; Male ; Female ; *Neoplasms/mortality/epidemiology ; Young Adult ; Adult ; Child ; Child, Preschool ; Infant ; Proportional Hazards Models ; Poverty/statistics &amp; numerical data ; Kaplan-Meier Estimate ; }, abstract = {BACKGROUND: Historical redlining has been associated with inferior survival in adult-onset cancers. However, its relationship with pediatric, adolescent, and young-adult-onset cancer outcomes is unknown.<br><br>METHODS: This study identified incident cancer among individuals <40 years of age living in Seattle and Tacoma between 2000-2019 via the population-based Cancer Surveillance System. The authors determined case redlining status using Home Owners' Loans Corporation data overlaid with 2000 and 2010 census tracts. Kaplan-Meier methods and multivariable Cox proportional hazards models were used to determine 5- and 10-year overall survival and hazard ratio (HR) of death according to redlined status. Cox models adjusted for patient and tumor characteristics and area-level poverty; interaction between redlining and area-level poverty was also assessed.<br><br>RESULTS: Among 4355 cases (median age at diagnosis 32 years), overall survival at 5 years was lower (85.1%; 95% confidence interval [CI], 83.5%-86.5%) among individuals residing in redlined neighborhoods compared with those in unexposed neighborhoods (90.3%; 95% CI, 89.0%-91.5%). Survival differences persisted at 10 years. The unadjusted hazard of death for redlined exposed individuals with cancer was higher than redlined unexposed (hazard ratio [HR], 1.62; 95% CI, 1.39-1.89). In the fully adjusted model, mortality remained higher for redlined cases (HR, 1.32; 95% CI, 1.12-1.56). There did not appear to be effect modification from area-level poverty in the relationship between redlining and death (p&#xa0;=&#xa0;.49).<br><br>CONCLUSIONS: Among young individuals with cancer, residence at diagnosis in previously redlined neighborhoods was associated with lower survival compared with those residing in nonredlined neighborhoods, supporting the hypothesis that structural racism exerts persistent effects on contemporary health outcomes.}, }
@article {pmid39865921, year = {2025}, author = {Yanes, R and Saridogan, T and Gorantla, V and Overacre, A and Hsieh, RW and Celebrezze, J and Magge, T and Singhi, M and Saeed, A and Zureikat, AH and Dasari, AN and Sahin, IH}, title = {Shedding Light on the Prognostic and Predictive Value of Circulating Tumor DNA for Management of Patients with Early-Stage Colon Cancer.}, journal = {Technology in cancer research &amp; treatment}, volume = {24}, number = {}, pages = {15330338251317094}, doi = {10.1177/15330338251317094}, pmid = {39865921}, issn = {1533-0338}, mesh = {Humans ; *Circulating Tumor DNA/blood ; *Colonic Neoplasms/pathology/blood/genetics/diagnosis/therapy ; Prognosis ; *Biomarkers, Tumor/blood ; *Neoplasm Staging ; *Disease Management ; Liquid Biopsy/methods ; }, abstract = {The management of early-stage colon cancer involves surgical resection of the primary tumor with or without chemotherapy, depending on pathological staging. The benefit of adjuvant chemotherapy for stage II and III colon cancer is approximately 5% and 15%, indicating the need for optimization for risk stratification and patient selection. Several studies have revealed that current clinicopathological factors lack precision. Circulating tumor DNA (ctDNA) is cell-free DNA originating from cancer cells and can be detected even in the absence of radiologically detectable disease among patients with colon cancer. Recent cohort studies revealed that ctDNA is one of the most significant prognostic factors for patients with early-stage colon cancer, surpassing pathological and clinical risk factors. Prospective cohort studies also suggest there may be a predictive role for ctDNA on the decision for consideration of adjuvant therapy. Currently, randomized clinical trials are enrolling to better define this role. In this review article, we review recent literature on ctDNA and its role in patients with colon cancer. We also elaborate on the future clinical utility of ctDNA in clinical practice and the unmet need for research to optimize currently available ctDNA assays.}, }
@article {pmid39863610, year = {2025}, author = {Reddi, S and Senyshyn, L and Ebadi, M and Podlesny, D and Minot, SS and Gooley, T and Kabage, AJ and Hill, GR and Lee, SJ and Khoruts, A and Rashidi, A}, title = {Fecal microbiota transplantation to prevent acute graft-versus-host disease: pre-planned interim analysis of donor effect.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {1034}, pmid = {39863610}, issn = {2041-1723}, support = {ACT9016-24//Leukemia and Lymphoma Society (Leukemia &amp; Lymphoma Society)/ ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Graft vs Host Disease/prevention &amp; control/microbiology ; *Fecal Microbiota Transplantation/methods ; Male ; Female ; Middle Aged ; Adult ; *Gastrointestinal Microbiome ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Double-Blind Method ; *Tissue Donors ; *Transplantation, Homologous/adverse effects ; Feces/microbiology ; Acute Disease ; Aged ; Young Adult ; }, abstract = {Gut microbiota disruptions after allogeneic hematopoietic cell transplantation (alloHCT) are associated with increased risk of acute graft-versus-host disease (aGVHD). We designed a randomized, double-blind placebo-controlled trial to test whether healthy-donor fecal microbiota transplantation (FMT) early after alloHCT reduces the incidence of severe aGVHD. Here, we report the results from the single-arm run-in phase which identified the best of 3 stool donors for the randomized phase. The primary and key secondary endpoints were microbiota engraftment and severe aGVHD, respectively. Three cohorts of patients (20 total) received FMT, each from a different donor. FMT was safe and effective in restoring microbiota diversity and commensal species. Microbiota engraftment, determined from shotgun sequencing data, correlated with larger microbiota compositional shifts toward donor and better clinical outcomes. Donor 3 yielded a median engraftment rate of 66%, higher than donors 1 (P = 0.02) and 2 (P = 0.03) in multivariable analysis. Three patients developed severe aGVHD; all 3 had received FMT from donor 1. Donor 3 was selected as the sole donor for the randomized phase. Our findings suggest a clinically relevant donor effect and demonstrate feasibility of evidence-based donor selection. FMT is a holistic microbiota restoration approach that can be performed as a precision therapeutic. ClinicalTrials.gov identifier NCT06026371.}, }
@article {pmid39862925, year = {2025}, author = {Nguyen, TK and Louie, AV and Kotecha, R and Saxena, A and Zhang, Y and Guckenberger, M and Kim, MS and Scorsetti, M and Slotman, BJ and Lo, SS and Sahgal, A and Tree, AC}, title = {Stereotactic body radiotherapy for non-spine bone metastases: A meta-analysis and international stereotactic radiosurgery society (ISRS) clinical practice guidelines.}, journal = {Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology}, volume = {}, number = {}, pages = {110717}, doi = {10.1016/j.radonc.2025.110717}, pmid = {39862925}, issn = {1879-0887}, abstract = {BACKGROUND: While SBRT to NSBM has become common, particularly in the oligometastatic population, the approach to treating non-spine bone metastases (NSBM) with stereotactic body radiotherapy (SBRT) varies widely across institutions and clinical trial protocols. We present a comprehensive systematic review of the literatures to inform practice recommendations on behalf of the International Stereotactic Radiosurgery Society (ISRS).<br><br>METHODS: A systematic literature review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies with at least 10 patients receiving SBRT for NSBM were identified and meta-analyses were completed to estimate pooled local control and overall survival rates. Published guidelines on NSBM SBRT were reviewed and consolidated.<br><br>RESULTS: There were 25 studies included for qualitative analysis and 18 studies for quantitative analysis consisting of 13 retrospective studies, 2 non-randomized prospective studies, 1 randomized phase 2/3 trial, and a subgroup analysis of a phase I trial. The pooled local control rates at 1 and 2&#x202f;years were 95&#x202f;% (95&#x202f;% CI: 89&#x202f;%-98&#x202f;%) and 94&#x202f;% (95&#x202f;% CI: 86&#x202f;%-98&#x202f;%), respectively. Pooled overall survival rates at 1&#x202f;year and 2&#x202f;years were 84&#x202f;% (95&#x202f;% CI: 73&#x202f;%-91&#x202f;%) and 81&#x202f;% (95&#x202f;% CI: 45&#x202f;%-95&#x202f;%), respectively. Consensus was reached on recommendations to inform treatment simulation, target delineation, dose fractionation, and anatomic site-specific recommendations.<br><br>CONCLUSION: We present ISRS-endorsed consensus recommendations to inform best practice of SBRT to NSBM, which we found to be efficacious and associated with low rates of adverse events.}, }
@article {pmid39862490, year = {2025}, author = {Nickel, B and Ayre, J and Marinovich, ML and Smith, DP and Chiam, K and Lee, CI and Wilt, TJ and Taba, M and McCaffery, K and Houssami, N}, title = {Are AI chatbots concordant with evidence-based cancer screening recommendations?.}, journal = {Patient education and counseling}, volume = {134}, number = {}, pages = {108677}, doi = {10.1016/j.pec.2025.108677}, pmid = {39862490}, issn = {1873-5134}, abstract = {OBJECTIVE: This study aimed to assess whether information from AI chatbots on benefits and harms of breast and prostate cancer screening were concordant with evidence-based cancer screening recommendations.<br><br>METHODS: Seven unique prompts (four breast cancer; three prostate cancer) were presented to ChatGPT in March 2024. A total of 60 criteria (30 breast; 30 prostate) were used to assess the concordance of information. Concordance was scored between 0 and 2 against the United States Preventive Services Task Force (USPSTF) breast and prostate cancer screening recommendations independently by international cancer screening experts.<br><br>RESULTS: 43 of 60 (71.7&#x202f;%) criteria were completely concordant, 3 (5&#x202f;%) were moderately concordant and 14 (23.3&#x202f;%) were not concordant or not present, with most of the non-concordant criteria (9 of 14, 64.3 %) being from prompts for the oldest age groups. ChatGPT hallucinations (i.e., completely made up, non-sensical or irrelevant information) were found in 9 of 60 criteria (15&#x202f;%).<br><br>CONCLUSIONS: ChatGPT provided information mostly concordant with USPSTF breast and prostate cancer screening recommendations, however, important gaps exist. These findings provide insights into the role of AI to communicate cancer screening benefits and harms and hold increased relevance for periods of guideline change.<br><br>PRACTICE IMPLICATIONS: AI generated information on cancer screening should be taken in conjunction with official screening recommendations and/or information from clinicians.}, }
@article {pmid39861671, year = {2024}, author = {Lee, YS and Kwon, RJ and Lee, HS and Chung, JH and Kim, YS and Jeong, HS and Park, SJ and Lee, SY and Kim, T and Yoon, SH}, title = {The Role of Pentacyclic Triterpenoids in Non-Small Cell Lung Cancer: The Mechanisms of Action and Therapeutic Potential.}, journal = {Pharmaceutics}, volume = {17}, number = {1}, pages = {}, pmid = {39861671}, issn = {1999-4923}, support = {2024 research grant//Pusan National University Yangsan Hospital/ ; }, abstract = {Lung cancer remains a major global health problem because of its high cancer-related mortality rate despite advances in therapeutic approaches. Non-small cell lung cancer (NSCLC), a major subtype of lung cancer, is more amenable to surgical intervention in its early stages. However, the prognosis for advanced NSCLC remains poor, owing to limited treatment options. This underscores the growing need for novel therapeutic strategies to complement existing treatments and improve patient outcomes. In recent years, pentacyclic triterpenoids, a group of natural compounds, have emerged as promising candidates for cancer therapy due to their anticancer properties. Pentacyclic triterpenoids, such as lupeol, betulinic acid, betulin, oleanolic acid, ursolic acid, glycyrrhetinic acid, glycyrrhizin, and asiatic acid, have demonstrated the ability to inhibit cell proliferation and angiogenesis, induce apoptosis, suppress metastasis, and modulate inflammatory and immune pathways in NSCLC cell line models. These compounds exert their effects by modulating important signaling pathways such as NF-κB, PI3K/Akt, and MAPK. Furthermore, advances in drug delivery technologies such as nanocarriers and targeted delivery systems have improved the bioavailability and therapeutic efficacy of triterpenoids. However, despite promising preclinical data, rigorous clinical trials are needed to verify their safety and efficacy. This review explores the role of triterpenoids in NSCLC and therapeutic potential in preclinical models, focusing on their molecular mechanisms of action.}, }
@article {pmid39858050, year = {2025}, author = {Hatashima, A and Shadman, M and Raghunathan, V}, title = {Chimeric Antigen Receptor-T Cells in the Modern Era of Chronic Lymphocytic Leukemia Treatment.}, journal = {Cancers}, volume = {17}, number = {2}, pages = {}, pmid = {39858050}, issn = {2072-6694}, abstract = {Pathway inhibitors targeting Bruton tyrosine kinase (BTK) and B-cell lymphoma-2 (BCL-2) have dramatically changed the treatment landscape for both treatment-naïve and relapsed/refractory chronic lymphocytic leukemia (CLL). However, with increased utilization, a growing number of patients will experience progressive disease on both agents. This subgroup of "double refractory" patients has limited treatment options and poor prognosis. Chimeric antigen receptor (CAR)-T cells have transformed the treatment of relapsed/refractory B-cell malignancies. Although the earliest success of CAR-T cell therapy was in CLL, the clinical application of this modality has lagged until the recent approval of the first CAR-T cell product for CLL. In this review, we describe the current treatment options for upfront and subsequent therapies and the unmet need for novel agents highlighted by the burgeoning role and challenges of CAR-T cell therapy.}, }
@article {pmid39857099, year = {2025}, author = {Cicero, KI and Banerjee, R and Kwok, M and Dima, D and Portuguese, AJ and Chen, D and Chalian, M and Cowan, AJ}, title = {Illuminating the Shadows: Innovation in Advanced Imaging Techniques for Myeloma Precursor Conditions.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {15}, number = {2}, pages = {}, pmid = {39857099}, issn = {2075-4418}, abstract = {Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), the asymptomatic precursors to multiple myeloma, affect up to 5% of the population over the age of 40. Bone involvement, a myeloma-defining event, represents a major source of morbidity for patients. Key goals for the management of myeloma precursor conditions include (1) identifying patients at the highest risk for progression to MM with bone involvement and (2) differentiating precursor states from active myeloma requiring treatment. Computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET)-CT with [[18]F]fluorodeoxyglucose (FDG) have improved sensitivity for the detection of myeloma bone disease compared to traditional skeletal surveys, and such advanced imaging also provides this field with better tools for detecting early signs of progression. Herein, we review the data supporting the use of advanced imaging for both diagnostics and prognostication in myeloma precursor conditions.}, }
@article {pmid39856213, year = {2025}, author = {Patel, SP and Cano-Linson, E and Chae, YK and Schokrpur, S and Lao, CD and Powers, BC and Victor, AI and Onitilo, AA and Shin, S and Takebe, N and Threlkel, S and McLeod, CM and Chen, HX and Sharon, E and Othus, M and Ryan, CW and Blanke, CD and Kurzrock, R}, title = {Dual anti-CTLA-4 and anti-PD-1 blockade in metastatic basal cell carcinoma.}, journal = {NPJ precision oncology}, volume = {9}, number = {1}, pages = {24}, pmid = {39856213}, issn = {2397-768X}, support = {CA180888 CA180819 U10CA180820 CA180821 CA233331 CA233320 CA180828//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; CA180888 CA180819 U10CA180820 CA180821 CA233331 CA233320 CA180828//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; CA180888 CA180819 U10CA180820 CA180821 CA233331 CA233320 CA180828//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; CA180888 CA180819 U10CA180820 CA180821 CA233331 CA233320 CA180828//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; CA180888 CA180819 U10CA180820 CA180821 CA233331 CA233320 CA180828//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; CA180888 CA180819 U10CA180820 CA180821 CA233331 CA233320 CA180828//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; CA180888 CA180819 U10CA180820 CA180821 CA233331 CA233320 CA180828//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; CA180888 CA180819 U10CA180820 CA180821 CA233331 CA233320 CA180828//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; CA180888 CA180819 U10CA180820 CA180821 CA233331 CA233320 CA180828//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; CA180888 CA180819 U10CA180820 CA180821 CA233331 CA233320 CA180828//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; CA180888 CA180819 U10CA180820 CA180821 CA233331 CA233320 CA180828//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; CA180888 CA180819 U10CA180820 CA180821 CA233331 CA233320 CA180828//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; CA180888 CA180819 U10CA180820 CA180821 CA233331 CA233320 CA180828//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; CA180888 CA180819 U10CA180820 CA180821 CA233331 CA233320 CA180828//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; CA180888 CA180819 U10CA180820 CA180821 CA233331 CA233320 CA180828//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; CA180888 CA180819 U10CA180820 CA180821 CA233331 CA233320 CA180828//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; CA180888 CA180819 U10CA180820 CA180821 CA233331 CA233320 CA180828//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; }, abstract = {We report the basal cell cancer (BCC) cohort of the SWOG/NCI 1609 Dual Anti-CTLA-4 &amp; Anti-PD-1 blockade in Rare Tumors (DART), a phase II prospective, multicenter basket trial of nivolumab and ipilimumab. The primary endpoint was objective response rate (ORR) (RECIST v1.1). Overall survival (OS), progression-free survival (PFS), and toxicity were secondary endpoints. Sixteen patients with advanced/metastatic BCC were evaluable. The ORR was 31% (95% CI, 19-50%), and the 12-month OS, 75% (95% CI, 57-100%). Median PFS was 9.3 months (95% CI, 3.3-NA). Of 15 patients evaluable for clinical benefit, five partial responses (PRs) and five stable disease >6 months (total = 10/15 (66.7%)) were seen. The most common toxicities included fatigue (37.5%), pruritis (31.3%), and diarrhea (25%). In patients with advanced/metastatic BCC, ipilimumab and nivolumab produced an ORR of 31% and prolonged (>6 months) PFS in 73% of patients, with seven PFS/iPFS of >1 year, including one with prior anti-PD-1. ClinicalTrials.gov ID: NCT02834013 (Registered 7/15/2016; https://clinicaltrials.gov/ct2/show/NCT02834013).}, }
@article {pmid39856067, year = {2025}, author = {Pareja, F and Bhargava, R and Borges, VF and Brogi, E and Canas Marques, R and Cardoso, F and Desmedt, C and Harigopal, M and Lakhani, SR and Lee, A and Leone, JP and Linden, H and Lord, CJ and Marchio, C and Merajver, SD and Rakha, E and Reis-Filho, JS and Richardson, A and Sawyer, E and Schedin, P and Schwartz, CJ and Tutt, A and Ueno, NT and Vincent-Salomon, A and Weigelt, B and Wen, YH and Schnitt, SJ and Oesterreich, S}, title = {Unraveling complexity and leveraging opportunities in uncommon breast cancer subtypes.}, journal = {NPJ breast cancer}, volume = {11}, number = {1}, pages = {6}, pmid = {39856067}, issn = {2374-4677}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; P30CA008748//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; AACR-BRCF 09-06-26BORG//Breast Cancer Research Foundation (BCRF)/ ; P50 CA24779 01//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; }, abstract = {Special histologic subtypes of breast cancer (BC) exhibit unique phenotypes and molecular profiles with diagnostic and therapeutic implications, often differing in behavior and clinical trajectory from common BC forms. Novel methodologies, such as artificial intelligence may improve classification. Genetic predisposition plays roles in a subset of cases. Uncommon BC presentations like male, inflammatory and pregnancy-related BC pose challenges. Emerging therapeutic strategies targeting genetic alterations or immune microenvironment are being explored.}, }
@article {pmid39855565, year = {2025}, author = {Dávila, SB and Schultz, K and Ramgopal, A and Boiko, JR and Beebe, K and Carpenter, P and Chan, S and Paczesny, S and Aguayo-Hiraldo, P and Cuvelier, G and Rotz, SJ and Duncan, CN and Williams, KM}, title = {Pediatric Transplant and Cellular Therapy Consortium RESILIENT Conference on Pediatric Chronic Graft-versus-Host Disease Survivorship after Hematopoietic Cell Transplantation: Part II. Organ Dysfunction and Immune Reconstitution Considerations for children with chronic GVHD after Hematopoietic Cell Transplantation.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.01.885}, pmid = {39855565}, issn = {2666-6367}, abstract = {While highly morbid forms of chronic graft versus host disease (cGVHD) and severe late effects of allogeneic hematopoietic cell transplant (HCT) can impact children and adults alike, unique considerations arise in pediatric cases regarding diagnosis, monitoring, treatment, and likelihood of resolution. As children can present with atypical features of cGVHD, and with more significant disease due to inability to communicate symptoms, they may be at increased risk for highly morbid forms of cGVHD and incur greater subsequent late effects, which may be more pronounced in those with underlying chromosomal breakage syndromes, with higher prevalence in pediatric HCT recipients. The long-term effects of cGVHD and its therapies include impaired immune reconstitution, leading to increased risks of infection and secondary malignant neoplasms. However, children also have the greatest potential for full immune reconstitution, due to thymus recovery that could impact the timing of vaccination with respect to tolerance and restoration of optimal immunity. Developing strategies to mitigate the late effects incurred with, and as a result of cGVHD, is of critical importance. The working group recommends surveillance strategies for late effects in patients with cGVHD, increased utilization of emerging diagnostic tools, integration of monitoring for cGVHD treatment response, development of new treatments, and provides aims for future research endeavors.}, }
@article {pmid39830263, year = {2025}, author = {Esmaeili, S and Owens, K and Standing, JF and Lowe, DM and Zhang, S and Watson, JA and Schilling, WHK and Wagoner, J and Polyak, SJ and Schiffer, JT}, title = {Molnupiravir clinical trial simulation suggests that polymerase chain reaction underestimates antiviral potency against SARS-CoV-2.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39830263}, abstract = {Molnupiravir is an antiviral medicine that induces lethal copying errors during SARS-CoV-2 RNA replication. Molnupiravir reduced hospitalization in one pivotal trial by 50% and had variable effects on reducing viral RNA levels in three separate trials. We used mathematical models to simulate these trials and closely recapitulated their virologic outcomes. Model simulations suggest lower antiviral potency against pre-omicron SARS-CoV-2 variants than against omicron. We estimate that in vitro assays underestimate in vivo potency 7-8 fold against omicron variants. Our model suggests that because polymerase chain reaction detects molnupiravir mutated variants, the true reduction in non-mutated viral RNA is underestimated by ~0.5 log10 in the two trials conducted while omicron variants dominated. Viral area under the curve estimates differ significantly between non-mutated and mutated viral RNA. Our results reinforce past work suggesting that in vitro assays are unreliable for estimating in vivo antiviral drug potency and suggest that virologic endpoints for respiratory virus clinical trials should be catered to the drug mechanism of action.}, }
@article {pmid39829847, year = {2025}, author = {Haddox, HK and Angehrn, G and Sesta, L and Jennings-Shaffer, C and Temple, SD and Galloway, JG and DeWitt, WS and Bloom, JD and Matsen, FA and Neher, RA}, title = {The mutation rate of SARS-CoV-2 is highly variable between sites and is influenced by sequence context, genomic region, and RNA structure.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39829847}, issn = {2692-8205}, support = {R01 AI146028/AI/NIAID NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, abstract = {RNA viruses like SARS-CoV-2 have a high mutation rate, which contributes to their rapid evolution. The rate of mutations depends on the mutation type (e.g., A→C, A→G, etc.) and can vary between sites in the viral genome. Understanding this variation can shed light on the mutational processes at play, and is crucial for quantitative modeling of viral evolution. Using the millions of available SARS-CoV-2 full-genome sequences, we estimate rates of synonymous mutations for all 12 possible nucleotide mutation types and examine how much these rates vary between sites. We find a surprisingly high level of variability and several striking patterns: the rates of four mutation types suddenly increase at one of two gene boundaries; the rates of most mutation types strongly depend on a site's local sequence context, with up to 56-fold differences between contexts; consistent with a previous study, the rates of some mutation types are lower at sites engaged in RNA secondary structure. A simple log-linear model of these features explains ~15-60% of the fold-variation of mutation rates between sites, depending on mutation type; more complex models only modestly improve predictive power out of sample. We estimate the fitness effect of each mutation based on the number of times it actually occurs versus the number of times it is expected to occur based on the model. We identify several small regions of the genome where synonymous or noncoding mutations occur much less often than expected, indicative of strong purifying selection on the RNA sequence that is independent of protein sequence. Overall, this work expands our basic understanding of SARS-CoV-2's evolution by characterizing the virus's mutation process at the level of individual sites and uncovering several striking mutational patterns that arise from unknown mechanisms.}, }
@article {pmid39829843, year = {2025}, author = {Xie, J and Chen, DG and Chour, W and Ng, RH and Zhang, R and Yuan, D and Choi, J and McKasson, M and Troisch, P and Smith, B and Jones, L and Webster, A and Rasheed, Y and Li, S and Edmark, R and Hong, S and Murray, KM and Logue, JK and Franko, NM and Lausted, CG and Piening, B and Algren, H and Wallick, J and Magis, AT and Watanabe, K and Mease, P and Greenberg, PD and Chu, H and Goldman, JD and Su, Y and Heath, JR}, title = {APMAT analysis reveals the association between CD8 T cell receptors, cognate antigen, and T cell phenotype and persistence.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39829843}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA264090/CA/NCI NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; }, abstract = {Elucidating the relationships between a class I peptide antigen, a CD8 T cell receptor (TCR) specific to that antigen, and the T cell phenotype that emerges following antigen stimulation, remains a mostly unsolved problem, largely due to the lack of large data sets that can be mined to resolve such relationships. Here, we describe Antigen-TCR Pairing and Multiomic Analysis of T-cells (APMAT), an integrated experimental-computational framework designed for the high-throughput capture and analysis of CD8 T cells, with paired antigen, TCR sequence, and single-cell transcriptome. Starting with 951 putative antigens representing a comprehensive survey of the SARS-CoV-2 viral proteome, we utilize APMAT for the capture and single cell analysis of CD8 T cells from 62 HLA A*02:01 COVID-19 participants. We leverage this unique, comprehensive dataset to integrate with peptide antigen properties, TCR CDR3 sequences, and T cell phenotypes to show that distinct physicochemical features of the antigen-TCR pairs strongly associate with both T cell phenotype and T cell persistence. This analysis suggests that CD8+ T cell phenotype following antigen stimulation is at least partially deterministic, rather than the result of stochastic biological properties.}, }
@article {pmid39829744, year = {2025}, author = {Tang, G and Carr, AV and Perez, C and Sarmiento, KR and Levy, L and Lampe, JW and Diener, C and Gibbons, SM}, title = {Metagenomic estimation of absolute bacterial biomass in the mammalian gut through host-derived read normalization.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39829744}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 DK133468/DK/NIDDK NIH HHS/United States ; }, abstract = {Absolute bacterial biomass estimation in the human gut is crucial for understanding microbiome dynamics and host-microbe interactions. Current methods for quantifying bacterial biomass in stool, such as flow cytometry, qPCR, or spike-ins (i.e., adding cells or DNA from an organism not normally found in a sample), can be labor-intensive, costly, and confounded by factors like water content, DNA extraction efficiency, PCR inhibitors, and other technical challenges that add bias and noise. We propose a simple, cost-effective approach that circumvents some of these technical challenges: directly estimating bacterial biomass from metagenomes using bacterial-to-host (B:H) read ratios. We compare B:H ratios to the standard methods outlined above, demonstrating that B:H ratios are useful proxies for bacterial biomass in stool and possibly in other host-associated substrates. We show how B:H ratios can be used to track antibiotic treatment response and recovery in both mice and humans, which showed 403-fold and 45-fold reductions in bacterial biomass during antibiotic treatment, respectively. Our results indicate that host and bacterial metagenomic DNA fractions in human stool fluctuate longitudinally around a stable mean in healthy individuals, and the average host read fraction varies across healthy individuals by < 8-9 fold. B:H ratios offer a convenient alternative to other absolute biomass quantification methods, without the need for additional measurements, experimental design considerations, or machine learning algorithms, enabling retrospective absolute biomass estimates from existing stool metagenomic data.}, }
@article {pmid39829743, year = {2025}, author = {Nguyen, A and Heim, JB and Cordara, G and Chan, MC and Johannesen, H and Charlesworth, C and Li, M and Azumaya, CM and Madden, B and Krengel, U and Meves, A and Campbell, MG}, title = {Structural and functional characterization of integrin α5-targeting antibodies for anti-angiogenic therapy.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39829743}, issn = {2692-8205}, support = {R35 GM147414/GM/NIGMS NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; P30 CA015083/CA/NCI NIH HHS/United States ; F31 HL174166/HL/NHLBI NIH HHS/United States ; T32 CA080416/CA/NCI NIH HHS/United States ; K08 CA215105/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {Integrins are a large family of heterodimeric receptors important for cell adhesion and signaling. Integrin α5β1, also known as the fibronectin receptor, is a key mediator of angiogenesis and its dysregulation is associated with tumor proliferation, progression, and metastasis. Despite numerous efforts, α5β1-targeting therapeutics have been unsuccessful in large part due to efficacy and off-target effects. To mediate activation and signaling, integrins undergo drastic conformational changes. However, how therapeutics influence or are affected by integrin conformation remains incompletely characterized. Using cell biology, biophysics, and electron microscopy, we shed light on these relationships by characterizing two potentially therapeutic anti-α5β1 antibodies, BIIG2 and MINT1526A. We show that both antibodies bind α5β1 with nanomolar affinity and reduce angiogenesis in vitro. We demonstrate BIIG2 reduces tumor growth in two human xenograft mouse models and exhibits a strong specificity for connective tissue-resident fibroblasts and melanoma cells. Using electron microscopy, we map out the molecular interfaces mediating the integrin-antibody interactions and reveal that although both antibodies have overlapping epitopes and block fibronectin binding via steric hindrance, the effect on the conformational equilibrium is drastically different. While MINT1526A constricts α5β1's range of flexibility, BIIG2 binds without restricting the available conformational states. These mechanistic insights, coupled with the functional analysis, guide which aspects should be prioritized to avoid off-target effects or partial agonism in the design of future integrin-targeted therapeutics.}, }
@article {pmid39855457, year = {2025}, author = {Jenkins, MT and Chu, YE and Franceski, AM and Potts, CR and Dubin, R and Dickerson, KM and Lee, SC and Lu, R and Welner, RS and Ferrell, PB}, title = {TET2-loss enhances immediate and time-resolved IFNγ signaling responses across myeloid differentiation.}, journal = {Experimental hematology}, volume = {}, number = {}, pages = {104727}, doi = {10.1016/j.exphem.2025.104727}, pmid = {39855457}, issn = {1873-2399}, abstract = {Signaling responses to cytokines are disrupted in clonal hematopoiesis and myeloid malignancies. To better identify specific signaling response alterations in the presence or absence of TET2, we developed a 36-parameter CyTOF panel of both surface marker and phosphoprotein antigens in murine BM. We show diverse, cell-type specific inflammatory cytokine responses in healthy hematopoietic cells. We next investigated changes associated with bone marrow cells from Tet2[KO] mice. High dimensional surface marker phenotyping revealed expansion of HSPCs, committed cKIT[+]Ly6C[+] myeloid progenitors, and monocytes. Loss of TET2 function increased the magnitude of response to extracellular perturbations, including IFNγ and H2O2. Response time courses revealed that IFNγ-mediated pSTAT1 remains elevated over time in Tet2[KO]. Further, IFNγ resulted in a more significant increase in major histocompatibility complex class II (MHCII) expression in Tet2[KO] immortalized progenitor cells than in Tet2[WT]. Inhibition of Janus kinase 1 and 2 (JAK1/2) with ruxolitinib significantly reduced STAT1 phosphorylation and MHCII expression in Tet2[KO] cells. Our results identify targetable disrupted signaling responses in Tet2[KO] cells.}, }
@article {pmid39854241, year = {2025}, author = {Langley, CA and Dietzen, PA and Emerman, M and Tenthorey, JL and Malik, HS}, title = {Antiviral Mx proteins have an ancient origin and widespread distribution among eukaryotes.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {4}, pages = {e2416811122}, doi = {10.1073/pnas.2416811122}, pmid = {39854241}, issn = {1091-6490}, support = {T32 GM007270/GM/NIGMS NIH HHS/United States ; Hannay Gray Fellowship GT11096/GT16732//Howard Hughes Medical Institute (HHMI)/ ; Mathilde Krim Fellowship 110298-71-RKHF/110537-74-RKHF//amfAR, The Foundation for AIDS Research (amfAR)/ ; U54 AI170792/AI/NIAID NIH HHS/United States ; Investigator Award//Howard Hughes Medical Institute (HHMI)/ ; }, mesh = {*Phylogeny ; *Myxovirus Resistance Proteins/genetics/metabolism ; Animals ; *Dynamins/metabolism/genetics ; *Eukaryota/genetics ; *Evolution, Molecular ; Humans ; Antiviral Agents ; DNA Viruses/genetics ; }, abstract = {Mx proteins, first identified in mammals, encode potent antiviral activity against a wide range of viruses. Mx proteins arose within the Dynamin superfamily of proteins (DSP), which mediate critical cellular processes, such as endocytosis and mitochondrial, plastid, and peroxisomal dynamics. Despite their crucial role, the evolutionary origins of Mx proteins are poorly understood. Through comprehensive phylogenomic analyses with progressively expanded taxonomic sampling, we demonstrate that Mx proteins predate the interferon signaling system in vertebrates. Our analyses find an ancient monophyletic DSP lineage in eukaryotes that groups vertebrate and invertebrate Mx proteins with fungal MxF proteins, the largely uncharacterized plant and algal Dynamin 4A/4C proteins, and representatives from several other eukaryotic lineages, suggesting that Mx-like proteins date back close to the origin of Eukarya. Our phylogenetic analyses also find host-encoded and nucleocytoplasmic large DNA viruses-encoded DSPs interspersed in four distinct DSP lineages, indicating recurrent viral theft of host DSPs. Our analyses thus reveal an ancient history of viral and antiviral functions encoded by the Dynamin superfamily in eukaryotes.}, }
@article {pmid39853979, year = {2025}, author = {Li, NHY and Li, CI}, title = {Incidence Rate Trends of Breast Cancer Overall and by Molecular Subtype by Race and Ethnicity and Age.}, journal = {JAMA network open}, volume = {8}, number = {1}, pages = {e2456142}, doi = {10.1001/jamanetworkopen.2024.56142}, pmid = {39853979}, issn = {2574-3805}, mesh = {Humans ; Female ; Middle Aged ; Incidence ; *Breast Neoplasms/ethnology/epidemiology/genetics ; Aged ; United States/epidemiology ; Adult ; *SEER Program ; Ethnicity/statistics &amp; numerical data ; Cohort Studies ; Hispanic or Latino/statistics &amp; numerical data ; Age Factors ; Racial Groups/statistics &amp; numerical data ; White People/statistics &amp; numerical data ; White ; }, abstract = {IMPORTANCE: Black and Hispanic women in the US experience higher incidence rates of aggressive molecular subtypes of breast cancer, including triple-negative disease. However, how these rates are changing, particularly across different age groups, has not been well documented.<br><br>OBJECTIVE: To assess changes in overall and subtype-specific breast cancer incidence rates in the US by age and race and ethnicity.<br><br>This cohort study used Surveillance, Epidemiology, and End Results program cancer registry data from 22 US cancer registries on 1&#x202f;123&#x202f;658 females who received a diagnosis of invasive breast cancer from 2010 to 2019. Statistical analysis was conducted from August 2023 to October 2024.<br><br>EXPOSURES: Age and race and ethnicity.<br><br>MAIN OUTCOMES AND MEASURES: Age-adjusted incidence rates of invasive breast cancer overall and across the 4 major molecular subtypes by age and by race and ethnicity, as well as their associated annual percentage changes using Joinpoint Trend Analysis software.<br><br>RESULTS: Of the 1&#x202f;123&#x202f;658 participants in the study, 219&#x202f;112 (19.5%) were younger than 50 years, 409&#x202f;257 (36.4%) were aged 50 to 64 years, and 495&#x202f;289 (44.1%) were 65 years or older. A total of 141&#x202f;703 participants (12.6%) were Hispanic, 3253 (0.3%) were non-Hispanic American Indian or Alaska Native, 78&#x202f;306 (7.0%) were non-Hispanic Asian or Pacific Islander, 124&#x202f;560 (11.1%) were non-Hispanic Black, 769&#x202f;043 (68.4%) were non-Hispanic White, and 6793 participants (0.6%) had an unknown race and/or ethnicity. Overall, breast cancer incidence rates increased 0.5% per year from 2010 to 2019. Variation by race and ethnicity was observed, with increases of 1.4% per year among Hispanic females, 1.9% per year among non-Hispanic American Indian or Alaska Native females, and 2.1% per year among non-Hispanic Asian or Pacific Islander females, while rates increased only 0.8% per year among non-Hispanic Black females and 0.5% per year among non-Hispanic White females. In subtype analyses, increases of the greatest magnitude in recent years were observed in the incidence rates of triple-negative breast cancer per year among participants aged 65 years or older (Hispanic females, 2.3%; non-Hispanic Asian or Pacific Islander females, 5.5%; and non-Hispanic Black females, 4.3%), while remaining unchanged among non-Hispanic White females.<br><br>CONCLUSIONS AND RELEVANCE: In this cohort study of 1&#x202f;123&#x202f;658 females with breast cancer over the 10-year period from 2010 to 2019, there were substantial differences in trends in the incidence rates of breast cancer overall and by subtype across different racial and ethnic groups. Further research is needed to understand the factors associated with these trends.}, }
@article {pmid39853273, year = {2025}, author = {Brown, JR and Li, J and Eichhorst, B and Lamanna, N and O'Brien, SM and Tam, CS and Qiu, L and Huang, R and Shi, Y and Idoine, A and Salmi, T and Cohen, AC and Shadman, M}, title = {ACQUIRED MUTATIONS IN PATIENTS WITH RELAPSED/REFRACTORY CLL WHO PROGRESSED IN THE ALPINE STUDY.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024014206}, pmid = {39853273}, issn = {2473-9537}, abstract = {Some CLL patients who develop progressive disease (PD) during treatment with covalent Bruton tyrosine kinase inhibitors (cBTKi) acquire pathway resistance mutations in BTK or PLCG2. Here, we report gene mutation data from paired baseline and PD peripheral blood samples from 52 patients (zanubrutinib, n=24; ibrutinib, n=28) who, at an early median follow-up time of 25.7 months, progressed on zanubrutinib or ibrutinib treatment in the ALPINE trial (NCT03734016). No BTK mutations were observed at baseline; at PD, eight patients (zanubrutinib, n=5, ibrutinib, n=3) acquired a total of 17 BTK mutations. Among BTK mutations, 82.4% (zanubrutinib, n=11/14; ibrutinib, n=3/3) were at C481. Non-C481 mutations were detected in 12.5% (3/24) of zanubrutinib-treated patients (L528W: n=2, cancer cell fraction [CCF]=9.58% and 17.6%; A428D, n=1, CCF=37.03%); these were not detected in ibrutinib-treated patients. At baseline, 48/52 patients had ≥1 driver gene mutation/s, most frequently in: NOTCH1 (n=21), TP53 (n=19), BRAF (n=10), SF3B1 (n=8), and ATM (n=8). At PD, acquired driver gene mutations were observed in one zanubrutinib-treated patient (TP53, XPO1) and five ibrutinib-treated patients (TP53, n=1 patient; SETD2, n=1; SF3B1, n=1; ASXL1, n=2). Baseline driver gene mutations were not associated with later development of BTK mutations, but patients with ≥2 baseline driver gene mutations were more likely to acquire BTK mutations at PD. In conclusion, patients in this data set had a short treatment duration and a low incidence of BTK mutations, suggesting that mechanisms other than BTK/PLCG2 mutations are driving most instances of early PD. NCT03734016.}, }
@article {pmid39847539, year = {2025}, author = {Bea, JW and Ochs-Balcom, HM and Valencia, CI and Chen, Z and Blew, RM and Lind, KE and Caan, BJ and Roe, DJ and Rohan, TE and Reeves, KW and Manson, JE and Ballinger, T and Reding, KW and Follis, S and Ziller, SG and Odegaard, AO}, title = {Abdominal visceral and subcutaneous adipose tissue associations with postmenopausal breast cancer incidence.}, journal = {JNCI cancer spectrum}, volume = {}, number = {}, pages = {}, doi = {10.1093/jncics/pkaf007}, pmid = {39847539}, issn = {2515-5091}, abstract = {BACKGROUND: Obesity, classified by body mass index (BMI), is associated with higher postmenopausal breast cancer (BCa) risk. Yet, the associations between abdominal visceral (VAT) and subcutaneous adipose tissue (SAT) with BCa are unclear.<br><br>METHODS: We assessed BCa associations with abdominal VAT and SAT in a prospective cohort of postmenopausal women without a history of cancer and with 27&#x2009;years follow-up (N&#x2009;=&#x2009;9950), during which all new cancers were adjudicated. Dual-energy X-ray absorptiometry scans assessed adiposity at baseline, year 3, and year 6. Competing risks multivariable sub-hazard ratios (SHR), with adjustments for sociodemographic, behavioral, reproductive, and anthropometric characteristics, were estimated for baseline and time-dependent associations between VAT, SAT, and incident BCa.<br><br>RESULTS: Participants averaged 63.3&#x2009;&#xb1;&#x2009;7.4&#x2009;years of age and a BMI of 28.20&#x2009;&#xb1;&#x2009;5.72&#x2009;kg/m2 at baseline. The models included 738 incident BCa cases (N&#x2009;=&#x2009;593 invasive; N&#x2009;=&#x2009;145 in situ). Baseline VAT and SAT area were associated with significantly increased BCa risk, by 36% and 19% respectively. Increasing VAT/SAT ratio was associated with an 8% increase in incident BCa. Time-dependent models produced similar results. VAT and VAT/SAT associated BCa risk was highest for African American/Black women, though not significantly different from other groups. Quartiles (Q) of VAT/SAT were also explored; the SHR for Q4 compared to Q1 was 1.49 (95% CI: 1.18, 1.87).<br><br>CONCLUSION: Higher abdominal VAT and SAT are associated with an increased risk of postmenopausal BCa, and VAT/SAT may provide a distinctive risk estimate. Potential racial and ethnic differences require replication in a larger sample.(NCT00000611).}, }
@article {pmid39846783, year = {2024}, author = {Lee, MA and Hatcher, CA and Hazelwood, E and Goudswaard, LJ and Tsilidis, KK and Vincent, EE and Martin, RM and Smith-Byrne, K and Brenner, H and Cheng, I and Kweon, SS and Le Marchand, L and Newcomb, PA and Schoen, RE and Peters, U and Gunter, MJ and Van Guelpen, B and Murphy, N}, title = {A proteogenomic analysis of the adiposity colorectal cancer relationship identifies GREM1 as a probable mediator.}, journal = {International journal of epidemiology}, volume = {54}, number = {1}, pages = {}, pmid = {39846783}, issn = {1464-3685}, support = {//Wereld Kanker Onderzoek Fonds/ ; INCa SHSESP20//French National Cancer Institute/ ; }, mesh = {Humans ; *Adiposity/genetics ; *Colorectal Neoplasms/genetics/epidemiology ; *Body Mass Index ; Female ; Male ; *Mendelian Randomization Analysis ; *Waist-Hip Ratio ; Risk Factors ; Intercellular Signaling Peptides and Proteins/genetics ; Obesity/genetics ; Proteomics ; Polymorphism, Single Nucleotide ; }, abstract = {BACKGROUND: Adiposity is an established risk factor for colorectal cancer (CRC). The pathways underlying this relationship, and specifically the role of circulating proteins, are unclear.<br><br>METHODS: Utilizing two-sample univariable Mendelian randomization (UVMR), multivariable Mendelian randomization (MVMR), and colocalization, based on summary data from large sex-combined and sex-specific genetic studies, we estimated the univariable associations between: (i) body mass index (BMI) and waist-hip ratio (WHR) and overall and site-specific (colon, proximal colon, distal colon, and rectal) CRC risk, (ii) BMI and WHR and circulating proteins, and (iii) adiposity-associated circulating proteins and CRC risk. We used MVMR to investigate the potential mediating role of adiposity- and CRC-related circulating proteins in the adiposity-CRC association.<br><br>RESULTS: BMI and WHR were positively associated with CRC risk, with similar associations by anatomical tumor site. In total, 6591 adiposity-protein (2628 unique circulating proteins) and 33 protein-CRC (7 unique circulating proteins) associations were identified using UVMR and colocalization. One circulating protein, GREM1, was associated with BMI (only) and CRC outcomes in a manner that was consistent with a potential mediating role in sex-combined and female-specific analyses. In MVMR, adjusting the BMI-CRC association for GREM1, effect estimates were attenuated-suggestive of a potential mediating role-most strongly for the BMI-overall CRC association in women.<br><br>CONCLUSION: Results highlight the impact of adiposity on the plasma proteome and of adiposity-associated circulating proteins on the risk of CRC. Supported by evidence from UVMR and colocalization analyses using cis-single-nucleotide polymorphisms, GREM1 was identified as a potential mediator of the BMI-CRC association, particularly in women.}, }
@article {pmid39845432, year = {2024}, author = {Santiago-Torres, M and Mull, KE and Sullivan, BM and Prochaska, JJ and Zvolensky, MJ and Bricker, JB}, title = {Can an Acceptance and Commitment Therapy-Based Smartphone App Help Individuals with Mental Health Disorders Quit Smoking?.}, journal = {Depression and anxiety}, volume = {2024}, number = {}, pages = {}, pmid = {39845432}, issn = {1520-6394}, support = {R01 CA192849/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Acceptance and Commitment Therapy/methods ; *Smoking Cessation/methods ; Female ; *Mobile Applications ; Adult ; Middle Aged ; *Smartphone ; Mental Disorders/therapy ; United States ; Schizophrenia/therapy ; Bipolar Disorder/therapy ; }, abstract = {BACKGROUND: Individuals with mental health disorders face major barriers in accessing smoking cessation care, often due to the stigmas associated with mental disorders and addiction. Consequently, accessible population-based smoking cessation interventions are needed for this vulnerable group.<br><br>OBJECTIVE: This secondary analysis utilized data from a 12-month randomized trial to examine whether an acceptance and commitment therapy-based app (iCanQuit) demonstrated greater efficacy, engagement, and satisfaction compared to a United States (US) Clinical Practice Guidelines-based app (QuitGuide) in helping adults with mental health disorders quit smoking.<br><br>MATERIALS AND METHODS: Participants self-reported having bipolar disorder or schizophrenia, or screened positive for depression, generalized anxiety, panic disorder, posttraumatic stress disorder, or social anxiety. We compared the primary outcome of self-reported 30-day cigarette abstinence at 12 months between iCanQuit (n = 770) and QuitGuide (n = 785) using complete-case and multiple imputation analyses and compared engagement and satisfaction between arms. Mediation analyses were conducted to examine whether the intervention apps functioned by reinforcing hypothesized mechanisms of action, namely, acceptance of triggers to smoke and through app engagement.<br><br>RESULTS: Participants represented all 50 US states and had 30.2% non-White or Hispanic backgrounds. Among participants with any mental health disorder, iCanQuit demonstrated higher 30-day cigarette abstinence than QuitGuide at 12 months (complete-case: 24.4% vs. 20.4%, P = 0.04; multiple imputation: 24.6% vs. 20.4%, P = 0.04). A comparable effect size was observed in iCanQuit participants with bipolar disorder or schizophrenia compared to QuitGuide, albeit not statistically significant (multiple imputation: 27.1% vs. 20.9%; P = 0.06). iCanQuit's cessation efficacy was mediated by acceptance of emotions triggering smoking (P < 0.001) and app engagement (P < 0.001). iCanQuit was more satisfying than QuitGuide (88.5% vs. 77.2%; P < 0.001).<br><br>CONCLUSIONS: In the largest known study of ACT for smoking cessation among adults with mental health disorders, the smoking cessation, engagement, and satisfaction outcomes were all significantly greater with iCanQuit than QuitGuide. Acceptance of emotions triggering smoking and iCanQuit app engagement were important mechanisms of efficacy. This trial is registered with NCT02724462.}, }
@article {pmid39844469, year = {2025}, author = {Cooper, N and Jansen, AJG and Bird, R and Mayer, J and Sholzberg, M and Tarantino, MD and Garg, M and Ypma, PF and McDonald, V and Percy, C and Košťál, M and Goncalves, I and Bogdanov, LH and Gernsheimer, TB and Diab, R and Yao, M and Daak, A and Kuter, DJ}, title = {Efficacy and Safety Results With Rilzabrutinib, an Oral Bruton Tyrosine Kinase Inhibitor, in Patients With Immune Thrombocytopenia: Phase 2 Part B Study.}, journal = {American journal of hematology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ajh.27539}, pmid = {39844469}, issn = {1096-8652}, support = {//Sanofi/ ; }, abstract = {Current treatments for persistent or chronic immune thrombocytopenia (ITP) are limited by inadequate response, toxicity, and impaired quality of life. The Bruton tyrosine kinase inhibitor rilzabrutinib was evaluated to further characterize safety and durability of platelet response. LUNA2 Part B is a multicenter, phase 1/2 study in adults with ITP (≥ 3 months duration, platelet count < 30 × 10[9]/L) who failed ≥ 1 ITP therapy (NCT03395210, EudraCT 2017-004012-19). Oral rilzabrutinib 400 mg bid was given over 24 weeks, with optional long-term extension (LTE). Primary endpoints were safety and platelet counts ≥ 50 × 10[9]/L on ≥ 8 of the last 12 weeks of main treatment without rescue medication. From 22 March2018 to 31 January2023, 26 patients were enrolled. Patients had baseline median platelet count 13 × 10[9]/L, ITP duration 10.3 years, and six prior ITP therapies (46% splenectomized). Nine (35%) patients achieved the primary endpoint. Platelet counts ≥ 50 × 10[9]/L or ≥ 30 × 10[9]/L and doubling from baseline without rescue therapy were sustained for a mean 9.3 weeks. 11 (42%) LTE-eligible patients were ongoing with median LTE platelet > 80 × 10[9]/L. Three (12%) patients received rescue medication during main treatment, none in LTE. Clinically meaningful improvements were observed in fatigue and women's health. With a median treatment duration of 167 days (main treatment), 16 (62%) patients had ≥ 1 treatment-related adverse event (AE), mainly grade 1, including diarrhea (35%), headache (23%), and nausea (15%). There was no treatment-related grade ≥ 2 bleeding/thrombotic events/infections, serious AE, or death. Rilzabrutinib continues to demonstrate durable platelet responses with favorable safety profile in previously treated ITP patients. Trial Registration: NCT03395210, EudraCT 2017-004012-19.}, }
@article {pmid39844041, year = {2025}, author = {Crisp, AM and Halloran, ME and Hitchings, MDT and Longini, IM and Dean, NE}, title = {Analysis methods for covariate-constrained cluster randomized trials with time-to-event outcomes.}, journal = {BMC medical research methodology}, volume = {25}, number = {1}, pages = {16}, pmid = {39844041}, issn = {1471-2288}, support = {U01-AI148069/NH/NIH HHS/United States ; U01-AI148069/NH/NIH HHS/United States ; U01-AI148069/NH/NIH HHS/United States ; U01-AI148069/NH/NIH HHS/United States ; U01-AI148069//National Institute of Allergy and Infectious Diseases/ ; U01-AI148069//National Institute of Allergy and Infectious Diseases/ ; U01-AI148069//National Institute of Allergy and Infectious Diseases/ ; U01-AI148069//National Institute of Allergy and Infectious Diseases/ ; }, mesh = {Humans ; *Randomized Controlled Trials as Topic/methods/statistics &amp; numerical data ; Cluster Analysis ; *Proportional Hazards Models ; Mexico ; Child ; Computer Simulation ; }, abstract = {BACKGROUND: Cluster randomized trials, which often enroll a small number of clusters, can benefit from constrained randomization, selecting a final randomization scheme from a set of known, balanced randomizations. Previous literature has addressed the suitability of adjusting the analysis for the covariates that were balanced in the design phase when the outcome is continuous or binary. Here we extended this work to time-to-event outcomes by comparing two model-based tests and a newly derived permutation test. A current cluster randomized trial of vector control for the prevention of mosquito-borne disease in children in Mexico is used as a motivating example.<br><br>METHODS: We assessed type I error rates and power between simple randomization and constrained randomization using both prognostic and non-prognostic covariates via a simulation study. We compared the performance of a semi-parametric Cox proportional hazards model with robust variance, a mixed effects Cox model, and a permutation test utilizing deviance residuals.<br><br>RESULTS: The permutation test generally maintained nominal type I error-with the exception of the unadjusted analysis for constrained randomization-and also provided power comparable to the two Cox model-based tests. The model-based tests had inflated type I error when there were very few clusters per trial arm. All three methods performed well when there were 25 clusters per trial arm, as in the case of the motivating example.<br><br>CONCLUSION: For time-to-event outcomes, covariate-constrained randomization was shown to improve power relative to simple randomization. The permutation test developed here was more robust to inflation of type I error compared to model-based tests. Gaining power by adjusting for covariates in the analysis phase was largely dependent on the number of clusters per trial arm.}, }
@article {pmid39841165, year = {2025}, author = {Peters, BA and Xue, X and Hanna, DB and Wang, Y and Wang, Z and Sharma, A and Floris-Moore, M and Konkle-Parker, D and Alcaide, ML and Sheth, AN and Topper, EF and Weber, KM and Tien, PC and Merenstein, D and Vásquez, E and Chen, Y and Mimiaga, MJ and Stosor, V and Brown, TT and Erlandson, KM and Dillon, SM and Elsayed, NS and Usyk, M and Sollecito, CC and Kaplan, RC and Burk, RD and Qi, Q}, title = {Healthy Aging and the Gut Microbiome in People With and Without HIV.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiae644}, pmid = {39841165}, issn = {1537-6613}, support = {U01-HL146241/HL/NHLBI NIH HHS/United States ; //Eunice Kennedy Shriver/ ; //National Institute of Child Health and Human Development/ ; /AG/NIA NIH HHS/United States ; /DE/NIDCR NIH HHS/United States ; //National Institute of Allergy and Infectious Diseases/ ; /NS/NINDS NIH HHS/United States ; /MH/NIMH NIH HHS/United States ; /DA/NIDA NIH HHS/United States ; /NR/NINR NIH HHS/United States ; /CA/NCI NIH HHS/United States ; /AA/NIAAA NIH HHS/United States ; /DC/NIDCD NIH HHS/United States ; /DK/NIDDK NIH HHS/United States ; /MD/NIMHD NIH HHS/United States ; /NH/NIH HHS/United States ; UL1 -TR000004//Office of AIDS Research/ ; }, abstract = {BACKGROUND: Aging-related comorbidities are more common in people with human immunodeficiency virus (HIV) compared to people without HIV. The gut microbiome may play a role in healthy aging; however, this relationship remains unexplored in the context of HIV.<br><br>METHODS: 16S rRNA gene sequencing was conducted on stool from 1409 women (69% with HIV; 2304 samples) and 990 men (54% with HIV; 1008 samples) in the MACS/WIHS Combined Cohort Study. Associations of age with gut microbiome diversity, uniqueness, and genus-level abundance were examined in women and men separately, followed by examining relationships of aging-related genera with frailty (Fried frailty phenotype) and mortality risk (Veterans Aging Cohort Study [VACS] index).<br><br>RESULTS: Older age was associated with greater microbiome diversity and uniqueness, greater abundance of Akkermansia and Streptococcus, and lower abundance of Prevotella and Faecalibacterium, among others; findings were generally consistent by sex and HIV status. An aging-related microbiome score, generated via combination of 18 age-related genera, significantly increased with age in both women and men independently of demographic, behavioral, and cardiometabolic factors. In general, age was more strongly related to microbiome features (eg, diversity, microbiome score) in men without compared to with HIV, but age-microbiome associations were similar in women with and without HIV. Some age-related genera associated with healthy/unhealthy aging, such as Faecalibacterium (related to reduced frailty) and Streptococcus (related to higher VACS index).<br><br>CONCLUSIONS: Age is associated with consistent changes in the gut microbiome in both women and men with or without HIV. Some aging-related microbiota are associated with aging-related declines in health.}, }
@article {pmid39838067, year = {2025}, author = {Haseli, S and Park, C and Azhideh, A and Karande, G and Chalian, M}, title = {Performance and reliability comparison: original vs. revised bone reporting and data system (Bone-RADS).}, journal = {Skeletal radiology}, volume = {}, number = {}, pages = {}, pmid = {39838067}, issn = {1432-2161}, abstract = {OBJECTIVE: To propose a revised bone reporting and data system (Bone-RADS) and evaluate its diagnostic performance and inter-reader reliability compared to the original Bone-RADS for solitary bone lesions on CT.<br><br>MATERIALS AND METHODS: This retrospective study included 159 adult patients (mean age: 56&#x2009;&#xb1;&#x2009;19&#xa0;years; 88 men) who underwent bone biopsy for solitary bone lesions between March 2005 and September 2021. Two radiologists (R1/2) independently categorized the lesions twice, once using the original Bone-RADS and once using the revised version. Lesions were classified as follows: (1, benign; 2, incompletely assessed; 3, indeterminate; 4, malignancy or requiring treatment). The revised Bone-RADS excluded the original criteria for lesion related pain and history of malignancy. Diagnostic performance was assessed using histopathology as the reference standard, and inter-reader reliability was analyzed.<br><br>RESULTS: The bone lesions included 96 lucent and 63 sclerotic/mixed lesions. Sensitivity showed no significant difference between the original and revised Bone-RADS for both readers across lucent and sclerotic/mixed lesions (all P&#x2009;&#x2265;&#x2009;.05). However, the specificity of the revised Bone-RADS was significantly higher than that of the original (lucent: 11% vs. 50% [R1], 11% vs. 46% [R2]; sclerotic/mixed: 32% vs. 92% [R1], 32% vs. 86% [R2]). Other performance metrics, including positive/negative predictive value and accuracy, were also higher in the revised Bone-RADS. Inter-reader reliability was higher for the revised Bone-RADS compared to the original (&#x3ba;&#x2009;=&#x2009;.744 vs .854).<br><br>CONCLUSION: The revised Bone-RADS significantly improved specificity while maintaining sensitivity compared to the original version.}, }
@article {pmid39834946, year = {2024}, author = {O'Halloran, K and Crotty, EE and Christodoulou, E and Leary, SE and Miller, A and Paulson, VA and Lockwood, CM and Margol, AS and Biegel, JA}, title = {Targeted detection of sequence variants in cell-free DNA from cerebrospinal fluid in pediatric central nervous system tumors.}, journal = {Frontiers in oncology}, volume = {14}, number = {}, pages = {1513073}, pmid = {39834946}, issn = {2234-943X}, abstract = {The emergence of liquid biopsy technologies holds great promise in the cancer setting, including in pediatric central nervous system (CNS) tumors. In contrast to broad lower-depth sequencing, commonly referred to as low pass whole genome sequencing (WGS), targeted platforms with a higher depth of coverage have also been established. Here, we review targeted liquid biopsy techniques with applicability to pediatric CNS tumors. These include polymerase chain reaction (PCR), both droplet digital PCR and reverse transcription-based PCR, Sanger sequencing, and next-generation sequencing approaches that incorporate amplicon- and hybrid capture-based methods. The goal of this paper is to facilitate an understanding of these targeted techniques and provide a context for clinical relevance within disease categories, as well as a discussion on optimizing real-world implementation for pediatric CNS tumors.}, }
@article {pmid39831734, year = {2025}, author = {Moussa, MJ and Tabet, GC and Siefker-Radtke, AO and Xiao, L and Wilson, NR and Gao, J and Logothetis, CJ and Grivas, P and Lee, B and Shah, AY and Msaouel, P and Li, R and Clemente, LC and Zhao, J and Tannir, NM and Kamat, AM and Hansel, DE and Guo, CC and Campbell, MT and Alhalabi, O}, title = {Histopathologic Progression and Metastatic Relapse Outcomes in Small Cell Neuroendocrine Carcinomas of the Urinary Tract.}, journal = {Cancer medicine}, volume = {14}, number = {2}, pages = {e70594}, pmid = {39831734}, issn = {2045-7634}, support = {//Ingram Family Fund/ ; }, mesh = {Humans ; Male ; Female ; *Carcinoma, Neuroendocrine/pathology/therapy/drug therapy/surgery ; Aged ; Middle Aged ; *Neoplasm Recurrence, Local/pathology ; *Carcinoma, Small Cell/pathology/therapy ; Disease Progression ; Urologic Neoplasms/pathology/therapy/mortality ; Neoadjuvant Therapy ; Prognosis ; Adult ; Retrospective Studies ; Aged, 80 and over ; }, abstract = {INTRODUCTION: Small cell neuroendocrine carcinoma of the urinary tract (SCNEC-URO) has an inferior prognosis compared to conventional urothelial carcinoma (UC). Here, we evaluate the predictors and patterns of relapse after surgery.<br><br>MATERIALS AND METHODS: We identified a definitive-surgery cohort (n&#x2009;=&#x2009;224) from an institutional database of patients with cT1-T4NxM0 SCNEC-URO treated in 1985-2021. Histopathologic review was conducted by independent pathologists. Relapse event was the time-to-event outcome, and relapse probabilities were estimated using a competing risk method with cumulative incidence functions (CIFs). Fine-Gray distribution models assessed covariate associations.<br><br>RESULTS: Most patients (161, 71.9%) received neoadjuvant chemotherapy (neoCTX). Ninety two (41%) patients had relapse with 77 (83.7%) having distant organs as first metastatic sites, including 10 (10.9%) with exclusive central nervous system (CNS) metastases, mostly (9/10) within 1&#x2009;year of surgery. Patients with pathologic complete response (pCR) after neoCTx had the lowest 5-year CIF (16.5% [95% CI 9.3%-25.6%]). Patients with remaining exclusively small cell (SC) histology had the highest CIF (85.7% [95% CI 46.6-96.9]). Patients with eradicated SCNEC but remaining UC components had an intermediate-risk CIF (32.5% [95% CI 18.6-47.2]). Multivariable analysis adjusting for neoCTx, clinical stage at diagnosis (T3/4, N0/N+ vs. T1/T2, N0), and pathologic stage (pN+ vs. pN0) demonstrated that any SCNEC histology at resection (vs. pCR) was associated with relapse risk (hazard ratio&#x2009;=&#x2009;3.69 [95% CI 1.91-7.13], p&#x2009;=&#x2009;0.0001).<br><br>CONCLUSIONS: SCNEC-URO is a systemic disease with high risk of distant relapse including CNS. Our findings highlight unmet needs for neoadjuvant/adjuvant approaches targeting the rare SCNEC subtype and suggest adding CNS surveillance within the first year after definitive surgery to high-risk patients. PR&#xc9;CIS (CONDENSED ABSTRACT): Alongside neoadjuvant chemotherapy and cancer stage, histology at resection strongly impacts relapse risk in small cell neuroendocrine carcinomas of the urinary tract. The incidence of brain metastasis is notably higher than in "traditional" urothelial cancer within the first year after surgery, especially if small cell cancer persists, thus necessitating close neurological monitoring during this period.}, }
@article {pmid39831552, year = {2025}, author = {Lichauco, C and Foss, EJ and Gatbonton-Schwager, T and Athow, NF and Lofts, B and Acob, R and Taylor, E and Marquez, JJ and Lao, U and Miles, S and Bedalov, A}, title = {Sir2 and Fun30 regulate ribosomal DNA replication timing via MCM helicase positioning and nucleosome occupancy.}, journal = {eLife}, volume = {13}, number = {}, pages = {}, pmid = {39831552}, issn = {2050-084X}, support = {R01GM117446/NH/NIH HHS/United States ; }, mesh = {*Silent Information Regulator Proteins, Saccharomyces cerevisiae/metabolism/genetics ; *Saccharomyces cerevisiae Proteins/metabolism/genetics ; *Sirtuin 2/metabolism/genetics ; *Saccharomyces cerevisiae/genetics/metabolism ; *Nucleosomes/metabolism ; *DNA, Ribosomal/genetics/metabolism ; DNA Replication Timing ; Transcription Factors/metabolism/genetics ; DNA Replication ; DNA Helicases/metabolism/genetics ; Gene Expression Regulation, Fungal ; }, abstract = {The association between late replication timing and low transcription rates in eukaryotic heterochromatin is well known, yet the specific mechanisms underlying this link remain uncertain. In Saccharomyces cerevisiae, the histone deacetylase Sir2 is required for both transcriptional silencing and late replication at the repetitive ribosomal DNA (rDNA) arrays. We have previously reported that in the absence of SIR2, a de-repressed RNA PolII repositions MCM replicative helicases from their loading site at the ribosomal origin, where they abut well-positioned, high-occupancy nucleosomes, to an adjacent region with lower nucleosome occupancy. By developing a method that can distinguish activation of closely spaced MCM complexes, here we show that the displaced MCMs at rDNA origins have increased firing propensity compared to the nondisplaced MCMs. Furthermore, we found that both activation of the repositioned MCMs and low occupancy of the adjacent nucleosomes critically depend on the chromatin remodeling activity of FUN30. Our study elucidates the mechanism by which Sir2 delays replication timing, and it demonstrates, for the first time, that activation of a specific replication origin in vivo relies on the nucleosome context shaped by a single chromatin remodeler.}, }
@article {pmid39830606, year = {2025}, author = {Adsul, P and Sanchez-Youngman, S and Dickson, E and Jacquez, B and Kuhlemeier, A and Muhammad, M and Briant, KJ and Hempstead, B and Mendoza, JA and Rosas, LG and Patel, A and Rodriguez Espinosa, P and Akintobi, T and Castro-Reyes, P and Carter-Edwards, L and Wallerstein, N}, title = {Assessing the context within academic health institutions toward improving equity-based, community and patient-engaged research.}, journal = {Journal of clinical and translational science}, volume = {9}, number = {1}, pages = {e6}, pmid = {39830606}, issn = {2059-8661}, abstract = {INTRODUCTION: The continued momentum toward equity-based, patient/community-engaged research (P/CenR) is pushing health sciences to embrace principles of community-based participatory research. Much of this progress has hinged on individual patient/community-academic partnered research projects and partnerships with minimal institutional support from their academic health institutions.<br><br>METHODS: We partnered with three academic health institutions and used mixed methods (i.e., institution-wide survey (n = 99); qualitative interviews with institutional leadership (n = 11); and focus group discussions (6 focus groups with patients and community members (n = 22); and researchers and research staff (n = 9)) to gain a deeper understanding of the institutional context.<br><br>RESULTS: Five key themes emerged that were supported by quantitative data. First, the global pandemic and national events highlighting social injustices sparked a focus on health equity in academic institutions; however, (theme 2) such a focus did not always translate to support for P/CenR nor align with institutional reputation. Only 52% of academics and 79% of community partners believed that the institution is acting on the commitment to health equity (&#x3a7;[2] = 6.466, p < 0.05). Third, institutional structures created power imbalances and community mistrust which were identified as key barriers to P/CenR. Fourth, participants reported that institutional resources and investments are necessary for recruitment and retention of community-engaged researchers. Finally, despite challenges, participants were motivated to transform current paradigms of research and noted that accountability, communication, and training were key facilitators.<br><br>CONCLUSIONS: Triangulating findings from this mixed-methods study revealed critical barriers which provide important targets for interventions to improving supportive policies and practices toward equity-based P/CenR.}, }
@article {pmid39828431, year = {2025}, author = {Begnel, ER and Ojee, E and Adhiambo, J and Mabele, E and Wandika, B and Ogweno, V and Lim, ES and Gantt, S and Kinuthia, J and Lehman, DA and Slyker, J and Wamalwa, D}, title = {The Linda Kizazi study: a comparison of morbidity and mortality from birth to 2 years between children who are HIV-unexposed and HIV-exposed, uninfected in the era of universal antiretroviral therapy.}, journal = {BMJ global health}, volume = {10}, number = {1}, pages = {}, pmid = {39828431}, issn = {2059-7908}, support = {R01 HD092311/HD/NICHD NIH HHS/United States ; }, mesh = {Humans ; *HIV Infections/drug therapy/mortality/epidemiology ; Female ; Infant ; Kenya/epidemiology ; Infant, Newborn ; Pregnancy ; Male ; Adult ; Child, Preschool ; Malaria/mortality/drug therapy/epidemiology ; Cohort Studies ; Diarrhea/epidemiology/mortality ; Respiratory Tract Infections/mortality/epidemiology ; Hospitalization/statistics &amp; numerical data ; Morbidity ; Pregnancy Complications, Infectious/drug therapy/epidemiology ; Anti-Retroviral Agents/therapeutic use ; }, abstract = {BACKGROUND: Historically, children who are HIV-exposed, uninfected (CHEU) have been found to have greater morbidity and mortality than children who are HIV-unexposed, uninfected (CHUU). To assess whether this difference persists in the era of universal antiretroviral therapy (ART), we conducted a cohort study to compare the risk of acute diarrhoea, respiratory tract infections (RTI), malaria, hospitalisation, and all-cause mortality between Kenyan CHEU and CHUU from birth to 2 years.<br><br>METHODS: From December 2018 to March 2020 at Mathare North Health Centre in Nairobi, we recruited pregnant women living with HIV on ART for &#x2265;6 months and pregnant women without HIV from the same community. We followed the mother-infant pairs for 2 years post partum and collected data on symptoms of illness, clinical visits and diagnoses, and infant feeding every 3 months; a self-selected subset of participants also received weekly data collection for up to 1 year. We compared the risk of each outcome between CHEU versus CHUU using HRs from Andersen-Gill (recurrent morbidity outcomes) and Cox proportional hazards (mortality) regression models adjusted for maternal age, marital status and education level.<br><br>RESULTS: Among 187 mother-infant pairs with postpartum data, 86 (46%) infants were CHEU and 101 (54%) were CHUU. All initiated breastfeeding, and 88% of CHEU and 57% of CHUU were exclusively breastfed (EBF) for &#x2265;6 months. There was no significant difference in risk of diarrhoea (HR=0.79, 95% CI 0.52 to 1.22), malaria (HR=0.44, 95%&#x2009;CI 0.16 to 1.21), hospitalisation (HR=1.11, 95%&#x2009;CI 0.30 to 4.14), or mortality (HR=1.87, 95%&#x2009;CI 0.17 to 20.5). However, CHEU had lower risk of any RTI (HR=0.60, 95%&#x2009;CI 0.44 to 0.82) and pneumonia (HR=0.29, 95%&#x2009;CI 0.091 to 0.89).<br><br>CONCLUSIONS: CHEU born to women on effective long-term ART experienced similar overall morbidity and mortality as CHUU. However, CHEU had substantially lower risk of pneumonia and other RTI, possibly due to longer EBF in this group.}, }
@article {pmid39827422, year = {2025}, author = {Sierra, J and de León, UA and Padilla-Longoria, P}, title = {Tumor microenvironment noise-induced polarization: the main challenge in macrophages' immunotherapy for cancer.}, journal = {Molecular and cellular biochemistry}, volume = {}, number = {}, pages = {}, pmid = {39827422}, issn = {1573-4919}, abstract = {Disturbance of epigenetic processes can lead to altered gene function and malignant cellular transformation. In particular, changes in the epigenetic landscape are a central topic in cancer biology. The initiation and progression of cancer are now recognized to involve both epigenetic and genetic alterations. In this paper, we study the epigenetic mechanism (related to the tumor microenvironment) responsible for increasing tumor-associated macrophages that promote the occurrence and metastasis of tumor cells, support tumor angiogenesis, inhibit T-cell-mediated anti-tumor immune response, and lead to tumor progression. We show that the tumor benefits from the macrophages' high degree of plasticity and larger epigenetic basins corresponding to phenotypes that favor cancer development through a process that we call noise-induced polarization. Moreover, we propose a mechanism to promote the appropriate epigenetic stability for immunotherapies involving macrophages, which includes p53 and APR-246 (eprenetapopt). Our results show that a combination therapy may be necessary to ensure the proper epigenetic stability of macrophages, which otherwise will contribute to cancer progression. On the other hand, we conclude that macrophages may remain in the anti-tumoral state in types of cancer that exhibit less TP53 mutation, like colorectal cancer; in these cases, macrophages' immunotherapy may be more suitable. We finally mention the relevance of the epigenetic potential (Waddington's landscape) as the backbone for our study, which encapsulates the biological information of the system.}, }
@article {pmid39826256, year = {2025}, author = {Lim, FY and Lea, HG and Dostie, AM and Kim, SY and van Neel, TL and Hassan, GW and Takezawa, MG and Starita, LM and Adams, KN and Boeckh, M and Schiffer, JT and Hyrien, O and Waghmare, A and Berthier, E and Theberge, AB}, title = {homeRNA self-blood collection enables high-frequency temporal profiling of presymptomatic host immune kinetics to respiratory viral infection: a prospective cohort study.}, journal = {EBioMedicine}, volume = {112}, number = {}, pages = {105531}, doi = {10.1016/j.ebiom.2024.105531}, pmid = {39826256}, issn = {2352-3964}, abstract = {BACKGROUND: Early host immunity to acute respiratory infections (ARIs) is heterogenous, dynamic, and critical to an individual's infection outcome. Due to limitations in sampling frequency/timepoints, kinetics of early immune dynamics in natural human infections remain poorly understood. In this nationwide prospective cohort study, we leveraged a Tasso-SST based self-blood collection and stabilization tool (homeRNA) to profile detailed kinetics of the presymptomatic to convalescence host immunity to contemporaneous respiratory pathogens.<br><br>METHODS: We enrolled non-symptomatic adults with recent exposure to ARIs who subsequently tested negative (exposed-uninfected) or positive for respiratory pathogens. Participants self-collected blood and nasal swabs daily for seven consecutive days followed by weekly blood collection for up to seven additional weeks. Symptom burden was assessed during each collection. Nasal swabs were tested for SARS-CoV-2 and common respiratory pathogens. 92 longitudinal blood samples spanning the presymptomatic to convalescence phase of eight participants with SARS-CoV-2 infection and 40 interval-matched samples from four exposed-uninfected participants were subjected to high-frequency longitudinal profiling of 785 immune genes. Generalized additive mixed models (GAMM) were used to identify temporally dynamic genes from the longitudinal samples and linear mixed models (LMM) were used to identify baseline differences between exposed-infected (n&#xa0;=&#xa0;8), exposed-uninfected (n&#xa0;=&#xa0;4), and uninfected (n&#xa0;=&#xa0;13) participant groups.<br><br>FINDINGS: Between June 2021 and April 2022, 68 participants across 26 U.S. states completed the study and self-collected a total of 691 and 466 longitudinal blood and nasal swab samples along with 688 symptom surveys. SARS-CoV-2 was detected in 17 out of 22 individuals with study-confirmed respiratory infection, of which five were still presymptomatic or pre-shedding, enabling us to profile detailed expression kinetics of the earliest blood transcriptional response to contemporaneous variants of concern. 51% of the genes assessed were found to be temporally dynamic during COVID-19 infection. During the pre-shedding phase, a robust but transient response consisting of genes involved in cell migration, stress response, and T cell activation were observed. This is followed by a rapid induction of many interferon-stimulated genes (ISGs), concurrent to onset of viral shedding and increase in nasal viral load and symptom burden. Finally, elevated baseline expression of antimicrobial peptides was observed in exposed-uninfected individuals.<br><br>INTERPRETATION: We demonstrated that unsupervised self-collection and stabilization of capillary blood can be applied to natural infection studies to characterize detailed early host immune kinetics at a temporal resolution comparable to that of human challenge studies. The remote (decentralized) study framework enables conduct of large-scale population-wide longitudinal mechanistic studies.<br><br>FUNDING: This study was funded by R35GM128648 to ABT for in-lab developments of homeRNA and data analysis, a Packard Fellowship for Science and Engineering from the David and Lucile Packard Foundation to ABT for the study execution, sample collection, and analysis, and R01AI153087 to AW for data analysis.}, }
@article {pmid39826253, year = {2025}, author = {Montaño, MA and Jatho, A and Nassolo, C and Mugisha, N and Bula, A and Chagomerana, MB and Borok, M and Mtisi, TJ and Joffe, M and Bender Ignacio, RA and Ndlovu, N}, title = {Healthcare provider perspectives on integrating HIV care into cancer centers in Malawi, South Africa, Uganda, and Zimbabwe.}, journal = {Translational oncology}, volume = {53}, number = {}, pages = {102273}, doi = {10.1016/j.tranon.2025.102273}, pmid = {39826253}, issn = {1936-5233}, abstract = {BACKGROUND: In East and Southern Africa, treatment of people with concomitant cancer and HIV is complicated by siloed service delivery pathways, which exacerbate barriers to care and impact clinical decision-making. Integrating HIV care into cancer treatment centers may improve service delivery and overall patient outcomes.<br><br>METHODS: We administered a questionnaire to clinicians and support staff at tertiary cancer referral centers in Malawi, Zimbabwe, Uganda, and South Africa to assess level of concern about clinical management of people with HIV (PWH) and cancer, barriers to integrating HIV service delivery into cancer treatment delivery, and beliefs related to HIV, antiretroviral therapy (ART), and integrated care.<br><br>RESULTS: Of 195 clinician and support staff participants, 165 (85 %) were direct providers of cancer-associated care. Over 50 % indicated that they held concerns about survival, treatment complications, co-morbidities, and drug-drug interactions in PWH compared to patients without HIV. Over 80 % agreed that knowing cancer patients' HIV status, ART status, and ART regimen would facilitate better care and should be considered in cancer care decision-making. Overall, respondents were optimistic that HIV-related care could be easily integrated into cancer care provision. The most-frequently endorsed barriers to integrated care were workspace limitations, disruptions to workflow, availability of staff, and cost to the hospital and to patients.<br><br>CONCLUSIONS: Cancer clinicians and support staff report overall positive attitudes toward integrating HIV and cancer service delivery. Research to elucidate service delivery pathways and contextualize system-based barriers to integrating care are critical next steps to optimize linked HIV and cancer care delivery.}, }
@article {pmid39825826, year = {2025}, author = {Mughal, TI and Mascarenhas, J and Rampal, RK and Bose, P and Lion, T and Ajufo, H and Yacoub, A and Meshinchi, S and Masarova, L and Mesa, R and Jamieson, C and Barbui, T and Saglio, G and Van Etten, RA}, title = {Impact of Recent Translational and Therapeutic Developments on Clinical Course of BCR::ABL1-Positive and -Negative Myeloproliferative Neoplasms.}, journal = {Hematological oncology}, volume = {43}, number = {1}, pages = {e70013}, doi = {10.1002/hon.70013}, pmid = {39825826}, issn = {1099-1069}, support = {//Alpine Oncology Foundation/ ; }, mesh = {Humans ; *Myeloproliferative Disorders/therapy/genetics/diagnosis/metabolism/drug therapy ; Protein Kinase Inhibitors/therapeutic use ; Proto-Oncogene Proteins c-abl/genetics/metabolism ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy/genetics/drug therapy/pathology ; Fusion Proteins, bcr-abl/genetics/antagonists &amp; inhibitors ; }, abstract = {Despite the study of BCR::ABL1-positive and -negative myeloproliferative neoplasms (MPNs) providing seminal insights into cancer biology, tumor evolution and precision oncology over the past half century, significant challenges remain. MPNs are clonal hematopoietic stem cell-derived neoplasms with heterogenous clinical phenotypes and a clonal architecture which impacts the often-complex underlying genetics and microenvironment. The major driving molecular abnormalities have been well characterized, but debate on their role as disease-initiating molecular lesions continues. The introduction of the ABL1 tyrosine kinase inhibitors have been extremely successful in the treatment of chronic myeloid leukemia with most patients having a near-normal life expectancy. Similar success has, however, not been achieved for BCR::ABL1-negative MPNs in terms of disease course modification and most patients remain incurable. In both disease categories, genomic instability seems to increase the risk of disease progression to accelerated/blast phase, which is resistant/refractory to conventional treatment and associated with a poor prognosis. To address some of these issues, the late John Goldman and Tariq Mughal founded a scientific and clinical platform in 2006, the Post-American Society of Hematology (ASH) MPN workshop, to appraise novel cancer biology, candidate therapeutic targets, treatments and other clinical challenges and pay tribute to all the many scientists and clinicians around the world instrumental to the progress made and continuing advances being made. This paper summarizes some of the recent data discussed at the 18[th] edition of the workshop and includes reference to some data presented or published after the workshop, including the 26[th] John Goldman CML conference.}, }
@article {pmid39825500, year = {2025}, author = {Prizment, A and Standafer, A and Qu, C and Beutel, KM and Wang, S and Huang, WY and Lindblom, A and Pearlman, R and Van Guelpen, B and Wolk, A and Buchanan, DD and Grant, RC and Schmit, SL and Platz, EA and Joshu, CE and Couper, DJ and Peters, U and Starr, TK and Scott, P and Pankratz, N}, title = {Functional variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are associated with increased risk of colorectal cancer.}, journal = {Human molecular genetics}, volume = {}, number = {}, pages = {}, doi = {10.1093/hmg/ddaf007}, pmid = {39825500}, issn = {1460-2083}, support = {/NH/NIH HHS/United States ; R21CA256749/CA/NCI NIH HHS/United States ; //University of Minnesota Academic Health Center/ ; //Whiteside Institute for Clinical Research/ ; }, abstract = {BACKGROUND: Individuals with cystic fibrosis (CF; a recessive disorder) have an increased risk of colorectal cancer (CRC). Evidence suggests individuals with a single CFTR variant may also have increased CRC risk.<br><br>METHODS: Using population-based studies (GECCO, CORECT, CCFR, and ARIC; 53&#x2009;785 CRC cases and 58&#x2009;010 controls), we tested for an association between the most common CFTR variant (Phe508del) and CRC risk. For replication, we used whole exome sequencing data from UK Biobank (UKB; 5126 cases and 20&#x2009;504 controls matched 4:1 based on genetic distance, age, and sex), and extended our analyses to all other heterozygous CFTR variants annotated as CF-causing.<br><br>RESULTS: In our meta-analysis of GECCO-CORECT-CCFR-ARIC, the odds ratio (OR) for CRC risk associated with Phe508del was 1.11 (P&#x2009;=&#x2009;0.010). In our UKB replication, the OR for CRC risk associated with Phe508del was 1.28 (P&#x2009;=&#x2009;0.002). The sequencing data from UKB also revealed an association between the presence of any other single CF-causing variant (excluding Phe508del) and CRC risk (OR&#x2009;=&#x2009;1.33; P&#x2009;=&#x2009;0.030). When stratifying CFTR variants by functional class, class I variants (no protein produced) had a stronger association (OR&#x2009;=&#x2009;1.77; p&#x2009;=&#x2009;0.002), while class II variants (misfolding and retention of the protein in the endoplasmic reticulum) other than Phe508del (OR&#x2009;=&#x2009;1.75; p&#x2009;=&#x2009;0.107) had similar effect size as Phe508del, and variants in classes III-VI had non-significant ORs less than 1.0 and/or were not present in cases.<br><br>CONCLUSIONS: CF-causing heterozygous variants, especially class I variants, are associated with a modest but statistically significant increased CRC risk. More research is needed to explain the biology underlying these associations.}, }
@article {pmid39819674, year = {2025}, author = {Bordeaux, J and Blitzblau, R and Aasi, SZ and Alam, M and Amini, A and Bibee, K and Bolotin, D and Chen, PL and Contreras, CM and DiMaio, D and Donigan, JM and Farma, JM and Ghosh, K and Harms, K and LeBoeuf, N and Lukens, JN and Manber, S and Mark, L and Medina, T and Nehal, KS and Nghiem, P and Olino, K and Paragh, G and Park, S and Patel, T and Rich, J and Shaha, AR and Sharma, B and Sokumbi, Y and Srivastava, D and Thomas, V and Tomblinson, C and Venkat, P and Xu, YG and Yu, S and Yusuf, M and McCullough, B and Espinosa, S}, title = {Dermatofibrosarcoma Protuberans, Version 1.2025, NCCN Clinical Practice Guidelines In Oncology.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {23}, number = {1}, pages = {}, doi = {10.6004/jnccn.2025.0001}, pmid = {39819674}, issn = {1540-1413}, mesh = {*Dermatofibrosarcoma/therapy/diagnosis/pathology ; Humans ; *Skin Neoplasms/therapy/diagnosis/pathology ; Medical Oncology/standards/methods ; Combined Modality Therapy/methods ; Neoplasm Recurrence, Local/therapy ; }, abstract = {Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous soft tissue sarcoma and affects an estimated 1,500 people annually in the United States. DFSP frequently exhibits extensive local infiltration. Initial treatment is through surgical excision, and care should be taken to ensure that negative margins are achieved to minimize recurrence. Although DFSP has a reported high rate of recurrence, metastasis is more uncommon. Fibrosarcomatous DFSP is an aggressive variant with an increased risk for local recurrence and metastasis. If achieving negative margins or resection is not feasible, radiation therapy or systemic treatment are options that may be considered by a multidisciplinary team. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) outline recommended treatment options available for DFSP.}, }
@article {pmid39819601, year = {2025}, author = {Wood, DE and Kazerooni, EA and Aberle, DR and Argento, C and Baines, J and Boer, B and Brown, LM and Donington, J and Eapen, GA and Ferguson, JS and Hou, L and Klippenstein, D and Kolansky, AS and Kumar, R and Leard, LE and Leung, ANC and Mazzone, P and Merritt, RE and Norris, K and Onaitis, M and Pipavath, S and Puri, V and Raz, D and Reddy, C and Reid, ME and Sandler, KL and Sands, J and Schabath, MB and Sears, CR and Studts, JL and Tanoue, L and Thacker, AL and Tong, BC and Travis, WD and Wei, B and Westover, K and McCullough, B and Ramakrishnan, S}, title = {NCCN Guidelines® Insights: Lung Cancer Screening, Version 1.2025.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {23}, number = {1}, pages = {}, doi = {10.6004/jnccn.2025.0002}, pmid = {39819601}, issn = {1540-1413}, mesh = {Humans ; *Lung Neoplasms/diagnosis ; *Early Detection of Cancer/standards/methods ; Mass Screening/standards/methods ; }, abstract = {The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Lung Cancer Screening provide criteria for selecting individuals for screening and offer recommendations for evaluating and managing lung nodules detected during initial and subsequent annual screening. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Lung Cancer Screening.}, }
@article {pmid39825152, year = {2025}, author = {Okines, AFC and Curigliano, G and Mizuno, N and Oh, DY and Rorive, A and Soliman, H and Takahashi, S and Bekaii-Saab, T and Burkard, ME and Chung, KY and Debruyne, PR and Fox, JR and Gambardella, V and Gil-Martin, M and Hamilton, EP and Monk, BJ and Nakamura, Y and Nguyen, D and O'Malley, DM and Olawaiye, AB and Pothuri, B and Reck, M and Sudo, K and Sunakawa, Y and Van Marcke, C and Yu, EY and Ramos, J and Tan, S and Bieda, M and Stinchcombe, TE and Pohlmann, PR}, title = {Tucatinib and trastuzumab in HER2-mutated metastatic breast cancer: a phase 2 basket trial.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {39825152}, issn = {1546-170X}, abstract = {Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) signaling promotes cell growth and differentiation, and is overexpressed in several tumor types, including breast, gastric and colorectal cancer. HER2-targeted therapies have shown clinical activity against these tumor types, resulting in regulatory approvals. However, the efficacy of HER2 therapies in tumors with HER2 mutations has not been widely investigated. SGNTUC-019 is an open-label, phase 2 basket study evaluating tucatinib, a HER2-targeted tyrosine kinase inhibitor, in combination with trastuzumab in patients with HER2-altered solid tumors. The study included a cohort of 31 heavily pretreated female patients with HER2-mutated metastatic breast cancer who were also HER2 negative per local testing. Hormone receptor (HR)-positive patients also received fulvestrant. The overall response rate (primary endpoint) was 41.9% (90% confidence interval (CI): 26.9-58.2). Secondary endpoints of duration of response and progression-free survival were 12.6 months (90% CI: 4.7 to not estimable) and 9.5 months (90% CI: 5.4-13.8), respectively. No new safety signals were detected. Responses were observed across various HER2 mutations, including mutations in the tyrosine kinase and extracellular domains. The chemotherapy-free regimen of tucatinib and trastuzumab showed clinically meaningful antitumor activity with durable responses and favorable tolerability in heavily pretreated patients with HER2 mutations. These data support further investigation of HER2-targeted therapies in this patient population. ClinicalTrials.gov registration: NCT04579380 .}, }
@article {pmid39824819, year = {2025}, author = {Zhang, B and Fong, Y and Dang, L and Fintzi, J and Chen, S and Wang, J and Rouphael, NG and Branche, AR and Diemert, DJ and Falsey, AR and Graciaa, DS and Baden, LR and Frey, SE and Whitaker, JA and Little, SJ and Kamidani, S and Walter, EB and Novak, RM and Rupp, R and Jackson, LA and Yu, C and Magaret, CA and Molitor, C and Borate, B and Busch, S and Benkeser, D and Netzl, A and Smith, DJ and Babu, TM and Kottkamp, AC and Luetkemeyer, AF and Immergluck, LC and Presti, RM and Bäcker, M and Winokur, PL and Mahgoub, SM and Goepfert, PA and Fusco, DN and Atmar, RL and Posavad, CM and Mu, J and Makowski, M and Makhene, MK and Nayak, SU and Roberts, PC and Gilbert, PB and Follmann, D and , }, title = {Neutralizing antibody immune correlates in COVAIL trial recipients of an mRNA second COVID-19 vaccine boost.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {759}, pmid = {39824819}, issn = {2041-1723}, support = {contract 75N910D00024, task order 75N91022F00007//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; contract 75N910D00024, task order no. 75N91022F00007//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; 75N93021C00012/AI/NIAID NIH HHS/United States ; UM1AI148684//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; 75N93021C00014/AI/NIAID NIH HHS/United States ; R37AI054165//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; Contract no. 75A50122C00008//U.S. Department of Health &amp; Human Services | Biomedical Advanced Research and Development Authority (BARDA)/ ; 75A50122C00008//U.S. Department of Health &amp; Human Services | Biomedical Advanced Research and Development Authority (BARDA)/ ; 75N93021D00021/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Antibodies, Neutralizing/immunology/blood ; *COVID-19/prevention &amp; control/immunology/virology ; *COVID-19 Vaccines/immunology/administration &amp; dosage ; *SARS-CoV-2/immunology ; *Antibodies, Viral/immunology/blood ; *Immunization, Secondary ; Female ; Male ; Adult ; Middle Aged ; Spike Glycoprotein, Coronavirus/immunology ; mRNA Vaccines/immunology ; }, abstract = {Neutralizing antibody titer has been a surrogate endpoint for guiding COVID-19 vaccine approval and use, although the pandemic's evolution and the introduction of variant-adapted vaccine boosters raise questions as to this surrogate's contemporary performance. For 985 recipients of an mRNA second bivalent or monovalent booster containing various Spike inserts [Prototype (Ancestral), Beta, Delta, and/or Omicron BA.1 or BA.4/5] in the COVAIL trial (NCT05289037), titers against 5 strains were assessed as correlates of risk of symptomatic COVID-19 ("COVID-19") and as correlates of relative (Pfizer-BioNTech Omicron vs. Prototype) booster protection against COVID-19 over 6 months of follow-up during the BA.2-BA.5 Omicron-dominant period. Consistently across the Moderna and Pfizer-BioNTech vaccine platforms and across all variant Spike inserts assessed, both peak and exposure-proximal ("predicted-at-exposure") titers correlated with lower Omicron COVID-19 risk in individuals previously infected with SARS-CoV-2, albeit significantly less so in naïve individuals [e.g., exposure-proximal hazard ratio per 10-fold increase in BA.1 titer 0.74 (95% CI 0.59, 0.94) for naïve vs. 0.41 (95% CI 0.23, 0.64) for non-naïve; interaction p = 0.013]. Neutralizing antibody titer was a strong inverse correlate of Omicron COVID-19 in non-naïve individuals and a weaker correlate in naïve individuals, posing questions about how prior infection alters the neutralization correlate.}, }
@article {pmid39822915, year = {2025}, author = {Cooper, DJ and Karten, J and Hoffe, SE and King, DA and Weiss, M and DePeralta, DK and Coveler, AL and Hingorani, SR and Shefter, T and Meguid, C and Roberts, H and Hong, TS and Narang, A and Hacker-Prietz, A and Fisher, GA and Sandler, J and Singer, L and Korah, B and Hoos, W and Stricker, CT and Herman, JM}, title = {The power of personas: Exploring an innovative model for understanding stakeholder perspectives in an oncology learning health network.}, journal = {Learning health systems}, volume = {9}, number = {1}, pages = {e10422}, pmid = {39822915}, issn = {2379-6146}, abstract = {INTRODUCTION: Learning health networks (LHNs) improve clinical outcomes by applying core tenets of continuous quality improvements (QI) to reach community-defined outcomes, data-sharing, and empowered interdisciplinary teams including patients and caregivers. LHNs provide an ideal environment for the rapid adoption of evidence-based guidelines and translation of research and best practices at scale. When an LHN is established, it is critical to understand the needs of all stakeholders. To accomplish this, we used ethnographic methods to develop personas of different stakeholders within The Canopy Cancer Collective, the first oncology LHN.<br><br>METHODS: We partnered with a firm experienced in qualitative research and human-centered design to conduct interviews with stakeholders of The Canopy Cancer Collective, a newly developed pancreatic cancer LHN. Together with the firm, we developed a personas model approach to represent the wide range of diverse perspectives among the representative stakeholders, which included care team members, patients, and caregivers.<br><br>RESULTS: Thirty-one stakeholders from all facets of pancreatic cancer care were interviewed, including 20 care team members, 8 patients, and 3 caregivers. Interview transcripts were analyzed to construct 10 personas felt to represent the broad spectrum of stakeholders within The Cancer Canopy Collective. These personas were used as a foundation for the design and development of The Cancer Canopy Cancer Collective key drivers and aims.<br><br>CONCLUSIONS: As LHNs continue to facilitate comprehensive approaches to patient-centered care, interdisciplinary teams who understand each other's needs can improve Network unity and cohesion. We present the first model utilizing personas for LHNs, demonstrating this framework holds significant promise for further study. If validated, such an approach could be used as a dynamic foundation for understanding individual stakeholder needs in similar LHN ecosystems in the future.}, }
@article {pmid39820690, year = {2025}, author = {Nascimento de Lima, P and Matrajt, L and Coronado, G and Escaron, AL and Rutter, CM}, title = {Cost-Effectiveness of Noninvasive Colorectal Cancer Screening in Community Clinics.}, journal = {JAMA network open}, volume = {8}, number = {1}, pages = {e2454938}, pmid = {39820690}, issn = {2574-3805}, mesh = {Humans ; *Colorectal Neoplasms/diagnosis/economics ; *Cost-Benefit Analysis ; Middle Aged ; *Early Detection of Cancer/economics/methods/statistics &amp; numerical data ; Female ; Male ; *Colonoscopy/economics/statistics &amp; numerical data ; California ; Occult Blood ; Aged ; Mass Screening/economics/methods ; Quality-Adjusted Life Years ; }, abstract = {IMPORTANCE: Several noninvasive tests for colorectal cancer screening are available, but their effectiveness in settings with low adherence to screening and follow-up colonoscopy is not well documented.<br><br>OBJECTIVE: To assess the cost-effectiveness of and outcomes associated with noninvasive colorectal cancer screening strategies, including new blood-based tests, in a population with low adherence to screening and ongoing surveillance colonoscopy.<br><br>The validated microsimulation model used for the decision analytical modeling study projected screening outcomes from 2025 to 2124 for a simulated cohort of 10 million individuals aged 50 years in 2025 and representative of a predominantly Hispanic or Latino patient population served by a Federally Qualified Health Center in Southern California. The simulated population had low adherence to first-step noninvasive testing (45%), second-step follow-up colonoscopy after an abnormal noninvasive test result (40%), and ongoing surveillance colonoscopy among patients with high-risk findings at follow-up colonoscopy (80%).<br><br>EXPOSURES: Colorectal cancer screening strategies included no screening, an annual or biennial fecal immunochemical test, a triennial multitarget stool DNA test, and a triennial blood-based test. Using a blood-based test was assumed to increase first-step adherence by 17.5 percentage points.<br><br>MAIN OUTCOMES AND MEASURES: Outcomes included colorectal cancer incidence and mortality, life-years gained and quality-adjusted life-years gained relative to no screening, costs, and net monetary benefit assuming a willingness to pay of $100&#x202f;000 per quality-adjusted life-year gained.<br><br>RESULTS: Under realistic adherence assumptions, a program of annual fecal immunochemical testing was the most effective and cost-effective strategy, yielding 121 life-years gained per 1000 screened individuals and a net monetary benefit of $5883 per person. Triennial blood testing was the least effective, yielding 23 life-years gained per 1000, and was not cost-effective, with a negative net monetary benefit. Annual fecal immunochemical testing with 45% first-step adherence and 80% adherence to follow-up and surveillance colonoscopy yielded greater benefit than triennial blood testing with perfect adherence (88 vs 77 life-years gained per 1000).<br><br>CONCLUSIONS AND RELEVANCE: This study suggests that in a federally qualified health care setting, prioritizing the convenience of blood tests over less costly and more effective existing stool-based tests could result in higher costs and worse population-level outcomes. Novel screening modalities should be carefully evaluated for performance in community settings before widespread adoption.}, }
@article {pmid39820359, year = {2025}, author = {Gauthier, J and Liang, EC and Huang, JJ and Kimble, EL and Hirayama, AV and Fiorenza, S and Voutsinas, JM and Wu, QV and Jaeger-Ruckstuhl, CA and Pender, BS and Kirchmeier, DR and Torkelson, A and Braathen, K and Basom, R and Shadman, M and Kopmar, NE and Cassaday, RD and Riddell, SR and Maloney, DG and Turtle, CJ}, title = {Phase I study of CD19 CAR T-cell therapy harboring a fully human scFv in CAR-naïve adult B-ALL patients.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024015314}, pmid = {39820359}, issn = {2473-9537}, abstract = {CD19-directed chimeric antigen receptor-engineered (CD19 CAR) T-cell therapy elicits high response rates but fails to induce durable responses in most adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). In a previous clinical trial (NCT01865617), we observed anti-CAR immune responses associated with impaired in vivo CAR T-cell expansion after second infusions. Because these CD8+ T-cell responses were predominantly directed at peptides derived from the murine single chain variable fragment (scFv) in the CAR, we conducted a clinical trial investigating the safety and efficacy of CD19 CAR T-cells engineered with a CAR incorporating a fully human scFv (JCAR021) in adults with R/R B-ALL (NCT03103971). Twenty-three patients received lymphodepletion chemotherapy and JCAR021 infusion. Nineteen patients developed CRS (any grade, 83%; grade 2, 61%) and 12 developed neurotoxicity (52%; grade ≥3, 35%). The overall response and CR/CRi rates were 82% and 64%, respectively. We observed MRD-negative marrow responses in 82% of those with marrow disease and extramedullary responses by PET-CT in 79% (CR, 50%) of those with measurable FDG-avid disease. The median duration of remission (DOR) was 10 months with a 4-year DOR probability of 29%. Four patients underwent allo-HCT while in CR/CRi after JCAR021. Durable remissions were observed in patients with low marrow disease burden. In contrast, the DOR was limited in those with high marrow burden, highlighting a remaining critical need to identify new strategies to prolong remissions. We observed similar outcomes in CAR-naïve adult B-ALL patients receiving CD19 CAR T-cells expressing a fully human or murine scFv-containing CAR.}, }
@article {pmid39818460, year = {2025}, author = {Daneshmand, S and Kamat, AM and Shore, ND and Meeks, JJ and Galsky, MD and Jacob, JM and van der Heijden, MS and Williams, SB and Powles, T and Chang, SS and Catto, JWF and Psutka, SP and Guerrero-Ramos, F and Xylinas, E and Miyake, M and Simone, G and Daniel, K and Sweiti, H and Cutie, C and Necchi, A}, title = {Development of TAR-200: A novel targeted releasing system designed to provide sustained delivery of gemcitabine for patients with bladder cancer.}, journal = {Urologic oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.urolonc.2024.12.264}, pmid = {39818460}, issn = {1873-2496}, abstract = {Treatment options for recurrent high-risk non-muscle-invasive bladder cancer (HR NMIBC) and muscle-invasive bladder cancer (MIBC) are limited, highlighting a need for clinically effective, accessible, and better-tolerated alternatives. In this review we examine the clinical development program of TAR-200, a novel targeted releasing system designed to provide sustained intravesical delivery of gemcitabine to address the needs of patients with NMIBC and of those with MIBC. We describe the concept and design of TAR-200 and the clinical development of this gemcitabine intravesical system in the SunRISe portfolio of studies. This includes 3 phase I studies evaluating the safety and initial tumor activity of TAR-200 and 5 phase II/III studies assessing the efficacy and safety of TAR-200, with or without systemic cetrelimab, as a treatment option for patients with HR NMIBC (bacillus Calmette-Guérin naive [papillary and carcinoma in situ] and MIBC (neoadjuvant and patients ineligible for or refusing radical cystectomy). Pharmacokinetics demonstrate intravesical gemcitabine delivery via TAR-200 over a prolonged period without detectable plasma levels. Phase I studies showed that TAR-200 is well tolerated, with preliminary antitumor activity in intermediate-risk NMIBC and MIBC. Preliminary data from the phase IIb SunRISe-1 study demonstrate that TAR-200 monotherapy is safe and effective in patients with bacillus Calmette-Guérin-unresponsive high-risk NMIBC. TAR-200 represents an innovative approach to the local treatment of bladder cancer.}, }
@article {pmid39817910, year = {2025}, author = {Termote, M and Marques, RC and Hyllner, E and Guryleva, MV and Henskens, M and Brutscher, A and Baken, IJL and Dopico, XC and Gasull, AD and Murrell, B and Stamatatos, L and Westerberg, LS and Dosenovic, P}, title = {Antigen affinity and site of immunization dictate B cell recall responses.}, journal = {Cell reports}, volume = {44}, number = {1}, pages = {115221}, doi = {10.1016/j.celrep.2024.115221}, pmid = {39817910}, issn = {2211-1247}, abstract = {Protective antibodies against HIV-1 require unusually high levels of somatic mutations introduced in germinal centers (GCs). To achieve this, a sequential vaccination approach was proposed. Using HIV-1 antibody knockin mice with fate-mapping genes, we examined if antigen affinity affects the outcome of B cell recall responses. Compared to a high-affinity boost, a low-affinity boost resulted in decreased numbers of memory-derived B cells in secondary GCs but with higher average levels of somatic mutations, indicating an affinity threshold for memory B cells to enter GCs. Furthermore, upon boosting local lymph nodes (LNs), the composition of primary GCs was modified in an antigen-affinity-dependent manner to constitute less somatically mutated B cells. Our results demonstrate that antigen affinity and location of the boost affect the outcome of the B cell recall response. These results can help guide the design of vaccine immunogens aiming to selectively engage specific B cell clones for further diversification.}, }
@article {pmid39817771, year = {2025}, author = {Cohen, P and Lambson, BE and Mkhize, NN and Moodley, C and Yssel, AEJ and Moyo-Gwete, T and York, T and Gwashu-Nyangiwe, A and Ndabambi, N and Thebus, R and Juraska, M and deCamp, AC and Williamson, BD and Magaret, CA and Gilbert, PB and Westfall, D and Deng, W and Mullins, JI and Morris, L and Williamson, C and Moore, PL}, title = {Resistance mutations that distinguish HIV-1 envelopes with discordant VRC01 phenotypes from multi-lineage infections in the HVTN703/HPTN081 trial: implications for cross-resistance.}, journal = {Journal of virology}, volume = {}, number = {}, pages = {e0173024}, doi = {10.1128/jvi.01730-24}, pmid = {39817771}, issn = {1098-5514}, abstract = {The Antibody Mediated Prevention (AMP) trials showed that passively infused VRC01, a broadly neutralizing antibody (bNAb) targeting the CD4 binding site (CD4bs) on the HIV-1 envelope protein (Env), protected against neutralization-sensitive viruses. We identified six individuals from the VRC01 treatment arm with multi-lineage breakthrough HIV-1 infections from HVTN703, where one variant was sensitive to VRC01 (IC50 < 25 ug/mL) but another was resistant. By comparing Env sequences of resistant and sensitive clones from each participant, we identified sites predicted to affect VRC01 neutralization and assessed the effect of their reversion in the VRC01-resistant clone on neutralization sensitivity. In four pairs, a single mutation restored partial or full sensitivity to VRC01, whereas in the fifth participant, transfer of the entire [Formula: see text]23-V5 loop was required. No VRC01 resistance mutations could be identified in the sixth participant, with the discordant clones differing by >100 amino acids. Mutations responsible for the differential neutralization phenotypes occurred at distinct sites across Env, including residues in loop D, the CD4-binding loop, and between the [Formula: see text]23 and V5 loops. Analysis of deep sequencing env data showed that VRC01 resistance was likely the property of the acquired virus, rather than occurring through post-acquisition evolution. Although VRC01-resistant parental clones generally retained sensitivity to other CD4-binding site bNAbs, they were less potently neutralized than the VRC01-sensitive clones. In conclusion, VRC01 resistance mutations occurred through multiple mutational pathways, but sensitivity to second-generation CD4bs bNAbs was retained even in VRC01-resistant transmitted viruses, confirming the potential of these bNAbs for HIV-1 prevention studies.IMPORTANCEThe Antibody Mediated Prevention (AMP) trials provided proof of principle that VRC01, a CD4-binding site (CD4bs) HIV-1 broadly neutralizing antibody (bNAb), prevented the acquisition of antibody-sensitive viruses. However, understanding common mutations that confer resistance to different bNAbs provides important insights into the genetic barrier to resistance. Here we studied six AMP trial participants with breakthrough infections mediated by multiple viral lineages with discordant VRC01 sensitivity. We identified different mutations across the CD4-binding site that conferred resistance to VRC01 and showed that these mutations were a property of the acquired virus, rather than a result of post-acquisition evolution. We found that although VRC01 resistance was associated with reduced neutralization potency of second-generation CD4-binding site bNAbs, overall neutralization sensitivity was generally retained, which is promising for future use of such bNAbs in clinical trials.}, }
@article {pmid39817189, year = {2025}, author = {Kundel, V and Devarakonda, K and Khan, S and Suarez-Farinas, M and Cohen, O and Santos-Gallego, C and Menegus, MA and Kini, A and Vengrenyuk, Y and Okamoto, N and Ueda, H and Gidwani, U and Kizer, JR and Redline, S and Kaplan, R and Shah, N}, title = {Exploring the Relationship Between Sleep Apnea, Myocardial Infarct Size, and Coronary Collaterals in Acute Myocardial Infarction: A Multidisciplinary Study.}, journal = {Nature and science of sleep}, volume = {17}, number = {}, pages = {27-42}, pmid = {39817189}, issn = {1179-1608}, support = {K23 HL125923/HL/NHLBI NIH HHS/United States ; K23 HL161324/HL/NHLBI NIH HHS/United States ; }, abstract = {PURPOSE: We designed a study investigating the cardioprotective role of sleep apnea (SA) in patients with acute myocardial infarction (AMI), focusing on its association with infarct size and coronary collateral circulation.<br><br>METHODS: We recruited adults with AMI, who underwent Level-III SA testing during hospitalization. Delayed-enhancement cardiac magnetic resonance (CMR) imaging was performed to quantify AMI size (percent-infarcted myocardium). Rentrop Score quantified coronary collateralization (scores 0-3, higher scores indicating augmented collaterals). Group differences in Rentrop grade and infarct size were compared using the Wilcoxon Rank-Sum test and Fisher's Exact test as appropriate, with a significance threshold set at p <0.05.<br><br>RESULTS: Among 33 adults, mean age was 54.4&#xb1;11.5 and mean BMI was 28.4&#xb1;5.9. 8 patients (24%) had no SA, and 25 (76%) had SA (mild n=10, moderate n=8, severe n=7). 66% (n=22) underwent CMR, and all patients had Rentrop scores. Median infarct size in the no-SA group was 22% versus 28% in the SA group (p=0.79). While we did not find statistically significant differences, moderate SA had a trend toward a smaller infarct size (median 15.5%; IQR 9.23) compared to the other groups (no SA [22.0%; 16.8,31.8], mild SA [27%; 23.8,32.5], and severe SA [34%; 31.53], p=0.12). A higher proportion of moderate SA patients had a Rentrop grade >0, with a trend toward significance (moderate SA versus other groups: 62.5% versus 28%, p=0.08).<br><br>CONCLUSION: Our study did not find statistically significant differences in cardiac infarct size and the presence of coronary collaterals by sleep apnea severity among patients with AMI. However, our results are hypothesis-generating, and suggest that moderate SA may potentially offer cardioprotective benefits through enhanced coronary collaterals. These insights call for future research to explore the heterogeneity in ischemic preconditioning by SA severity and hypoxic burden to guide tailored clinical strategies for SA management in patients with AMI.}, }
@article {pmid39817081, year = {2024}, author = {Tereshchenko, LG and Haq, KT and Howell, SJ and Mitchell, EC and Hyde, J and Martínez, J and Ahmed, CA and Briceno, G and Patel, H and Pena, J and Khan, A and Soliman, EZ and Lima, JAC and Kapadia, SR and Misra-Hebert, AD and Kattan, MW and Kansal, MM and Daviglus, ML and Kaplan, R}, title = {Electrical Heterogeneity in Hispanic Background Subpopulations: The HCHS/SOL.}, journal = {JACC. Advances}, volume = {3}, number = {12}, pages = {101225}, pmid = {39817081}, issn = {2772-963X}, abstract = {BACKGROUND: The Hispanic/Latino population is not uniform. Prevalence and clinical outcomes of cardiac arrhythmias in ethnic background subgroups are variable, but the reasons for differences are unclear. Vectorcardiographic Global Electrical Heterogeneity (GEH) has been shown to be associated with adverse cardiovascular outcomes.<br><br>OBJECTIVES: The purpose of this study was to compare GEH in Hispanic/Latino background subpopulations. We hypothesized that ethnicity category moderates an association of prevalent cardiovascular disease (CVD) with GEH.<br><br>METHODS: Cross-sectional analysis of the HCHS/SOL (Hispanic Community Health Study/Study of Latinos) included 15,684 participants (mean age 41&#xa0;years; 38% Mexican, 20% Cuban, 16% Puerto Rican, 10% Dominican, 7% Central American, 5% South American, 4% mixed Hispanic/Latino background). Acculturation and socioeconomic data were collected. GEH was measured as spatial QRS-T angle, spatial ventricular gradient (SVG) azimuth, SVG elevation, SVG magnitude, and sum absolute QRST integral. Linear regression models included interaction terms of ethnic background category by CVD and were adjusted for age, sex, education attainment, hypertension, diabetes, smoking, dyslipidemia, obesity, chronic kidney disease, physical activity, diet quality, heart rate, and rhythm.<br><br>RESULTS: The adjusted spatial QRS-T angle was significantly (P&#xa0;<&#xa0;0.0001) narrower in Dominican background (-3.4&#xb0;[95%&#xa0;CI&#xa0;-5.0&#xb0; to&#xa0;-1.7&#xb0;]) as compared to a total mean. SVG azimuth pointed farther posteriorly in Dominican (+2.9 [95% CI: 1.6-4.2]) and Puerto Rican (+3.8 [2.4-5.2]), but farther anteriorly in South American (-2.9 [95% CI: -4.4 to&#xa0;-1.4]) and Mexican (-3.5 [95% CI: -4.3 to&#xa0;-2.6]) vs total mean. An association of coronary heart disease with GEH was especially strong in Cuban background subpopulation.<br><br>CONCLUSIONS: In CVD-free Hispanic/Latino subpopulations, cardiovascular risk factors do not fully explain GEH differences across ethnic background categories, which likely reflect unmeasured health disparities.}, }
@article {pmid39817038, year = {2025}, author = {Bradley, J and Floyd, S and Piwowar-Manning, E and Laeyendecker, O and Baker, OR and Bell-Mandla, N and Bwalya, J and Moore, A and Eshleman, SH and Donnell, D and Bock, P and Fidler, S and Ayles, H and Hayes, RJ}, title = {Strong Association Between HIV Incidence and Herpes Simplex Virus Type 2 in Zambia and South Africa: Prospective Data From the HPTN 071 (PopART) Trial.}, journal = {Open forum infectious diseases}, volume = {12}, number = {1}, pages = {ofae721}, pmid = {39817038}, issn = {2328-8957}, abstract = {BACKGROUND: Herpes simplex virus type 2 (HSV2) is an important cofactor for HIV acquisition and transmission. Associations between the infections are reexamined in longitudinal data from an HIV prevention trial.<br><br>METHODS: The HPTN 071 (PopART) trial evaluated a combination prevention intervention in 21 urban communities in Zambia and South Africa. HIV incidence was measured in a cohort of approximately 2000 adults (age, 18-44 years) selected randomly from each community and followed up for 36 months. Incidence of HSV2 infection was estimated, and the effects of risk factors were examined. The association between HIV incidence and HSV2 infection was examined at individual and community levels.<br><br>RESULTS: An overall 10 539 participants were HSV2 negative at baseline and retested after 36 months. Estimated HSV2 incidence was 5.4 per 100 person-years (95% CI, 5.0-5.7) for women and 2.9 per 100 person-years (95% CI, 2.6-3.2) for men. When compared with those remaining HSV2 negative, HIV incidence was higher in those who were HSV2 positive at baseline (women: adjusted rate ratio [aRR], 3.24 [95% CI, 2.50-4.20]; men: aRR, 2.57 [95% CI, 1.60-4.11]) and even higher in those who seroconverted to HSV2 during follow-up (women: aRR, 5.94 [95% CI, 4.42-7.98]; men: aRR, 8.37 [95% CI, 5.18-13.52]). At the community level, strong associations were seen between HIV incidence and HSV2 prevalence (R [2] = 0.48, P < .001) and incidence (R [2] = 0.36, P = .004).<br><br>CONCLUSIONS: There were strong associations between HIV incidence and HSV2 prevalence and incidence at individual and community levels. HSV2 control could contribute to HIV prevention.}, }
@article {pmid39815807, year = {2025}, author = {Lim, SYT and Cole, FM and Laszlo, GS and Lunn-Halbert, MC and Huo, J and Li, J and Kehret, AR and Walter, RB}, title = {Targeting the membrane-proximal domain of CD33 to maximize the efficacy of natural killer cell-based immunotherapies.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2024.286593}, pmid = {39815807}, issn = {1592-8721}, abstract = {Not available.}, }
@article {pmid39815460, year = {2025}, author = {Moseley, A and LeBlanc, M and Freidlin, B and Shallis, RM and Zeidan, AM and Sallman, DA and Erba, HP and Little, RF and Othus, M}, title = {Evaluating the impact of stratification on the power and cross-arm balance of randomized phase 2 clinical trials.}, journal = {Clinical trials (London, England)}, volume = {}, number = {}, pages = {17407745241304065}, doi = {10.1177/17407745241304065}, pmid = {39815460}, issn = {1740-7753}, abstract = {BACKGROUND/AIMS: Randomized clinical trials often use stratification to ensure balance between arms. Analysis of primary endpoints of these trials typically uses a "stratified analysis," in which analyses are performed separately in each subgroup defined by the stratification factors, and those separate analyses are weighted and combined. In the phase 3 setting, stratified analyses based on a small number of stratification factors can provide a small increase in power. The impact on power and type-1 error of stratification in the setting of smaller sample sizes as in randomized phase 2 trials has not been well characterized.<br><br>METHODS: We performed computational studies to characterize the power and cross-arm balance of modestly sized clinical trials (less than 170 patients) with varying numbers of stratification factors (0-6), sample sizes, randomization ratios (1:1 vs 2:1), and randomization methods (dynamic balancing vs stratified block).<br><br>RESULTS: We found that the power of unstratified analyses was minimally impacted by the number of stratification factors used in randomization. Analyses stratified by 1-3 factors maintained power over 80%, while power dropped below 80% when four or more stratification factors were used. These trends held regardless of sample size, randomization ratio, and randomization method. For a given randomization ratio and sample size, increasing the number of factors used in randomization had an adverse impact on cross-arm balance. Stratified block randomization performed worse than dynamic balancing with respect to cross-arm balance when three or more stratification factors were used.<br><br>CONCLUSION: Stratified analyses can decrease power in the setting of phase 2 trials when the number of patients in a stratification subgroup is small.}, }
@article {pmid39763725, year = {2024}, author = {Aditham, AK and Radford, CE and Carr, CR and Jasti, N and King, NP and Bloom, JD}, title = {Deep mutational scanning of rabies glycoprotein defines mutational constraint and antibody-escape mutations.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39763725}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 AI141707/AI/NIAID NIH HHS/United States ; }, abstract = {Rabies virus causes nearly 60,000 human deaths annually. Antibodies that target the rabies glycoprotein (G) are being developed as post-exposure prophylactics, but mutations in G can render such antibodies ineffective. Here, we use pseudovirus deep mutational scanning to measure how all single amino-acid mutations to G affect cell entry and neutralization by a panel of antibodies. These measurements identify sites critical for rabies G's function, and define constrained regions that are attractive epitopes for clinical antibodies, including at the apex and base of the protein. We provide complete maps of escape mutations for eight monoclonal antibodies, including some in clinical use or development. Escape mutations for most antibodies are present in some natural rabies strains. Overall, this work provides comprehensive information on the functional and antigenic effects of G mutations that can help inform development of stabilized vaccine antigens and antibodies that are resilient to rabies genetic variation.}, }
@article {pmid38088119, year = {2024}, author = {Brown, JR and Eichhorst, B and Hillmen, P and Jurczak, W and Kaźmierczak, M and Lamanna, N and O'Brien, SM and Tam, CS and Qiu, L and Zhou, K and Simkovic, M and Mayer, J and Gillespie-Twardy, A and Ferrajoli, A and Ganly, PS and Weinkove, R and Grosicki, S and Mital, A and Robak, T and Osterborg, A and Yimer, HA and Salmi, T and Wang, MD and Fu, L and Li, J and Wu, K and Cohen, A and Shadman, M}, title = {Plain language summary of zanubrutinib or ibrutinib in chronic lymphocytic leukemia that is resistant to treatment or has come back after treatment.}, journal = {Future oncology (London, England)}, volume = {20}, number = {12}, pages = {717-726}, doi = {10.2217/fon-2023-0849}, pmid = {38088119}, issn = {1744-8301}, mesh = {Humans ; *Adenine/analogs &amp; derivatives ; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/pathology ; *Lymphoma, B-Cell/drug therapy ; Piperidines/therapeutic use ; Pyrazoles/adverse effects ; *Pyrimidines ; }, abstract = {WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of a research study called ALPINE. The study involved people who had been diagnosed with, and previously treated at least once for, relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Lymphocytes help to find and fight off viruses and infections in the body, but when someone has CLL or SLL, the body creates abnormal lymphocytes, leaving the patient with a weakened immune system and susceptible to illness. In CLL, these lymphocytes are in the bone marrow and bloodstream, whereas for SLL, they are mostly found in the lymph nodes, such as those in the neck.<br><br>HOW WAS THE RESEARCH DONE?: The ALPINE study was designed to directly compare the cancer-fighting effects and side effects of zanubrutinib and ibrutinib as treatment for patients with relapsed or refractory CLL/SLL.<br><br>WHAT WERE THE RESULTS?: After 30&#xa0;months, zanubrutinib was more effective than ibrutinib at reducing and keeping the cancer from coming back. Clinical Trial Registration: NCT03734016 (ClinicalTrials.gov).}, }
@article {pmid39815416, year = {2025}, author = {Powles, T and Park, SH and Gurney, H and Loriot, Y and Sridhar, SS and Bellmunt, J and di Pietro, A and Grivas, P}, title = {Avelumab maintenance treatment for advanced urothelial cancer: plain language summary of long-term results from the JAVELIN Bladder 100 study.}, journal = {Future oncology (London, England)}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/14796694.2024.2435208}, pmid = {39815416}, issn = {1744-8301}, }
@article {pmid39814501, year = {2025}, author = {Karvonen, KA}, title = {Challenging the Status Quo: Multi-level Solutions for Equitable Hematopoietic Cell Transplantation Clinical Trial Representation.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {1}, pages = {7-9}, doi = {10.1016/j.jtct.2024.12.014}, pmid = {39814501}, issn = {2666-6367}, }
@article {pmid39814200, year = {2025}, author = {Rangelova, E and Stoop, TF and van Ramshorst, TME and Ali, M and van Bodegraven, EA and Javed, AA and Hashimoto, D and Steyerberg, E and Banerjee, A and Jain, A and Sauvanet, A and Serrablo, A and Giani, A and Giardino, A and Zerbi, A and Arshad, A and Wijma, AG and Coratti, A and Zironda, A and Socratous, A and Rojas, A and Halimi, A and Ejaz, A and Oba, A and Patel, BY and Björnsson, B and Reames, BN and Tingstedt, B and Goh, BKP and Payá-Llorente, C and Domingo Del Pozo, C and González-Abós, C and Medin, C and van Eijck, CHJ and de Ponthaud, C and Takishita, C and Schwabl, C and Månsson, C and Ricci, C and Thiels, CA and Douchi, D and Hughes, DL and Kilburn, D and Flanking, D and Kleive, D and Sousa Silva, D and Edil, BH and Pando, E and Moltzer, E and Kauffman, EF and Warren, E and Bozkurt, E and Sparrelid, E and Thoma, E and Verkolf, E and Ausania, F and Giannone, F and Hüttner, FJ and Burdio, F and Souche, FR and Berrevoet, F and Daams, F and Motoi, F and Saliba, G and Kazemier, G and Roeyen, G and Nappo, G and Butturini, G and Ferrari, G and Kito Fusai, G and Honda, G and Sergeant, G and Karteszi, H and Takami, H and Suto, H and Matsumoto, I and Mora-Oliver, I and Frigerio, I and Fabre, JM and Chen, J and Sham, JG and Davide, J and Urdzik, J and de Martino, J and Nielsen, K and Okano, K and Kamei, K and Okada, K and Tanaka, K and Labori, KJ and Goodsell, KE and Alberici, L and Webber, L and Kirkov, L and de Franco, L and Miyashita, M and Maglione, M and Gramellini, M and Ramera, M and João Amaral, M and Ramaekers, M and Truty, MJ and van Dam, MA and Stommel, MWJ and Petrikowski, M and Imamura, M and Hayashi, M and D'Hondt, M and Brunner, M and Hogg, ME and Zhang, C and Ángel Suárez-Muñoz, M and Luyer, MD and Unno, M and Mizuma, M and Janot, M and Sahakyan, MA and Jamieson, NB and Busch, OR and Bilge, O and Belyaev, O and Franklin, O and Sánchez-Velázquez, P and Pessaux, P and Strandberg Holka, P and Ghorbani, P and Casadei, R and Sartoris, R and Schulick, RD and Grützmann, R and Sutcliffe, R and Mata, R and Patel, RB and Takahashi, R and Rodriguez Franco, S and Sánchez Cabús, S and Hirano, S and Gaujoux, S and Festen, S and Kozono, S and Maithel, SK and Chai, SM and Yamaki, S and van Laarhoven, S and Mieog, JSD and Murakami, T and Codjia, T and Sumiyoshi, T and Karsten, TM and Nakamura, T and Sugawara, T and Boggi, U and Hartman, V and de Meijer, VE and Bartholomä, W and Kwon, W and Koh, YX and Cho, Y and Takeyama, Y and Inoue, Y and Nagakawa, Y and Kawamoto, Y and Ome, Y and Soonawalla, Z and Uemura, K and Wolfgang, CL and Jang, JY and Padbury, R and Satoi, S and Messersmith, W and Wilmink, JW and Abu Hilal, M and Besselink, MG and Del Chiaro, M and , }, title = {The impact of neoadjuvant therapy in patients with left-sided resectable pancreatic cancer: an international multicenter study.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.annonc.2024.12.015}, pmid = {39814200}, issn = {1569-8041}, abstract = {PURPOSE: To assess the association between neoadjuvant therapy and overall survival (OS) in patients with left-sided resectable pancreatic cancer (RPC) compared to upfront surgery.<br><br>BACKGROUND: Left-sided pancreatic cancer is associated with worse OS compared to right-sided pancreatic cancer. Although neoadjuvant therapy is currently seen as not effective in patients with RPC, current randomized trials included mostly patients with right-sided RPC.<br><br>METHODS: International multicenter retrospective study including consecutive patients after left-sided pancreatic resection for pathology-proven RPC, either after neoadjuvant therapy or upfront surgery in 76 centers from 18 countries on 4 continents (2013-2019). Primary endpoint is OS from diagnosis. Time-dependent Cox regression analysis was performed to investigate the association of neoadjuvant therapy with OS, adjusting for confounders at time of diagnosis. Adjusted OS probabilities were calculated.<br><br>RESULTS: Overall, 2,282 patients after left-sided pancreatic resection for RPC were included of whom 290 patients (13%) received neoadjuvant therapy. The most common neoadjuvant regimens were (m)FOLFIRINOX (38%) and gemcitabine-nab-paclitaxel (22%). After upfront surgery, 72% of patients received adjuvant chemotherapy, mostly a single-agent regimen (74%). Neoadjuvant therapy was associated with prolonged OS compared to upfront surgery (adjusted HR=0.69 [95%CI 0.58-0.83]) with an adjusted median OS of 53 vs. 37 months (P=0.0003) and adjusted 5-year OS rates of 47% vs. 35% (P=0.0001) compared to upfront surgery. Interaction analysis demonstrated a stronger effect of neoadjuvant therapy in patients with a larger tumor (Pinteraction=0.003) and higher serum CA19-9 (Pinteraction=0.005). In contrast, the effect of neoadjuvant therapy was not enhanced for splenic artery (Pinteraction=0.43), splenic vein (Pinteraction=0.30), retroperitoneal (Pinteraction=0.84), and multivisceral (Pinteraction=0.96) involvement.<br><br>CONCLUSIONS: Neoadjuvant therapy in patients with left-sided RPC was associated with improved OS compared to upfront surgery. The impact of neoadjuvant therapy increased with larger tumor size and higher serum CA19-9 at diagnosis. Randomized controlled trials on neoadjuvant therapy specifically in patients with left-sided RPC are needed.}, }
@article {pmid39813621, year = {2025}, author = {Gore, S and Blyth, E and Bleakley, M and Lee, K and Micklethwaite, KP and Gowrishankar, K}, title = {Current developments in T-cell receptor therapy for Acute Myeloid Leukaemia.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024014105}, pmid = {39813621}, issn = {2473-9537}, abstract = {T-cell receptor (TCR) therapies are a promising modality for the treatment of cancers, with significant efforts being directed towards acute myeloid leukaemia (AML), a particularly challenging disease. Chimeric antigen receptor (CAR) T-cells targeting single surface antigens have shown remarkable efficacy for B-cell lymphoblastic leukaemia, lymphomas and multiple myeloma. However, AML presents formidable obstacles to the effectiveness of CAR T-cells due to the widespread expression of heterogenous leukaemia immunophenotypes and surface antigen targets additionally present on normal myeloid cells. TCR therapies are an evolving field of cell therapies that allow targeting intracellular antigenic peptides presented via HLA molecules. The development of TCR therapy for AML is progressing rapidly through preclinical research and successful clinical trials. This review specifically explores the antigens targeted in AML, the diverse methodologies and strategies employed in TCR identification and preclinical TCR T-cell development. The review also discusses innovative molecular designs to improve functional efficacy, mitigate safety concerns and overcome HLA restriction. Specific outcomes of early clinical trials targeting important antigens WT1, PRAME and HA-1 are also highlighted. Ultimately, this review underscores why TCR therapy is poised to become an indispensable component of AML immunotherapy.}, }
@article {pmid39812506, year = {2025}, author = {Little, A and Zhao, N and Mikhaylova, A and Zhang, A and Ling, W and Thibord, F and Johnson, AD and Raffield, LM and Curran, JE and Blangero, J and O'Connell, JR and Xu, H and Rotter, JI and Rich, SS and Rice, KM and Chen, MH and Reiner, A and Kooperberg, C and Vu, T and Hou, L and Fornage, M and Loos, RJF and Kenny, E and Mathias, R and Becker, L and Smith, AV and Boerwinkle, E and Yu, B and Thornton, T and Wu, MC}, title = {General Kernel Machine Methods for Multi-Omics Integration and Genome-Wide Association Testing With Related Individuals.}, journal = {Genetic epidemiology}, volume = {49}, number = {1}, pages = {e22610}, doi = {10.1002/gepi.22610}, pmid = {39812506}, issn = {1098-2272}, support = {//U.S. Department of Health and Human Services, National Institute on Minority Health and Health Disparities, National Institutes of Health, National Human Genome Research Institute, National Center for Research Resources, COPD Foundation, National Heart, Lung, and Blood Institute, National Science Foundation, National Institute on Aging, and National Institute of Neurological Disorders and Stroke./ ; }, mesh = {Humans ; *Genome-Wide Association Study/methods ; *Genomics/methods ; Phenotype ; Algorithms ; Models, Genetic ; Polymorphism, Single Nucleotide ; Genotype ; Computer Simulation ; Machine Learning ; Multiomics ; }, abstract = {Integrating multi-omics data may help researchers understand the genetic underpinnings of complex traits and diseases. However, the best ways to integrate multi-omics data and use them to address pressing scientific questions remain a challenge. One important and topical problem is how to assess the aggregate effect of multiple genomic data types (e.g. genotypes and gene expression levels) on a phenotype, particularly while accommodating routine issues, such as having related subjects' data in analyses. In this paper, we extend an existing composite kernel machine regression model to integrate two multi-omics data types, while accommodating for general correlation structures amongst outcomes. Due to the kernel machine regression framework, our methods allow for the integration of high-dimensional omics data with small, nonlinear, and interactive effects, and accommodation of general study designs. Here, we focus on scientific questions that aim to assess the association between a functional grouping (such as a gene or a pathway) and a quantitative trait of interest. We use a kernel machine regression to integrate the two multi-omics data types, as they may relate to the trait, and perform a global test of association. We demonstrate the advantage of this approach over single data type association tests via simulation. Finally, we apply this method to a large, multi-ethnic data set to investigate how predicted gene expression and rare genetic variation may be related to two platelet traits.}, }
@article {pmid39809874, year = {2025}, author = {Mao, JJ and Bryl, K and Gillespie, EF and Green, A and Hung, TKW and Baser, R and Panageas, K and Postow, MA and Daly, B}, title = {Randomized clinical trial of a digital integrative medicine intervention among patients undergoing active cancer treatment.}, journal = {NPJ digital medicine}, volume = {8}, number = {1}, pages = {29}, pmid = {39809874}, issn = {2398-6352}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; K08 CA252640/CA/NCI NIH HHS/United States ; 1P50CA271357-01//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; }, abstract = {Exercise and mindfulness-based interventions have growing evidence for managing fatigue and comorbid symptoms; however, packaging them in a cohesive digital way for patients undergoing cancer treatment has not been evaluated. We conducted a randomized controlled trial to assess the impact of a 12 week digital integrative medicine program, Integrative Medicine at Home (IM@Home), versus enhanced usual care on fatigue severity (primary outcome), comorbid symptoms and acute healthcare utilization (secondary outcomes), in 200 patients with solid tumors experiencing fatigue during treatment. Fatigue severity decreased more in IM@Home than in the control (1.99 vs. 1.51 points; p = 0.04). IM@Home participants also had reduced symptom distress (p = 0.003), anxiety (p = 0.03), and depression (p = 0.02). Acute healthcare utilization was lower with IM@Home, with fewer emergency department visits (rate ratio 0.49; p = 0.04), hospitalizations (4% vs. 12.9%; p = 0.03), and shorter hospital stays (4.25 vs. 10 days; p < 0.001). These promising findings should be confirmed in phase III clinical trials. "Study registered at clinicaltrials.gov (NCT05053230) on 09-20-2021".}, }
@article {pmid39809842, year = {2025}, author = {Popchock, AR and Hedouin, S and Mao, Y and Asbury, CL and Stergachis, AB and Biggins, S}, title = {Stable centromere association of the yeast histone variant Cse4 requires its essential N-terminal domain.}, journal = {The EMBO journal}, volume = {}, number = {}, pages = {}, pmid = {39809842}, issn = {1460-2075}, support = {NIH 1DP5OD029630//HHS | National Institutes of Health (NIH)/ ; P30 CA015704/CA/NCI NIH HHS/United States ; NIH R35GM134842//HHS | National Institutes of Health (NIH)/ ; R35 GM149357/GM/NIGMS NIH HHS/United States ; NIH R35 GM149357//HHS | National Institutes of Health (NIH)/ ; NIH F32GM136010//HHS | National Institutes of Health (NIH)/ ; }, abstract = {Chromosome segregation relies on kinetochores that assemble on specialized centromeric chromatin containing a histone H3 variant. In budding yeast, a single centromeric nucleosome containing Cse4 assembles at a sequence-defined 125 bp centromere. Yeast centromeric sequences are poor templates for nucleosome formation in vitro, suggesting the existence of mechanisms that specifically stabilize Cse4 nucleosomes in vivo. The extended Cse4 N-terminal tail binds to the chaperone Scm3, and a short essential region called END within the N-terminal tail binds the inner kinetochore complex Okp1/Ame1. To address the roles of these interactions, we utilized single-molecule fluorescence assays to monitor Cse4 during kinetochore assembly. We found that Okp1/Ame1 and Scm3 independently stabilize Cse4 at centromeres via their END interaction. Scm3 and Cse4 stability at the centromere are enhanced by Ipl1/Aurora B phosphorylation of the Cse4 END, identifying a previously unknown role for Ipl1 in ensuring Cse4 stability. Strikingly, a phosphomimetic mutation in the Cse4 END restores Cse4 recruitment in mutants defective in Okp1/Ame1 binding. Together, these data suggest that a key function of the essential Cse4 N-terminus is to ensure Cse4 localization at centromeres.}, }
@article {pmid39808799, year = {2025}, author = {Baumrin, E and Pidala, JA and Mitchell, S and Onstad, L and Lee, SJ}, title = {Development of the Lee Symptom Scale-Skin Sclerosis for chronic GVHD-associated sclerosis.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024027334}, pmid = {39808799}, issn = {1528-0020}, abstract = {Sclerosis is a highly morbid manifestation of chronic GVHD (cGVHD), associated with distressing symptoms and significant long-term disability. A patient-reported outcome measure (PRO) for cGVHD-associated sclerosis is essential to advance therapeutic trials. We aimed to develop a PRO for adults with cGVHD-associated sclerosis and evaluate and refine its content validity. Adults age ≥18 years with cGVHD-associated sclerosis participated in semi-structured interviews to identify salient symptoms and functions. Sclerosis-relevant symptoms and functions from existing PROs were also used to prompt discussion of topics not spontaneously mentioned. Symptoms and functions (subcodes) of importance were clustered and mapped to overarching domains (codes) using inductive analysis, and candidate items were developed. Cognitive interviews were employed to evaluate content validity of the items, response options, recall period, and respondent instructions.Thirty-five open-ended interviews, conducted to saturation, revealed the breadth of the patient experience with cGVHD-associated sclerosis including 5 overarching domains: (1) skin changes, (2) symptoms, (3) emotional and social functioning, (4) mobility restrictions, and (4) activity limitations. A pool of 54 items was tested and iteratively refined through cognitive debriefing interviews (n=25). Phrasing changes were made to improve relevance and comprehension. One item was removed and two items were added to address respondent feedback, resulting in 55 items. Results support the relevance, comprehensibility, and comprehensiveness of the provisional Lee Symptom Scale-Skin Sclerosis. Concept elicitation and cognitive interviewing have informed the development of the Lee Symptom Scale-Skin Sclerosis. Psychometric testing and determination of minimal clinically important difference are underway in an external cohort to validate the PRO.}, }
@article {pmid39808648, year = {2025}, author = {Friedland, BA and Gundacker, H and Achilles, SL and Chen, BA and Hoesley, C and Richardson, BA and Kelly, CW and Piper, J and Johnson, S and Devlin, B and Steytler, J and Kleinbeck, K and Dangi, B and Friend, C and Song, M and Mensch, B and van der Straten, A and Jacobson, C and Hendrix, CW and Brown, J and Blithe, D and Hiller, SL and , }, title = {Acceptability of a dapivirine levonorgestrel vaginal ring in two Phase 1 trials (MTN-030/IPM 041 and MTN-044/IPM 053/CCN019): Implications for multipurpose prevention technology development.}, journal = {PloS one}, volume = {20}, number = {1}, pages = {e0312957}, pmid = {39808648}, issn = {1932-6203}, mesh = {Humans ; Female ; Adult ; *Levonorgestrel/administration &amp; dosage ; *Pyrimidines/administration &amp; dosage/therapeutic use ; *Contraceptive Devices, Female ; *HIV Infections/prevention &amp; control ; Young Adult ; Adolescent ; Middle Aged ; Patient Acceptance of Health Care ; Anti-HIV Agents/administration &amp; dosage/therapeutic use ; Contraceptive Agents, Female/administration &amp; dosage ; Pregnancy ; }, abstract = {End-user feedback early in product development is important for optimizing multipurpose prevention technologies for HIV and pregnancy prevention. We evaluated the acceptability of the 90-day dapivirine levonorgestrel ring (DPV-LNG ring) used for 14 days compared to a dapivirine-only ring (DVR-200mg) in MTN-030/IPM 041 (n = 23), and when used for 90 days cyclically or continuously in MTN-044/IPM 053/CCN019 (n = 25). We enrolled healthy, non-pregnant, HIV-negative women aged 18-45 in Pittsburgh, PA and Birmingham, AL (MTN-030 only). Self-reports of vaginal bleeding and adherence (ring removals, expulsions) were collected via daily short message service. Acceptability data were recorded in face-to-face interviews at study exit. We assessed differences in acceptability by product characteristics and adherence; and associations between baseline characteristics/demographics, number of bleeding days, adherence, and overall acceptability. Most (21/23) women in the 14-day MTN-030 study and about half (13/25) in the 90-day MTN-044 study liked their assigned rings. In MTN-030 there were no significant associations between any variables and overall acceptability of either ring. In MTN-044, women who disliked the DPV-LNG ring had a significantly higher incidence of unanticipated vaginal bleeding, and reporting that vaginal bleeding changes were unacceptable than those who liked it. Although we found no overall association between adherence and acceptability, significantly more women who disliked (versus liked) the DPV-LNG ring reported expulsions during toileting. The DPV-LNG ring could meet the needs of women seeking simultaneous protection from HIV and unintended pregnancy. Addressing issues related to vaginal bleeding and expulsions early in product development will likely enhance acceptability of the DPV-LNG ring. Trial registration: Clinical Trial Registration: MTN-030/IPM 041: ClinicalTrials.gov NCT02855346; MTN-044/IPM 053/CCN019: ClinicalTrials.gov NCT03467347.}, }
@article {pmid39764024, year = {2024}, author = {Arends, T and Bennett, SR and Tapscott, SJ}, title = {DUX4-induced HSATII RNA accumulation drives protein aggregation impacting RNA processing pathways.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39764024}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 AR045203/AR/NIAMS NIH HHS/United States ; T32 CA009657/CA/NCI NIH HHS/United States ; }, abstract = {RNA-driven protein aggregation leads to cellular dysregulation by sequestering regulatory proteins, disrupting normal cellular processes, and contributing to the development of diseases and tumorigenesis. Here, we show that double homeobox 4 (DUX4), an early embryonic transcription factor and causative gene of facioscapulohumeral muscular dystrophy (FSHD), induces the accumulation of stable intranuclear RNAs, including nucleolar-associated RNA and human satellite II (HSATII) repeat RNA. Stable intranuclear RNAs drive protein aggregation in DUX4-expressing muscle cells. Specifically, HSATII RNA sequesters m[6]A and m[5]C RNA methylation factors. Furthermore, HSATII-YBX1 ribonucleoprotein (RNP) complex formation is mediated by HSATII RNA accumulation, NSUN2 activity and RNA methylation. YBX-1 specifically associates with HSATII double-stranded RNA. Aberrant HSATII-RNP complexes affect key RNA processing pathways, including mRNA splicing. Differential splicing of genes mediated by HSATII-RNP complexes are associated with pathways known to be dysregulated by DUX4 expression. These findings highlight the broader influence of DUX4 on nuclear RNA dynamics and suggest that HSATII RNA could be a critical mediator of RNA processing regulation in DUX4-expressing cells. Understanding the impact of HSATII-RNP formation on RNA processing pathways provides valuable insight into the molecular mechanisms underlying FSHD.}, }
@article {pmid39763963, year = {2024}, author = {Frouard, J and Telwatte, S and Luo, X and Elphick, N and Thomas, R and Arneson, D and Roychoudhury, P and Butte, AJ and Wong, JK and Hoh, R and Deeks, SG and Lee, SA and Roan, NR and Yukl, S}, title = {HIV-SEQ REVEALS GLOBAL HOST GENE EXPRESSION DIFFERENCES BETWEEN HIV-TRANSCRIBING CELLS FROM VIREMIC AND SUPPRESSED PEOPLE WITH HIV.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39763963}, issn = {2692-8205}, support = {P01 AI169606/AI/NIAID NIH HHS/United States ; UM1 AI164559/AI/NIAID NIH HHS/United States ; R01 AI183286/AI/NIAID NIH HHS/United States ; R01 DK120387/DK/NIDDK NIH HHS/United States ; UM1 AI164560/AI/NIAID NIH HHS/United States ; P30 AI027763/AI/NIAID NIH HHS/United States ; R21 AI170166/AI/NIAID NIH HHS/United States ; UM1 AI164567/AI/NIAID NIH HHS/United States ; R01 AI132128/AI/NIAID NIH HHS/United States ; R01 DK131526/DK/NIDDK NIH HHS/United States ; R01 AI147777/AI/NIAID NIH HHS/United States ; }, abstract = {"Active" reservoir cells transcribing HIV can perpetuate chronic inflammation in virally suppressed people with HIV (PWH) and likely contribute to viral rebound after antiretroviral therapy (ART) interruption, so they represent an important target for new therapies. These cells, however, are difficult to study using single-cell RNA-seq (scRNA-seq) due to their low frequency and low levels of HIV transcripts, which are usually not polyadenylated. Here, we developed "HIV-seq" to enable more efficient capture of HIV transcripts - including non-polyadenylated ones - for scRNA-seq analysis of cells from PWH. By spiking in a set of custom-designed capture sequences targeting conserved regions of the HIV genome during scRNA-seq, we increased our ability to find HIV RNA+ cells from PWH by up to 44%. Implementing HIV-seq in conjunction with surface phenotyping by CITE-seq on paired blood specimens from PWH before vs. after ART suppression, we found that HIV RNA+ cells were enriched among T effector memory (Tem) cells during both viremia and ART suppression, but exhibited a cytotoxic signature during viremia only. By contrast, HIV RNA+ cells from the ART-suppressed timepoints exhibited a distinct anti-inflammatory signature involving elevated TGF-β and diminished IFN signaling. Overall, these findings demonstrate that active reservoir cells exhibit transcriptional features distinct from HIV RNA+ cells during viremia, and underscore HIV-seq as a useful tool to better understand the mechanisms by which HIV-transcribing cells can persist during ART.}, }
@article {pmid39808447, year = {2025}, author = {Koyama, M}, title = {Control of antigen-independent T-cell migration after HSCT.}, journal = {Blood advances}, volume = {9}, number = {1}, pages = {207-208}, doi = {10.1182/bloodadvances.2024014584}, pmid = {39808447}, issn = {2473-9537}, }
@article {pmid39808074, year = {2024}, author = {Ho, K and Hoesley, C and Anderson, PL and Fernández-Romero, JA and Friedland, BA and Kelly, CW and Jiao, Y and Edick, S and Brand, R and Kunjara Na Ayudhya, RP and Zyhowski, A and Hartman, DJ and Reddy, NB and Al-Khouja, A and Piper, J and Bauermeister, JA and Teleshova, N and Melo, C and Cornejal, N and Barnable, P and Singh, D and Scheckter, R and McClure, T and Hillier, SL and Hendrix, CW and , }, title = {Phase I Dose Volume Escalation of Rectally Administered PC-1005 to Assess Safety, Pharmacokinetics, and Antiviral Pharmacodynamics as a Multipurpose Prevention Technology (MTN-037).}, journal = {Journal of acquired immune deficiency syndromes (1999)}, volume = {97}, number = {4}, pages = {379-386}, pmid = {39808074}, issn = {1944-7884}, support = {UM1AI068633//Division of AIDS, National Institute of Allergy and Infectious Diseases/ ; }, mesh = {Humans ; Female ; Adult ; *Antiviral Agents/pharmacokinetics/administration &amp; dosage/adverse effects ; Male ; Middle Aged ; Administration, Rectal ; Carrageenan/pharmacokinetics/administration &amp; dosage ; HIV Infections/prevention &amp; control/drug therapy ; Pre-Exposure Prophylaxis/methods ; Young Adult ; Rectum/virology ; Papillomavirus Infections/prevention &amp; control ; Pyridines ; Urea/analogs &amp; derivatives ; }, abstract = {BACKGROUND: On demand, topical PrEP is desired by those preferring episodic, nonsystemic PrEP. PC-1005 gel (MIV-150, zinc, and carrageenan) exhibits in vitro antiviral HIV-1, human papillomavirus (HPV), and herpes simplex virus type 2 (HSV-2) activity, attractive for a multipurpose prevention technology candidate. We evaluated the safety, pharmacokinetics, and antiviral effect of rectally applied PC-1005.<br><br>METHODS: HIV-uninfected adults received a series of 3 rectal PC-1005 doses-4, 16, and 32 mL separated by 2-week washout periods. Following each dose, plasma, rectal fluid and tissue, and vaginal fluid were collected over 48 hours.<br><br>RESULTS: Thirteen adults enrolled; 12 completed all 3 doses. All 13 adverse events reported were grade 1 or 2; 5 were judged study drug related. Plasma MIV-150 peaked 1-2 h after dosing with a median peak concentrations range of 0.07-0.23 ng/mL and median half-life range of 4.9-7.4 hours across dose volumes; median concentrations were below assay quantitation limits (BLQ) 24 hours after dosing. Rectal tissue MIV-150 peaked 0.5-1 hours after dosing at 1.4 ng/g (ng/mL) (0.8, 1.9), 46.0 (30.7, 831.0), and 79.7 (11.9, 116.0), respectively, after each dose volume; median tissue concentrations were BLQ beyond 5 hours for all doses. All vaginal fluid samples were BLQ. Ex vivo antiviral assays showed 5 hours of antiviral HPV and HSV effects but no anti-HIV activity.<br><br>CONCLUSIONS: MIV-150 rectal tissue concentrations were below the 100 ng/g target concentration and transient. Ex vivo assays demonstrated antiviral HSV and HPV effects but not against HIV. PC-1005 requires a more potent antiviral and longer-lasting formulation for further consideration as a multipurpose prevention technology candidate.<br><br>CLINICAL TRIALS: NCT03408899.}, }
@article {pmid39764056, year = {2024}, author = {Samorodnitsky, S and Campbell, K and Little, A and Ling, W and Zhao, N and Chen, YC and Wu, MC}, title = {Detecting Clinically Relevant Topological Structures in Multiplexed Spatial Proteomics Imaging Using TopKAT.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39764056}, issn = {2692-8205}, support = {U10 CA180819/CA/NCI NIH HHS/United States ; }, abstract = {Novel multiplexed spatial proteomics imaging platforms expose the spatial architecture of cells in the tumor microenvironment (TME). The diverse cell population in the TME, including its spatial context, has been shown to have important clinical implications, correlating with disease prognosis and treatment response. The accelerating implementation of spatial proteomic technologies motivates new statistical models to test if cell-level images associate with patient-level endpoints. Few existing methods can robustly characterize the geometry of the spatial arrangement of cells and also yield both a valid and powerful test for association with patient-level outcomes. We propose a topology-based approach that combines persistent homology with kernel testing to determine if topological structures created by cells predict continuous, binary, or survival clinical endpoints. We term our method TopKAT (Topological Kernel Association Test) and show that it can be more powerful than statistical tests grounded in the spatial point process model, particularly when cells arise along the boundary of a ring. We demonstrate the properties of TopKAT through simulation studies and apply it to two studies of triple negative breast cancer where we show that TopKAT recovers clinically relevant topological structures in the spatial distribution of immune and tumor cells.}, }
@article {pmid39807974, year = {2025}, author = {Kang, SK and Gulati, R and Moise, N and Hur, C and Elkin, EB}, title = {Multi-Cancer Early Detection Tests: State of the Art and Implications for Radiologists.}, journal = {Radiology}, volume = {314}, number = {1}, pages = {e233448}, doi = {10.1148/radiol.233448}, pmid = {39807974}, issn = {1527-1315}, mesh = {Humans ; *Early Detection of Cancer/methods ; *Neoplasms/diagnostic imaging ; Radiologists ; Biomarkers, Tumor/blood ; }, abstract = {Multi-cancer early detection (MCED) tests are already being marketed as noninvasive, convenient opportunities to test for multiple cancer types with a single blood sample. The technology varies-involving detection of circulating tumor DNA, fragments of DNA, RNA, or proteins unique to each targeted cancer. The priorities and tradeoffs of reaching diagnostic resolution in the setting of possible false positives and negatives remain under active study. Given the well-established role of imaging in lesion detection and characterization for most cancers, radiologists have an essential role to play in selecting diagnostic pathways, determining the validity of test results, resolving false-positive MCED test results, and evaluating tradeoffs for clinical policy. Appropriate access to and use of imaging tests will also factor into clinical guidelines. Thus, all clinicians potentially involved with MCED tests for cancer screening will need to weigh the benefits and harms of MCED testing, including consideration of how the tests will be used alongside or in place of other screening options, how diagnostic confirmation tests should be selected, and what the implications are for policy and reimbursement decisions. Further, patients will need regular support to make informed decisions about screening using MCED tests in the context of their personal cancer risks, health-related values, and access to care.}, }
@article {pmid39806218, year = {2025}, author = {Bajunaid, R and Niu, C and Hambly, C and Liu, Z and Yamada, Y and Aleman-Mateo, H and Anderson, LJ and Arab, L and Baddou, I and Bandini, L and Bedu-Addo, K and Blaak, EE and Bouten, CVC and Brage, S and Buchowski, MS and Butte, NF and Camps, SGJA and Casper, R and Close, GL and Cooper, JA and Cooper, R and Das, SK and Davies, PSW and Dabare, P and Dugas, LR and Eaton, S and Ekelund, U and Entringer, S and Forrester, T and Fudge, BW and Gillingham, M and Goris, AH and Gurven, M and El Hamdouchi, A and Haisma, HH and Hoffman, D and Hoos, MB and Hu, S and Joonas, N and Joosen, AM and Katzmarzyk, P and Kimura, M and Kraus, WE and Kriengsinyos, W and Kuriyan, R and Kushner, RF and Lambert, EV and Lanerolle, P and Larsson, CL and Leonard, WR and Lessan, N and Löf, M and Martin, CK and Matsiko, E and Medin, AC and Morehen, JC and Morton, JP and Must, A and Neuhouser, ML and Nicklas, TA and Nyström, CD and Ojiambo, RM and Pietiläinen, KH and Pitsiladis, YP and Plange-Rhule, J and Plasqui, G and Prentice, RL and Racette, SB and Raichlen, DA and Ravussin, E and Redman, LM and Reilly, JJ and Reynolds, R and Roberts, SB and Samaranayakem, D and Sardinha, LB and Silva, AM and Sjödin, AM and Stamatiou, M and Stice, E and Urlacher, SS and Van Etten, LM and van Mil, EGAH and Wilson, G and Yanovski, JA and Yoshida, T and Zhang, X and Murphy-Alford, AJ and Sinha, S and Loechl, CU and Luke, AH and Pontzer, H and Rood, J and Sagayama, H and Schoeller, DA and Westerterp, KR and Wong, WW and Speakman, JR}, title = {Predictive equation derived from 6,497 doubly labelled water measurements enables the detection of erroneous self-reported energy intake.}, journal = {Nature food}, volume = {}, number = {}, pages = {}, pmid = {39806218}, issn = {2662-1355}, support = {CAS 153E11KYSB20190015//Bureau of International Cooperation, Chinese Academy of Sciences/ ; BCS-1824466//National Science Foundation (NSF)/ ; }, abstract = {Nutritional epidemiology aims to link dietary exposures to chronic disease, but the instruments for evaluating dietary intake are inaccurate. One way to identify unreliable data and the sources of errors is to compare estimated intakes with the total energy expenditure (TEE). In this study, we used the International Atomic Energy Agency Doubly Labeled Water Database to derive a predictive equation for TEE using 6,497 measures of TEE in individuals aged 4 to 96 years. The resultant regression equation predicts expected TEE from easily acquired variables, such as body weight, age and sex, with 95% predictive limits that can be used to screen for misreporting by participants in dietary studies. We applied the equation to two large datasets (National Diet and Nutrition Survey and National Health and Nutrition Examination Survey) and found that the level of misreporting was >50%. The macronutrient composition from dietary reports in these studies was systematically biased as the level of misreporting increased, leading to potentially spurious associations between diet components and body mass index.}, }
@article {pmid39805421, year = {2025}, author = {Ajelli, M and Muyembe, JJ and Touré, A and Diallo, A and Litvinova, M and Merler, S and Mulangu, S and Bagayoko, A and Bah, A and Bah, I and Barry, A and Barry, F and Chérif, M and Condé, D and Diallo, AA and Diallo, F and Diakité, M and Doré, K and Mapan, KA and Koundouno, T and Onivogui, PK and Lamah, F and Maneno, H and Nomou, A and Sekouba, K and Sani, I and Soumah, A and Sy, MM and Gsell, PS and Halloran, ME and Henao-Restrepo, AM and Fall, IS and Ryan, MJ and Salama, P and Vespignani, A and Longini, IM}, title = {Vaccination Strategies for Ebola in the Democratic Republic of Congo: The WHO-Ebola Modeling Collaboration.}, journal = {International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases}, volume = {}, number = {}, pages = {107779}, doi = {10.1016/j.ijid.2025.107779}, pmid = {39805421}, issn = {1878-3511}, abstract = {OBJECTIVES: Assess the effectiveness of ring vaccination in controlling an Ebola virus outbreak in the Democratic Republic of Congo.<br><br>METHODS: This analysis focuses on two areas of the Democratic Republic of Congo, Beni and Butembo/Katwa, which were affected during the 2018-2020 Ebola outbreak. To simulate Ebola virus transmission, we used a spatially explicit agent-based model with households, health care facilities, and Ebola treatment units. Model parameters were calibrated using data collected under the ring-vaccination expanded-access protocol implemented during the outbreak. The model was used to estimate the impact of the deployed ring vaccination strategy, compared to what would have happened if there had been no ring vaccination. The impact of alternative vaccination strategies (mass vaccination, targeted geographic vaccination, and ring-plus) was evaluated as well.<br><br>RESULTS: Compared to a hypothetical scenario where vaccination was not implemented, ring vaccination was estimated to have averted 54.3% (SD, 32.5%) and 62.7% (SD, 23.2%) of potential cases in Beni and Butembo/Katwa, respectively. Under ring vaccination, the average number of averted cases per 1000 vaccine doses administered was 15.1 (SD, 16.8) and 27.8 (SD, 22.9), in Beni and Butembo/Katwa, respectively. In terms of number of averted cases per vaccine dose, ring vaccination was estimated to be more efficient than any of the other evaluated vaccination strategies.<br><br>CONCLUSION: Despite some level of social instability, ring vaccination with the rVSV-ZEBOV vaccine was highly effective during the 2018-2020 Ebola outbreak in the Democratic Republic of Congo. As compared to alternative vaccination strategies, ring vaccination was estimated to be the most efficient.}, }
@article {pmid39804957, year = {2025}, author = {Zakerzade, R and Chang, CH and Chatla, K and Krishnapura, A and Appiah, SP and Zhang, J and Unckless, RL and Blumenstiel, JP and Bachtrog, D and Wei, KH}, title = {Diversification and recurrent adaptation of the synaptonemal complex in Drosophila.}, journal = {PLoS genetics}, volume = {21}, number = {1}, pages = {e1011549}, doi = {10.1371/journal.pgen.1011549}, pmid = {39804957}, issn = {1553-7404}, abstract = {The synaptonemal complex (SC) is a protein-rich structure essential for meiotic recombination and faithful chromosome segregation. Acting like a zipper to paired homologous chromosomes during early prophase I, the complex is a symmetrical structure where central elements are connected on two sides by the transverse filaments to the chromatin-anchoring lateral elements. Despite being found in most major eukaryotic taxa implying a deeply conserved evolutionary origin, several components of the complex exhibit unusually high rates of sequence turnover. This is puzzlingly exemplified by the SC of Drosophila, where the central elements and transverse filaments display no identifiable homologs outside of the genus. Here, we exhaustively examine the evolutionary history of the SC in Drosophila taking a comparative phylogenomic approach with high species density to circumvent obscured homology due to rapid sequence evolution. Contrasting starkly against other genes involved in meiotic chromosome pairing, SC genes show significantly elevated rates of coding evolution due to a combination of relaxed constraint and recurrent, widespread positive selection. In particular, the central element cona and transverse filament c(3) G have diversified through tandem and retro-duplications, repeatedly generating paralogs with novel germline activity. In a striking case of molecular convergence, c(3) G paralogs that independently arose in distant lineages evolved under positive selection to have convergent truncations to the protein termini and elevated testes expression. Surprisingly, the expression of SC genes in the germline is prone to change suggesting recurrent regulatory evolution which, in many species, resulted in high testes expression even though Drosophila males are achiasmic. Overall, our study recapitulates the poor conservation of SC components, and further uncovers that the lack of conservation extends to other modalities including copy number, genomic locale, and germline regulation. Considering the elevated testes expression in many Drosophila species and the common ancestor, we suggest that the activity of SC genes in the male germline, while still poorly understood, may be a prime target of constant evolutionary pressures driving repeated adaptations and innovations.}, }
@article {pmid39801002, year = {2025}, author = {Schaub, SK and Simone, CB and Lo, SS and Choi, JI}, title = {The current landscape of oncologic emergencies: the role of radiotherapy.}, journal = {Annals of palliative medicine}, volume = {}, number = {}, pages = {}, doi = {10.21037/apm-24-159}, pmid = {39801002}, issn = {2224-5839}, }
@article {pmid39800921, year = {2025}, author = {Chen, A and Baek, G and Russell, K and Shaw, C and Othus, M and Cohen, J and Palmer, S and Rasmussen, J and Bubalo, J and Tsomo, T and Schwarz, T and Namburi, S and Halpern, A}, title = {Evaluation of the Toxicity and Outcomes of the Combination of Midostaurin and CLAG-M in Patients With FLT3-Mutated Acute Myeloid Leukemia (AML): A Multicenter Retrospective Analysis.}, journal = {The Annals of pharmacotherapy}, volume = {}, number = {}, pages = {10600280241305608}, doi = {10.1177/10600280241305608}, pmid = {39800921}, issn = {1542-6270}, abstract = {BACKGROUND: Addition of midostaurin to standard "7+3" (cytarabine and anthracycline) significantly prolongs overall and event-free survival. At University of Washington/Fred Hutchinson Cancer Center (UW/FHCC), the standard regimen for newly diagnosed (ND) and relapsed/refractory (R/R) AML is cladribine, high-dose cytarabine, GCSF, and mitoxantrone (CLAG-M); midostaurin is added if FLT3-mutated. There is limited data on the use of FLT3-inhibitors with high-dose cytarabine regimens in AML.<br><br>OBJECTIVE: This study aimed to evaluate the safety and efficacy of the combination of midostaurin with CLAG-M versus midostaurin plus 7+3 in FLT3-mutated AML patients.<br><br>METHODS: This is a retrospective, multicenter review including FLT3-mutated AML patients undergoing (re)induction chemotherapy with either CLAG-M or 7+3 at UW/FHCC, Oregon Health &amp; Science University, and Swedish Cancer Institute. The primary outcome was incidence of adverse events. Secondary outcomes included disease response per ELN2017 criteria and 28-day mortality. Excluded were patients on clinical trials or who started midostaurin 30 days after chemotherapy.<br><br>RESULTS: Eighty patients treated from September 2016 to December 2023 were included; 36 patients received CLAG-M, and 44 patients 7+3. Baseline characteristics were similar across all institutions. Adverse event rates were similar between the 2 cohorts, except diarrhea and bleeding which were more common in the 7+3 cohort. The rate of complete remission (CR) plus CR with incomplete blood count recovery did not significantly differ between the 2 cohorts: CLAG-M, 86% versus 7+3, 70% (P = 0.11).<br><br>CONCLUSION &amp; RELEVANCE: The toxicity profile of CLAG-M combined with midostaurin is comparable with the combination of 7+3 with midostaurin, and induces high remissions rates in adults with FLT3-mutated AML.}, }
@article {pmid39800670, year = {2025}, author = {Najjar, R and Wang, X and Pineda, JMB and Alessi, H and Bays, A and Bradley, RK and Jarvis, JN and Mustelin, T}, title = {Altered Protein Structures and Neoepitopes in Lupus Neutrophils From Dysregulated Splicing of Messenger RNA.}, journal = {ACR open rheumatology}, volume = {7}, number = {1}, pages = {e11770}, pmid = {39800670}, issn = {2578-5745}, support = {AI188952/RG/CSR NIH HHS/United States ; AR075134, AR074939, and AR081654 to T.M./RG/CSR NIH HHS/United States ; AI-186337 and AI-183320 (to Dr Mustelin)/GF/NIH HHS/United States ; }, abstract = {OBJECTIVE: To test whether messenger RNA (mRNA) splicing is altered in neutrophils from patients with systemic lupus erythematosus (SLE) and can produce neoantigens.<br><br>METHODS: RNA sequencing of neutrophils from patients with SLE (n = 15) and healthy donors (n = 12) were analyzed for mRNA splicing using the RiboSplitter pipeline, an event-focused tool based on SplAdder with subsequent translation and protein domain annotation. RNA sequencing from SARS-CoV2-infected individuals was used as an additional comparator.<br><br>RESULTS: Neutrophils from patients with SLE contained 521 statistically significant altered mRNA splicing events compared with healthy donor neutrophils, many of them affecting important immunologic pathways, myeloid function, transcription factors, and proteins involved in mRNA splicing. A subset of splicing events were only present in SLE samples, and some of them occurred at unannotated splice acceptor or donor sites. Two patients were particularly rich in such events. Only a small number of dysregulated splicing events were more pronounced in patients with active disease or with high type I interferons but were not detected in SARS-CoV2-infected individuals, who also had high type I interferons. Besides causing a range of structural changes, 80 mRNA splice variants exclusive to SLE were predicted to translate into novel amino acid sequences. Peptides derived from these novel amino acid sequences were predicted to bind to the individual patients' class I and II major histocompatibility complex molecules with high affinity.<br><br>CONCLUSION: We conclude that aberrant mRNA splicing in SLE has the potential to affect both the function of granulocytes and to generate novel autoantigens.}, }
@article {pmid39763936, year = {2024}, author = {Fang, A and Kumar, L and Creevy, KE and ,  and Promislow, DEL and Ma, J}, title = {The first comorbidity networks in companion dogs in the Dog Aging Project.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39763936}, issn = {2692-8205}, support = {U19 AG057377/AG/NIA NIH HHS/United States ; }, abstract = {Comorbidity and its association with age are of great interest in geroscience. However, there are few model organisms that are well-suited to study comorbidities that will have high relevance to humans. In this light, we turn our attention to the companion dog. The companion dog shares many morbidities with humans. Thus, a better understanding of canine comorbidity relationships could benefit both humans and dogs. We present an analysis of canine comorbidity networks from the Dog Aging Project, a large epidemiological cohort study of companion dogs in the United States. We included owner-reported health conditions that occurred in at least 60 dogs (n=166) and included only dogs that had at least one of those health conditions (n=26,523). We constructed an undirected comorbidity network using a Poisson binomial test, adjusting for age, sex, sterilization status, breed background (i.e., purebred vs. mixed-breed), and weight. The comorbidity network reveals well-documented comorbidities, such as diabetes with blindness and hypertension with chronic kidney disease. In addition, this network also supports less well-studied comorbidity relationships, such as proteinuria with anemia. A directed comorbidity network accounting for time of reported condition onset suggests that diabetes occurs before cataracts, which is consistent with the canine literature. Analysis of age-stratified networks reveals that global centrality measures increase with age and are the highest in the Senior group compared to the Young Adult and Mature Adult groups. Our results suggest that comorbidity network analysis is a promising method to enhance clinical knowledge and canine healthcare management.}, }
@article {pmid39763889, year = {2024}, author = {Park, J and Prokopchuk, G and Popchock, AR and Hao, J and Liao, TW and Yan, S and Hedman, DJ and Larson, JD and Walther, BK and Becker, NA and Basu, A and Maher, LJ and Wheeler, RJ and Asbury, CL and Biggins, S and Lukeš, J and Ha, T}, title = {Probing mechanical selection in diverse eukaryotic genomes through accurate prediction of 3D DNA mechanics.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39763889}, issn = {2692-8205}, support = {R35 GM143949/GM/NIGMS NIH HHS/United States ; R35 GM149357/GM/NIGMS NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; R35 GM122569/GM/NIGMS NIH HHS/United States ; R35 GM134842/GM/NIGMS NIH HHS/United States ; }, abstract = {Connections between the mechanical properties of DNA and biological functions have been speculative due to the lack of methods to measure or predict DNA mechanics at scale. Recently, a proxy for DNA mechanics, cyclizability, was measured by loop-seq and enabled genome-scale investigation of DNA mechanics. Here, we use this dataset to build a computational model predicting bias-corrected intrinsic cyclizability, with near-perfect accuracy, solely based on DNA sequence. Further, the model predicts intrinsic bending direction in 3D space. Using this tool, we aimed to probe mechanical selection - that is, the evolutionary selection of DNA sequence based on its mechanical properties - in diverse circumstances. First, we found that the intrinsic bend direction of DNA sequences correlated with the observed bending in known protein-DNA complex structures, suggesting that many proteins co-evolved with their DNA partners to capture DNA in its intrinsically preferred bent conformation. We then applied our model to large-scale yeast population genetics data and showed that centromere DNA element II, whose consensus sequence is unknown, leaving its sequence-specific role unclear, is under mechanical selection to increase the stability of inner-kinetochore structure and to facilitate centromeric histone recruitment. Finally, in silico evolution under strong mechanical selection discovered hallucinated sequences with cyclizability values so extreme that they required experimental validation, yet, found in nature in the densely packed mitochondrial(mt) DNA of Namystynia karyoxenos, an ocean-dwelling protist with extreme mitochondrial gene fragmentation. The need to transmit an extraordinarily large amount of mtDNA, estimated to be > 600 Mb, in combination with the absence of mtDNA compaction proteins may have pushed mechanical selection to the extreme. Similarly extreme DNA mechanics are observed in bird microchromosomes, although the functional consequence is not yet clear. The discovery of eccentric DNA mechanics in unrelated unicellular and multicellular eukaryotes suggests that we can predict extreme natural biology which can arise through strong selection. Our methods offer a way to study the biological functions of DNA mechanics in any genome and to engineer DNA sequences with desired mechanical properties.}, }
@article {pmid39763555, year = {2024}, author = {Li, R and Taliun, SAG and Liao, K and Flickinger, M and Sobell, JL and Genovese, G and Locke, AE and Chiu, RR and LeFaive, J and Martins, T and Chapman, S and Neumann, A and Handsaker, RE and Arnett, DK and Barnes, KC and Boerwinkle, E and Braff, D and Cade, BE and Fornage, M and Gibbs, RA and Hoth, KF and Hou, L and Kooperberg, C and Loos, RJF and Metcalf, GA and Montgomery, CG and Morrison, AC and Qin, ZS and Redline, S and Reiner, AP and Rich, SS and Rotter, JI and Taylor, KD and Viaud-Martinez, KA and ,  and ,  and Bigdeli, TB and Gabriel, S and Zollner, S and Smith, AV and Abecasis, G and McCarroll, S and Pato, MT and Pato, CN and Boehnke, M and Knowles, J and Kang, HM and Ophoff, RA and Ernst, J and Scott, LJ}, title = {Whole genome sequence-based association analysis of African American individuals with bipolar disorder and schizophrenia.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39763555}, support = {R01 HL120393/HL/NHLBI NIH HHS/United States ; U54 HG003067/HG/NHGRI NIH HHS/United States ; DP1 DA044371/DA/NIDA NIH HHS/United States ; U01 HG012079/HG/NHGRI NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; HHSN268201500014C/HL/NHLBI NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; HHSN268201600033C/HL/NHLBI NIH HHS/United States ; R01 HL055673/HL/NHLBI NIH HHS/United States ; U01 MH105653/MH/NIMH NIH HHS/United States ; R01 HL089856/HL/NHLBI NIH HHS/United States ; U54 HG003273/HG/NHGRI NIH HHS/United States ; R01 HL098433/HL/NHLBI NIH HHS/United States ; R01 HL113326/HL/NHLBI NIH HHS/United States ; HHSN268201500015C/HL/NHLBI NIH HHS/United States ; R01 MH115676/MH/NIMH NIH HHS/United States ; R01 HL104608/HL/NHLBI NIH HHS/United States ; R01 HG009976/HG/NHGRI NIH HHS/United States ; }, abstract = {In studies of individuals of primarily European genetic ancestry, common and low-frequency variants and rare coding variants have been found to be associated with the risk of bipolar disorder (BD) and schizophrenia (SZ). However, less is known for individuals of other genetic ancestries or the role of rare non-coding variants in BD and SZ risk. We performed whole genome sequencing of African American individuals: 1,598 with BD, 3,295 with SZ, and 2,651 unaffected controls (InPSYght study). We increased power by incorporating 14,812 jointly called psychiatrically unscreened ancestry-matched controls from the Trans-Omics for Precision Medicine (TOPMed) Program for a total of 17,463 controls. To identify variants and sets of variants associated with BD and/or SZ, we performed single-variant tests, gene-based tests for singleton protein truncating variants, and rare and low-frequency variant annotation-based tests with conservation and universal chromatin states and sliding windows. We found suggestive evidence of BD association with single-variants on chromosome 18 and of lower BD risk associated with rare and low-frequency variants on chromosome 11 in a region with multiple BD GWAS loci, using a sliding window approach. We also found that chromatin and conservation state tests can be used to detect differential calling of variants in controls sequenced at different centers and to assess the effectiveness of sequencing metric covariate adjustments. Our findings reinforce the need for continued whole genome sequencing in additional samples of African American individuals and more comprehensive functional annotation of non-coding variants.}, }
@article {pmid39799046, year = {2024}, author = {Ramasamy, K and Vij, R and Kuter, D and Cella, D and Durie, BGM and Abonour, R and Rifkin, RM and Ailawadhi, S and Lee, HC and Cowan, AJ and Ho, C and Dhanasiri, S and Fish, S and Yu, E and Dhamane, AD and Fang, J and Marshall, TS and Samuel, A and Liu, L and Katz, J and Gu, T and Jagannath, S}, title = {Real-World Treatment Patterns and Clinical Outcomes in Patients With Multiple Myeloma Previously Treated With Lenalidomide and an Anti-CD38 Monoclonal Antibody.}, journal = {Clinical lymphoma, myeloma &amp; leukemia}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.clml.2024.12.002}, pmid = {39799046}, issn = {2152-2669}, abstract = {BACKGROUND: This analysis explored real-world characteristics, treatment patterns and clinical outcomes in patients with relapsed or refractory multiple myeloma (RRMM) previously treated with lenalidomide and an anti-CD38 monoclonal antibody (mAb) and requiring subsequent treatment.<br><br>MATERIALS AND METHODS: The PREAMBLE and Connect MM prospective registries of patients with multiple myeloma (MM), and the US nationwide Flatiron Health electronic health record-derived de-identified database were analysed. MM-specific treatment patterns (prior/index therapies) and outcomes (progression-free survival [PFS]/overall survival [OS]) were assessed.<br><br>RESULTS: This analysis included: PREAMBLE n = 215; Connect MM n = 232; Flatiron Health n = 845. Median age at index was 69.0 years, median 3 prior lines of therapy; > 50% male. The most common index regimens accounted < 15% of treatments (most common PREAMBLE, Connect MM: carfilzomib&#xb1;dexamethasone; Flatiron Health: pomalidomide+daratumumab+dexamethasone); most patients received classes that they had previously; &#x2265; 93% were triple-class exposed (immunomodulatory drug, proteasome inhibitor, anti-CD38 mAb). In PREAMBLE, Connect MM and Flatiron Health, respectively: 80.9%, 68.1% and 77.2% were lenalidomide- and anti-CD38 mAb-refractory; 69.3%, 67.2% and 71.1% were triple-class refractory (TCR); median PFS: 5.2 (95% CI 3.7-6.7), 4.4 (3.5-5.6) and 5.3 months (4.8-6.0); median OS: 19.3 (15.8-26.1), 14.2 (11.0-16.9) and 23.1 months (19.0-28.6). PFS and OS were shorter in lenalidomide- and anti-CD38 mAb-refractory patients versus those who were not refractory to both. A similar pattern was observed for TCR patients versus non-TCR patients.<br><br>CONCLUSION: There is no uniform standard of care for patients with RRMM with prior exposure to lenalidomide and anti-CD38 mAbs. Survival outcomes are poor, with a need for effective treatments for these patients.}, }
@article {pmid39798802, year = {2025}, author = {Petersdorf, EW and McKallor, C and Malkki, M and Hsu, K and He, M and Spellman, SR and Gooley, T and Stevenson, P}, title = {The Association of HLA-E Ligand and NKG2 Receptor Variation with Relapse and Mortality after Haploidentical Related Donor Transplantation.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.01.004}, pmid = {39798802}, issn = {2666-6367}, abstract = {BACKGROUND: Recurrence of blood malignancy is the major cause of mortality after hematopoietic cell transplantation. NKG2 receptor/HLA-E ligand complexes play a fundamental role in the surveillance and elimination of transformed cells but their role in the control of leukemia in transplantation is unknown.<br><br>OBJECTIVE: We tested the hypothesis that gene variation of patient and/or donor HLA-E ligand and donor NKG2C-NKG2A receptors are associated with the risks of relapse and mortality (primary endpoints) and GVHD and non-relapse mortality (secondary endpoints) after haploidentical transplantation.<br><br>STUDY DESIGN: We retrospectively defined donor NKG2 receptor haplotypes and patient HLA-E ligands in 1629 haploidentical related transplantations. HLA-E residue 107 was genotyped in patients and donors. Single nucleotide polymorphisms descriptive of NKG2C and NKG2A haplotypes were characterized in donors. Overall mortality, relapse, non-relapse mortality and chronic GVHD were studied using Cox regression models. Acute GVHD was studied by logistic regression.<br><br>RESULTS: The hazard of relapse for patients transplanted from NKG2C-del/del donors was 51% lower than that from wt/wt donors (hazard ratio, HR, 0.49 [95% confidence interval, CI, 0.26-0.89) contributing to a HR for mortality of 0.62 (95% CI, 0.38-1.02). The HR of mortality among patients transplanted from a donor with 2 vs. 0 copies of the NKG2A rs35909400-rs2734440-rs12824474 CCC haplotype was HR 2.28 (95% CI, 1.34-3.86). The HRs of mortality for ArgArg and ArgGly patients compared to GlyGly patients were 1.42 (95% CI, 1.11-1.82) and 1.43 (95% CI, 1.13-1.81), respectively. Hazard ratios for non-relapse mortality for patients with ArgGly or ArgArg genotypes compared to patients with GlyGly genotype were HR 1.60 (95% CI, 1.06-2.41) and HR 1.79 (95% CI, 1.21-2.66), respectively. Assessment of donor receptor/patient ligand pairings showed that among Arg-positive patients, the HR of mortality from donors with any wt-CCC/CCC haplotype was HR 2.52 (95% CI, 1.45-4.38) relative to donors with any wt-non CCC/CCC haplotype.<br><br>CONCLUSIONS: The success of haploidentical transplantation may be defined by the cumulative effects of donor NKG2 receptor and patient HLA-E ligand polymorphisms. Patient HLA-E ligand and donor NKG2C-NKG2A receptor haplotypes shed new light on their role in the control of malignancy.}, }
@article {pmid39798608, year = {2025}, author = {Marshall, A and Kassim, S and Brown-Korsah, J and Chang, C and Hippe, DS and Kim, EJ and Shinohara, MM}, title = {Black Patients with Mycosis Fungoides and Sézary Syndrome Experience Worse Health-Related Quality of Life: A Cross-Sectional Study.}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2025.01.006}, pmid = {39798608}, issn = {1097-6787}, }
@article {pmid39798390, year = {2024}, author = {Talukder, R and Bakaloudi, DR and Makrakis, D and Diamantopoulos, LN and Enright, T and Leary, JB and Raychaudhuri, R and Tripathi, N and Agarwal, N and Jindal, T and Brown, JR and Zakharia, Y and Rey-Cárdenas, M and Castellano, D and Nguyen, CB and Alva, A and Zakopoulou, R and Bamias, A and Barrera, RM and Marmolejo, D and Drakaki, A and Pinato, DJ and Korolewicz, J and Buznego, LA and Duran, I and Carballeira, CC and McKay, RR and Stewart, TF and Gupta, S and Barata, P and Yu, EY and Koshkin, VS and Khaki, AR and Grivas, P}, title = {Clinical Outcomes With Immune Checkpoint Inhibitors in Patients With FGFR2/3, MTAP or ERBB2 Genomic Alterations in Advanced Urothelial Carcinoma.}, journal = {Clinical genitourinary cancer}, volume = {23}, number = {1}, pages = {102284}, doi = {10.1016/j.clgc.2024.102284}, pmid = {39798390}, issn = {1938-0682}, abstract = {BACKGROUND: FGFR2/3, MTAP and ERBB2 genomic alterations have treatment targets in advanced urothelial carcinoma (aUC). These alterations may affect tumor microenvironment and outcomes with immune checkpoint inhibitors (ICIs) in aUC.<br><br>PATIENTS AND METHODS: We identified patients with available genomic data in our multi-institution cohort of patients with aUC treated with ICI. Outcomes (observed response rate [ORR], progression-free and overall survival [PFS, OS]) with ICI were compared between patients with and without FGFR 2/3, MTAP, ERBB2 alterations. We compared ORR using logistic regression and PFS/OS using Cox proportional hazards.<br><br>RESULTS: Out of 1,514 patients, 276 (18%), 174 (11%) and 208 (14%) patients had known FGFR2/3, MTAP and ERBB2 alteration status, respectively. and were treated with ICI in 1L or 2 + L. In patients with (vs. without) FGFR2/3 alteration, ORR with ICI was 21% vs. 32% (OR 0.54; [95%CI 0.32-0.91]), PFS was significantly shorter in patients with FGFR2/3 alterations (HR = 1.36 [95%CI 1.03-1.80]; P=0.03); OS was not significantly different (HR = 1.22 [95%CI 0.86-1.47]). In patients with (vs. without) MTAP alteration, ORR with ICI was 25% versus 40% (OR 0.52 [95%CI 0.20-1.38]); PFS and OS were nonsignificantly different. In patients with (vs. without) ERBB2 alteration, ORR with ICI was similar (37% vs. 35%; OR 1.06; 95%CI 0.57-1.97); PFS and OS were significantly longer in patients with ERBB2 alteration [HR 0.63 (95%CI 0.41-0.95); P=0.03; HR 0.66, [95% CI 0.44-0.97]), respectively.<br><br>CONCLUSION: Our results support further evaluation of FGFR2/3, MTAP and ERBB2 alterations as putative biomarkers in patients with aUC treated with ICI.}, }
@article {pmid39796789, year = {2024}, author = {Dekker, SE and Deng, L}, title = {Correction: Dekker, S.E.; Deng, L. Clinical Advances and Challenges in Targeting KRAS Mutations in Non-Small Cell Lung Cancer. Cancers 2024, 16, 3885.}, journal = {Cancers}, volume = {17}, number = {1}, pages = {}, pmid = {39796789}, issn = {2072-6694}, abstract = {In the original publication [...].}, }
@article {pmid39763863, year = {2024}, author = {Farrell-Sherman, A and de la Force, N and Prator, C and Valieris, R and Azam, W and Da Silva, I and Deeks, SG and Thanh, C and Bosch, R and Henrich, TJ and Cohn, L}, title = {Inflammatory Monocytes Increase Prior to Detectable HIV-1 Rebound Viremia.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39763863}, issn = {2692-8205}, support = {K24 AI174971/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 AI141003/AI/NIAID NIH HHS/United States ; UM1 AI164560/AI/NIAID NIH HHS/United States ; }, abstract = {The persistence of HIV-1 proviruses in latently infected cells allows viremia to resume upon treatment cessation. To characterize the resulting immune response, we compare plasma proteomics and single-cell transcriptomics of peripheral blood mononuclear cells (PBMCs) before, during, and after detectable plasma viremia. We observe unique transcriptional signatures prior to viral rebound including a significant increase in CD16[++] monocytes with increased anti-viral gene expression. Inflammatory proteins were identified in plasma after detectable rebound. Identifying early signals of imminent viral rebound after treatment cessation will aid in the development of strategies to prolong time to viral rebound and cure HIV-1.}, }
@article {pmid39793544, year = {2025}, author = {Wheeler, SB and Thom, B and Waters, AR and Shankaran, V}, title = {Interventions to Address Cancer-Related Financial Hardship: A Scoping Review and Call to Action.}, journal = {JCO oncology practice}, volume = {21}, number = {1}, pages = {29-40}, doi = {10.1200/OP.24.00375}, pmid = {39793544}, issn = {2688-1535}, mesh = {Humans ; *Neoplasms/therapy/economics/epidemiology ; *Financial Stress ; }, abstract = {PURPOSE: As oncology practices implement routine screening for financial hardship (FH) and health-related social needs, interventions that address these needs must be implemented. A growing body of literature has reported on FH interventions.<br><br>METHODS: We conducted a scoping review of the literature using PubMed, EMBASE, PsychInfo, and CINAHL to identify key studies (2000-2024) reporting on interventions to address cancer-related FH. Full-length manuscripts were included in the review if they detailed a research, quality improvement, or community-based intervention to address at least one element of FH and drew association with an outcome of interest. Studies were categorized by intervention type and qualitatively analyzed to identify critical components, outcomes, and limitations.<br><br>RESULTS: Forty-four publications reporting on 43 interventions were included in the final analysis and were categorized as research interventions (n = 20) and real-world programs (n = 20). Studies reporting on financial navigation programs (n = 17) and specialty pharmacy assistance programs (n = 11) were most common; enrolled patients received concrete assistance with direct medical costs and cost-of-living expenses (eg, transportation and food). In addition, several of these programs improved overall patient-reported financial toxicity, decreased appointment no-shows, and improved enrollment in clinical trials.<br><br>CONCLUSION: Interventions to address FH are feasible and can address all domains of FH-material, behavioral, and psychosocial. Future research should address the uptake and implementation of these interventions across diverse cancer care delivery settings. Such programs will be an essential part of cancer care delivery until broad social and policy changes can address the underlying factors that contribute to FH in Americans with cancer.}, }
@article {pmid39792043, year = {2025}, author = {Galvin, RT and Chen, Y and Yuan, Y and Cooney, T and Howell, R and Smith, S and Arnold, MA and Conces, M and Leisenring, W and Armstrong, GT and Neglia, JP and Turcotte, LM}, title = {Temporal Trends of Subsequent CNS Malignancies Among Survivors of Childhood Cancer.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djaf005}, pmid = {39792043}, issn = {1460-2105}, abstract = {PURPOSE: It is not known whether temporal changes in childhood cancer therapy have reduced risk of subsequent malignant neoplasms (SMNs) of the central nervous system (CNS), a frequently fatal late effect of cancer therapy.<br><br>METHODS: Five-year survivors of primary childhood cancers diagnosed between 1970-1999 in the Childhood Cancer Survivor Study with a subsequent CNS SMN were identified. Cumulative incidence rates and standardized incidence ratios (SIR) were compared among survivors diagnosed between 1970-1979 (N&#x2009;=&#x2009;6223), 1980-1989 (N&#x2009;=&#x2009;9680), and 1990-1999 (N&#x2009;=&#x2009;8999). Multivariable models assessed risk factors for CNS SMN.<br><br>RESULTS: 157 CNS SMNs (1970s, 52; 1980s, 63; 1990s, 42) were identified, excluding meningiomas, which were most often malignant gliomas. The proportion of survivors receiving any cranial radiotherapy (CRT) exposure was reduced over time (1970s 77.0%, 1980s 54.3%, 1990s 33.9%), while the proportion receiving >35Gy CRT showed a smaller reduction (11.4%, 10.8%, and 8.5%, respectively). Twenty-year cumulative incidence (95% CI) and SIR (95% CI) for CNS SMN by treatment decade were 0.32% (0.18-0.46%) and 6.6 (5.0-8.7); 0.55% (0.41-0.70%) and 8.3 (6.6-10.4); and 0.43% (0.31-0.55%) and 9.2 (7.0-12.0), respectively, with no statistically significant decreases between eras. Multivariable analyses showed increased risk for CRT dose levels >10Gy and for primary diagnoses of medulloblastoma/PNET (HR 18.7, 9.2-37.9) and astrocytoma (HR 10.1, 5.3-19.5). Three-year cumulative incidence of death after CNS SMN, by treatment decade, were 76%, 74%, and 73%, respectively.<br><br>CONCLUSION: CNS SMN incidence has not decreased despite fewer survivors exposed to CNS-directed radiotherapy. CNS SMNs remain a substantial source of mortality for affected patients.}, }
@article {pmid39790992, year = {2024}, author = {Ruiz, RA and Lehavot, K and Heffner, JL and Kava, CM and Ornelas, IJ}, title = {Coping and Social Support in Relation to Minority Stress and Cigarette Smoking Among Lesbian, Gay, and Bisexual Veterans.}, journal = {Annals of LGBTQ public and population health}, volume = {5}, number = {4}, pages = {335-352}, pmid = {39790992}, issn = {2688-4518}, support = {I01 HX002423/HX/HSRD VA/United States ; T32 CA092408/CA/NCI NIH HHS/United States ; T32 CA193193/CA/NCI NIH HHS/United States ; }, abstract = {The intersection between a minoritized sexual orientation identity and a U.S. military Veteran status places lesbian, gay, and bisexual (LGB) Veterans at increased risk for cigarette smoking. Guided by the Minority Stress Model, this study assessed whether coping and three types of social support (general, Veteran-specific, and lesbian, gay, bisexual, and transgender [LGBT]-specific) moderated the association between minority stressors and past-year smoking among LGB Veterans. Participants were recruited online for a prospective cohort study. We conducted secondary data analysis of baseline surveys collected from September 2019 to December 2020. The study sample included cisgender LGB Veterans (N = 463). Adjusted multivariable logistic regression models estimated the odds of past-year smoking with interaction terms between minority stressors and coping/social support to test for moderation. Four statistically significant interaction terms were found. Higher versus lower levels (i.e., one-point score increase) of coping buffered the relationship between victimization and past-year smoking; Veteran-specific social support buffered the relationship between interpersonal LGB military stress and past-year smoking; and LGBT-specific social support buffered the relationship between intrapersonal LGB military stress and past-year smoking. However, general social support strengthened the relationship between social exclusion and past-year smoking. Findings provide some evidence for the minority stress model; however, regarding cigarette smoking, coping and social support may mitigate stress in some cases and exacerbate stress in others. LGB Veterans may benefit from learning positive coping skills and leveraging social support linked to LGB and Veteran identities to support smoking cessation.}, }
@article {pmid39789324, year = {2025}, author = {Du, Z and Pandey, A and Moghadas, SM and Bai, Y and Wang, L and Matrajt, L and Singer, BH and Galvani, AP}, title = {Impact of RSVpreF vaccination on reducing the burden of respiratory syncytial virus in infants and older adults.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {39789324}, issn = {1546-170X}, abstract = {Respiratory syncytial virus (RSV) causes a substantial health burden among infants and older adults. Prefusion F protein-based vaccines have shown high efficacy against RSV disease in clinical trials, offering promise for mitigating this burden through maternal and older adult immunization. Employing an individual-based model, we evaluated the impact of RSV vaccination on hospitalizations and deaths in 13 high-income countries, assuming that the vaccine does not prevent infection or transmission. Using country-specific vaccine uptake rates for seasonal influenza, we found that vaccination of older adults would prevent hospitalizations by a median of 35-64% across the countries studied here. Vaccination of pregnant women could avert infant hospitalizations by 5-50%. Reductions in RSV-related mortality mirrored those estimated for hospitalizations. While substantial hospitalization costs could be averted, the impact of vaccination depends critically on uptake rates. Enhancing uptake and accessibility is crucial for maximizing the real-world impact of vaccination on reducing RSV burden among vulnerable populations.}, }
@article {pmid39788927, year = {2025}, author = {Cardle, II and Raman, J and Nguyen, DC and Wang, T and Wu, AY and Sellers, DL and Pichon, TJ and Cheng, EL and Kacherovsky, N and Salipante, SJ and Jensen, MC and Pun, SH}, title = {DNA Aptamer-Polymer Conjugates for Selective Targeting of Integrin α4β1[+] T-Lineage Cancers.}, journal = {ACS applied materials &amp; interfaces}, volume = {}, number = {}, pages = {}, doi = {10.1021/acsami.4c17788}, pmid = {39788927}, issn = {1944-8252}, abstract = {Selective therapeutic targeting of T-cell malignancies is difficult due to the shared lineage between healthy and malignant T cells. Current front-line chemotherapy for these cancers is largely nonspecific, resulting in frequent cases of relapsed/refractory disease. The development of targeting approaches for effectively treating T-cell leukemia and lymphoma thus remains a critical goal for the oncology field. Here, we report the discovery of a DNA aptamer, named HR7A1, that displays low nanomolar affinity for the integrin α4β1 (VLA-4), a marker associated with chemoresistance and relapse in leukemia patients. After truncation of HR7A1 to a minimal binding motif, we demonstrate elevated binding of the aptamer to T-lineage cancer cells over healthy immune cells. Using cryo-EM and competition studies, we find that HR7A1 shares an overlapping binding site on α4β1 with fibronectin and VCAM-1, which has implications for sensitizing blood cancers to chemotherapy. We last characterize barriers to in vivo aptamer translation, including serum stability, temperature-sensitive binding, and short circulation half-life, and synthesize an aptamer-polymer conjugate that addresses these challenges. Future work will seek to validate in vivo targeting of α4β1[+] tumors with the conjugate, establishing an aptamer-based biomaterial that can be readily adapted for targeted treatment of T-cell malignancies.}, }
@article {pmid39787437, year = {2025}, author = {Yu, EY and Rumble, RB and Agarwal, N and Cheng, HH and Eggener, SE and Bitting, RL and Beltran, H and Giri, VN and Spratt, D and Mahal, B and Lu, K and Crispino, T and Trabulsi, EJ}, title = {Germline and Somatic Genomic Testing for Metastatic Prostate Cancer: ASCO Guideline.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2402608}, doi = {10.1200/JCO-24-02608}, pmid = {39787437}, issn = {1527-7755}, abstract = {PURPOSE: To evaluate evidence on germline and somatic genomic testing for patients with metastatic prostate cancer and provide recommendations.<br><br>METHODS: A systematic review by a multidisciplinary panel with patient representation was conducted. The PubMed database was searched from January 2018 to May 2024. Articles were selected for inclusion if they reported on patients with metastatic prostate cancer who received a germline or somatic genomic test and/or made comparisons between those tests, reported detection rates, prognostic information, or treatment implications.<br><br>RESULTS: A total of 1,713 papers were identified in the literature search. After applying the eligibility criteria, 14 remained: eight systematic reviews and six clinical trials.<br><br>RECOMMENDATIONS: Patients with metastatic prostate cancer should undergo both germline and somatic DNA sequencing using panel-based assays. These tests can guide the use of poly(ADP-ribose) polymerase inhibitors, which have a survival benefit in metastatic castration-resistant prostate cancer. In addition, germline testing may have screening implications for additional cancers for patients and cascade testing implications for family members. The data supporting when to perform repeat testing and optimal tissue type to use (eg, primary tumor v metastatic biopsy versus circulating tumor DNA [ctDNA] testing) are more limited, but this panel recommends considering retesting in patients whose results were previously negative or uninformative, and to consider either a metastatic biopsy or ctDNA when a significant change in clinical status occurs. Next-generation genomic sequencing findings that are associated with prognostic only (and not predictive) value should not be used to guide treatment outside of a clinical trial.Additional information is available at www.asco.org/genitourinary-cancer-guidelines.}, }
@article {pmid39787247, year = {2025}, author = {Welti, J and Bogdan, D and Figueiredo, I and Coleman, I and Jiménez Vacas, J and Liodaki, K and Weigl, F and Buroni, L and Zeng, W and Bernett, I and Bertan, C and Roumeliotis, TI and Bhamra, A and Rekowski, J and Gurel, B and Neeb, AJ and Ning, J and Li, D and Gil, VS and Riisnaes, R and Miranda, S and Crespo, M and Ferreira, A and Tunariu, N and Pasqua, E and Chessum, N and Cheeseman, M and Te Poele, R and Powers, M and Carreira, S and Choudhary, J and Clarke, P and Banerji, U and Swain, A and Jones, K and Yuan, W and Workman, P and Nelson, PS and de Bono, JS and Sharp, A}, title = {NXP800 activates the unfolded protein response, altering AR and E2F function to impact castration-resistant prostate cancer growth.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-24-2386}, pmid = {39787247}, issn = {1557-3265}, abstract = {PURPOSE: Advanced prostate cancer (PCa) is invariably fatal with the androgen receptor (AR) being a major therapeutic target. AR signaling inhibitors have improved overall survival for men with advanced PCa, but treatment resistance is inevitable and includes reactivation of AR signaling. Novel therapeutic approaches targeting these mechanisms to block tumor growth is an urgent unmet clinical need. One attractive strategy is to target heat shock proteins critical to AR functional activity.<br><br>EXPERIMENTAL DESIGN: We first did transcriptome analysis on multiple castration-resistant PCa (CRPC) cohorts to correlate the association between the GO Cellular Response to Heat gene expression signature and overall survival. Next, we analyzed the impact of targeting the heat shock factor 1 (HSF1) pathway, with an inhibitor in clinical development, namely NXP800, in models of treatment-resistant PCa. Finally, we confirmed our mechanistic and phenotypic findings using an NXP800-resistant model and an in-vivo model of CRPC.<br><br>RESULTS: We report that in multiple CRPC transcriptome cohorts the GO Cellular Response to Heat gene expression signature associates with AR signaling and worse clinical outcome. We demonstrate the effects of targeting the HSF1 pathway, central to cellular stress, with an inhibitor in clinical development, namely NXP800 (formerly CCT361814), in PCa. Targeting the HSF1 pathway with the inhibitor NXP800 decreases HSP72 expression, activates the unfolded protein response, and inhibits AR- and E2F-mediated activity, inhibiting the growth of treatment-resistant PCa models.<br><br>CONCLUSIONS: Overall, NXP800 has anti-tumor activity against treatment-resistant PCa models, including molecular subtypes with limited treatment options, supporting its consideration for PCa-specific clinical development.}, }
@article {pmid39786434, year = {2024}, author = {Lee, SJ and Zeiser, R}, title = {FDA-approved therapies for chronic GVHD.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024026633}, pmid = {39786434}, issn = {1528-0020}, abstract = {Despite novel prophylactic regimens, chronic graft-versus-host disease (cGVHD) remains a challenging complication after allogeneic hematopoietic cell transplantation. Chronic GVHD can affect multiple organs and reduces quality of life, and treatment can cause serious side effects. In the last ten years, the drugs ibrutinib, ruxolitinib, belumosudil and axatilimab were FDA-approved for cGVHD. Here we discuss which signaling pathways and cell types are targeted, the clinical studies that were the basis for FDA-approval, and future directions for clinical research.}, }
@article {pmid39763564, year = {2024}, author = {Huang, YJ and Kurniansyah, N and Goodman, MO and Spitzer, BW and Wang, J and Stilp, A and Laurie, C and de Vries, PS and Chen, H and Min, YI and Sims, M and Peloso, GM and Guo, X and Bis, JC and Brody, JA and Raffield, LM and Smith, JA and Zhao, W and Rotter, JI and Rich, SS and Redline, S and Fornage, M and Kaplan, R and Franceschini, N and Levy, D and Morrison, AC and Boerwinkle, E and Smith, NL and Kooperberg, C and Psaty, BM and Zöllner, S and ,  and Sofer, T}, title = {The expected polygenic risk score (ePRS) framework: an equitable metric for quantifying polygenetic risk via modeling of ancestral makeup.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39763564}, support = {R56 HG013163/HG/NHGRI NIH HHS/United States ; OT2 OD026556/OD/NIH HHS/United States ; R01 HL139553/HL/NHLBI NIH HHS/United States ; U2C OD023196/OD/NIH HHS/United States ; OT2 OD025315/OD/NIH HHS/United States ; OT2 OD026551/OD/NIH HHS/United States ; U24 OD023121/OD/NIH HHS/United States ; OT2 OD026549/OD/NIH HHS/United States ; OT2 OD025337/OD/NIH HHS/United States ; OT2 OD025277/OD/NIH HHS/United States ; OT2 OD026555/OD/NIH HHS/United States ; OT2 OD026550/OD/NIH HHS/United States ; OT2 OD026553/OD/NIH HHS/United States ; OT2 OD023205/OD/NIH HHS/United States ; OT2 OD025276/OD/NIH HHS/United States ; OT2 OD026557/OD/NIH HHS/United States ; OT2 OD026554/OD/NIH HHS/United States ; U24 OD023163/OD/NIH HHS/United States ; R01 HG011031/HG/NHGRI NIH HHS/United States ; OT2 OD023206/OD/NIH HHS/United States ; R01 HL154385/HL/NHLBI NIH HHS/United States ; U24 OD023176/OD/NIH HHS/United States ; OT2 OD026548/OD/NIH HHS/United States ; OT2 OD026552/OD/NIH HHS/United States ; R01 HL161012/HL/NHLBI NIH HHS/United States ; R01 HL142711/HL/NHLBI NIH HHS/United States ; R01 AG080598/AG/NIA NIH HHS/United States ; }, abstract = {Polygenic risk scores (PRSs) depend on genetic ancestry due to differences in allele frequencies between ancestral populations. This leads to implementation challenges in diverse populations. We propose a framework to calibrate PRS based on ancestral makeup. We define a metric called "expected PRS" (ePRS), the expected value of a PRS based on one's global or local admixture patterns. We further define the "residual PRS" (rPRS), measuring the deviation of the PRS from the ePRS. Simulation studies confirm that it suffices to adjust for ePRS to obtain nearly unbiased estimates of the PRS-outcome association without further adjusting for PCs. Using the TOPMed dataset, the estimated effect size of the rPRS adjusting for the ePRS is similar to the estimated effect of the PRS adjusting for genetic PCs. Similarly, we applied the ePRS framework to six cardiovascular-related traits in the All of Us dataset, and the results are consistent with those from the TOPMed analysis. The ePRS framework can protect from population stratification in association analysis and provide an equitable strategy to quantify genetic risk across diverse populations.}, }
@article {pmid39763516, year = {2024}, author = {Mazziotta, F and Martin, LE and Eagan, DN and Bar, M and Kinsella, S and Paulson, KG and Voillet, V and Lahman, MC and Hunter, D and Schmitt, TM and Duerkopp, N and Yeung, C and Tang, TH and Gottardo, R and Asano, Y and Wilcox, EC and Lee, B and Zhang, T and Lopedote, P and Penter, L and Wu, CJ and Milano, F and Greenberg, PD and Chapuis, AG}, title = {Acute Myeloid Leukemia Skews Therapeutic WT1-specific CD8 TCR-T Cells Towards an NK-like Phenotype that Compromises Function and Persistence.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39763516}, support = {K08 CA169485/CA/NCI NIH HHS/United States ; P01 CA018029/CA/NCI NIH HHS/United States ; T32 CA080416/CA/NCI NIH HHS/United States ; }, abstract = {Acute myeloid leukemia (AML) that is relapsed and/or refractory post-allogeneic hematopoietic cell transplantation (HCT) is usually fatal. In a prior study, we demonstrated that AML relapse in high-risk patients was prevented by post-HCT immunotherapy with Epstein-Barr virus (EBV)-specific donor CD8[+] T cells engineered to express a high-affinity Wilms Tumor Antigen 1 (WT1)-specific T-cell receptor (TTCR-C4). However, in the present study, infusion of EBV- or Cytomegalovirus (CMV)-specific TTCR-C4 did not clearly improve outcomes in fifteen patients with active disease post-HCT. TCRC4-transduced EBV-specific T cells persisted longer post-transfer than CMV-specific T cells. Persisting TTCR-C4 skewed towards dysfunctional natural killer-like terminal differentiation, distinct from the dominant exhaustion programs reported for T-cell therapies targeting solid tumors. In one patient with active AML post-HCT, a sustained TTCR-C4 effector-memory profile correlated with long-term TTCR-C4 persistence and disease control. These findings reveal complex mechanisms underlying AML-induced T-cell dysfunction, informing future therapeutic strategies for addressing post-HCT relapse.}, }
@article {pmid39786405, year = {2024}, author = {Reiner, AS and Watt, GP and Malone, KE and Lynch, CF and John, EM and Knight, JA and Woods, M and Liang, X and Tischkowitz, M and Conti, DV and Robson, ME and Mellemkjær, L and Teraoka, SN and Concannon, P and Bernstein, JL}, title = {Breast Cancer Susceptibility Gene Sequence Variations and Development of Contralateral Breast Cancer.}, journal = {JAMA network open}, volume = {7}, number = {12}, pages = {e2452158}, doi = {10.1001/jamanetworkopen.2024.52158}, pmid = {39786405}, issn = {2574-3805}, mesh = {Humans ; Female ; *Genetic Predisposition to Disease ; Case-Control Studies ; Middle Aged ; Adult ; *Breast Neoplasms/genetics/epidemiology ; Receptors, Estrogen/genetics ; Checkpoint Kinase 2/genetics ; BRCA2 Protein/genetics ; Ataxia Telangiectasia Mutated Proteins/genetics ; Germ-Line Mutation/genetics ; BRCA1 Protein/genetics ; }, abstract = {IMPORTANCE: Heterogeneity in development of estrogen receptor (ER)-specific first primary breast cancer exists due to deleterious germline variants in moderate- to high-penetrance breast cancer susceptibility genes, but it is unknown if these associations occur in ER-specific CBC.<br><br>OBJECTIVE: To determine the association of deleterious germline variants in breast cancer susceptibility genes with ER-specific CBC development and whether ER status of the first primary breast cancer modifies these associations.<br><br>This case-control study included CBC cases and matched unilateral breast cancer controls from The Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study, a population-based case-control study. Eligible women were diagnosed between 1985 and 2000 with data and biospecimens collected from 2001 to 2004. Eligible participants were women younger than 55 years at first invasive breast cancer diagnosis. Participants were matched on age, diagnosis year, cancer registry region, and race and ethnicity, and countermatched on radiation treatment. For cases, CBC occurred 1 year or more following first breast cancer diagnosis. Analyses were performed from May to October 2024.<br><br>EXPOSURES: CHEK2 1100delC and deleterious variants in ATM, BRCA1, and BRCA2.<br><br>MAIN OUTCOME AND MEASURE: Development of CBC, measured as a rate ratio (RR).<br><br>RESULTS: A total of 1290 women were included in analysis (median [IQR] age at first diagnosis, 47 [42-51] years). The ER-positive CBC rate for women with deleterious ATM variants was 4 times higher than for women without deleterious ATM variants (RR, 4.84; 95% CI, 1.11-21.08; P&#x2009;=&#x2009;.04); no women with ER-negative CBC carried deleterious ATM variants. The ER-positive CBC rates for women with deleterious variants in BRCA2 or CHEK2 1100delC were 5 to 6 times higher than for women without deleterious variants in BRCA2 or CHEK2 1100delC, respectively (BRCA2: RR, 5.88; 95% CI, 2.61-13.26, P&#x2009;<&#x2009;.001; CHEK2 1100delC: RR, 6.06; 95% CI, 1.26-29.04; P&#x2009;=&#x2009;.02). The ER-negative CBC rate for women with deleterious BRCA1 variants was 26 times higher than for women without deleterious BRCA1 variants (RR, 26.16; 95% CI, 8.01-85.44; P&#x2009;<&#x2009;.001). First primary breast cancer ER status did not modify associations between deleterious variants and ER-specific CBC development.<br><br>CONCLUSIONS AND RELEVANCE: In this case-control study of CBC, deleterious variants in breast cancer susceptibility genes were differentially associated with ER-specific CBC development. Germline variation profile may inform estimates of outcomes for ER-specific CBC subtypes.}, }
@article {pmid39786387, year = {2024}, author = {Mina, A and McGraw, KL and Cunningham, L and Kim, N and Jen, EY and Calvo, KR and Ehrlich, LA and Aplan, PD and Garcia-Manero, G and Foran, JM and Garcia, JS and Zeidan, AM and DeZern, AE and Komrokji, RS and Sekeres, MA and Scott, BL and Buckstein, RJ and Tinsley-Vance, S and Verma, A and Wroblewski, T and Pavletic, SZ and Norsworthy, KJ}, title = {Advancing Drug Development in Myelodysplastic Syndromes.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024014865}, pmid = {39786387}, issn = {2473-9537}, abstract = {Myelodysplastic syndromes/neoplasms (MDS) are heterogeneous stem cell malignancies characterized by poor prognosis and no curative therapies outside of allogeneic hematopoietic stem cell transplantation. Despite some recent approvals by the United States Food and Drug Administration (FDA), (e.g., luspatercept, ivosidenib, decitabine/cedazuridine and imetelstat), there has been little progress in the development of truly transformative therapies for the treatment of patients with MDS. Challenges to advancing drug development in MDS are multifold but may be grouped into specific categories including criteria for risk stratification and eligibility, response definitions, time-to-event endpoints, transfusion endpoints, functional assessments, and biomarker development. Strategies to address these challenges and optimize future clinical trial design for patients with MDS are presented here.}, }
@article {pmid39783874, year = {2024}, author = {Palacios, N and Gordon, S and Wang, T and Huttenhower, C and Gonzalez, HM and Knight, R and Decarli, C and Daviglus, ML and Lamar, M and Tarraf, W and Cai, J and Burk, R and Qi, Q and Kaplan, RC}, title = {Biomarkers.}, journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association}, volume = {20 Suppl 2}, number = {}, pages = {e092828}, doi = {10.1002/alz.092828}, pmid = {39783874}, issn = {1552-5279}, mesh = {Humans ; Female ; Male ; *Gastrointestinal Microbiome/physiology ; Aged ; Cross-Sectional Studies ; *Biomarkers/blood ; Feces/microbiology ; Cognition/physiology ; Middle Aged ; Alzheimer Disease/genetics/microbiology ; Hispanic or Latino ; Metagenome ; Cohort Studies ; White ; }, abstract = {BACKGROUND: Few large microbiome studies on Alzheimer's Disease and Related Dementia (AD/ADRD) have been conducted, especially among US Latinos. We conducted a study within the Study of Latinos- Investigation of Neurocognitive Aging (SOL-INCA) cohort to examine the role of the gut microbiota in cognitive function.<br><br>METHODS: We analyzed the fecal metagenomes of 2,470 SOL-INCA participants to, cross-sectionally, identify microbial taxonomic and functional features associated with cognitive function. Global cognition was defined as an aggregate score based on a cognitive battery (executive function, working memory, among others). Omnibus (PERMANOVA) and feature-wise analyses (MaAsLin2) were conducted to identify microbiome-cognition associations, and specific microbial species and pathways (Kyoto Encyclopedia of Genes and Genomes (KEGG modules) associated with cognition. We assessed the accuracy of a Random Forest classifier to distinguish SOL participants with the best (>=1SD above mean) vs. the worst (>=1SD below mean) cognition. We also tested the association of identified taxa and KEGG modules with concurrently collected serum metabolites.<br><br>RESULT: We identified several taxa and pathways significantly associated with cognitive function in SOL. B. longum was the taxa most strongly associated with worse cognition, whereas Eubacterium species (E. siraeum and E.eligens), were associated with better cognition. Several KEGG modules, most strongly Ornithine and Serine biosynthesis, were associated with worse cognition. A microbiome species-based Random Forest classifier had moderate accuracy (AUC = 0.62) to discriminate between high (1SD or more above mean) vs low (1SD or more below mean) cognition.<br><br>CONCLUSION: In a large Latino cohort, we identified several microbial taxa and KEGG pathways associated with cognition, further implicating the microbiome in AD/ADRD risk.}, }
@article {pmid39780444, year = {2025}, author = {Zainal, NH and Benjet, C and Albor, Y and Nuñez-Delgado, M and Zambrano-Cruz, R and Contreras-Ibáñez, CC and Cudris-Torres, L and de la Peña, FR and González, N and Guerrero-López, JB and Gutierrez-Garcia, RA and Jiménez-Peréz, AL and Medina-Mora, ME and Patiño, P and Cuijpers, P and Gildea, SM and Kazdin, AE and Kennedy, CJ and Luedtke, A and Sampson, NA and Petukhova, MV and Zubizarreta, JR and Kessler, RC}, title = {Statistical methods to adjust for the effects on intervention compliance in randomized clinical trials where precision treatment rules are being developed.}, journal = {International journal of methods in psychiatric research}, volume = {34}, number = {1}, pages = {e70005}, doi = {10.1002/mpr.70005}, pmid = {39780444}, issn = {1557-0657}, support = {R01MH120648/MH/NIMH NIH HHS/United States ; R01MH120648/TW/FIC NIH HHS/United States ; }, mesh = {Humans ; *Cognitive Behavioral Therapy/methods ; Female ; Male ; Adult ; Young Adult ; Patient Compliance/statistics &amp; numerical data ; Outcome Assessment, Health Care/standards ; Randomized Controlled Trials as Topic ; Data Interpretation, Statistical ; Anxiety Disorders/therapy ; }, abstract = {BACKGROUND: Heterogeneity of treatment effects (HTEs) can occur because of either differential treatment compliance or differential treatment effectiveness. This distinction is important, as it has action implications, but it is unclear how to distinguish these two possibilities statistically in precision treatment analysis given that compliance is not observed until after randomization. We review available statistical methods and illustrate a recommended method in secondary analysis in a trial focused on HTE.<br><br>METHODS: The trial randomized n&#xa0;=&#xa0;880 anxious and/or depressed university students to guided internet-delivered cognitive behavioral therapy (i-CBT) or treatment-as-usual (TAU) and evaluated joint remission. Previously reported analyses documented superiority of i-CBT but significant HTE. In the reanalysis reported here, we used baseline (i.e., pre-randomization) covariates to predict compliance among participants randomized to guided i-CBT, generated a cross-validated within-person expected compliance score based on this model in both intervention groups, and then used this expected composite score as a predictor in an expanded HTE analysis.<br><br>RESULTS: The significant intervention effect was limited to participants with high expected compliance. Residual HTE was nonsignificant.<br><br>CONCLUSIONS: Future psychotherapy HTE trials should routinely develop and include expected compliance composite scores to distinguish the effects of differential treatment compliance from the effects of differential treatment effectiveness.}, }
@article {pmid39779669, year = {2025}, author = {Papier, K and Bradbury, KE and Balkwill, A and Barnes, I and Smith-Byrne, K and Gunter, MJ and Berndt, SI and Le Marchand, L and Wu, AH and Peters, U and Beral, V and Key, TJ and Reeves, GK}, title = {Diet-wide analyses for risk of colorectal cancer: prospective study of 12,251 incident cases among 542,778 women in the UK.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {375}, pmid = {39779669}, issn = {2041-1723}, support = {C570/A16491 and A29186//Cancer Research UK (CRUK)/ ; }, mesh = {Humans ; Female ; *Colorectal Neoplasms/epidemiology/genetics ; United Kingdom/epidemiology ; Prospective Studies ; Middle Aged ; *Diet ; Risk Factors ; Adult ; Dairy Products ; Aged ; Incidence ; Alcohol Drinking/epidemiology/adverse effects ; Calcium, Dietary/administration &amp; dosage ; }, abstract = {Uncertainty remains regarding the role of diet in colorectal cancer development. We examined associations of 97 dietary factors with colorectal cancer risk in 542,778 Million Women Study participants (12,251 incident cases over 16.6 years), and conducted a targeted genetic analysis in the ColoRectal Transdisciplinary Study, Colon Cancer Family Registry, and Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Alcohol (relative risk per 20 g/day=1.15, 95% confidence interval 1.09-1.20) and calcium (per 300 mg/day=0.83, 0.77-0.89) intakes had the strongest associations, followed by six dairy-related factors associated with calcium. We showed a positive association with red and processed meat intake and weaker inverse associations with breakfast cereal, fruit, wholegrains, carbohydrates, fibre, total sugars, folate, and vitamin C. Genetically predicted milk consumption was inversely associated with risk of colorectal, colon, and rectal cancers. We conclude that dairy products help protect against colorectal cancer, and that this is driven largely or wholly by calcium.}, }
@article {pmid39778191, year = {2025}, author = {Marks, DI and Cassaday, RD and Ribera, JM and Schuh, AC and Park, JH and Chiaretti, S and Stelljes, M}, title = {Characterizing the ideal patient for treatment with inotuzumab ozogamicin for relapsed/refractory acute lymphoblastic leukemia: a systematic literature review.}, journal = {Expert review of hematology}, volume = {}, number = {}, pages = {}, doi = {10.1080/17474086.2025.2450223}, pmid = {39778191}, issn = {1747-4094}, abstract = {INTRODUCTION: Inotuzumab ozogamicin(InO) is indicated for the treatment of adults with relapsed or refractory(R/R) acute lymphoblastic leukemia (ALL). This systematic literature review (CRD42022330496) assessed outcomes bybaseline characteristics for patients with R/R ALL treated with InO to identifywhich patients may benefit most.<br><br>METHODS: In adherencewith PRISMA guidelines, searches were run in Embase and MEDLINE. Inclusioncriteria were real-world evidence, observational studies, and phase 2-4 trials.The Cochrane Risk of Bias tool and Newcastle-Ottawa instrument assessedquality.<br><br>RESULTS: 34 publicationswere included; 11 described the phase 3 INO-VATE trial. Patients treated withInO who were CD22-positive, in first salvage, and eligible for subsequent hematopoieticstem cell transplant (HSCT) had improved outcomes. Reduced incidence ofveno-occlusive disease was observed in patients with normal transaminase levels and bilirubin, no priorliver disease, and who did not receive dual alkylators.<br><br>CONCLUSIONS: The idealpatient for InO treatment has CD22-positive disease (&#x2265;20% leukemic blasts), normal liverfunction, no history of liver disease, is in first salvage, hasnot previously received HSCT, prefers outpatient treatment, or has high diseaseburden. Limitations included potentially missing publications that werenon-English, not identified in the searches, or available after the date thesearches were conducted.<br><br>REGISTRATION: This systematic review was registered on theProspective Register of Systematic Reviews (PROSPERO), registration number:CRD42022330496.}, }
@article {pmid39778123, year = {2025}, author = {Rotz, SJ and Stratton, K and Leisenring, WM and Smith, SA and Howell, RM and Bates, JE and Pappo, AS and Neglia, JP and Armstrong, GT and Turcotte, LM}, title = {Melanoma Among Adult Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2401519}, doi = {10.1200/JCO-24-01519}, pmid = {39778123}, issn = {1527-7755}, abstract = {PURPOSE: Melanoma as a subsequent malignant neoplasm has been described among childhood cancer survivors; however, the risk factors and long-term survival are not well understood.<br><br>METHODS: We assessed incidence, risk factors, and outcomes for melanoma among participants in the Childhood Cancer Survivor Study cohort. Cumulative incidence and standardized incidence ratios (SIRs) were calculated, and multivariable Cox models were used to determine hazard ratios (HRs) and associated 95% CI for melanoma risk factors. Radiation exposure to seven body regions and melanoma status for each of eight regions per survivor were integrated into the Cox model.<br><br>RESULTS: Among 25,716 participants, 177 melanomas developed in 160 survivors (110 invasive, 62 in situ cutaneous, five ocular). The 40-year melanoma cumulative incidence was 1.1% (95% CI, 0.9 to 1.4) for all participants and 1.5% (95% CI, 1.0 to 2.1) among those receiving a cumulative radiation dose of &#x2265;40 Gy. Compared with the general population, the SIR for invasive skin or ocular melanoma was 2.0 (95% CI, 1.6 to 2.4). A cumulative radiation dose of &#x2265;40 Gy to the corresponding body region(s) of the melanoma (HR, 2.0 [95% CI, 1.1 to 3.7]), a cumulative cyclophosphamide equivalent dose of &#x2265;20,000 mg/m[2] (HR, 1.9 [95% CI, 1.1 to 3.6]), and bleomycin exposure (HR, 2.2 [95% CI, 1.2 to 4.1]) were associated with increased cutaneous melanoma. Invasive melanoma at any site was associated with an increased risk of death (HR, 2.4 [95% CI, 1.7 to 3.3]).<br><br>CONCLUSION: Childhood cancer survivors have more than a two-fold increased risk of melanoma compared with the general population, and those with an invasive melanoma have more than a two-fold risk of death. High-dose radiation and alkylating agent exposure, and bleomycin are important risk factors for melanoma and should be considered in future patient guidance and screening.}, }
@article {pmid39777681, year = {2025}, author = {Hall, MS and Harris, HR and As-Sanie, S and Upson, K}, title = {Early-Life Exposures and Odds of Adenomyosis: A Population-Based Case-Control Study.}, journal = {Paediatric and perinatal epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1111/ppe.13165}, pmid = {39777681}, issn = {1365-3016}, support = {R01HD040398//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; R00NR017191/NR/NINR NIH HHS/United States ; /NH/NIH HHS/United States ; }, abstract = {BACKGROUND: Adenomyosis can confer life-altering symptoms such as pelvic pain. Yet, the epidemiologic study of this uterine condition lags other gynaecologic conditions. This includes the investigation of intrauterine exposures that could disrupt foetal development and contribute to the presence of adenomyosis in adulthood.<br><br>OBJECTIVE: We investigated nine early-life factors and the odds of adenomyosis using data from a population-based case-control study of enrollees of an integrated healthcare system in Washington State ages 18-59.<br><br>METHODS: Cases (n&#x2009;=&#x2009;386) had incident, pathology-confirmed adenomyosis diagnosed between 2001 and 2006. Two control groups were employed: hysterectomy controls (n&#x2009;=&#x2009;233) and randomly selected age-matched enrollees with an intact uterus ('population controls', n&#x2009;=&#x2009;323). The primary study activity was a structured in-person interview; participants were also mailed a family history questionnaire that included questions on early-life factors. We conducted logistic regression to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI) for the associations between early-life factors and adenomyosis.<br><br>RESULTS: Comparing cases to population controls, our data suggested an 80% increased odds of adenomyosis with younger maternal age at participant's birth (&#x2264;&#x2009;19 vs. ages 25-29) (aOR 1.81, 95% CI 0.94, 3.50) and a 50% increased odds of adenomyosis for participants who were the fourth or later live birth (vs. firstborn) (aOR 1.51, 95% CI 0.88, 2.59). Among never-smoking participants, our data suggested a 50% increased odds of adenomyosis with intrauterine exposure to cigarette smoking (aOR 1.50, 95% CI 0.92, 2.46). In analyses using hysterectomy controls, these associations were attenuated.<br><br>CONCLUSIONS: These data suggested that several intrauterine exposures were associated with increased odds of adenomyosis in adulthood. The intrauterine period may be a susceptible window for subsequent development of adenomyosis and warrants further investigation.}, }
@article {pmid39777474, year = {2025}, author = {Tau, S and Chamberlin, MD and Yang, H and Marotti, JD and Muskus, PC and Roberts, AM and Carmichael, MM and Cressey, L and Dragnev, CPC and Demidenko, E and Hampsch, RA and Soucy, SM and Kolling, FW and Samkoe, KS and Alvarez, JV and Kettenbach, AN and Miller, TW}, title = {Oxidative Phosphorylation is a Metabolic Vulnerability of Endocrine Therapy-Tolerant Persister Cells in ER+ Breast Cancer.}, journal = {Cancer research}, volume = {}, number = {}, pages = {}, doi = {10.1158/0008-5472.CAN-24-1204}, pmid = {39777474}, issn = {1538-7445}, abstract = {Despite adjuvant treatment with endocrine therapies, estrogen receptor-positive (ER+) breast cancers recur in a significant proportion of patients. Recurrences are attributable to clinically undetectable endocrine-tolerant persister cancer cells that retain tumor-forming potential. Therefore, strategies targeting such persister cells may prevent recurrent disease. Using CRISPR-Cas9 genome-wide knockout screening in ER+ breast cancer cells, we identified a survival mechanism involving metabolic reprogramming with reliance upon mitochondrial respiration in endocrine-tolerant persister cells. Quantitative proteomic profiling showed reduced levels of glycolytic proteins in persisters. Metabolic tracing of glucose revealed an energy-depleted state in persisters where oxidative phosphorylation was required to generate ATP. A phase II clinical trial was conducted to evaluate changes in mitochondrial markers in primary ER+/HER2- breast tumors induced by neoadjuvant endocrine therapy (NCT04568616). In an analysis of tumor specimens from 32 patients, tumors exhibiting residual cell proliferation after aromatase inhibitor-induced estrogen deprivation with letrozole showed increased mitochondrial content. Genetic profiling and barcode lineage tracing showed that endocrine-tolerant persistence occurred stochastically without genetic predisposition. Pharmacological inhibition of mitochondrial complex I suppressed the tumor-forming potential of persisters in mice and synergized with the anti-estrogen fulvestrant to induce regression of patient-derived xenografts. These findings indicate that mitochondrial metabolism is essential in endocrine-tolerant persister ER+ breast cancer cells and warrant the development of treatment strategies to leverage this vulnerability for treating breast cancer.}, }
@article {pmid39777359, year = {2024}, author = {Suraci, CM and Morrison, ML and Roth, MB}, title = {Oxygen is toxic in the cold in C. elegans.}, journal = {Frontiers in physiology}, volume = {15}, number = {}, pages = {1471249}, doi = {10.3389/fphys.2024.1471249}, pmid = {39777359}, issn = {1664-042X}, abstract = {INTRODUCTION: Temperature and oxygen are two factors that profoundly affect survival limits of animals; too much or too little of either is lethal. However, humans and other animals can exhibit exceptional survival when oxygen and temperature are simultaneously low. This research investigates the role of oxygen in the cold shock death of Caenorhabditis elegans.<br><br>METHODS: The survival of C. elegans populations in combinations of oxygen concentrations and was assayed. Additionally, the effect of cold acclimatization, mutations in the cold acclimatization pathway, compounds, and antioxidant proteins on survival in low temperatures and high oxygen were investigated.<br><br>RESULTS: We demonstrate that C. elegans have increased survival in 2&#xb0;C when deprived of oxygen, and an increase to just 0.25&#xa0;kPa of oxygen decreased survival. Additionally, we show that oxygen toxicity produced by a 35-fold increase above atmospheric oxygen levels was fatal for nematodes in 8&#xa0;h at room temperature and 2&#xa0;h at 2&#xb0;C. We found that cold acclimatization and mutations in the cold acclimatization pathway improve survival in room temperature oxygen toxicity. Furthermore, we found that the compounds glucose, manganese (II), and ascorbate improve both cold shock and high oxygen survival, while the antioxidant proteins catalase and peroxiredoxin are essential to wild type survival in these conditions.<br><br>DISCUSSION: Our results suggest that oxygen toxicity contributes to the death of C. elegans during cold shock. The changes in survival induced by cold acclimatization and mutations in the cold acclimatization pathway suggest that oxygen toxicity in the cold exerts evolutionary pressure, leading to the development of protections against it. Additionally, the resistance provided by diverse compounds and antioxidant proteins in both low temperature and high oxygen suggests these conditions have similar chemical environments. We discuss evidence that similar phenomena may function in humans.}, }
@article {pmid39776913, year = {2024}, author = {Chen, XT and Leisegang, M and Gavvovidis, I and Pollack, SM and Lorenz, FKM and Schumacher, TN and Daumke, O and Blankenstein, T}, title = {Generation of effective and specific human TCRs against tumor/testis antigen NY-ESO-1 in mice with humanized T cell recognition system.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1524629}, doi = {10.3389/fimmu.2024.1524629}, pmid = {39776913}, issn = {1664-3224}, mesh = {Animals ; Humans ; *Antigens, Neoplasm/immunology ; Mice ; *Receptors, Antigen, T-Cell/immunology/genetics ; *Mice, Transgenic ; *Membrane Proteins/immunology/genetics ; HLA-A2 Antigen/immunology ; Immunotherapy, Adoptive/methods ; T-Lymphocytes/immunology/metabolism ; Male ; Cell Line, Tumor ; }, abstract = {Generation of high avidity T cell receptors (TCRs) reactive to tumor-associated antigens (TAA) is impaired by tolerance mechanisms, which is an obstacle to effective T cell therapies for cancer treatment. NY-ESO-1, a human cancer-testis antigen, represents an attractive target for such therapies due to its broad expression in different cancer types and the restricted expression in normal tissues. Utilizing transgenic mice with a diverse human TCR repertoire, we isolated effective TCRs against NY-ESO-1157-165 restricted to HLA-A*02:01. We compared the functions of the murine-derived TCR with human-derived TCRs and an affinity matured TCR, using in vitro co-culture and in vivo adoptive T cell transfer in tumor-bearing mice. Alanine scan, x-scan, LCL assay were employed to address the cross-reactivity of the NY-ESO-1157-165 specific TCRs. We also used human tissue cDNA library and human primary cells to assess the safety of adoptive T cell therapies targeting NY-ESO-1 antigen in the clinic. One of the murine-derived human TCRs, TCR-ESO, exhibited higher functional avidity compared to human-derived NY-ESO-1157-165 specific TCRs. TCR-ESO appeared to have similar efficiency in antigen recognition as an in vitro affinity-matured TCR, TCR 1G4-α95LY, which was applied in clinical trials. TCR-ESO showed little cross-reactivity, in contrast to TCR 1G4-α95LY. Our data indicate that highly effective TCRs against NY-ESO-1 are likely deleted in humans due to tolerance mechanisms, and that the TCR gene loci transgenic mice represent a reliable source to isolate effective and highly-specific TCRs for adoptive T cell therapies.}, }
@article {pmid39775835, year = {2025}, author = {Wooldridge, TB and Ford, SM and Conwell, HC and Hyde, J and Harris, K and Shapiro, B}, title = {Direct Measurement of the Mutation Rate and Its Evolutionary Consequences in a Critically Endangered Mollusk.}, journal = {Molecular biology and evolution}, volume = {42}, number = {1}, pages = {}, doi = {10.1093/molbev/msae266}, pmid = {39775835}, issn = {1537-1719}, support = {2307479//National Science Foundation Ocean Science Department (NSF-OCE/ ; }, mesh = {Animals ; *Mutation Rate ; *Endangered Species ; *Gastropoda/genetics ; Biological Evolution ; Evolution, Molecular ; Germ-Line Mutation ; Mollusca/genetics ; Population Density ; }, abstract = {The rate at which mutations arise is a fundamental parameter of biology. Despite progress in measuring germline mutation rates across diverse taxa, such estimates are missing for much of Earth's biodiversity. Here, we present the first estimate of a germline mutation rate from the phylum Mollusca. We sequenced three pedigreed families of the white abalone Haliotis sorenseni, a long-lived, large-bodied, and critically endangered mollusk, and estimated a de novo mutation rate of 8.60 × 10-9 single nucleotide mutations per site per generation. This mutation rate is similar to rates measured in vertebrates with comparable generation times and longevity to abalone, and higher than mutation rates measured in faster-reproducing invertebrates. The spectrum of de novo mutations is also similar to that seen in vertebrate species, although an excess of rare C > A polymorphisms in wild individuals suggests that a modifier allele or environmental exposure may have once increased C > A mutation rates. We use our rate to infer baseline effective population sizes (Ne) across multiple Pacific abalone and find that abalone persisted over most of their evolutionary history as large and stable populations, in contrast to extreme fluctuations over recent history and small census sizes in the present day. We then use our mutation rate to infer the timing and pattern of evolution of the abalone genus Haliotis, which was previously unknown due to few fossil calibrations. Our findings are an important step toward understanding mutation rate evolution and they establish a key parameter for conservation and evolutionary genomics research in mollusks.}, }
@article {pmid39775763, year = {2025}, author = {Levis, MJ and Hamadani, M and Logan, BR and Jones, RJ and Singh, AK and Litzow, MR and Wingard, JR and Papadopoulos, EB and Perl, AE and Soiffer, RJ and Ustun, C and Ueda Oshima, M and Uy, GL and Waller, EK and Vasu, S and Solh, MM and Mishra, A and Muffly, L and Kim, HJ and Stelljes, M and Najima, Y and Onozawa, M and Thomson, KJ and Nagler, A and Wei, AH and Marcucci, G and Chen, C and Hasabou, N and Rosales, M and Hill, JE and Gill, SC and Nuthethi, R and King, D and Mendizabal, AM and Devine, SM and Horowitz, MM and Chen, YB}, title = {Measurable residual disease and posttransplantation gilteritinib maintenance for patients with FLT3-ITD-mutated AML.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024025154}, pmid = {39775763}, issn = {1528-0020}, abstract = {BMT CTN 1506 ("MORPHO"; NCT02997202) was a randomized phase 3 study of gilteritinib compared to placebo as maintenance therapy after hematopoietic stem cell transplantation (HCT) for patients with FLT3-ITD-mutated acute myeloid leukemia (AML). A key secondary endpoint was to determine the impact on survival of pre- and/or post-HCT measurable residual disease (MRD), as determined using a highly sensitive assay for FLT3-ITD mutations. Generally, gilteritinib maintenance therapy was associated with improved relapse-free survival (RFS) for participants with detectable peri-HCT MRD, whereas no benefit was evident for those lacking detectable MRD. We conducted a post-hoc analysis of the data and found that the level of MRD detected with this approach correlated remarkably with RFS and relapse risk, and that MRD detectable at any level negatively impacted RFS. In the placebo arm, 42.2% of participants with detectable FLT3-ITD MRD relapsed compared to 13.4% of those without detectable MRD. We found that 14.8% of participants had multiple FLT3-ITD clones detected as MRD and had worse survival irrespective of treatment arm. Finally, we examined the kinetics of FLT3-ITD clonal relapse or eradication and found that participants on the placebo arm with detectable MRD relapsed rapidly after HCT, often within a few weeks. MRD-positive participants on the gilteritinib arm relapsed either with FLT3 wild type clones (as assessed by capillary electrophoresis), after cessation of gilteritinib with persistent MRD, or on progression of multi-clonal disease. These data demonstrate the potential of using FLT3-ITD MRD to guide therapy with gilteritinib for this subtype of AML.}, }
@article {pmid39774957, year = {2025}, author = {Liu, H and Zhang, W and Di, M and Lee, H and Shi, L and Wang, X and Xingyu, Z and Powers, CA and Sethi, V and Li, X and Xiao, Y and Crane, A and Kaltenmeier, C and Alberola, RB and Behari, J and Duarte-Rojo, A and Hughes, D and Malik, S and Jonassaint, N and Geller, D and Tohme, S and Gunabushanam, V and Tevar, A and Cruz, R and Hughes, C and Dharmayan, S and Ayloo, S and Humar, A and Molinari, M}, title = {Survival benefit associated with liver transplantation for hepatocellular carcinoma based on tumor burden scores at listing.}, journal = {Hepatology communications}, volume = {9}, number = {1}, pages = {}, doi = {10.1097/HC9.0000000000000619}, pmid = {39774957}, issn = {2471-254X}, mesh = {Humans ; *Liver Transplantation/mortality ; *Carcinoma, Hepatocellular/surgery/mortality ; *Liver Neoplasms/surgery/mortality/pathology ; Male ; Female ; Middle Aged ; *Waiting Lists/mortality ; *Tumor Burden ; United States ; Aged ; Adult ; Survival Rate ; Tissue and Organ Procurement ; Registries ; }, abstract = {INTRODUCTION: Liver transplantation (LT) provides significant survival benefits to patients with unresectable HCC. In the United States, organ allocation policies for HCCs within the United Network for Organ Sharing criteria do not prioritize patients based on their differences in oncological characteristics. This study assessed whether transplant-associated survival benefits (TASBs) vary among patients with different tumor burden scores (TBS) measured at the time of listing.<br><br>METHODS: We analyzed data from adults applying for HCC MELD exception points between 2002 and 2019, with follow-up until December 2023, using the Scientific Registry of Transplant Recipients. TBS was determined based on the largest tumor diameter and number of HCCs. Patients were categorized into low (&#x2264;3), intermediate (3.1-5), and high (>5) TBS groups. TASB was measured as the difference in 5-year survival with and without LT.<br><br>RESULTS: This study included 36,634 LT candidates. High-TBS patients had higher waitlist dropout rates and marginally lower post-transplant survival, resulting in a significantly greater TASB. The 5-year TASB for the low, intermediate, and high TBS groups were 15.7, 22.1, and 25.0 months, respectively. The adjusted survival benefit expressed in 5-year survival differences was 21.9%, 34.5%, and 39.4% in the low, intermediate, and high TBS groups, respectively (p<0.001).<br><br>CONCLUSIONS: Higher TBS during listing correlates with greater LT benefits for patients with unresectable HCC within UNOS criteria. We conclude that organ allocation policies in the United States should prioritize patients with high TBS due to their increased risk of dropout and comparable post-transplant survival when compared to patients with less advanced tumors.}, }
@article {pmid39774938, year = {2024}, author = {Munoz, FM and Beigi, R and Posavad, CM and Kelly, C and Badell, ML and Bunge, K and Mulligan, MJ and Parameswaran, L and Richardson, BA and Olsen-Chen, C and Novak, RM and Brady, RC and DeFranco, E and Gerber, JS and Shriver, M and Suthar, MS and Coler, R and Berube, BJ and Kim, SH and Piper, JM and Miedema, J and Pasetti, M and Neuzil, KM and Cardemil, CV and , }, title = {Enhanced D614G and Omicron Variants Antibody Persistence in Infants at 2 Months of Age Following Maternal mRNA Booster Vaccination During Pregnancy or Postpartum.}, journal = {The Pediatric infectious disease journal}, volume = {43}, number = {11}, pages = {1065-1073}, pmid = {39774938}, issn = {1532-0987}, mesh = {Humans ; Female ; Pregnancy ; *SARS-CoV-2/immunology ; *COVID-19/prevention &amp; control/immunology ; *Antibodies, Viral/blood ; *Immunization, Secondary ; *Milk, Human/immunology ; Prospective Studies ; *COVID-19 Vaccines/immunology/administration &amp; dosage ; Infant ; Adult ; *Postpartum Period ; Antibodies, Neutralizing/blood/immunology ; Immunoglobulin G/blood ; Vaccination ; Infant, Newborn ; Male ; Young Adult ; Spike Glycoprotein, Coronavirus/immunology ; }, abstract = {BACKGROUND: Following maternal COVID-19 vaccination, the persistence of antibodies in sera and breast milk for mothers and infants is not well characterized. We sought to describe the persistence of antibodies through 2 months after delivery in maternal and infant serum and breast milk following maternal COVID-19 mRNA vaccination and to examine differences by receipt of booster dose during pregnancy or postpartum.<br><br>METHODS: This is a prospective cohort study with enrollment from July 2021 to January 2022 at 9 US academic sites. Pregnant or postpartum participants and their infants were enrolled after COVID-19 mRNA monovalent vaccination during pregnancy (primary 2-dose series) with booster (third dose) vaccination during pregnancy or within 2 months post-partum. SARS-CoV-2-binding and functional antibody responses at delivery and 2 months after delivery in mothers and infants were measured by spike and receptor-binding domain immunoglobulin (Ig) G, pseudovirus and live neutralizing antibody (nAb) titers to ancestral and Omicron BA.1 and BA.5 strains. Breast milk spike and receptor-binding domain IgG and IgA titers were also measured.<br><br>RESULTS: A total of 237 maternal/infant dyads were included (110 primary series during pregnancy, 99 pregnancy booster and 28 postpartum booster). A pregnancy booster resulted in 2.2-4.7-fold higher IgG and nAb at delivery and 2 months for both mothers and infants compared to the primary series alone (P < 0.001 for all comparisons). While infant IgG and nAb titers decreased by 2 months of age, the proportion of infants with detectable nAb at 2 months was greater in infants of mothers boosted during pregnancy compared with primary series for all variants (D614G: 99% vs. 56%; BA.1: 56% vs. 4% and BA.5: 57% vs. 9%; P < 0.001 for all comparisons). Breast milk spike IgA and IgG were present in 64%-100% and 100% of participants, respectively, and those boosted during pregnancy or postpartum had 3.1-4.6-fold higher levels of breast milk antibodies at 2 months compared to primary series during pregnancy (P < 0.001).<br><br>CONCLUSIONS: mRNA COVID-19 monovalent booster vaccination during pregnancy results in significantly higher maternal and infant serum-binding IgG and nAb titers compared to a primary 2-dose series, including against Omicron variants, through 2 months of age. Breast milk antibodies following maternal vaccination during pregnancy or postpartum may provide additional protection during early infancy.}, }
@article {pmid39772633, year = {2025}, author = {Portuguese, AJ and Banerjee, R and Chen, G and Reddi, S and Cowan, AJ}, title = {Novel Treatment Options for Multiple Myeloma.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2400752}, doi = {10.1200/OP-24-00752}, pmid = {39772633}, issn = {2688-1535}, abstract = {Multiple myeloma (MM), the second most common hematologic malignancy in the United States, is characterized by repeated cycles of remission and relapse, with increasing resistance to treatment after each line of therapy. Despite the virtually incurable nature of MM, recent therapeutic breakthroughs have fundamentally reshaped its treatment landscape. This review explores evolving care paradigms, spanning from newly diagnosed MM to relapsed or refractory disease. In the frontline setting, treatment strategies have shifted beyond their traditional emphasis on autologous stem-cell transplant eligibility to a broader categorization of patients on the basis of their suitability for quadruplet therapy. In the relapsed/refractory setting, novel immunotherapies, including chimeric antigen receptor T-cell (CAR-T) therapies and bispecific antibodies, have revolutionized treatment, offering new hope for patients with previously limited options. Precision medicine is playing a growing role in MM treatment, with venetoclax showing significant efficacy in patients with t(11;14) translocation, advancing targeted therapy for this subgroup. On the horizon, investigational CAR-T products and cereblon E3 ligase modulators, such as mezigdomide and iberdomide, may provide faster, more durable responses compared with current therapies. In addition, belantamab mafodotin, an antibody-drug conjugate withdrawn from the US market in 2022, is on the verge of reapproval after positive results from recent randomized trials. While these therapies offer significant potential, challenges remain in managing toxicity, ensuring treatment accessibility, and optimizing sequencing strategies. As the therapeutic arsenal expands, the need for personalized MM treatment plans that balance efficacy with quality of life becomes even more essential.}, }
@article {pmid39767189, year = {2024}, author = {Masroori, Z and Haseli, S and Abbaspour, E and Pouramini, A and Azhideh, A and Fathi, M and Kafi, F and Chalian, M}, title = {Patellar Non-Traumatic Pathologies: A Pictorial Review of Radiologic Findings.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {14}, number = {24}, pages = {}, doi = {10.3390/diagnostics14242828}, pmid = {39767189}, issn = {2075-4418}, abstract = {Patellar pathologies are a common cause of knee dysfunction, with Patellofemoral Pain Syndrome (PFPS) alone responsible for 25% of knee-related visits to sports medicine clinics. Non-traumatic conditions, while often overlooked, can also lead to significant discomfort and functional limitations, highlighting the importance of accurate and timely diagnosis for effective management and prevention of complications. This pictorial review examines the radiologic characteristics of various non-traumatic patellar disorders, focusing on imaging modalities such as radiography, computed tomography (CT), and magnetic resonance imaging (MRI). Key diagnostic markers, including patellar tilt, tibial tuberosity-trochlear groove distance (TT-TG), and congruence angle (CA), are discussed for their significance in non-traumatic pathology identification. Furthermore, this review highlights specific radiologic features for a range of non-traumatic patellar conditions, including patellar tendinopathy, chondromalacia patellae, and trochlear dysplasia, emphasizing how distinct radiologic findings facilitate precise diagnosis and clinical assessment. Ultimately, it provides a practical guide for clinicians in diagnosing non-traumatic patellar pathologies through a comprehensive review of key radiologic features while also discussing advancements in imaging technologies and management strategies to support accurate diagnosis and effective clinical decision-making.}, }
@article {pmid39763680, year = {2024}, author = {Thomas, CE and Takashima, Y and Wesselink, E and Ugai, T and Steinfelder, RS and Buchanan, DD and Qu, C and Hsu, L and Dias Costa, A and Gallinger, S and Grant, RC and Huyghe, JR and Thomas, SS and Ogino, S and Phipps, AI and Nowak, JA and Peters, U}, title = {Association between somatic microsatellite instability, hypermutation status, and specific T cell subsets in colorectal cancer tumors.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1505896}, pmid = {39763680}, issn = {1664-3224}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Colorectal Neoplasms/genetics/immunology ; *Lymphocytes, Tumor-Infiltrating/immunology/metabolism ; *Microsatellite Instability ; Mutation ; *T-Lymphocyte Subsets/immunology/metabolism ; Observational Studies as Topic ; }, abstract = {BACKGROUND: Microsatellite instability-high (MSI-high) tumors comprise ~15% of sporadic colorectal cancers (CRC) and are associated with elevated T cell infiltration. However, the universality of this response across T cell subtypes with distinct functions is unknown.<br><br>METHODS: Including 1,236 CRC tumors from three observational studies, we conducted in-situ T cell profiling using a customized 9-plex (CD3, CD4, CD8, CD45RA, CD45RO, FOXP3, KRT, MKI67, and DAPI) multispectral immunofluorescence assay. MSI status was assessed through polymerase chain reaction or immunohistochemical assays. We used multivariable ordinal logistic regression to estimate odds ratios (OR per increasing quantile) and 95% confidence intervals (CIs) for the association of MSI status with quantiles of T cell densities in either tumor epithelial or stromal tissue areas.<br><br>RESULTS: Compared to microsatellite instability low or microsatellite stable (MSI-low/MSS) tumors, MSI-high status was associated with higher density for the majority of immune subsets (twelve out of eighteen) in both epithelial and stromal tissue areas. The strongest associations were for CD3[+]CD8[+] T cells in epithelial areas [OR (95% CI) for naive, memory, and regulatory subsets = 3.49 (2.57, 4.75); 2.82 (2.10, 3.78); 3.04 (2.24, 4.13), respectively]. Conversely, stromal area CD3[+]CD4[+] memory T cells were inversely associated [OR (95% CI) = 0.68 (0.51, 0.91)].<br><br>DISCUSSION: MSI-high status was strongly associated with higher densities of most T cell subsets in both epithelial and stromal tissue areas. Our investigation supports efforts to identify patients who may be more likely to respond to current immunotherapy treatments.<br><br>SIGNIFICANCE: This study helps us better understand how a clinically relevant tumor phenotype, microsatellite instability status, is related to different functioning T cell densities in colorectal tumors, which may impact future immunotherapy strategies.}, }
@article {pmid39762553, year = {2025}, author = {Granadier, D and Acenas, D and Dudakov, JA}, title = {Endogenous thymic regeneration: restoring T cell production following injury.}, journal = {Nature reviews. Immunology}, volume = {}, number = {}, pages = {}, pmid = {39762553}, issn = {1474-1741}, abstract = {Despite its importance for generating and maintaining a healthy and broad T cell repertoire, the thymus is exquisitely sensitive to acute damage. Marked thymic involution occurs in response to stimuli as diverse as infection, stress, pregnancy, malnutrition, drug use and cytoreductive chemotherapy. However, the thymus also has a remarkable capacity for repair, although this regenerative capacity declines with age. Endogenous thymic regeneration is a crucial process that allows for the recovery of immune competence after acute damage and delay to this recovery can have important clinical effects. Until recently, the mechanisms that drive endogenous thymic regeneration were not well understood, but recent work in mice has revealed multiple distinct pathways of regeneration and the molecular mechanisms that trigger these pathways after damage. In this Review, we discuss the effects of different types of damage to the thymus, with a focus on an emerging body of work in mice that provides insight into the cellular and molecular mechanisms that regulate endogenous tissue regeneration in the thymus. We also highlight some of the clinical challenges that are presented by dysregulated thymic regeneration.}, }
@article {pmid39761503, year = {2025}, author = {Raghav, KPS and Guthrie, KA and Tan, B and Denlinger, CS and Fakih, M and Overman, MJ and Dasari, NA and Corum, LR and Hicks, LG and Patel, MS and Esparaz, BT and Kazmi, SM and Alluri, N and Colby, S and Gholami, S and Gold, PJ and Chiorean, EG and Kopetz, S and Hochster, HS and Philip, PA}, title = {Trastuzumab Plus Pertuzumab Versus Cetuximab Plus Irinotecan in Patients With RAS/BRAF Wild-Type, HER2-Positive, Metastatic Colorectal Cancer (S1613): A Randomized Phase II Trial.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2401710}, doi = {10.1200/JCO-24-01710}, pmid = {39761503}, issn = {1527-7755}, abstract = {PURPOSE: ERBB2 overexpression/amplification in RAS/BRAF wild-type (WT) metastatic colorectal cancer (mCRC; human epidermal growth factor receptor 2 [HER2]-positive mCRC) appears to be associated with limited benefit from anti-EGFR antibodies and promising responses to dual-HER2 inhibition; however, comparative efficacy has not been investigated. We conducted a randomized phase II trial to evaluate efficacy and safety of dual-HER2 inhibition against standard-of-care anti-EGFR antibody-based therapy as second/third-line treatment in HER2-positive mCRC.<br><br>METHODS: Patients with RAS/BRAF-WT mCRC after central confirmation of HER2 positivity (immunohistochemistry 3+ or 2+ and in situ hybridization amplified [HER2/CEP17 ratio >2.0]) were assigned (1:1) to either trastuzumab plus pertuzumab (TP; trastuzumab 6 mg/kg and pertuzumab 420 mg once every 3 weeks) or cetuximab plus irinotecan (CETIRI; cetuximab 500 mg/m[2] and irinotecan 180 mg/m[2] once every 2 weeks) until progression or unacceptable toxicity. Crossover to TP was allowed after progression on CETIRI. The primary end point was progression-free survival (PFS). Secondary end points included objective response rate (ORR), overall survival, safety, and HER2 gene copy number (GCN &#x2265;20/<20) as a predictive factor.<br><br>RESULTS: Between October 2017 and March 2022, 54 participants were assigned to TP (n = 26) and CETIRI (n = 28). Median PFS did not vary significantly by treatment: 4.7 (95% CI, 1.9 to 7.6) and 3.7 (95% CI, 1.6 to 6.7) months in the TP and CETIRI groups, respectively. Efficacy of TP versus CETIRI differed significantly by HER2 GCN (median PFS, GCN &#x2265;20 [9.9 v 2.9 months] and GCN <20 [3.0 v 4.2 months], respectively; P interaction = .003). On TP, ORR was 34.6% (57.1% with GCN &#x2265;20 v 9.1% with GCN <20) with median GCN of 29.7 versus 13.2 for responders and nonresponders, respectively (P = .004). Grade &#x2265;3 adverse events occurred in 23.1% and 46.1% of participants with TP and CETIRI, respectively.<br><br>CONCLUSION: TP appears to be a safe and effective cytotoxic chemotherapy-free option for patients with RAS/BRAF-WT, HER2-positive mCRC. Higher levels of HER2 amplification were associated with greater degree of clinical benefit from TP vis-&#xe0;-vis CETIRI.}, }
@article {pmid39761015, year = {2024}, author = {Nguyen, HH and Talbot, J and Li, D and Raghavan, V and Littman, DR}, title = {Modulating intestinal neuroimmune VIPergic signaling attenuates the reduction in ILC3-derived IL-22 and hepatic steatosis in MASLD.}, journal = {Hepatology communications}, volume = {8}, number = {11}, pages = {}, pmid = {39761015}, issn = {2471-254X}, mesh = {Animals ; *Interleukin-22 ; *Interleukins ; Mice ; *Vasoactive Intestinal Peptide ; *Diet, High-Fat/adverse effects ; *Non-alcoholic Fatty Liver Disease/immunology ; *Lymphocytes/immunology/metabolism ; Disease Models, Animal ; Signal Transduction ; Male ; Mice, Inbred C57BL ; Immunity, Innate ; Fatty Liver/immunology ; Neurons/immunology/metabolism ; Neuroimmunomodulation ; }, abstract = {BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as NAFLD) is a major driver of cirrhosis and liver-related mortality. However, therapeutic options for MASLD, including prevention of liver steatosis, are limited. We previously described that vasoactive intestinal peptide-producing neurons (VIP-neurons) regulate the efficiency of intestinal dietary fat absorption and IL-22 production by type 3 innate lymphoid cells (ILC3) in the intestine. Given the described hepatoprotective role of IL-22, we hypothesize that modulation of this neuroimmune circuit could potentially be an innovative approach for the control of liver steatosis.<br><br>METHODS: We used a model of diet-induced MASLD by exposing mice to a high-fat diet (HFD) for 16 weeks, when the development of liver steatosis was first observed in our animals. We characterized IL-22 production by intestinal ILC3 at this dietary endpoint. We then evaluated whether communication between VIP-neurons and ILC3 affected IL-22 production and MASLD development by exposing mice with a conditional genetic deletion of Vipr2 in ILC3 (Rorc(t)CreVipr2fl/fl) to the HFD. We also performed intermittent global inhibition of VIP-neurons using a chemogenetic inhibitory approach (VipIres-CrehM4DiLSL) in HFD-fed mice.<br><br>RESULTS: Production of IL-22 by intestinal ILC3 is reduced in steatotic mice that were exposed to an HFD for 16 weeks. Targeted deletion of VIP receptor 2 in ILC3 resulted in higher production of IL-22 in ILC3 and was associated with a significant reduction in liver steatosis in mice under HFD. Global inhibition of VIP-producing neurons also resulted in a significant reduction in liver steatosis.<br><br>CONCLUSIONS: Modulating VIPergic neuroimmune signaling can ameliorate the development of hepatic steatosis induced by a surplus of fat ingestion in the diet. This neuroimmune pathway should be further investigated as a potential therapeutic avenue in MASLD.}, }
@article {pmid39760096, year = {2024}, author = {McDougall, JA and Briant, KJ and Carosso, E and Cole, AM and Dee, C and Doody, DR and Hannon, PA and Henderson, V and Johnson, S and Parker, M and Schwartz, SM and Mendoza, JA}, title = {Data-Driven Community Engagement: Using Quantitative and Qualitative Data to Set Priorities and Launch New Initiatives in a Growing Catchment Area.}, journal = {Preventive oncology &amp; epidemiology}, volume = {2}, number = {1}, pages = {}, pmid = {39760096}, issn = {2832-2134}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {In 2022, the catchment area of the Fred Hutchinson/University of Washington/Seattle Children's Cancer Consortium (the Consortium) grew from 13-counties in Western Washington State to include all 39 counties in Washington. Widening the catchment area provided new opportunities for the Consortium to monitor the cancer burden, identify cancer-related health disparities, use a bidirectional approach to develop cancer focused programming, and facilitate research in clinical and community settings. In this commentary, we describe the exploratory process of catchment area change led by the Consortium's Office of Community Outreach and Engagement and new initiatives that followed that growth. We hope that by sharing the ongoing, data-driven community engagement approach in the Consortium's current, statewide catchment area, our experience will be of value to other cancer centers looking to engage with communities and develop bidirectional partnerships in new areas.}, }
@article {pmid39759131, year = {2024}, author = {Biswas, D and Hippe, DS and Winter, AM and Li, I and Rahbar, H and Partridge, SC}, title = {Diffusion weighted imaging for improving the diagnostic performance of screening breast MRI: impact of apparent diffusion coefficient quantitation methods and cutoffs.}, journal = {Frontiers in oncology}, volume = {14}, number = {}, pages = {1437506}, pmid = {39759131}, issn = {2234-943X}, abstract = {INTRODUCTION: Diffusion weighted MRI (DWI) has emerged as a promising adjunct to reduce unnecessary biopsies prompted by breast MRI through use of apparent diffusion coefficient (ADC) measures. The purpose of this study was to investigate the effects of different lesion ADC measurement approaches and ADC cutoffs on the diagnostic performance of breast DWI in a high-risk MRI screening cohort to identify the optimal approach for clinical incorporation.<br><br>METHODS: Consecutive screening breast MRI examinations (August 2014-Dec 2018) that prompted a biopsy for a suspicious breast lesion (BI-RADS 4 or 5) were retrospectively evaluated. On DWI, ADC (b=0/100/600/800s/mm[2]) measures were calculated with three different techniques for defining lesion region-of-interest (ROI; single slice('2D'), whole volume('3D') and lowest ADC region('hotspot')). An optimal data-derived ADC cutoff for each technique was retrospectively identified to reduce benign biopsies while avoiding any false negatives, inherently producing cutoffs with 100% sensitivity in this particular cohort. Further, diagnostic performance of these measures was validated using two prespecified ADC cutoffs: 1.53x10[-3]mm[2]/s from the ECOG-ACRIN A6702 trial and 1.30x10[-3]mm[2]/s from the international EUSOBI group. Diagnostic performance was compared between ADC maps generated with 2(0/800s/mm[2]) and 4(0/100/600/800s/mm[2]) b-values. Benign biopsy reduction rate was calculated (number of benign lesions with ADC >cutoff)/(total number of benign lesions).<br><br>RESULTS: 137 suspicious lesions (in 121 women, median age 44 years [range, 20-75yrs]) were detected on contrast-enhanced screening breast MRI and recommended for biopsy. Of those, 30(21.9%) were malignant and 107(78.1%) were benign. Hotspot ADC measures were significantly lower (p<0.001) than ADCs from both 2D and 3D ROI techniques. Applying the optimal data-derived ADC cutoffs resulted in comparable reduction in benign biopsies across ROI techniques (range:16.8% -17.8%). Applying the prespecified A6702 and EUSOBI cutoffs resulted in benign biopsy reduction rates of 11.2-19.6%(with 90.0-100% sensitivity) and 36.4-51.4%(with 70.0-83.3% sensitivity), respectively, across ROI techniques. ADC measures and benign biopsy reduction rates were similar when calculated with only 2 b-values (0,800 s/mm[2]) versus all 4 b-values.<br><br>DISCUSSION: Our findings demonstrate that with appropriate ADC thresholds, comparable reduction in benign biopsies can be achieved using lesion ADC measurements computed from a variety of approaches. Choice of ADC cutoff depends on ROI approach and preferred performance tradeoffs (biopsy reduction vs sensitivity).}, }
@article {pmid39758135, year = {2024}, author = {Langley, BO and Rillamas-Sun, E and Huang, Y and Indorf, A and Robles, M and Feaster, R and D'Addario, L and Ergas, IJ and Roh, JM and Kushi, LH and Greenlee, H}, title = {Validation and Utility of Drug-Nutrient Interaction and Dietary Supplement Mechanistic Activity in the Natural Medicines Database.}, journal = {JCO oncology advances}, volume = {1}, number = {}, pages = {e2400062}, pmid = {39758135}, issn = {2994-9750}, abstract = {PURPOSE: The increasing use of dietary supplements by patients with cancer and other chronic diseases requires the systematized review of potential interactions between prescription drugs and nutrients from supplements by health care and clinical research teams. Dietary supplement interaction databases are positioned to fill a gap in quantifying potential risks for patients, although none have been assessed for reliability in data interpretation. The NatMed database, a source for comprehensive reports on mechanistic and safety data for dietary supplement ingredients, was evaluated for use in future investigations.<br><br>METHODS: Data from NatMed were retrieved using licensed end points for ingredient monographs with drug-nutrient interactions with doxorubicin across five pharmacokinetic and metabolic pathways, and for ingredient monographs with antioxidant activity. Interactions between dietary supplements and doxorubicin treatment and antioxidant monographs were independently reviewed and characterized by clinical pharmacists. Cohen's K was used to measure interrater reliability and the degree of agreement between pharmacists.<br><br>RESULTS: Three hundred fifteen potential interactions with doxorubicin (n = 115 monographs) and 455 other antioxidant ingredients were identified and reviewed by clinical pharmacists. There was substantial to near-perfect agreement for drug-nutrient interactions with doxorubicin (Cohen's K = 0.64-0.85) and for antioxidants (Cohen's K = 0.84). A small proportion of retrieved monographs were not validated by the clinical pharmacists for interactions with doxorubicin (n = 20 occurrences, 6.4%) or for antioxidant activity (n = 28, 6.2%).<br><br>CONCLUSION: A high degree of reliability in data on dietary supplement interactions with doxorubicin and mechanisms of action suggests NatMed may be a dependable source of data for future investigators. Additional procedures including independent data validation and use of multiple dietary supplement interaction databases will strengthen the quality of findings in future studies.}, }
@article {pmid39756456, year = {2025}, author = {Lapen, K and Feliciano, EJG and Dee, EC and Gillespie, EF and Yahalom, J and Imber, BS}, title = {Electronic patient-reported outcomes for CAR T-cell therapies.}, journal = {The Lancet. Oncology}, volume = {26}, number = {1}, pages = {e6}, doi = {10.1016/S1470-2045(24)00644-2}, pmid = {39756456}, issn = {1474-5488}, }
@article {pmid39756444, year = {2025}, author = {Choueiri, TK and Merchan, JR and Figlin, R and McDermott, DF and Arrowsmith, E and Michaelson, MD and Tykodi, SS and Heath, EI and Spigel, DR and D'Souza, A and Kassalow, L and Perini, RF and Vickery, D and Bauer, TM}, title = {Belzutifan plus cabozantinib as first-line treatment for patients with advanced clear-cell renal cell carcinoma (LITESPARK-003): an open-label, single-arm, phase 2 study.}, journal = {The Lancet. Oncology}, volume = {26}, number = {1}, pages = {64-73}, doi = {10.1016/S1470-2045(24)00649-1}, pmid = {39756444}, issn = {1474-5488}, mesh = {Humans ; *Anilides/therapeutic use/administration &amp; dosage/adverse effects ; Female ; Male ; Middle Aged ; *Carcinoma, Renal Cell/drug therapy/pathology ; *Pyridines/administration &amp; dosage/therapeutic use/adverse effects ; Aged ; *Kidney Neoplasms/drug therapy/pathology ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Adult ; }, abstract = {BACKGROUND: Belzutifan, a first-in-class HIF-2α inhibitor, has shown antitumour activity as monotherapy and in combination with cabozantinib in patients with previously treated advanced kidney cancer. The phase 2 LITESPARK-003 study was designed to determine the antitumour activity and safety of belzutifan in combination with cabozantinib in patients with advanced clear-cell renal cell carcinoma that was previously untreated (cohort 1) or previously treated with immunotherapy (cohort 2). Here, we report results from cohort 1 of this clinical trial.<br><br>METHODS: LITESPARK-003 is an open-label, single-arm, phase 2 study at ten hospitals and cancer centres in the USA. In cohort 1, eligible patients were at least 18 years of age, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had received no previous systemic therapy for locally advanced or metastatic renal cell carcinoma. Patients received belzutifan 120 mg orally once daily and cabozantinib 60 mg orally once daily until unacceptable adverse events, disease progression, or patient withdrawal. The primary endpoint was investigator-assessed confirmed objective response according to Response Evaluation Criteria in Solid Tumors version 1.1. Antitumour activity and safety were assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT03634540, and is ongoing.<br><br>FINDINGS: Between Sept 27, 2018, and Jan 10, 2023, we screened 138 patients for eligibility, and 50 (36%) were enrolled and assigned to cohort 1. The median age was 64 years (IQR 57-72). 40 (80%) of 50 patients were male and ten (20%) were female. 48 (96%) patients were White, one (2%) patient was Black or African American, and one (2%) was of a race in the other category. As of the data cutoff (May 15, 2023), median follow-up was 24&#xb7;3 months (IQR 13&#xb7;9-32&#xb7;0). 35 (70%, 95% CI 55-82) of 50 patients had a confirmed objective response, including four (8%) who had a complete response and 31 (62%) who had a partial response. The most frequent grade 3-4 treatment-related adverse events were hypertension (six [12%] patients), anaemia (five [10%] patients), and fatigue (four [8%] patients). Seven (14%) of 50 patients had serious treatment-related adverse events. No treatment-related deaths occurred.<br><br>INTERPRETATION: Belzutifan plus cabozantinib has promising antitumour activity in treatment-naive patients with advanced clear-cell renal cell carcinoma and further investigation of an HIF-2&#x3b1; inhibitor in combination with a multitargeted tyrosine kinase inhibitor as a treatment option in this population is warranted.<br><br>FUNDING: Merck Sharp &amp; Dohme LLC, a subsidiary of Merck &amp; Co, Inc, Rahway, NJ, USA, and the National Cancer Institute.}, }
@article {pmid39755942, year = {2025}, author = {Yan, L and He, Q and Verma, SP and Zhang, X and Giel, AS and Maj, C and Graz, K and Naderi, E and Chen, J and Ali, MW and Gharahkhani, P and Shu, X and Offit, K and Shah, PM and Gerdes, H and Molena, D and Srivastava, A and MacGregor, S and ,  and Palles, C and Thieme, R and Vieth, M and Gockel, I and Vaughan, TL and Schumacher, J and Buas, MF}, title = {Biologically-targeted discovery-replication scan identifies G×G interaction in relation to risk of Barrett's esophagus and esophageal adenocarcinoma.}, journal = {HGG advances}, volume = {}, number = {}, pages = {100399}, doi = {10.1016/j.xhgg.2025.100399}, pmid = {39755942}, issn = {2666-2477}, abstract = {Inherited genetics represents an important contributor to risk of esophageal adenocarcinoma (EAC), and its precursor Barrett's esophagus (BE). Genome-wide association studies have identified ∼30 susceptibility variants for BE/EAC, yet genetic interactions remain unexamined. To address challenges in large-scale G×G scans, we combined knowledge-guided filtering and machine learning approaches, focusing on genes with (A) known/plausible links to BE/EAC pathogenesis (n=493) or (B) prior evidence of biological interactions (n=4,196). ∼75 x 10[6] SNP×SNP interactions were screened via hierarchical group lasso (glinternet) using BEACON GWAS data. The top ∼2000 interactions retained in each scan were prioritized using P values from single logistic models. Identical scans were repeated among males only (78%), with two independent GWAS datasets used for replication. In overall and male-specific primary replications, 11 of 187 and 20 of 191 interactions satisfied P<0.05, respectively. The strongest evidence for secondary replication was for rs17744726×rs3217992 among males, with consistent directionality across all cohorts (Pmeta=2.19×10[-8]); rs3217992 "T" was associated with reduced risk only in individuals homozygous for rs17744726 "G". Rs3217992 maps to the CDKN2B 3'UTR and reportedly disrupts microRNA-mediated repression. Rs17744726 maps to an intronic enhancer region in BLK. Through in-silico prioritization and experimental validation, we identified a nearby proxy variant (rs4841556) as a functional modulator of enhancer activity. Enhancer-gene mapping and eQTLs implicated BLK and FAM167A as targets. The first systematic G×G investigation in BE/EAC, this study uncovers differential risk associations for CDKN2B variation by BLK genotype, suggesting novel biological dependency between two risk loci encoding key mediators of tumor suppression and inflammation.}, }
@article {pmid39755595, year = {2025}, author = {Omollo, V and Roche, SD and Zhang, S and Asewe, M and Rono, BK and Kwach, B and Rota, G and Ong'wen, P and Harkey, K and Odoyo, J and Were, D and Ngure, K and Bukusi, EA and Ortblad, KF}, title = {Measuring the uptake of clinic-based HIV treatment and prevention services following HIV testing and referral at private pharmacies in Kenya.}, journal = {BMC health services research}, volume = {25}, number = {1}, pages = {23}, pmid = {39755595}, issn = {1472-6963}, support = {INV-033052/GATES/Bill &amp; Melinda Gates Foundation/United States ; INV-033052/GATES/Bill &amp; Melinda Gates Foundation/United States ; INV-033052/GATES/Bill &amp; Melinda Gates Foundation/United States ; INV-033052/GATES/Bill &amp; Melinda Gates Foundation/United States ; INV-033052/GATES/Bill &amp; Melinda Gates Foundation/United States ; INV-033052/GATES/Bill &amp; Melinda Gates Foundation/United States ; INV-033052/GATES/Bill &amp; Melinda Gates Foundation/United States ; INV-033052/GATES/Bill &amp; Melinda Gates Foundation/United States ; INV-033052/GATES/Bill &amp; Melinda Gates Foundation/United States ; INV-033052/GATES/Bill &amp; Melinda Gates Foundation/United States ; INV-033052/GATES/Bill &amp; Melinda Gates Foundation/United States ; INV-033052/GATES/Bill &amp; Melinda Gates Foundation/United States ; INV-033052/GATES/Bill &amp; Melinda Gates Foundation/United States ; INV-033052/GATES/Bill &amp; Melinda Gates Foundation/United States ; R00 MH121166/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; Kenya/epidemiology ; *HIV Infections/diagnosis/prevention &amp; control/drug therapy/epidemiology ; Female ; Male ; Adult ; *Referral and Consultation/statistics &amp; numerical data ; Pilot Projects ; *Pharmacies/statistics &amp; numerical data ; *HIV Testing/statistics &amp; numerical data ; Pre-Exposure Prophylaxis/statistics &amp; numerical data ; Adolescent ; Young Adult ; Middle Aged ; Patient Acceptance of Health Care/statistics &amp; numerical data ; }, abstract = {BACKGROUND: Despite their ubiquity across sub-Saharan Africa, private pharmacies are underutilized for HIV service delivery beyond the sale of HIV self-test kits. To understand what uptake of HIV prevention and treatment services might look like if private pharmacies offered clients free HIV self-testing and referral to clinic-based HIV services, we conducted a pilot study in Kenya.<br><br>METHODS: At 20 private pharmacies in Kisumu County, Kenya, pharmacy clients (&#x2265;&#x2009;18&#xa0;years) purchasing sexual health-related products (e.g., contraception) were offered free HIV testing. Based on their test result and recent self-reported behaviors associated with HIV risk, clients were encouraged to consider pre-exposure prophylaxis (PrEP), post-exposure prophylaxis (PEP), or antiretroviral therapy (ART) initiation, informed where they could access free services, and issued a referral. We called clients three months after study completion to see if they had initiated the recommended service. Among clients who reported PrEP referral, we used Poisson regression models to examine characteristics associated with PrEP initiation and calculated adjusted prevalence ratios (aPRs).<br><br>RESULTS: From March to June 2022, 1500 pharmacy clients completed HIV testing and were referred to clinic-based HIV services; in October 2022, 1178 (79%) were reached and meet our criteria for follow-up. Among those reached, the majority (63%, 742/1178) were women, the median age was 26&#xa0;years (IQR 22-31), and few (4%, 51/1178) reported any prior PrEP use. At the pharmacy, most clients (96%, 1136/1178) tested HIV-negative and reported PrEP (95%, 1122/1178) or PEP (1%, 14/1178) referral; the remainder (4%, 42/1178) tested HIV-positive and reported ART referral. The uptake of ART (90%, 38/42) and PEP (86%, 12/14) among clients referred was high. The uptake of PrEP was only 9% (101/1122) among those referred and prior PrEP use was the only characteristic significantly associated with initiation (aPR 2.45, 95% confidence interval 1.19 to 5.07).<br><br>CONCLUSIONS: Although offering free HIV testing at private pharmacies led to the identification and referral of clients who could benefit from HIV services, additional interventions (e.g., incentives, patient navigators) may be needed to support PrEP referral follow-through. Alternatively, new delivery models that circumvent the need for referrals, such as same-day PrEP initiation at pharmacies, should be considered.}, }
@article {pmid39755256, year = {2025}, author = {Hickey, CL and Zhang, MJ and Allbee-Johnson, M and Romee, R and Majhail, NS and Malki, MMA and Antin, JH and Benjamin, CL and Bredeson, C and Chhabra, S and Grunwald, MR and Inamoto, Y and Kanakry, CG and Milano, F and Soiffer, RJ and Solomon, SR and Spellman, SR and Brunstein, CG and Cutler, C}, title = {Donor Type Does Not Impact Late Graft Failure Following Reduced Intensity Allogeneic Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide Based Graft-Versus-Host Disease Prophylaxis.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2024.12.021}, pmid = {39755256}, issn = {2666-6367}, abstract = {BACKGROUND: Post-transplant cyclophosphamide (PTCy) is a commonly used graft-vs-host disease (GVHD) prophylaxis, particularly in the setting of haploidentical (haplo) hematopoietic cell transplantation (HCT). The rate of graft failure has been reported to be as high as 12-20% in haplo-HCT recipients using PTCy. The objective of this study was to determine if donor type influenced the risk of late graft failure following RIC HCT using PTCy-based GVHD prophylaxis.<br><br>STUDY DESIGN: A retrospective cohort analysis using the CIBMTR research database among adult patients who underwent first reduced intensity conditioning (RIC) haplo or 8/8 MUD HCT between 2011 and 2018 for AML, ALL or MDS with PTCy GVHD prophylaxis. The primary outcome was incidence of late graft failure, defined as secondary graft loss in the absence of relapse, or poor graft function requiring a cellular therapy intervention.<br><br>RESULTS: A total of 1336 patients met the eligibility criteria (1151 haplo, 185 MUD). Patients in the MUD group were older (65 vs 61), less ethnically diverse (95% vs 72% Caucasian), received fewer bone marrow grafts (45% vs 16%), and had younger donors (median age 28 vs 37 years old). Conditioning regimens were predominately fludarabine, cyclophosphamide and total body irradiation (87% haplo and 38% MUD). At 2 years, the adjusted probabilities of late graft failure for the haplo group was 6.5% ((95% confidence interval (CI) 5.2-8.0)) vs 5.9% (95% CI 2.7-10.9) for the MUD group (p=0.79). Multivariate analysis for risk factors associated with late graft failure found associations with a diagnosis of MDS (HR 1.98; 95% CI 1.22-3.20; p=0.005), and earlier year of HCT (2015-2018 vs. 2011-2014; HR 0.39; 95% CI 0.24-0.64; p=0.0002). A post-hoc sensitivity analysis was performed to evaluate the effect of donor age and use of PBSC grafts. Graft failure did not differ between haplo and MUD HCT (HR 1.19; p=0.67) when adjusted for donor age nor when restricted to PBSC grafts only (HR 0.85; p=0.70).<br><br>CONCLUSION: In this registry-based analysis of patients undergoing RIC HCT for AML, ALL or MDS using GVHD prophylaxis with PTCy, there was no significant difference in late graft failure rates between haplo and MUD donors. Overall rates of late graft failure were high.}, }
@article {pmid39755170, year = {2025}, author = {Besse, B and Goto, K and Wang, Y and Lee, SH and Marmarelis, ME and Ohe, Y and Caro, RB and Kim, DW and Lee, JS and Cousin, S and Ichihara, E and Li, Y and Paz-Ares, L and Ono, A and Sanborn, RE and Watanabe, N and Jose de Miguel, M and Helissey, C and Shu, CA and Spira, AI and Tomasini, P and Chih-Hsin Yang, J and Zhang, Y and Felip, E and Griesinger, F and Waqar, SN and Calles, A and Neal, JW and Baik, CS and Jänne, PA and Shreeve, SM and Curtin, JC and Patel, B and Gormley, M and Lyu, X and Chen, J and Chu, PL and Mahoney, J and Trani, L and Bauml, JM and Thayu, M and Knoblauch, RE and Cho, BC}, title = {Amivantamab Plus Lazertinib in Patients With EGFR-mutant Non-small Cell Lung Cancer (NSCLC) After Progression on Osimertinib and Platinum-based Chemotherapy: Results From CHRYSALIS-2 Cohort A.}, journal = {Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtho.2024.12.029}, pmid = {39755170}, issn = {1556-1380}, abstract = {INTRODUCTION: Treatment options for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) with disease progression on/after osimertinib and platinum-based chemotherapy are limited.<br><br>METHODS: CHRYSALIS-2 Cohort A evaluated amivantamab+lazertinib in patients with EGFR exon 19 deletion- or L858R-mutated NSCLC with disease progression on/after osimertinib and platinum-based chemotherapy. Primary endpoint was investigator-assessed objective response rate (ORR). Patients received intravenous amivantamab 1050 mg (1400 mg if &#x2265;80 kg) plus oral lazertinib 240 mg.<br><br>RESULTS: In Cohort A (n=162), investigator-assessed ORR was 28% (95% CI, 22-36). Blinded independent central review (BICR)-assessed ORR was 35% (95% CI, 27-42), with median duration of response (DoR) of 8.3 months (95% CI, 6.7-10.9) and clinical benefit rate of 58% (95% CI, 50-66). At a median follow-up of 12 months, 32/56 responders (57%) achieved a DoR &#x2265;6 months. Median progression-free survival by BICR was 4.5 months (95% CI, 4.1-5.8); median overall survival was 14.8 months (95% CI, 12.2-18.0). Preliminary evidence of central nervous system-anti-tumor activity was reported among 7 patients with baseline brain lesions and no prior brain radiation/surgery. Exploratory biomarker analyses using circulating tumor DNA next-generation sequencing showed responses in patients with and without identified EGFR/MET-dependent resistance. Most frequent adverse events were rash (grouped term; 81%), infusion-related reaction (68%), and paronychia (52%). Most common grade &#x2265;3 treatment-related adverse events were rash (grouped term; 10%), infusion-related reaction (9%), and hypoalbuminemia (6%).<br><br>CONCLUSIONS: For patients with limited treatment options, amivantamab+lazertinib demonstrated anti-tumor activity with a safety profile characterized by EGFR/MET-realated adverse events, which were generally manageable.}, }
@article {pmid39754855, year = {2024}, author = {Hill, M and Garcia, LR and Nguyen, E and Korolkova, A and Cohn, L and Rodriguez, A and Hoh, R and Deeks, SG and Peluso, MJ and Sauceda, JA and Dubé, K}, title = {Evaluating the psychosocial experiences of participants in HIV cure research before, during, and after analytical treatment interruptions: A longitudinal qualitative study in the United States.}, journal = {Social science &amp; medicine (1982)}, volume = {366}, number = {}, pages = {117644}, doi = {10.1016/j.socscimed.2024.117644}, pmid = {39754855}, issn = {1873-5347}, abstract = {The lack of socio-behavioral research on stress and psychosocial experiences among research participants who undergo analytical treatment interruption (ATI) in HIV cure studies underscores a critical gap in cure science. Existing literature acknowledges mixed and potentially adverse mental health impacts of ATIs among trial participants, but empirical insights before, during, and after clinical studies are scarce. We used longitudinal in-depth interviews with 11 participants in HIV cure-related research to explore their experiences with stress, coping, and psychological well-being before, during, and after an ATI. Our framework analyses of participant interviews suggest an evolving interplay between person- and environment-oriented factors that shape psychosocial well-being through multiple pathways. Key emergent themes surrounding stress, coping, and psychological adaptation before the ATI encompass the stress-protective effects of pill (in)significance, curiosity in natural immunological control, and perceived support, and trust with professional help networks comprised of providers and research staff. Themes that promoted positive secondary appraisals of stressors during ATIs involved generativity and meaning-based coping, and the stress-adaptive benefits of support-seeking and actualization. Finally, a theme exposing post-ATI stress revolved around the disappointment that participants noted feeling from needing to restart their HIV medications after the ATI and accepting the permanency of HIV and medications in their lives. Our findings emphasize the importance of building supportive and trusting relationships with research teams, and specify the stress-buffering mechanisms between emotional, informational, and appraisal support on ATI-related stress. Additionally, we outline multiple implications that advocate for the adoption of several precautionary measures in HIV cure research to mitigate psychosocial risks. By documenting the evolution of psychosocial experiences, we offer valuable insights to inform the design of future studies, ensuring their ethicality, acceptability, and inclusivity.}, }
@article {pmid39753771, year = {2025}, author = {Jia, G and Chen, Z and Ping, J and Cai, Q and Tao, R and Li, C and Bauer, JA and Xie, Y and Ambs, S and Barnard, ME and Chen, Y and Choi, JY and Gao, YT and Garcia-Closas, M and Gu, J and Hu, JJ and Iwasaki, M and John, EM and Kweon, SS and Li, CI and Matsuda, K and Matsuo, K and Nathanson, KL and Nemesure, B and Olopade, OI and Pal, T and Park, SK and Park, B and Press, MF and Sanderson, M and Sandler, DP and Shen, CY and Troester, MA and Yao, S and Zheng, Y and Ahearn, T and Brewster, AM and Falusi, A and Hennis, AJM and Ito, H and Kubo, M and Lee, ES and Makumbi, T and Ndom, P and Noh, DY and O'Brien, KM and Ojengbede, O and Olshan, AF and Park, MH and Reid, S and Yamaji, T and Zirpoli, G and Butler, EN and Huang, M and Low, SK and Obafunwa, J and Weinberg, CR and Zhang, H and Zhao, H and Cote, ML and Ambrosone, CB and Huo, D and Li, B and Kang, D and Palmer, JR and Shu, XO and Haiman, CA and Guo, X and Long, J and Zheng, W}, title = {Refining breast cancer genetic risk and biology through multi-ancestry fine-mapping analyses of 192 risk regions.}, journal = {Nature genetics}, volume = {}, number = {}, pages = {}, pmid = {39753771}, issn = {1546-1718}, support = {R01CA202981//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01CA235553//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01CA148667//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01CA148667//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; }, abstract = {Genome-wide association studies have identified approximately 200 genetic risk loci for breast cancer, but the causal variants and target genes are mostly unknown. We sought to fine-map all known breast cancer risk loci using genome-wide association study data from 172,737 female breast cancer cases and 242,009 controls of African, Asian and European ancestry. We identified 332 independent association signals for breast cancer risk, including 131 signals not reported previously, and for 50 of them, we narrowed the credible causal variants down to a single variant. Analyses integrating functional genomics data identified 195 putative susceptibility genes, enriched in PI3K/AKT, TNF/NF-κB, p53 and Wnt/β-catenin pathways. Single-cell RNA sequencing or in vitro experiment data provided additional functional evidence for 105 genes. Our study uncovered large numbers of association signals and candidate susceptibility genes for breast cancer, uncovered breast cancer genetics and biology, and supported the value of including multi-ancestry data in fine-mapping analyses.}, }
@article {pmid39751344, year = {2024}, author = {Funk, CC and Darvas, M and Johnston, C and Robinson, M and Schaffer, C and Battaglia, C and Aubert, M and Wiley, JC}, title = {Basic Science and Pathogenesis.}, journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association}, volume = {20 Suppl 1}, number = {}, pages = {e093497}, doi = {10.1002/alz.093497}, pmid = {39751344}, issn = {1552-5279}, mesh = {Animals ; Mice ; *Herpesvirus 1, Human ; *Disease Models, Animal ; *Alzheimer Disease/genetics/pathology ; Mice, Transgenic ; Humans ; Mice, Inbred C57BL ; Brain/pathology ; Azepines/pharmacology ; Triazoles/pharmacology ; }, abstract = {BACKGROUND: The immerging role of CD8+T cells, interferon and the adaptive immune response in AD is consistent with previous observations of the putative role of neurotrophic herpesvirus family infections contributing to Alzheimer's Disease pathophysiology. An outstanding question is how chronic viral infections over decades may contribute to AD pathogenesis. Our HSV-1 reactivation model aims to provide insights to this question.<br><br>METHOD: We infected 2 month old C57B6/J mice containing humanized APP and APOE4 with 10[6] PFU HSV-1 strain 17 via corneal scarification. We reactivated the virus with the bromo-domain compound JQ1 at 4, 7 and 10 months, with 1x, 3x and 6x reactivations respectively and harvested the brainstem, hippocampus, entorhinal cortex and dural sinuses, for RNAseq. To identify common changes in gene expression between our HSV-1 reactivation model and AD, we compared the gene expression profiles of our mice to both human and mouse model gene profiles using 19 AD-specific categories (BioDomains).<br><br>RESULT: We found reactivation by JQ1 resulted in increased HSV-1 detection by qPCR in a progressive manner, emanating outward from the trigeminal ganglion, towards more distal brain regions. We observed changes in RNAseq expression profiles in a time-dependent manner, with the greatest number of differentially expressed genes at 7 months. We observed changes in synaptic and immune genes in both the entorhinal cortex and hippocampus. We also saw decreases in gene expression in lipid metabolism, myelination, and the endolysosomal pathways.<br><br>CONCLUSION: Our HSV-1 reactivation mouse model identifies changes in gene expression that are similar to those observed in humans and mouse AD models, with observed, distinct changes in synaptic- and immune-associated genes in multiple brain regions. Activation of immune genes was highest in the brain stem, where detection of HSV-1 was highest. The greatest changes in gene expression occurred at 7 months, with fewer changes following at 10 months. These changes are most similar to changes in early disease and support the role of HSV-1 contributing to AD pathophysiology.}, }
@article {pmid39751084, year = {2024}, author = {Prater, KE and Rose, S and Johnson, CSC and Strohbehn, S and Cochoit, AJ and Mamde, S and Sun, W and Keene, CD and Shojaie, A and Garden, GA and Blue, EE and Young, JE and Jayadev, S}, title = {Basic Science and Pathogenesis.}, journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association}, volume = {20 Suppl 1}, number = {}, pages = {e087986}, doi = {10.1002/alz.087986}, pmid = {39751084}, issn = {1552-5279}, mesh = {Humans ; *Alzheimer Disease/genetics/pathology ; *Genome-Wide Association Study ; *Lysosomes/metabolism ; *Endosomes/metabolism ; Genetic Predisposition to Disease ; Brain/pathology/metabolism ; Multifactorial Inheritance/genetics ; Male ; Female ; Aged ; }, abstract = {BACKGROUND: Late onset Alzheimer disease is a complex syndrome, genetically, clinically and pathogenetically heterogeneous. Genome Wide association studies have identified risk alleles for AD harboring genes in the endolysosomal network (ELN). We hypothesize that aggregate burden of these endolysosomal risk alleles impacts cell type specific ELN function, thus contributing to LOAD pathogenesis.<br><br>METHOD: To test this hypothesis, we first developed an endolysosomal polygenic risk score (ePRS) using a curated list of established GWAS AD risk loci. We identified a cohort in the top quartile (high) and bottom quartile (low) of ePRS scores within our LOAD biobank with rich clinical and pathological phenotype data, enabling brain tissue omics and cell based functional studies from the same donor. To explore cell type specific implications of ePRS burden, we studied frozen cortical brain tissue and primary cells derived from the same set of LOAD cases.<br><br>RESULT: We identified cell type-specific gene expression and regulatory network shifts associated with ePRS burden. Immunohistochemistry revealed that high ePRS was associated with enlarged neuronal endosomes and microglial lysosomes. We explored whether ePRS itself predicted ELN changes in cells that are not exposed to pathologic protein deposition. Leptomeningeal cells isolated from the ePRS cohort also manifested changes to ELN morphology and bulk RNA sequencing revealed ePRS-dependent gene expression changes, suggesting that ePRS directly influences ELN related transcriptomic phenotype.<br><br>CONCLUSION: Taken together, our data suggests that AD risk loci implicating genes within the endolysosomal system do in fact impact the cellular ELN, giving more confidence to the pathogenic relevance of "endolysosomal" risk loci. Dysfunction of endolysosomal pathways likely contributes to AD pathogenesis in LOAD and may highlight more specific points of intervention. Pathway-specific polygenic risk scores can enhance our understanding of the complex mechanisms contributing to AD and pave the way for more specific targeted therapies in the clinic.}, }
@article {pmid39749518, year = {2025}, author = {O'Halloran, K and Christodoulou, E and Paulson, VA and Cole, BL and Margol, AS and Biegel, JA and Leary, SES and Lockwood, CM and Crotty, EE}, title = {Low-Pass Whole Genome Sequencing of Cell-Free DNA from Cerebrospinal Fluid: A Focus on Pediatric Central Nervous System Tumors.}, journal = {Clinical chemistry}, volume = {71}, number = {1}, pages = {87-96}, doi = {10.1093/clinchem/hvae140}, pmid = {39749518}, issn = {1530-8561}, mesh = {Humans ; *Central Nervous System Neoplasms/cerebrospinal fluid/genetics/diagnosis ; Child ; *Cell-Free Nucleic Acids/cerebrospinal fluid ; *Whole Genome Sequencing/methods ; Liquid Biopsy/methods ; }, abstract = {BACKGROUND: Cell-free DNA (cfDNA) technology has allowed for cerebrospinal fluid (CSF), a previously underutilized biofluid, to be analyzed in new ways. The interrogation of CSF-derived cfDNA is giving rise to novel molecular insights, particularly in pediatric central nervous system (CNS) tumors, where invasive tumor tissue acquisition may be challenging. Contemporary disease monitoring is currently restricted to radiographic surveillance by magnetic resonance imaging and CSF cytology to directly detect abnormal cells and cell clusters. Alternatively, cfDNA is often present in the CSF from pediatric patients with both malignant and nonmalignant CNS tumors and can be accessed by minimally invasive lumbar puncture and other CSF-liberating procedures, offering a promising alternative for longitudinal molecular disease analysis and surveillance.<br><br>CONTENT: This review explores the use of low-pass whole genome sequencing (LP-WGS) to analyze cfDNA from the CSF of pediatric patients with CNS tumors. This platform is uniquely poised for the detection of tumors harboring copy number variants, which are prevalent in this population. The utility and sensitivity of LP-WGS as a clinical tool is explored and discussed in the context of alternative CSF liquid biopsy interrogation modalities, including nanopore sequencing and methylation array.<br><br>SUMMARY: Analysis of CSF-derived cfDNA by LP-WGS has broad diagnostic, prognostic, and clinical implications for pediatric patients with CNS tumors. Careful interpretation of LP-WGS results may aid in therapeutic targeting of pediatric CNS tumors and may provide insight into tumor heterogeneity and evolution over time, without the need for invasive and potentially risky tissue sampling.}, }
@article {pmid39749508, year = {2025}, author = {Casto, AM and Paredes, MI and Bennett, JC and Luiten, KG and Han, PD and Gamboa, LS and McDermot, E and Gottlieb, GS and Acker, Z and Lo, NK and McDonald, D and McCaffrey, KM and Figgins, MD and Lockwood, CM and Shendure, J and Uyeki, TM and Starita, LM and Bedford, T and Chu, HY and Weil, AA}, title = {SARS-CoV-2 Diversity and Transmission on a University Campus across Two Academic Years during the Pandemic.}, journal = {Clinical chemistry}, volume = {71}, number = {1}, pages = {192-202}, doi = {10.1093/clinchem/hvae194}, pmid = {39749508}, issn = {1530-8561}, mesh = {Humans ; *COVID-19/transmission/epidemiology/virology ; Universities ; *SARS-CoV-2/genetics/isolation &amp; purification ; *Genome, Viral ; Washington/epidemiology ; Phylogeny ; Students ; }, abstract = {BACKGROUND: Institutions of higher education (IHE) have been a focus of SARS-CoV-2 transmission studies but there is limited information on how viral diversity and transmission at IHE changed as the pandemic progressed.<br><br>METHODS: Here we analyze 3606 viral genomes from unique COVID-19 episodes collected at a public university in Seattle, Washington from September 2020 to September 2022.<br><br>RESULTS: Across the study period, we found evidence of frequent viral transmission among university affiliates with 60% (n = 2153) of viral genomes from campus specimens genetically identical to at least one other campus specimen. Moreover, viruses from students were observed in transmission clusters at a higher frequency than in the overall dataset while viruses from symptomatic infections were observed in transmission clusters at a lower frequency. Although only a small percentage of community viruses were identified as possible descendants of viruses isolated in university study specimens, phylodynamic modeling suggested a high rate of transmission events from campus into the local community, particularly during the 2021-2022 academic year.<br><br>CONCLUSIONS: We conclude that viral transmission was common within the university population throughout the study period but that not all university affiliates were equally likely to be involved. In addition, the transmission rate from campus into the surrounding community may have increased during the second year of the study, possibly due to return to in-person instruction.}, }
@article {pmid39749107, year = {2024}, author = {He, Q and Gao, F and Dukes, O and Delany-Moretlwe, S and Zhang, B}, title = {Generalizing the intention-to-treat effect of an active control from historical placebo-controlled trials: A case study of the efficacy of daily oral TDF/FTC in the HPTN 084 study.}, journal = {Journal of the American Statistical Association}, volume = {119}, number = {548}, pages = {2478-2492}, pmid = {39749107}, issn = {0162-1459}, abstract = {In many clinical settings, an active-controlled trial design (e.g., a non-inferiority or superiority design) is often used to compare an experimental medicine to an active control (e.g., an FDA-approved, standard therapy). One prominent example is a recent phase 3 efficacy trial, HIV Prevention Trials Network Study 084 (HPTN 084), comparing long-acting cabotegravir, a new HIV pre-exposure prophylaxis (PrEP) agent, to the FDA-approved daily oral tenofovir disoproxil fumarate plus emtricitabine (TDF/FTC) in a population of heterosexual women in 7 African countries. One key complication of interpreting study results in an active-controlled trial like HPTN 084 is that the placebo arm is not present and the efficacy of the active control (and hence the experimental drug) compared to the placebo can only be inferred by leveraging other data sources. In this article, we study statistical inference for the intention-to-treat (ITT) effect of the active control using relevant historical placebo-controlled trials data under the potential outcomes (PO) framework. We highlight the role of adherence and unmeasured confounding, discuss in detail identification assumptions and two modes of inference (point versus partial identification), propose estimators under identification assumptions permitting point identification, and lay out sensitivity analyses needed to relax identification assumptions. We applied our framework to estimating the intention-to-treat effect of daily oral TDF/FTC versus placebo in HPTN 084 using data from an earlier Phase 3, placebo-controlled trial of daily oral TDF/FTC (Partners PrEP).}, }
@article {pmid39748218, year = {2025}, author = {Delany-Moretlwe, S and Hanscom, B and Guo, X and Nkabiito, C and Mandima, P and Nahirya, PN and Mpendo, J and Bhondai-Mhuri, M and Mgodi, N and Berhanu, R and Farrior, J and Piwowar-Manning, E and Ford, SL and Hendrix, CW and Rinehart, AR and Rooney, JF and Adeyeye, A and Landovitz, RJ and Cohen, MS and Hosseinipour, MC and Marzinke, MA and , }, title = {Evaluation of long-acting cabotegravir safety and pharmacokinetics in pregnant women in eastern and southern Africa: a secondary analysis of HPTN 084.}, journal = {Journal of the International AIDS Society}, volume = {28}, number = {1}, pages = {e26401}, doi = {10.1002/jia2.26401}, pmid = {39748218}, issn = {1758-2652}, support = {//National Institute of Allergy and Infectious Diseases/ ; /NH/NIH HHS/United States ; /DA/NIDA NIH HHS/United States ; UM1AI068619/MH/NIMH NIH HHS/United States ; UM1AI068617/MH/NIMH NIH HHS/United States ; UM1AI068613/MH/NIMH NIH HHS/United States ; OPP1154174/GATES/Bill &amp; Melinda Gates Foundation/United States ; //ViiV Healthcare/ ; }, mesh = {Humans ; Female ; Pregnancy ; Adult ; *Anti-HIV Agents/pharmacokinetics/adverse effects/therapeutic use ; *HIV Infections/drug therapy ; Young Adult ; *Pyridones/pharmacokinetics/adverse effects ; Africa, Eastern/epidemiology ; Pre-Exposure Prophylaxis ; Africa, Southern/epidemiology ; Pregnancy Complications, Infectious/drug therapy ; Pregnancy Outcome ; Tenofovir/pharmacokinetics/adverse effects/therapeutic use/administration &amp; dosage ; Adolescent ; Emtricitabine/pharmacokinetics/therapeutic use/adverse effects/administration &amp; dosage ; Diketopiperazines ; }, abstract = {INTRODUCTION: Long-acting injectable cabotegravir (CAB-LA) for pre-exposure prophylaxis significantly reduced HIV acquisition in HPTN 084. We report on the safety and CAB-LA pharmacokinetics in pregnant women during the blinded period of HPTN 084.<br><br>METHODS: Participants were randomized 1:1 to either active cabotegravir (CAB) plus tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) placebo or active TDF/FTC plus CAB placebo. Pregnancy testing was performed at each visit; participants with a positive test had study product withheld and were offered open-label TDF/FTC. Pregnancies were confirmed on two tests at least 4 weeks apart. All participants with a positive pregnancy test prior to November 5, 2020 are included in this analysis. Pregnancy incidence, maternal adverse event (AE) incidence, pregnancy outcomes (including composite outcome of spontaneous abortion <20 weeks, intrauterine foetal death or stillbirth &#x2265;20 weeks, premature birth <37 weeks, or small for gestational age) were assessed. The apparent terminal phase half-life (t1/2app) of CAB-LA in pregnant women in HPTN 084 was compared to non-pregnant women from the phase 2a HPTN 077 trial. Multivariable models assessed associations with t1/2app. RESULTS: Fifty-seven pregnancies (30 CAB-LA, 27 TDF/FTC) were confirmed over 3845 person-years [py] (incidence 1.5/100 py, 95% CI 1.1-1.9). CAB-LA group participants had a median 342 days (IQR 192, 497) of CAB-LA exposure prior to pregnancy detection. Grade 2 or higher maternal AE incidence did not differ by study arm (CAB 157, 95% CI 91-271 per 100 py vs. TDF/FTC 217, 95% CI 124-380 per 100 py; p = 0.256). Most pregnancies (81%) resulted in live births (25 CAB-LA, 22 TDF/FTC). Composite poor pregnancy outcomes did not differ significantly by group (CAB 6/30 vs. TDF/FTC 4/27; p = 0.476). No congenital anomalies were observed. The CAB t1/2app geometric mean was 52.8 days (95% CI 40.7-68.4) in pregnant women compared to 60.3 days (95% CI 47.7-76.3; p = 0.66) in non-pregnant women; neither pregnancy nor body mass index were significantly associated with t1/2app.<br><br>CONCLUSIONS: CAB-LA concentrations post-cessation of injections were generally well tolerated in pregnant women. The t1/2app was comparable between pregnant and non-pregnant women. Ongoing studies will examine the safety and pharmacology of CAB-LA in women who choose to continue CAB-LA through pregnancy and lactation.}, }
@article {pmid39747003, year = {2025}, author = {Alsaed, B and Lin, L and Son, J and Li, J and Smolander, J and Lopez, T and Eser, P&#xd6; and Ogino, A and Ambrogio, C and Eum, Y and Thai, T and Wang, H and Sutinen, E and Mutanen, H and Duàn, H and Bobik, N and Borenius, K and Feng, WW and Nabet, B and Mustjoki, S and Laaksonen, S and Eschle, BK and Poitras, MJ and Barbie, D and Ilonen, I and Gokhale, P and Jänne, PA and Haikala, HM}, title = {Intratumor heterogeneity of EGFR expression mediates targeted therapy resistance and formation of drug tolerant microenvironment.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {28}, pmid = {39747003}, issn = {2041-1723}, mesh = {*ErbB Receptors/metabolism/genetics/antagonists &amp; inhibitors ; *Tumor Microenvironment/drug effects/genetics ; *Drug Resistance, Neoplasm/genetics ; Humans ; *Carcinoma, Non-Small-Cell Lung/genetics/drug therapy/metabolism/pathology ; *Lung Neoplasms/genetics/drug therapy/metabolism/pathology ; Cell Line, Tumor ; *Protein Kinase Inhibitors/pharmacology ; Animals ; Mutation ; Epithelial-Mesenchymal Transition/genetics/drug effects ; Mice ; Cancer-Associated Fibroblasts/metabolism/drug effects/pathology ; Transforming Growth Factor beta/metabolism ; Female ; Gene Expression Regulation, Neoplastic ; Antineoplastic Agents/pharmacology/therapeutic use ; }, abstract = {Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are commonly used to treat non-small cell lung cancers with EGFR mutations, but drug resistance often emerges. Intratumor heterogeneity is a known cause of targeted therapy resistance and is considered a major factor in treatment failure. This study identifies clones of EGFR-mutant non-small cell lung tumors expressing low levels of both wild-type and mutant EGFR protein. These EGFR-low cells are intrinsically more tolerant to EGFR inhibitors, more invasive, and exhibit an epithelial-to-mesenchymal-like phenotype compared to their EGFR-high counterparts. The EGFR-low cells secrete Transforming growth factor beta (TGFβ) family cytokines, leading to increased recruitment of cancer-associated fibroblasts and immune suppression, thus contributing to the drug-tolerant tumor microenvironment. Notably, pharmacological induction of EGFR using epigenetic inhibitors sensitizes the resistant cells to EGFR inhibition. These findings suggest that intrinsic drug resistance can be prevented or reversed using combination therapies.}, }
@article {pmid39746969, year = {2025}, author = {Duan, S and Nodelman, IM and Zhou, H and Tsukiyama, T and Bowman, GD and Zhang, Z}, title = {H3K56 acetylation regulates chromatin maturation following DNA replication.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {134}, pmid = {39746969}, issn = {2041-1723}, support = {R35GM118015//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; }, mesh = {*Histones/metabolism ; *DNA Replication ; Acetylation ; Humans ; *Chromatin/metabolism ; *Nucleosomes/metabolism ; *Saccharomyces cerevisiae/metabolism/genetics ; Chromatin Assembly and Disassembly ; Transcription Factors/metabolism/genetics ; Adenosine Triphosphatases/metabolism/genetics ; Genomic Instability ; Saccharomyces cerevisiae Proteins/metabolism/genetics ; Chromosomal Proteins, Non-Histone ; }, abstract = {Following DNA replication, the newly reassembled chromatin is disorganized and must mature to its steady state to maintain both genome and epigenome integrity. However, the regulatory mechanisms governing this critical process remain poorly understood. Here, we show that histone H3K56 acetylation (H3K56ac), a mark on newly-synthesized H3, facilitates the remodeling of disorganized nucleosomes in nascent chromatin, and its removal at the subsequent G2/M phase of the cell cycle marks the completion of chromatin maturation. In vitro, H3K56ac enhances the activity of ISWI chromatin remodelers, including yeast ISW1 and its human equivalent SNF2h. In vivo, a deficiency of H3K56ac in nascent chromatin results in the formation of closely packed di-nucleosomes and/or tetra-nucleosomes. In contrast, abnormally high H3K56ac levels disrupt chromatin maturation, leading to genome instability. These findings establish a central role of H3K56ac in chromatin maturation and reveal a mechanism regulating this critical aspect of chromosome replication.}, }
@article {pmid39745736, year = {2025}, author = {Baumrin, E and Cronholm, PF and Kearney, MD and Mengesha, M and Cesar, LG and Keddem, S and Schapira, MM and Lee, SJ and Loren, AW and Gelfand, JM}, title = {Outcomes of Importance to Patients Living With Cutaneous Chronic Graft-vs-Host Disease.}, journal = {JAMA dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamadermatol.2024.5380}, pmid = {39745736}, issn = {2168-6084}, abstract = {IMPORTANCE: Cutaneous chronic graft-vs-host disease (GVHD) is independently associated with morbidity and mortality after allogeneic hematopoietic cell transplant. However, the health-related quality-of-life (HRQOL) domains that are most important to patients are poorly understood.<br><br>OBJECTIVE: To perform a concept elicitation study to define HRQOL in cutaneous chronic GVHD from the patient perspective and to compare experiences of patients with epidermal vs sclerotic disease.<br><br>A single-center qualitative analysis from open-ended, semistructured interviews and free-listing terms conducted between April and September 2023. Participants were 18 years or older with a diagnosis of active cutaneous chronic GVHD, purposefully sampled for epidermal and sclerotic disease features, with ongoing sampling until thematic saturation.<br><br>MAIN OUTCOMES: HRQOL domains and codes from patient perspectives of living with cutaneous chronic GVHD were identified by inductive analysis of semistructured interviews. Smith salience index (Smith S) score, a measure of saliency for each list term, was calculated from free-listing terms from deidentified patient interviews.<br><br>RESULTS: A total of 31 adults with cutaneous chronic GVHD (median [IQR] age, 61.1 [52.9-68.7] years) participated in interviews; 17 participants (54.8%) were male and 14 (45.2%) were female. Nine participants (29.0%) had epidermal, 13 (41.9%) sclerotic, and 9 (29.0%) a combination of disease types. The study identified 40 codes of importance grouped within 5 HRQOL domains: skin changes and symptoms, social functioning, psychological and emotional functioning, physical functioning, and general health perceptions. The most frequent symptoms were dry skin (n&#x2009;=&#x2009;20 [65%]), tight skin (n&#x2009;=&#x2009;19 [61%]), itch (n&#x2009;=&#x2009;15 [48%]), and discoloration (n&#x2009;=&#x2009;14 [45%]), which were seen in all disease subtypes. Impairment in social functioning was noted by all participants. Psychological and emotional functioning, including frustration (Smith S score, 0.32) and worry or concern (Smith S score, 0.12), and symptoms including discomfort (Smith S score, 0.20) were the most salient to patients. Individual and environmental factors, such as social comparison, illness comparison with cancer, anatomic location of disease involvement, and disease duration, affected the relationship between skin changes and symptoms and downstream functioning and general health perceptions.<br><br>CONCLUSIONS AND RELEVANCE: This qualitative analysis demonstrated the direct relationship between cutaneous chronic GVHD and HRQOL domains and identified codes not represented in existing GVHD- and dermatology-specific patient-reported outcome measures. These results can guide patient-reported outcome development and instrument selection for clinical trials and improve clinical decision-making.}, }
@article {pmid39745448, year = {2024}, author = {Arnold, EA and Smith, JR and Leung, K and Nguyen, DH and Kelnhofer-Millevolte, LE and Guo, MS and Smith, JG and Avgousti, DC}, title = {Post-translational modifications on protein VII are important during the early stages of adenovirus infection.}, journal = {Journal of virology}, volume = {}, number = {}, pages = {e0146224}, doi = {10.1128/jvi.01462-24}, pmid = {39745448}, issn = {1098-5514}, abstract = {UNLABELLED: Due to the importance of post-translational modification (PTM) in cellular function, viruses have evolved to both take advantage of and be susceptible to such modification. Adenovirus encodes a multifunctional protein called protein VII, which is packaged with the viral genome in the core of virions and disrupts host chromatin during infection. Protein VII has several PTMs whose addition contributes to the subnuclear localization of protein VII. Here, we used mutant viruses that abrogate or mimic these PTMs on protein VII to interrogate their impact on protein VII function during adenovirus infection. We discovered that acetylation of the lysine in positions 2 or 3 (K2 or K3) is deleterious during early infection as mutation to alanine led to greater intake of protein VII and viral DNA to the nucleus and enhanced early gene expression. Furthermore, we determined that protein VII is acetylated at alternative residues late during infection which may compensate for the mutated sites. Lastly, due to the role of the early viral protein E1A in viral gene activation, we investigated the interaction between protein VII and E1A and demonstrated that protein VII interacts with E1A through a chromatin-mediated interaction. Together, these results emphasize that the complexity of virus-host interactions is intimately tied to post-translational modification.<br><br>IMPORTANCE: Adenoviruses are ubiquitous human pathogens that cause a variety of diseases, such as respiratory infections, gastroenteritis, and conjunctivitis. While often viewed as a self-limiting infection in healthy individuals, adenoviruses are particularly harmful to immunocompromised patients. Here, we investigate the functional role of post-translational modifications (PTMs) on an essential adenovirus core protein, protein VII, describing how they regulate its function during the early and late stages of infection. Our study focuses on how specific PTMs on protein VII influence transcription, localization, and interactions with other proteins, highlighting how PTMs are employed by viruses to alter protein function.}, }
@article {pmid39743015, year = {2024}, author = {Unger, JM and Szarama, K}, title = {Cancer clinical trial participation in socioeconomically vulnerable patients; A risk model to aid in targeted interventions.}, journal = {Contemporary clinical trials}, volume = {}, number = {}, pages = {107803}, doi = {10.1016/j.cct.2024.107803}, pmid = {39743015}, issn = {1559-2030}, abstract = {BACKGROUND: In patients with cancer, those with lower incomes are less likely to participate in clinical trials. A broad-based evaluation of variables that could contribute to this disparity has not been conducted.<br><br>METHODS: We used data from Health Information National Trends Survey (HINTS) databases for survey years 2014, 2017, and 2020, the survey years that included questions about whether patients with cancer participated in a clinical trial. We examined 21 demographic, socioeconomic, behavioral, geographic, and health information questions. We derived a risk model to predict clinical trial participation using a training/validation approach with best subset selection and k-fold cross-validation. Logistic regression was used.<br><br>RESULTS: We examined N&#x202f;=&#x202f;1023 participants with household income <$75,000 (the U.S. median). In the training dataset (n&#x202f;=&#x202f;614), a 5-variable model was identified including race/ethnicity, education, trust, anxiety/depression, and geographic locale. A quartile-level risk score was constructed based on the sum of adverse risk factors. In the validation cohort (n&#x202f;=&#x202f;409), each increase in quartile level was associated with a 73&#x202f;% increase in the odds of trial nonparticipation (OR&#x202f;=&#x202f;1.73, 95&#x202f;%-CI, 1.19-2.53, p&#x202f;=&#x202f;0.004), indicating successful model validation. Among all individuals, trial participation rates decreased from 18.6&#x202f;% to 7.5&#x202f;% to 4.6&#x202f;% to 2.8&#x202f;%, respectively, as the number of adverse risk factors increased from 0 to 1 to 2 to 3 to 4-5.<br><br>CONCLUSIONS: We developed and validated a 5-variable risk model that identified a large set of lower-income individuals at lower risk of trial participation. These findings could aid in identification of patients who may benefit from additional support to navigate the treatment trial decision-making process.}, }
@article {pmid39741979, year = {2024}, author = {Ahmed, M and Beyreuther, E and Gantz, S and Horst, F and Meyer, J and Pawelke, J and Schmid, TE and Stolz, J and Wilkens, JJ and Bartzsch, S}, title = {Design and dosimetric characterization of a transportable proton minibeam collimation system.}, journal = {Frontiers in oncology}, volume = {14}, number = {}, pages = {1473625}, pmid = {39741979}, issn = {2234-943X}, abstract = {BACKGROUND: Proton Minibeam Radiation Therapy has shown to widen the therapeutic window compared to conventional radiation treatment in pre-clinical studies. The underlying biological mechanisms, however, require more research.<br><br>PURPOSE: The purpose of this study was to develop and characterize a mechanical collimation setup capable of producing 250&#xb5;m wide proton minibeams with a center-to-center distance of 1000&#xb5;m.<br><br>METHODS: To find the optimal arrangement Monte Carlo simulations were employed using the Geant4 toolkit TOPAS to maximize key parameters such as the peak-to-valley dose ratio (PVDR) and the valley dose rate. The experimental characterization of the optimized setup was carried out with film dosimetry at the University Proton Therapy beamline in Dresden and the proton beamline of the University of Washington Medical Center in Seattle with 150MeV and 50.5MeV, respectively. A microDiamond detector (PTW, Freiburg, Germany) was utilized at both beamlines for online proton minibeam dosimetry.<br><br>RESULTS: A PVDR of 10 was achieved in Dresden and a PVDR of 14 in Seattle. Dosimetry measurements were carried out with EBT3 films at a depth of 5mm in a polymethylmethacrylate (PMMA) phantom. When comparing film dosimetry with the microDiamond, excellent agreement was observed in the valleys. However, the peak dose showed a discrepancy of approximately 10% in the 150MeV beam and 20% in the 50.5MeV beam between film and microDiamond.<br><br>DISCUSSION: The characteristics of the minibeams generated with our system compares well with those of other collimated minibeams despite being smaller. The deviations of microDiamond measurements from film readings might be subject to the diamond detector responding differently in the peak and valley regions. Applying previously reported correction factors aligns the dose profile measured by the microDiamond with the profile acquired with EBT3 films in Dresden.<br><br>CONCLUSION: The novel proton minibeam system can be operated independently of specific beamlines. It can be transported easily and hence used for inter-institutional comparative studies. The quality of the minibeams allows us to perform in vitro and in vivo experiments in the future. The microDiamond was demonstrated to have great potential for online dosimetry for proton minibeams, yet requires more research to explain the observed discrepancies.}, }
@article {pmid39741337, year = {2024}, author = {Braun, C and Takeuchi, T and Lambert, J and Liu, L and Roberts, S and Carter, S and Beaubien-Souligny, W and Tolwani, A and Neyra, JA}, title = {Association of continuous renal replacement therapy downtime with fluid balance gap and clinical outcomes: a retrospective cohort analysis utilizing EHR and machine data.}, journal = {Journal of intensive care}, volume = {12}, number = {1}, pages = {55}, pmid = {39741337}, issn = {2052-0492}, support = {R01DK133539/DK/NIDDK NIH HHS/United States ; }, abstract = {BACKGROUND: Fluid balance gap (FBgap-prescribed vs. achieved) is associated with hospital mortality. Downtime is an important quality indicator for the delivery of continuous renal replacement therapy (CRRT). We examined the association of CRRT downtime with FBgap and clinical outcomes including mortality.<br><br>METHODS: This is a retrospective cohort study of critically ill adults receiving CRRT utilizing both electronic health records (EHR) and CRRT machine data. FBgap was calculated as achieved minus prescribed fluid balance. Downtime, or percent treatment time loss (%TTL), was defined as CRRT downtime in relation to the total CRRT time. Data collection stopped upon transition to intermittent hemodialysis when applicable. Linear and logistic regression models were used to analyze the association of %TTL with FBgap and hospital mortality, respectively. Covariates included demographics, Sequential Organ Failure Assessment (SOFA) score at CRRT initiation, use of organ support devices, and the interaction between %TTL and machine alarms.<br><br>RESULTS: We included 3630 CRRT patient-days from 500 patients with a median age of 59.5&#xa0;years (IQR 50-67). Patients had a median SOFA score at CRRT initiation of 13 (IQR 10-16). Median %TTL was 8.1% (IQR 4.3-12.5) and median FBgap was 17.4&#xa0;mL/kg/day (IQR 8.2-30.4). In adjusted models, there was a significant positive relationship between FBgap and %TTL only in the subgroup with higher alarm frequency (6&#x2009;+&#x2009;alarms per CRRT-day) (&#x3b2;&#x2009;=&#x2009;0.87 per 1% increase, 95%CI 0.48-1.26). No association was found in the subgroups with lower alarm frequency (0-2 and 3-5 alarms). There was no statistical evidence for an association between %TTL and hospital mortality in the adjusted model with the interaction term of alarm frequency.<br><br>CONCLUSIONS: In critically ill adult patients undergoing CRRT, %TTL was associated with FBgap only in the subgroup with higher alarm frequency, but not in the other subgroups with lower alarms. No association between %TTL and mortality was observed. More frequent alarms, possibly indicating unexpected downtime, may suggest compromised CRRT delivery and could negatively impact FBgap.}, }
@article {pmid39738571, year = {2024}, author = {Antony, A and Mukherjee, S and Bi, Y and Collisson, EA and Nagaraj, M and Murlidhar, M and Wallace, MB and Goenka, AH}, title = {AI-Driven insights in pancreatic cancer imaging: from pre-diagnostic detection to prognostication.}, journal = {Abdominal radiology (New York)}, volume = {}, number = {}, pages = {}, pmid = {39738571}, issn = {2366-0058}, support = {R01CA256969/NH/NIH HHS/United States ; R01CA256969/NH/NIH HHS/United States ; N/A//Hoveida Family Foundation/ ; N/A//Centene Charitable Foundation/ ; N/A//Champions for Hope Pancreatic Cancer Research Program of the Funk Zitiello Foundation/ ; N/A//Mayo Clinic Comprehensive Cancer Center/ ; }, abstract = {Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the United States, largely due to its poor five-year survival rate and frequent late-stage diagnosis. A significant barrier to early detection even in high-risk cohorts is that the pancreas often appears morphologically normal during the pre-diagnostic phase. Yet, the disease can progress rapidly from subclinical stages to widespread metastasis, undermining the effectiveness of screening. Recently, artificial intelligence (AI) applied to cross-sectional imaging has shown significant potential in identifying subtle, early-stage changes in pancreatic tissue that are often imperceptible to the human eye. Moreover, AI-driven imaging also aids in the discovery of prognostic and predictive biomarkers, essential for personalized treatment planning. This article uniquely integrates a critical discussion on AI's role in detecting visually occult PDAC on pre-diagnostic imaging, addresses challenges of model generalizability, and emphasizes solutions like standardized datasets and clinical workflows. By focusing on both technical advancements and practical implementation, this article provides a forward-thinking conceptual framework that bridges current gaps in AI-driven PDAC research.}, }
@article {pmid39737444, year = {2025}, author = {Parino, F and Gustani-Buss, E and Bedford, T and Suchard, MA and Trovão, NS and Rambaut, A and Colizza, V and Poletto, C and Lemey, P}, title = {Integrating dynamical modeling and phylogeographic inference to characterize global influenza circulation.}, journal = {PNAS nexus}, volume = {4}, number = {1}, pages = {pgae561}, pmid = {39737444}, issn = {2752-6542}, abstract = {Global seasonal influenza circulation involves a complex interplay between local (seasonality, demography, host immunity) and global factors (international mobility) shaping recurrent epidemic patterns. No studies so far have reconciled the two spatial levels, evaluating the coupling between national epidemics, considering heterogeneous coverage of epidemiological, and virological data, integrating different data sources. We propose a novel-combined approach based on a dynamical model of global influenza spread (GLEAM), integrating high-resolution demographic, and mobility data, and a generalized linear model of phylogeographic diffusion that accounts for time-varying migration rates. Seasonal migration fluxes across countries simulated with GLEAM are tested as phylogeographic predictors to provide model validation and calibration based on genetic data. Seasonal fluxes obtained with a specific transmissibility peak time and recurrent travel outperformed the raw air-transportation predictor, previously considered as optimal indicator of global influenza migration. Influenza A subtypes supported autumn-winter reproductive number as high as 2.25 and an average immunity duration of 2 years. Similar dynamics were preferred by influenza B lineages, with a lower autumn-winter reproductive number. Comparing simulated epidemic profiles against FluNet data offered comparatively limited resolution power. The multiscale approach enables model selection yielding a novel computational framework for describing global influenza dynamics at different scales-local transmission and national epidemics vs. international coupling through mobility and imported cases. Our findings have important implications to improve preparedness against seasonal influenza epidemics. The approach can be generalized to other epidemic contexts, such as emerging disease outbreaks to improve the flexibility and predictive power of modeling.}, }
@article {pmid39733839, year = {2024}, author = {Rotz, SJ and Wiener, L and Baker, KS and Choi, SW and Phelan, R and Cuvelier, GDE and Duncan, C and Williams, KM and Qayed, M}, title = {Pediatric Transplant and Cellular Therapy Consortium RESILIENT Conference on Pediatric Chronic Graft-Versus-Host Disease Survivorship After Hematopoietic Cell Transplantation: Part IV. Patient Important Outcomes.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2024.12.019}, pmid = {39733839}, issn = {2666-6367}, abstract = {Chronic graft versus host disease (cGVHD), occurs in approximately one in five pediatric allogeneic HCT patients and is a leading cause of late morbidity and mortality. Late effects of HCT may lead to long-term chronic health conditions and shortened life expectancy. In addition to direct physiological challenges from cGVHD and other late-effects, numerous patient-important outcomes impact the quality of life (QOL) of patients and their families. The Research and Education towards Solutions for Late Effects to Innovate, Excel, and Nurture (RESILIENT) after GVHD Consensus Conference was convened to better understand the overlap of cGVHD and late effects in pediatric HCT survivors. Working Committee IV: Patient Important Outcomes identified four key areas for focus: 1) What are the key mental health and quality of life (QOL) concerns of survivors of pediatric cGVHD? 2) What is the impact of cGVHD on cognitive performance and social development? 3) What multi-level social determinants of health impact cGVHD survivors, families, and communities? 4) What is the role of racial, ethnic, and socioeconomic factors on the development of cGVHD and the risk for adverse outcomes related to survivorship? For each focus area the working committee reviewed the current state of the field, develop recommendations for clinical practice, and highlighted areas to prioritize for future research. Eleven total recommendations were adapted and approved. Substantial overlap exists between the role of cGVHD and late effects on the quality of life and mental health of childhood HCT survivors. Recommendations based on available data and consensus opinion may be helpful to improve outcomes for these patients, but several gaps remain which need further study.}, }
@article {pmid39733276, year = {2024}, author = {Landy, R and Katki, HA and Huang, WY and Wang, D and Thomas, M and Qu, F and Freedman, ND and Loftfield, E and Shi, J and Peters, U and Hsu, L and Schoen, RE and Berndt, SI}, title = {Evaluating the Use of Environmental and Polygenic Risk Scores to Inform Colorectal Cancer Risk-Based Surveillance Intervals.}, journal = {Clinical and translational gastroenterology}, volume = {15}, number = {12}, pages = {e00782}, doi = {10.14309/ctg.0000000000000782}, pmid = {39733276}, issn = {2155-384X}, support = {//Division of Cancer Epidemiology and Genetics, National Cancer Institute/ ; }, mesh = {Humans ; *Colorectal Neoplasms/genetics/diagnosis/epidemiology ; Male ; Female ; *Colonoscopy ; Middle Aged ; Aged ; *Early Detection of Cancer/methods ; Risk Factors ; Risk Assessment/methods ; *Adenoma/genetics/diagnosis/epidemiology ; Sigmoidoscopy ; United States/epidemiology ; Time Factors ; Genetic Risk Score ; }, abstract = {INTRODUCTION: United States Multi-Society Task Force colonoscopy surveillance intervals are based solely on adenoma characteristics, without accounting for other risk factors. We investigated whether a risk model including demographic, environmental, and genetic risk factors could individualize surveillance intervals under an "equal management of equal risks" framework.<br><br>METHODS: Using 14,069 individuals from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial who had a diagnostic colonoscopy following an abnormal flexible sigmoidoscopy, we modeled the risk of colorectal cancer, considering the diagnostic colonoscopy finding, baseline risk factors (e.g., age and sex), 19 lifestyle and environmental risk factors, and a polygenic risk score for colorectal cancer. Ten-year absolute cancer risks for each diagnostic colonoscopy finding (advanced adenomas [N = 2,446], &#x2265;3 non-advanced adenomas [N = 483], 1-2 non-advanced adenomas [N = 4,400], and no adenoma [N = 7,183]) were used as implicit risk thresholds for recommended surveillance intervals.<br><br>RESULTS: The area under the curve for the model including colonoscopy findings, baseline characteristics, and polygenic risk score was 0.658. Applying the equal management of equal risks framework, 28.2% of individuals with no adenoma and 42.7% of those with 1-2 non-advanced adenomas would be considered high risk and assigned a significantly shorter surveillance interval than currently recommended. Among individuals who developed cancer within 10 years, 52.4% with no adenoma and 48.3% with 1-2 non-advanced adenomas would have been considered high risk and assigned a shorter surveillance interval.<br><br>DISCUSSION: Using a personalized risk-based model has the potential to identify individuals with no adenoma or 1-2 non-advanced adenomas, who are higher risk and may benefit from shorter surveillance intervals.}, }
@article {pmid39730463, year = {2024}, author = {Touré, H and Durand, N and Rincheval, V and Girard-Misguich, F and Guénal, I and Herrmann, JL and Szuplewski, S}, title = {Remote disruption of intestinal homeostasis by Mycobacterium abscessus is detrimental to Drosophila survival.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {30775}, pmid = {39730463}, issn = {2045-2322}, mesh = {Animals ; *Drosophila melanogaster/microbiology ; *Homeostasis ; *Intestines/microbiology ; *Mycobacterium abscessus ; Mycobacterium Infections, Nontuberculous/microbiology ; Enterocytes/microbiology/metabolism ; Receptors, Notch/metabolism ; Drosophila Proteins/metabolism ; Signal Transduction ; Janus Kinases/metabolism ; STAT Transcription Factors/metabolism ; Cell Differentiation ; }, abstract = {Mycobacterium abscessus (Mabs), an intracellular and opportunistic pathogen, is considered the most pathogenic fast-growing mycobacterium, and causes severe pulmonary infections in patients with cystic fibrosis. While bacterial factors contributing to its pathogenicity are well studied, the host factors and responses that worsen Mabs infection are not fully understood. Here, we report that Mabs systemic infection alters Drosophila melanogaster intestinal homeostasis. Mechanistically, Mabs remotely induces a self-damaging oxidative burst, leading to excessive differentiation of intestinal stem cells into enterocytes. We demonstrated that the subsequent increased intestinal renewal is mediated by both the Notch and JAK/STAT pathways and is deleterious to Drosophila survival. In conclusion, this work highlights that the ability of Mabs to induce an exacerbated and self-damaging response in the host contributes to its pathogenesis.}, }
@article {pmid39713455, year = {2024}, author = {Cucinotta, C and Dell, R and Alavattam, K and Tsukiyama, T}, title = {Sir2 is required for the quiescence-specific condensed three-dimensional chromatin structure of rDNA.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39713455}, issn = {2692-8205}, abstract = {Quiescence in Saccharomyces cerevisiae is a reversible G0 crucial for long-term survival under nutrient-deprived conditions. During quiescence, the genome is hypoacetylated and chromatin undergoes significant compaction. However, the 3D structure of the ribosomal DNA (rDNA) locus in this state is not well understood. Here, we report that the rDNA locus in quiescent cells forms a distinct condensed loop-like structure, different from structures observed during the mitotic cell cycle. Deletion of SIR2 disrupts this structure, causing it to collapse into a small dot and resulting in quiescence entry and exit defects. In contrast, Sir2 affects rDNA structure only modestly in G2/M phase. In the absence of Sir2, occupancy of both RNA Polymerase II and histone H3 increase at the rDNA locus during quiescence and through quiescence exit, further indicating gross defects in chromatin structure. Together, these results uncover a previously undescribed rDNA chromatin structure specific to quiescent cells and underscore the importance of Sir2 in facilitating the transition between cellular states.}, }
@article {pmid39713402, year = {2024}, author = {Ellison, ST and Hayman, I and Derr, K and Derr, P and Frebert, S and Itkin, Z and Shen, M and Jones, A and Olson, W and Corey, L and Wald, A and Johnston, C and Fong, Y and Ferrer, M and Zhu, J}, title = {Identification of potent HSV antivirals using 3D bioprinted human skin equivalents.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39713402}, issn = {2692-8205}, abstract = {Herpes simplex virus (HSV) infection has worldwide public health concerns and lifelong medical impacts. The standard therapy, acyclovir, has limited efficacy in preventing HSV subclinical virus shedding, and drug resistance occurs in immunocompromised patients, highlighting the need for novel therapeutics. HSV infection manifests in the skin epidermal layer, but current drug discovery utilizes Vero cells and fibroblasts monolayer cultures, capturing neither in vivo relevance nor tissue environment. To bridge the gap, we established 3D bioprinted human skin equivalents that recapitulate skin architecture in a 96-well plate format amenable for antiviral screening and preclinical testing. Screening a library of 738 compounds with broad targets and mechanisms of action, we identified potent antivirals, including most of the known anti-HSV compounds, validating the translational relevance of our assay. Acyclovir was dramatically less potent for inhibiting HSV in keratinocytes compared to donor-matched fibroblasts. In contrast, antivirals against HSV helicase/primase or host replication pathways displayed similar potency across cell types and donor sources in 2D and 3D models. The reduced potency of acyclovir in keratinocytes, the primary cell type encountered by HSV reactivation, helps explain the limited benefit acyclovir and its congeners play in reducing sexual transmission. Finally, we demonstrated that our 3D bioprinted skin platform can integrate patient-derived cells, facilitating the incorporation of variable genetic backgrounds early into drug testing. Thus, these data indicate that the 3D bioprinted human skin equivalent assay platform provides a more physiologically relevant approach to identifying potential antivirals for HSV-directed drug development.}, }
@article {pmid39713327, year = {2024}, author = {Malladi, SK and Jaiswal, D and Ying, B and Alsoussi, WB and Darling, TL and Dadonaite, B and Civljak, A and Horvath, SC and Zhou, JQ and Kim, W and Turner, JS and Schmitz, AJ and Han, F and Scheaffer, SM and Farnsworth, CW and Nachbagauer, R and Nestorova, B and Chalkias, S and Klebert, MK and Edwards, DK and Paris, R and Strnad, BS and Middleton, WD and O'Halloran, JA and Presti, RM and Bloom, JD and Boon, ACM and Diamond, MS and Bajic, G and Ellebedy, AH}, title = {Defining a highly conserved B cell epitope in the receptor binding motif of SARS-CoV-2 spike glycoprotein.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39713327}, issn = {2692-8205}, abstract = {SARS-CoV-2 mRNA vaccines induce robust and persistent germinal centre (GC) B cell responses in humans. It remains unclear how the continuous evolution of the virus impacts the breadth of the induced GC B cell response. Using ultrasound-guided fine needle aspiration, we examined draining lymph nodes of nine healthy adults following bivalent booster immunization. We show that 77.8% of the B cell clones in the GC expressed as representative monoclonal antibodies recognized the spike protein, with a third (37.8%) of these targeting the receptor binding domain (RBD). Strikingly, only one RBD-targeting mAb, mAb-52, neutralized all tested SARS-CoV-2 strains, including the recent KP.2 variant. mAb-52 utilizes the IGHV3-66 public clonotype, protects hamsters challenged against the EG.5.1 variant and targets the class I/II RBD epitope, closely mimicking the binding footprint of ACE2. Finally, we show that the remarkable breadth of mAb-52 is due to the somatic hypermutations accumulated within vaccine-induced GC reaction.}, }
@article {pmid39711573, year = {2024}, author = {Lamba, J and Marchi, F and Landwehr, M and Schade, AK and Shastri, V and Ghavami, M and Sckaff, F and Marrero, R and Nguyen, N and Mansinghka, V and Cao, X and Slayton, W and Starostik, P and Ribeiro, R and Rubnitz, J and Klco, J and Gamis, A and Triche, T and Ries, R and Kolb, EA and Aplenc, R and Alonzo, T and Pounds, S and Meshinchi, S and Cogle, C and Elsayed, A}, title = {Long-read epigenomic diagnosis and prognosis of Acute Myeloid Leukemia.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39711573}, issn = {2693-5015}, abstract = {Acute Myeloid Leukemia (AML) is an aggressive cancer with dismal outcomes, vast subtype heterogeneity, and suboptimal risk stratification. In this study, we harmonized DNA methylation data from 3,314 patients across 11 cohorts to develop the Acute Leukemia Methylome Atlas (ALMA) of diagnostic relevance that predicted 27 WHO 2022 acute leukemia subtypes with an overall accuracy of 96.3% in discovery and 90.1% in validation cohorts. Specifically, for AML, we also developed AML Epigenomic Risk, a prognostic classifier of overall survival (OS) (HR=4.40; 95% CI=3.45-5.61; P<0.0001), and a targeted 38CpG AML signature using a stepwise EWAS-CoxPH-LASSO model predictive of OS (HR=3.84; 95% CI=3.01-4.91; P<0.0001). Finally, we developed a specimen-to-result protocol for simultaneous whole-genome and epigenome sequencing that accurately predicted diagnoses and prognoses from twelve prospectively collected patient samples using long-read sequencing. Our study unveils a new paradigm in acute leukemia management by leveraging DNA methylation for diagnostic and prognostic applications.}, }
@article {pmid39724103, year = {2024}, author = {Garcia-Toscano, L and Currey, HN and Hincks, JC and Stair, JG and Lehrbach, NJ and Liachko, NF}, title = {Decreased Hsp90 activity protects against TDP-43 neurotoxicity in a C. elegans model of amyotrophic lateral sclerosis.}, journal = {PLoS genetics}, volume = {20}, number = {12}, pages = {e1011518}, doi = {10.1371/journal.pgen.1011518}, pmid = {39724103}, issn = {1553-7404}, abstract = {Neuronal inclusions of hyperphosphorylated TDP-43 are hallmarks of disease for most patients with amyotrophic lateral sclerosis (ALS). Mutations in TARDBP, the gene coding for TDP-43, can cause some cases of familial inherited ALS (fALS), indicating dysfunction of TDP-43 drives disease. Aggregated, phosphorylated TDP-43 may contribute to disease phenotypes; alternatively, TDP-43 aggregation may be a protective cellular response sequestering toxic protein away from the rest of the cell. The heat shock responsive chaperone Hsp90 has been shown to interact with TDP-43 and stabilize its normal conformation; however, it is not known whether this interaction contributes to neurotoxicity in vivo. Using a C. elegans model of fALS mutant TDP-43 proteinopathy, we find that loss of function of HSP-90 protects against TDP-43 neurotoxicity and subsequent neurodegeneration in adult animals. This protection is accompanied by a decrease in both total and phosphorylated TDP-43 protein. We also find that hsp-90 mutation or inhibition upregulates key stress responsive heat shock pathway gene expression, including hsp-70 and hsp-16.1, and we demonstrate that normal levels of hsp-16.1 are required for hsp-90 mutation effects on TDP-43. We also observe that the neuroprotective effect due to HSP-90 dysfunction does not involve direct regulation of proteasome activity in C. elegans. Our data demonstrate for the first time that Hsp90 chaperone activity contributes to adverse outcomes in TDP-43 proteinopathies in vivo using a whole animal model of ALS.}, }
@article {pmid39724000, year = {2024}, author = {Stacey, AW and Nakamichi, K and Huey, J and Stevens, J and Waligorski, N and Crotty, EE and Van Gelder, RN and Mustafi, D}, title = {Prognostic importance of direct assignment of parent-of-origin via long-read genome and epigenome sequencing in retinoblastoma.}, journal = {JCI insight}, volume = {}, number = {}, pages = {}, doi = {10.1172/jci.insight.188216}, pmid = {39724000}, issn = {2379-3708}, abstract = {BACKGROUND: Current clinical sequencing methods cannot effectively detect DNA methylation and allele-specific variation to provide parent-of-origin information from the proband alone. Parent-of-origin effects can lead to differential disease and the inability to assign this in de novo cases limits prognostication in the majority of affected individuals with retinoblastoma, a hereditary cancer with suspected parent-of-origin effects.<br><br>METHODS: To directly assign parent-of-origin in retinoblastoma patients, genomic DNA was extracted from blood samples for sequencing using a programmable, targeted single-molecule long-read DNA genomic and epigenomic approach. This allowed germline variant calling and simultaneous haplotype-resolved CpG methylation in subjects with familial (n=7) and de novo (n=9) retinoblastoma.<br><br>RESULTS: Targeted long-read sequencing allowed phasing genomic variation with a differentially methylated region in intron 2 of the RB1 gene to confirm parent-of-origin in known familial samples. Leveraging this approach allowed us to directly assign parent-of-origin rapidly in simple and complex de novo cases from the proband alone. The ability to assign parent-of-origin in all cases of retinoblastoma showed that harboring disease-causing variants on the paternally inherited allele, whether arising familial or de novo, is associated with more advanced cancer staging at presentation and significantly greater risk of chemotherapy failure (P=0.002).<br><br>CONCLUSION: This study demonstrates the diagnostic potential of multi-omic long-read profiling to unveil the parent-of-origin effect in hereditary cancer. The approach in this work will be instrumental in assigning parent-of-origin to other genetic diseases using local and distant imprinting signals in the genome.<br><br>FUNDING: National Eye Institute, NIH (K08EY033789); Gerber Foundation; Research to Prevent Blindness.}, }
@article {pmid39723472, year = {2024}, author = {de la Fuente, MI and Touat, M and van den Bent, MJ and Preusser, M and Peters, KB and Young, RJ and Huang, RY and Ellingson, BM and Capper, D and Phillips, JJ and Halasz, LM and Shih, HA and Rudà, R and Lim-Fat, MJ and Blumenthal, DT and Weller, M and Arakawa, Y and Whittle, JR and Ducray, F and Reardon, DA and Bi, WL and Minniti, G and Rahman, R and Hervey-Jumper, S and Chang, SM and Wen, PY}, title = {The role of vorasidenib in the treatment of isocitrate dehydrogenase-mutant glioma.}, journal = {Neuro-oncology}, volume = {}, number = {}, pages = {}, doi = {10.1093/neuonc/noae259}, pmid = {39723472}, issn = {1523-5866}, abstract = {Isocitrate dehydrogenase (IDH)-mutant gliomas are the most common malignant primary brain tumors in young adults. This condition imposes a substantial burden on patients and their caregivers, marked by neurocognitive deficits and high mortality rates due to tumor progression, coupled with significant morbidity from current treatment modalities. Although surgery, radiation therapy, and chemotherapy improve survival, these treatments can adversely affect cognitive function, quality of life, finances, employment status, and overall independence. Consequently, there is an urgent need for innovative strategies that delay progression and the use of radiation therapy and chemotherapy. The recent Federal Drug Administration (FDA) approval of vorasidenib, a brain-penetrant small molecule targeting mutant IDH1/2 proteins, heralds a shift in the therapeutic landscape for IDH-mutant gliomas. In this review, we address the role of vorasidenib in the treatment of IDH-mutant gliomas, providing a roadmap for its incorporation into daily practice. We discuss ongoing clinical trials with vorasidenib and other IDH inhibitors, as single-agent or in combination with other therapies, as well as current challenges and future directions.}, }
@article {pmid39722539, year = {2025}, author = {Zepeda-Rivera, MA and Eisele, Y and Baryiames, A and Wu, H and Mengoni, C and Piccinno, G and McMahon, EF and LaCourse, KD and Jones, DS and Hauner, H and Minot, SS and Segata, N and Dewhirst, FE and Johnston, CD and Bullman, S}, title = {Fusobacterium sphaericum sp. nov., isolated from a human colon tumor adheres to colonic epithelial cells and induces IL-8 secretion.}, journal = {Gut microbes}, volume = {17}, number = {1}, pages = {2442522}, doi = {10.1080/19490976.2024.2442522}, pmid = {39722539}, issn = {1949-0984}, mesh = {Humans ; *Interleukin-8/metabolism/genetics ; *Colonic Neoplasms/microbiology/pathology ; *Fusobacterium/isolation &amp; purification/genetics ; *Epithelial Cells/microbiology ; *Phylogeny ; Bacterial Adhesion ; Colon/microbiology/pathology ; Feces/microbiology ; Adenocarcinoma/microbiology/pathology ; Gastrointestinal Microbiome ; RNA, Ribosomal, 16S/genetics ; Genome, Bacterial ; }, abstract = {Cancerous tissue is a largely unexplored microbial niche that provides a unique environment for the colonization and growth of specific bacterial communities, and with it, the opportunity to identify novel bacterial species. Here, we report distinct features of a novel Fusobacterium species, F. sphaericum sp. nov. (Fs), isolated from primary colon adenocarcinoma tissue. We acquire the complete closed genome and associated methylome of this organism and phylogenetically confirm its classification into the Fusobacterium genus, with F. perfoetens as its closest neighbor. Fs is phenotypically and genetically distinct, with morphological analysis revealing its coccoid shape, that while similar to F. perfoetens is rare for most Fusobacterium members. Fs displays a metabolic profile and antibiotic resistance repertoire consistent with other Fusobacterium species. In vitro, Fs has adherent and immunomodulatory capabilities, as it intimately associates with human colon cancer epithelial cells and promotes IL-8 secretion. An analysis of the prevalence and abundance of Fs in > 20,000 human metagenomic samples shows that it is a rarely detected member within human stool with variable relative abundance, found in both healthy controls and patients with colorectal cancer (CRC). Our study sheds light on a novel bacterial species isolated directly from the human CRC tumor niche and given its in vitro interaction with cancer epithelial cells suggests that its role in human health and disease warrants further investigation.}, }
@article {pmid39722322, year = {2024}, author = {Qu, X and Stevens, E and Fitzgibbon, MP and Beppu, L and Monahan, TM and Yeung, C and Stirewalt, DL and Wu, D and Radich, JP and Deeg, HJ and Fang, M}, title = {Pre-Transplant Chromosome Genomic Array Testing Improves Prognosis for Myelofibrosis Patients Undergoing Transplantation.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2024.12.018}, pmid = {39722322}, issn = {2666-6367}, abstract = {BACKGROUND: Despite its known superior diagnostic yield for chromosomal anomalies compared to karyotype and FISH studies, Chromosome Genomic Array Testing (CGAT) is not used as a routine clinical test for myelofibrosis. Meanwhile, although many prognostic systems exist that risk stratify patients at diagnosis, limited tools are available to prognosticate transplant outcome.<br><br>OBJECTIVE: The current study aimed at testing if CGAT results obtained before transplantation improves prognosis of post-transplant outcome in myelofibrosis patients compared with current risk categorization systems namely DIPSS plus.<br><br>STUDY DESIGN: We studied myelofibrosis patients who underwent hematopoietic cell transplantation between 2000 and 2017 at our center (n=44). We assessed the prognostic significance of CGAT, DIPSS plus, and the total count of gene mutations, for post-transplant clinical outcomes including relapse-free survival (RFS), overall survival (OS), and graft-versus-host-disease (GVHD).<br><br>RESULTS: Abnormal CGAT results were seen in 24 patients (55%), including 18 with copy-neutral loss of heterozygosity (cnLOH, 41%). With a median follow-up of 91 (range 2-258) months starting from the CGAT sample date, RFS was 59%, and OS was 68%. The outcome analysis showed significant prognostic implication from CGAT (normal vs abnormal), specifically for patients with intermediate-risk by DIPSS-plus scores and those with 0&#x223c;2 mutations. CGAT alone significantly stratified the patients' RFS outcome (P=0.03). The addition of CGAT to DIPSS-plus improved the significance from a P value of 0.08 to 0.003, while the addition of CGAT to mutation count improved the P value from 0.02 to 0.01. The best stratification system for RFS was achieved when CGAT, DIPSS-plus, and mutation count were all considered (P = 1e-08). The current study also confirmed individual anomalies that are prognostically significant, including U2AF1 mutation (n=5, P=0.03) and 1q gain (n=3, P=0.01), which were associated with worse RFS. ASXL1 mutations (n=14) appeared to associate with a later onset of chronic GVHD (P=0.03).<br><br>CONCLUSION: Pre-transplant CGAT analysis augments the existing risk stratification tools and may be considered as routine clinical testing for myelofibrosis.}, }
@article {pmid39720913, year = {2024}, author = {Omole, TE and Nguyen, HM and Marcinow, A and Oo, MM and Jahan, N and Ssemaganda, A and Severini, G and Thomas, KK and Celum, C and Mugo, N and Mujugira, A and Kublin, J and Corey, L and Sivro, A and Lingappa, JR and Gray, G and McKinnon, LR}, title = {Pre-HIV α4β7hi CD4+ T cells and HIV risk among heterosexual individuals in Africa.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiae638}, pmid = {39720913}, issn = {1537-6613}, abstract = {BACKGROUND: CD4+ T cells expressing α4β7 are optimal targets for HIV infections, with higher pre-HIV α4β7hi expression linked to increased HIV acquisition and progression in South African women. However, similar associations were not observed in men who have sex with men (MSM) or people who inject drugs (PWID) in the Americas, indicating need for further research.<br><br>METHODS: This retrospective case-control study enrolled heterosexual men and women from South Africa (HIV Vaccine Trials Network; HVTN 503) and East Africa (Partners Pre-Exposure Prophylaxis/Couples' Observational Study; PP/COS), quantifying &#x3b1;4&#x3b2;7 expression on CD4+ T cells as a predictor of subsequent HIV risk using flow cytometry analyses.<br><br>RESULTS: Associations between &#x3b1;4&#x3b2;7hi expression and HIV acquisition varied across cohorts. In HVTN 503, women had a higher risk estimate compared to men, but this was not significant. In PP/COS, &#x3b1;4&#x3b2;7hi expression was generally protective, particularly in Ugandans. Additionally, &#x3b1;4&#x3b2;7hi expression inversely correlated with peak viral load in PP/COS but not in HVTN 503; in the latter cohort, &#x3b1;4&#x3b2;7hi expression was inversely correlated with the CD4/CD8 ratio and predicted rapid CD4+ T cell decline, similar to what was observed previously in South Africa.<br><br>CONCLUSIONS: These findings suggest that &#x3b1;4&#x3b2;7hi expression on CD4+ T cells may not predict HIV acquisition and progression in all contexts, which may be due to cohort effects, modes of transmission, viral clade, or other factors.}, }
@article {pmid39720621, year = {2025}, author = {Reiner, AP and Raffield, LM and Ekunwe, L and Olson, NC and Auer, PL and Doyle, MF}, title = {Alterations of T Cell Subsets Associated with Sickle Cell Trait.}, journal = {Blood and genomics discovery}, volume = {9}, number = {1}, pages = {}, pmid = {39720621}, issn = {3078-221X}, abstract = {Sickle cell trait (SCT) has been associated with alterations in various immune-related laboratory parameters including lower circulating lymphocyte counts. To further characterize the impact of SCT on the immune system, we performed flow cytometry of monocyte and lymphocyte immune cell subsets from peripheral blood mononuclear cells collected in a large, community-based cohort of SCT-positive (n = 68) and SCT-negative (n = 959) Black adults. SCT was significantly associated with lower proportions of CD8[+] and CD4[+] T cell subsets that include senescent-like markers of repeated immune system challenges. These immune alterations could have potential implications for the susceptibility of individuals with SCT to various infectious diseases.}, }
@article {pmid39719543, year = {2024}, author = {Guo, H and Malone, KE and Heckbert, SR and Li, CI}, title = {Statin use after cancer diagnosis and survival among patients with cancer.}, journal = {Cancer causes &amp; control : CCC}, volume = {}, number = {}, pages = {}, pmid = {39719543}, issn = {1573-7225}, support = {T32CA09168/NH/NIH HHS/United States ; }, abstract = {PURPOSE: The association between statin use and cancer survival has been investigated in previous studies with conflicting findings. This study aimed to assess the association between statin use following cancer diagnosis and survival in six common cancers using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database.<br><br>METHODS: Individuals aged&#x2009;&#x2265;&#x2009;66&#xa0;years diagnosed with prostate cancer, colorectal cancer, lung cancer, bladder cancer, pancreatic cancer, or non-Hodgkin lymphoma (NHL) from 2008 through 2017 were identified. Statin use was defined as two or more statin prescription fills after cancer diagnosis. Time-dependent Cox proportional hazard regression models were used to estimate the association between statin use and cancer-specific mortality for each cancer.<br><br>RESULTS: This study included 34,618 patients with prostate cancer (median follow-up 4.0 years), 20,579 with colorectal cancer (2.9 years), 20,133 with lung cancer (1.7 years), 6,163 with bladder cancer (2.1 years), 4,538 with pancreatic cancer (0.8 years), and 3,270 with NHL (2.9 years). Statin use post-diagnosis was associated with a reduced risk of cancer-specific mortality in lung cancer (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.74-0.88) and pancreatic cancer (HR, 0.72; 95% CI, 0.59-0.87). The association was not statistically significant for prostate cancer, colorectal cancer, bladder cancer, or NHL. A dose-response relationship by duration of statin use was observed in lung cancer and pancreatic cancer.<br><br>CONCLUSION: Statin use after cancer diagnosis appears associated with improved survival in lung cancer and pancreatic cancer. Clinical trials of statin therapy in lung and pancreatic cancer patients are warranted to confirm these findings.}, }
@article {pmid39719506, year = {2024}, author = {Phelps, A and Pazos-Castro, D and Urselli, F and Grydziuszko, E and Mann-Delany, O and Fang, A and Walker, TD and Guruge, RT and Tome-Amat, J and Diaz-Perales, A and Waserman, S and Boonyaratanakornkit, J and Jordana, M and Taylor, JJ and Koenig, JFE}, title = {Author Correction: Production and use of antigen tetramers to study antigen-specific B cells.}, journal = {Nature protocols}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41596-024-01131-7}, pmid = {39719506}, issn = {1750-2799}, }
@article {pmid39713477, year = {2024}, author = {Baele, G and Carvalho, LM and Brusselmans, M and Dudas, G and Ji, X and McCrone, JT and Lemey, P and Suchard, MA and Rambaut, A}, title = {HIPSTR: highest independent posterior subtree reconstruction in TreeAnnotator X.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39713477}, issn = {2692-8205}, abstract = {In Bayesian phylogenetic and phylodynamic studies it is common to summarise the posterior distribution of trees with a time-calibrated consensus phylogeny. While the maximum clade credibility (MCC) tree is often used for this purpose, we here show that a novel consensus tree method - the highest independent posterior subtree reconstruction, or HIPSTR - contains consistently higher supported clades over MCC. We also provide faster computational routines for estimating both consensus trees in an updated version of TreeAnnotator X, an open-source software program that summarizes the information from a sample of trees and returns many helpful statistics such as individual clade credibilities contained in the consensus tree. HIPSTR and MCC reconstructions on two Ebola virus and two SARS-CoV-2 data sets show that HIPSTR yields consensus trees that consistently contain clades with higher support compared to MCC trees. The MCC trees regularly fail to include several clades with very high posterior probability (≥ 0.95) as well as a large number of clades with moderate to high posterior probability (≥ 0.50), whereas HIPSTR achieves near-perfect performance in this respect. HIPSTR also exhibits favorable computational performance over MCC in TreeAnnotator X. Comparison to the recently developed CCD0-MAP algorithm yielded mixed results, and requires more in-depth exploration in follow-up studies. TreeAnnotator X - which is part of the BEAST X (v10.5.0) software package - is available at https://github.com/beast-dev/beast-mcmc/releases.}, }
@article {pmid39711698, year = {2024}, author = {Guo, Y and Akcicek, EY and Hippe, DS and HashemizadehKolowri, S and Wang, X and Akcicek, H and Canton, G and Balu, N and Geleri, DB and Kim, T and Shibata, D and Zhang, K and Ma, X and Ferguson, MS and Mossa-Basha, M and Hatsukami, TS and Yuan, C}, title = {Long-Term Carotid Plaque Progression and the Role of Intraplaque Hemorrhage: Analysis from Deep Learning-based Longitudinal Vessel Wall Imaging.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39711698}, abstract = {BACKGROUND: Carotid atherosclerosis is a major etiology of stroke. Although intraplaque hemorrhage (IPH) is known to increase stroke risk and plaque burden, its long-term effects on plaque dynamics remain unclear.<br><br>OBJECTIVES: This study aimed to evaluate the long-term impact of IPH on carotid plaque burden progression using deep learning-based segmentation on multi-contrast vessel wall imaging (VWI).<br><br>METHODS: Twenty-eight asymptomatic subjects with carotid atherosclerosis underwent an average of 4.7 &#xb1; 0.6 VWI scans over 5.8 &#xb1; 1.1 years. Deep learning pipelines segmented the carotid vessel walls and IPH. Bilateral plaque progression was analyzed using generalized estimating equations, and linear mixed-effects models evaluated long-term associations between IPH occurrence, IPH volume (%HV), and plaque burden (%WV) progression.<br><br>RESULTS: Two subjects with ipsilateral IPH developed new ischemic infarcts during follow-up. IPH was detected in 23/50 of arteries. Of arteries without IPH at baseline, 11/39 developed new IPH that persisted, while 5/11 arteries with baseline IPH exhibited it throughout the study. Bilateral plaque growth was significantly correlated (r = 0.54, p < 0.001), but this symmetry was weakened with IPH presence. The progression rate for arteries without IPH was -0.001 %/year (p = 0.895). However, IPH presence or development at any point was associated with a 2.34% absolute increase in %WV (p < 0.001), and %HV was associated with 0.73% per 2-fold increase over the mean of %HV (p = 0.005).<br><br>CONCLUSIONS: IPH may persist asymptomatically for extended periods. While arteries without IPH demonstrated minimal progression under contemporary treatment, IPH significantly accelerated long-term plaque growth.}, }
@article {pmid38853984, year = {2024}, author = {Marsh, NM and MacEwen, MJS and Chea, J and Kenerson, HL and Kwong, AA and Locke, TM and Miralles, FJ and Sapre, T and Gozali, N and Hart, ML and Bammler, TK and MacDonald, JW and Sullivan, LB and Atilla-Gokcumen, GE and Ong, SE and Scott, JD and Yeung, RS and Sancak, Y}, title = {Mitochondrial Calcium Signaling Regulates Branched-Chain Amino Acid Catabolism in Fibrolamellar Carcinoma.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38853984}, issn = {2692-8205}, support = {R35 GM136234/GM/NIGMS NIH HHS/United States ; }, abstract = {Metabolic adaptations in response to changes in energy supply and demand are essential for survival. The mitochondrial calcium uniporter plays a key role in coordinating metabolic homeostasis by regulating TCA cycle activation, mitochondrial fatty acid oxidation, and cellular calcium signaling. However, a comprehensive analysis of uniporter-regulated mitochondrial pathways has remained unexplored. Here, we investigate metabolic consequences of uniporter loss- and gain-of-function using uniporter knockout cells and the liver cancer fibrolamellar carcinoma (FLC), which we demonstrate to have elevated mitochondrial calcium levels. Our results reveal that branched-chain amino acid (BCAA) catabolism and the urea cycle are uniporter-regulated metabolic pathways. Reduced uniporter function boosts expression of BCAA catabolism genes, and the urea cycle enzyme ornithine transcarbamylase (OTC). In contrast, high uniporter activity in FLC suppresses their expression. This suppression is mediated by reduced expression of the transcription factor KLF15, a master regulator of liver metabolism. Thus, uniporter responsive calcium signaling plays a central role in FLC-associated metabolic changes, including hyperammonemia. Our study identifies an important role for mitochondrial calcium signaling in metabolic adaptation through transcriptional regulation of metabolism and elucidates its importance for BCAA and ammonia metabolism in FLC.}, }
@article {pmid39718987, year = {2024}, author = {Yalagapati, SP and Ahmadli, U and Sinha, A and Kalidass, M and Dabravolski, S and Zuo, S and Yadala, R and Rutten, T and Talbert, P and Berr, A and Lermontova, I}, title = {Centromeric localization of αKNL2 and CENP-C proteins in plants depends on their centromere-targeting domain and DNA-binding regions.}, journal = {Nucleic acids research}, volume = {}, number = {}, pages = {}, doi = {10.1093/nar/gkae1242}, pmid = {39718987}, issn = {1362-4962}, support = {LE2299/3-1//German Research Foundation/ ; 03THWST001//WIPANO Wissens und Technologietransfer durch Patente und Nomen/ ; }, abstract = {In eukaryotes, accurate chromosome segregation during cell division relies on the centromeric histone H3 variant, CENH3. Our previous work identified KINETOCHORE NULL2 (αKNL2) as a plant CENH3 assembly factor, which contains a centromere-targeting motif, CENPC-k, analogous to the CENPC motif found in CENP-C. We also demonstrated that αKNL2 can bind DNA in vitro in a sequence-independent manner, without the involvement of its CENPC-k motif. In this study, we show that the CENPC-k and CENPC motifs alone are insufficient for centromere targeting in Nicotiana benthamiana and Arabidopsis thaliana. In silico analysis identified adjacent DNA-binding regions near the CENPC-k and CENPC motifs, suggesting their role in centromeric DNA interaction. We further demonstrated that protein fragments containing these motifs effectively target centromeres. Deletion of these DNA-binding domains reduced the centromeric localization of αKNL2-C, while fusing CENPC-k to the non-specific DNA-binding domain of histone-like nucleoid structuring protein from Escherichia coli successfully targeted it to centromeres. Our findings suggest that the centromeric targeting of αKNL2 and CENP-C proteins relies on the CENPC-k/CENPC motifs, and that their sequence-independent DNA-binding activity enhances their centromere anchoring. These insights into the mechanisms of αKNL2 and CENP-C targeting may facilitate the engineering of kinetochore structures by directing chromatin-modifying proteins to centromeres.}, }
@article {pmid39718828, year = {2024}, author = {Li, D and Geng, K and Hao, Y and Gu, J and Kumar, S and Olson, AT and Kuismi, CC and Kim, HM and Pan, Y and Sherman, F and Williams, AM and Li, Y and Li, F and Chen, T and Thakurdin, C and Ranieri, M and Meynardie, M and Levin, DS and Stephens, J and Chafitz, A and Chen, J and Donald-Paladino, MS and Powell, JM and Zhang, ZY and Chen, W and Ploszaj, M and Han, H and Gu, S and Zhang, T and Hu, B and Nacev, BA and Kaiza, ME and Berger, AH and Wang, X and Li, J and Sun, X and Liu, Y and Zhang, X and Bruno, TC and Gray, NS and Nabet, B and Wong, KK and Zhang, H}, title = {Targeted degradation of oncogenic KRASG12V triggers antitumor immunity in lung cancer models.}, journal = {The Journal of clinical investigation}, volume = {}, number = {}, pages = {}, doi = {10.1172/JCI174249}, pmid = {39718828}, issn = {1558-8238}, abstract = {KRAS is the most frequently mutated oncogene in lung adenocarcinoma, with G12C and G12V being the most predominant forms. Recent breakthroughs in KRASG12C inhibitors have transformed the clinical management of patients with G12C mutation and advanced our understanding of its function. However, little is known about the targeted disruption of KRASG12V, partly due to a lack of specific inhibitors. Here, we leverage the degradation tag (dTAG) system to develop a KRASG12V transgenic mouse model. We explore the therapeutic potential of KRASG12V degradation and characterize its impact on the tumor microenvironment (TME). Our study reveals that degrading KRASG12V abolishes lung and pancreatic tumors in mice and causes a robust inhibition of KRAS-regulated cancer intrinsic signaling. Importantly, targeted degradation of KRASG12V reprograms the TME towards a stimulatory milieu and drives antitumor immunity, elicited mainly by effector and cytotoxic CD8+ T cells. Our work provides important insights into the impact of degrading KRASG12V on both tumor progression and immune response, highlighting degraders as a powerful strategy for targeting KRAS mutant cancers.}, }
@article {pmid39718776, year = {2024}, author = {Nascimento de Lima, P and Rutter, CM and van den Puttelaar, R and Hahn, AI and Ozik, J and Collier, N and Zauber, AG and Lansdorp-Vogelaar, I and Inadomi, JM}, title = {Response to Hu, Yang, and Sun.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djae341}, pmid = {39718776}, issn = {1460-2105}, }
@article {pmid39718625, year = {2024}, author = {Beigrezaei, S and Dianati, M and Salehi-Abargouei, A and Fararouei, M and Akbari-Beni, A and Brinkman, M and White, E and Weiderpass, E and Le Calvez-Kelm, F and Gunter, MJ and Huybrechts, I and Liedberg, F and Skeie, G and Tjonneland, A and Riboli, E and Zeegers, MP and Wesselius, A}, title = {The association between animal protein, plant protein, and their substitution with bladder cancer risk: a pooled analysis of 10 cohort studies.}, journal = {European journal of nutrition}, volume = {64}, number = {1}, pages = {55}, pmid = {39718625}, issn = {1436-6215}, support = {WCRF 2012/590//World Cancer Research Fund International/ ; FP7-PEOPLE-618308//European Commission/ ; }, mesh = {Humans ; *Urinary Bladder Neoplasms/epidemiology ; Female ; Male ; Middle Aged ; Risk Factors ; Prospective Studies ; Animal Proteins, Dietary/administration &amp; dosage ; Proportional Hazards Models ; Aged ; Cohort Studies ; Europe/epidemiology ; Dietary Proteins/administration &amp; dosage ; Follow-Up Studies ; United Kingdom/epidemiology ; Plant Proteins, Dietary/administration &amp; dosage ; United States/epidemiology ; Adult ; Animals ; Plant Proteins/administration &amp; dosage ; Diet/methods/statistics &amp; numerical data ; }, abstract = {PURPOSE: Although total dietary protein intake has been associated with bladder cancer (BC) risk, the effect of the origin (plant or animal) and the substitutions remain to be understood. This study aimed to investigate the effect of total dietary protein, animal-based protein, plant-based protein, and their substitutions with each other on the risk of BC using a pooled analysis of 10 cohort studies.<br><br>METHODS: The study was conducted within the "BLadder cancer Epidemiology and Nutritional Determinants" (BLEND) study, including 10 prospective cohort studies from several European countries, the United Kingdom, and the United States. Individual data from 10 prospective cohorts containing 434,412 participants (overall male/female ratio was almost 3:1) with a total of 4,224,643.8 person-years of follow-up was analyzed. Hazard ratios (HRs) and 95% confidence intervals (CIs) for BC risk for animal and plant-based protein substitutions of 30gram (g) per day (g/day) were estimated by multivariable adjusted HRs using Cox proportional hazards models.<br><br>RESULTS: During 11.4 years of follow-up, among 434,412 participants (73.28% female), 1,440 new cases of BC were identified. After multivariable adjustment, no association was observed between the intake of total, animal-based protein, and plant-based protein and BC risk. Replacement of every 30&#xa0;g/day of animal-based protein intake by the same amount of plant-based protein intake or vice versa was not associated with the risk of BC.<br><br>CONCLUSION: In conclusion, our study found no association between protein intake-whether from animal or plant sources-and the risk of BC. Substituting animal-based protein with plant-based protein, or the reverse, did not influence BC risk. Future studies are required to provide information on the link between animal- and plant-based proteins and BC risk.}, }
@article {pmid39718528, year = {2024}, author = {Drover, CM and Srinivasan, S and Tapia, KA and Munch, M and Rowlinson, E and Chambers, LC and Fiedler, TL and Lowens, MS and Khosropour, CM and Manhart, LE and Fredricks, DN}, title = {Fannyhessea vaginae and clearance of Lactobacillus iners are associated with incident non-chlamydial non-Mycoplasma genitalium urethritis in men who have sex with women.}, journal = {Sexually transmitted diseases}, volume = {}, number = {}, pages = {}, doi = {10.1097/OLQ.0000000000002129}, pmid = {39718528}, issn = {1537-4521}, abstract = {BACKGROUND: The etiology of nongonococcal urethritis (NGU) is incompletely understood. We sought to determine if genitourinary bacterial diversity or specific taxa were associated with incident NGU.<br><br>METHODS: From August 2014-July 2018, men who have sex with women attending a sexual health clinic were clinically evaluated, including Mycoplasma genitalium (MG) and Chlamydia trachomatis (CT) testing, at enrollment and six monthly visits. New cases of NGU (&#x2265;5 PMNs/HPF in urethral exudates plus either symptoms or visible discharge) and their visit preceding NGU diagnosis were matched 1:1 to two sequential visits without NGU (controls). We determined associations with incident NGU and applied broad-range 16S rRNA gene polymerase chain reaction and sequencing to urine samples from each visit. We used conditional logistic regression to evaluate the association of Shannon Diversity Index (SDI), species richness, Haemophilus influenzae, Fannyhessea vaginae, Lactobacillus iners, and Streptococcus mitis group with incident non-CT-non-MG-NGU (NCNM-NGU).<br><br>RESULTS: Of 62 matched case-control pairs, median age was 32. Higher SDI the previous month was associated with higher odds of incident NCNM-NGU (adjusted odds ratio [aOR] = 2.8 per unit increase; 95% CI = 1.03-7.47), as was F. vaginae at NGU diagnosis (aOR = 5.1; 95% CI = 1.28-20.15), F. vaginae acquisition (aOR = 13.8; 95% CI = 1.96-97.33) and consistent carriage of F. vaginae (aOR = 16.1; 95% CI = 1.66-156.29). Odds of NCNM-NGU were higher when L. iners cleared between visits (aOR = 18.0; 95% CI = 1.08-299.24). Neither H. influenzae nor S. mitis group were associated with incident NCNM-NGU.<br><br>CONCLUSIONS: F. vaginae acquisition/detection and L. iners clearance were associated with urethritis. This merits investigation in larger longitudinal studies using species-specific detection methods.}, }
@article {pmid39717769, year = {2024}, author = {Hou, J and Nakaya, HI}, title = {Editorial: Systems immunology to advance vaccine development.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1527238}, doi = {10.3389/fimmu.2024.1527238}, pmid = {39717769}, issn = {1664-3224}, }
@article {pmid39713041, year = {2024}, author = {Dmello, C and Brenner, A and Piccioni, D and Wen, PY and Drappatz, J and Mrugala, M and Lewis, LD and Schiff, D and Fadul, CE and Chamberlain, M and Kesari, S and Ahluwalia, M and Ghosh, D and Sonabend, AM and Kumthekar, P}, title = {Phase II trial of blood-brain barrier permeable peptide-paclitaxel conjugate ANG1005 in patients with recurrent high-grade glioma.}, journal = {Neuro-oncology advances}, volume = {6}, number = {1}, pages = {vdae186}, pmid = {39713041}, issn = {2632-2498}, abstract = {BACKGROUND: This study is a phase II clinical trial to evaluate the efficacy, safety, and tolerability of the blood-brain barrier (BBB) permeable peptide-paclitaxel conjugate ANG1005 in patients with recurrent high-grade glioma (HGG) (NCT01967810).<br><br>METHODS: Seventy-three patients were enrolled in 3 separate arms-recurrent glioblastoma (GBM) (Arm 1), bevacizumab refractory GBM (Arm 2), and grade 3 anaplastic gliomas (AGs) (Arm 3). The study was started in October 2013, and the data were locked on September 29, 2017. Safety was evaluated for all three arms (n&#x2005;=&#x2005;73), and the primary endpoint for Arms 1 and 3 was objective response rate (ORR), and Arm 2 primary endpoint was progression-free survival rate at 3 months (PFS3).<br><br>RESULTS: Overall, the safety of ANG1005 was found to be consistent with a taxane toxicity profile. Otherwise, the primary efficacy endpoints of ORR and PFS were not met. The most common adverse events (AEs) were hematologic (32.9%), alopecia (31.5%), and fatigue (30.1%). The median PFS was 1.4 months (95% CI: 1.4, 2.1) and similar across all the treatment arms. The median overall survival was 13.4 months (95% CI: 3.4, 14.6) in Arm 1, 5.8 months (95% CI: 1.9, 9.7) in Arm 2, and 18.2 months (95% CI: 10.7, 35.3) in Arm 3.<br><br>CONCLUSION: A dose of 600 mg/m[2] was determined to be safe in this study. However, the primary efficacy endpoint was not met in the NCT01967810-ANG1005 trial, and no further studies are planned in the glioma setting with this compound.}, }
@article {pmid39712972, year = {2024}, author = {Abad, PJB and Tumulak, MJR and Yoon, SY and Laurino, MY and Hasan, Q}, title = {Bibliometric analysis of genetic counseling publications in Asia: Insights and implications.}, journal = {Genetics in medicine open}, volume = {2}, number = {Suppl 2}, pages = {101861}, pmid = {39712972}, issn = {2949-7744}, abstract = {PURPOSE: Investigation of genetic counseling-related published papers offers a historical assessment of the cumulative scientific knowledge produced by members of the profession and can be the basis for future practice, training, and research. This paper aims to present a bibliometric analysis of genetic counseling publications in Asia.<br><br>METHODS: We conducted a bibliometric analysis of genetic counseling-related manuscripts published in Asia from 1947 to 2023. We excluded articles published in 2024 given an incomplete year of data source. The articles were retrieved through the Scopus database using the search terms "genetic counsel&#x2217;" OR "genomic counsel&#x2217;" in the article titles. The bibliographic information was downloaded and analyzed descriptively through Microsoft Excel. Network visualization was done through VOSViewer.<br><br>RESULTS: A total of 449 genetic counseling-related publications authored by at least one researcher from Asian countries were identified. The most common publication type was original articles (332, 74%) and a total of 299 manuscripts were published from 2012 to 2023, representing 66.5% (299/449) of total publications. Among Asian countries, India had the highest number of publications accounting for 19.4% of the total (n&#xa0;= 87) and publications from Israel had the most citations (n&#xa0;= 1882). Out of the 29 Asian countries represented in the document corpus, 15 have links with other Asian countries. The most common keywords used are genetic counseling, prenatal diagnosis, genetic counselling, genetic testing, and genetics.<br><br>CONCLUSION: There is an overall increase in the number of genetic counseling publications authored by at least one researcher affiliated with an Asian institution. This increase has corresponded to various developments in genetic counseling in the continent and is possibly driven by collaboration between and among Asian researchers and other researchers outside of Asia. The analysis of keywords also shows the evolution of topics of genetic counseling publications which also corresponded to the development of genetic counseling as a profession in the region.}, }
@article {pmid39712486, year = {2024}, author = {Song, H and Wu, MC}, title = {Multivariate differential association analysis.}, journal = {Stat (International Statistical Institute)}, volume = {13}, number = {2}, pages = {}, pmid = {39712486}, issn = {2049-1573}, abstract = {Identifying how dependence relationships vary across different conditions plays a significant role in many scientific investigations. For example, it is important for the comparison of biological systems to see if relationships between genomic features differ between cases and controls. In this paper, we seek to evaluate whether relationships between two sets of variables are different or not across two conditions. Specifically, we assess: do two sets of high-dimensional variables have similar dependence relationships across two conditions? We propose a new kernel-based test to capture the differential dependence. Specifically, the new test determines whether two measures that detect dependence relationships are similar or not under two conditions. We introduce the asymptotic permutation null distribution of the test statistic and it is shown to work well under finite samples such that the test is computationally efficient, significantly enhancing its usability in analyzing large datasets. We demonstrate through numerical studies that our proposed test has high power for detecting differential linear and non-linear relationships. The proposed method is implemented in an R package kerDAA.}, }
@article {pmid39711614, year = {2024}, author = {Visani, GM and Pun, MN and Angaji, A and Nourmohammad, A}, title = {Holographic-(V)AE: An end-to-end SO(3)-equivariant (variational) autoencoder in Fourier space.}, journal = {Physical review research}, volume = {6}, number = {2}, pages = {}, pmid = {39711614}, issn = {2643-1564}, abstract = {Group-equivariant neural networks have emerged as an efficient approach to model complex data, using generalized convolutions that respect the relevant symmetries of a system. These techniques have made advances in both the supervised learning tasks for classification and regression, and the unsupervised tasks to generate new data. However, little work has been done in leveraging the symmetry-aware expressive representations that could be extracted from these approaches. Here, we present holographic-(variational) autoencoder [H-(V)AE], a fully end-to-end SO(3)-equivariant (variational) autoencoder in Fourier space, suitable for unsupervised learning and generation of data distributed around a specified origin in 3D. H-(V)AE is trained to reconstruct the spherical Fourier encoding of data, learning in the process a low-dimensional representation of the data (i.e., a latent space) with a maximally informative rotationally invariant embedding alongside an equivariant frame describing the orientation of the data. We extensively test the performance of H-(V)AE on diverse datasets. We show that the learned latent space efficiently encodes the categorical features of spherical images. Moreover, the low-dimensional representations learned by H-VAE can be used for downstream data-scarce tasks. Specifically, we show that H-(V)AE's latent space can be used to extract compact embeddings for protein structure microenvironments, and when paired with a random forest regressor, it enables state-of-the-art predictions of protein-ligand binding affinity.}, }
@article {pmid39711146, year = {2024}, author = {Nguyen, T and Koric, A and Chang, CE and Barul, C and Radoi, L and Serraino, D and Purdue, MP and Kelsey, KT and McClean, MD and Negri, E and Edefonti, V and Moysich, K and Zhang, ZF and Morgenstern, H and Levi, F and Vaughan, TL and La Vecchia, C and Garavello, W and Hayes, RB and Benhamou, S and Schantz, SP and Yu, GP and Brenner, H and Chuang, SC and Boffetta, P and Hashibe, M and Lee, YA}, title = {Coffee and tea consumption and the risk of head and neck cancer: An updated pooled analysis in the International Head and Neck Cancer Epidemiology Consortium.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.35620}, pmid = {39711146}, issn = {1097-0142}, support = {T32CA009142/CA/NCI NIH HHS/United States ; T32CA190194/CA/NCI NIH HHS/United States ; }, abstract = {INTRODUCTION: The relations between coffee and tea consumption and head and neck cancer (HNC) incidence are unclear. With increasing global HNC burden, this study aims to examine the association between coffee, tea, and HNC.<br><br>METHODS: A pooled analysis of 9548 HNC cases and 15,783 controls from 14 individual-level case-control studies was conducted from the International Head and Neck Cancer Epidemiology consortium. Random-effects logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for HNC and its subsites, adjusting for sociodemographic and lifestyle factors.<br><br>RESULTS: Compared to non-coffee drinkers, drinking >4 cups of caffeinated coffee daily was inversely associated with HNC (OR, 0.83; 95% CI, 0.69-1.00), oral cavity (OR, 0.70; 95% CI, 0.55-0.89), and oropharyngeal cancers (OR, 0.78; 95% CI, 0.61-0.99). Drinking 3-4 cups of caffeinated coffee was inversely associated with hypopharyngeal cancer (OR, 0.59; 95% CI, 0.39-0.91). Drinking decaffeinated coffee and drinking between >0 to <1 cup daily were inversely associated with oral cavity cancer (OR, 0.75; 95% CI, 0.64-0.87 and OR, 0.66; 95% CI, 0.54-0.81). Drinking tea was inversely associated with hypopharyngeal cancer (OR, 0.71; 95% CI, 0.59-0.87). Daily tea consumption of >0 to &#x2264;1 cup was inversely associated with HNC (OR, 0.91; 95% CI, 0.84-0.98) and hypopharyngeal cancer (OR, 0.73; 95% CI, 0.59-0.91), but drinking >1 cup was associated with laryngeal cancer (OR, 1.38; 95% CI, 1.09-1.74).<br><br>CONCLUSION: These findings support reduced HNC risk among coffee and tea drinkers. Future studies are needed to address geographical differences in types of coffee and tea to improve our understanding of the association of coffee and tea and global HNC risk.}, }
@article {pmid39710572, year = {2024}, author = {Donzella, SM and VoPham, T and Patel, AV and McCullough, ML and Phipps, AI and Zhong, C}, title = {Associations of sleep duration and weekend catch up sleep with cancer risk among US adults in the Cancer Prevention Study-3 cohort.}, journal = {Sleep health}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.sleh.2024.10.011}, pmid = {39710572}, issn = {2352-7226}, abstract = {OBJECTIVE: Our objective was to investigate the associations of sleep duration and weekend catch-up sleep with cancer risk among US adults in the Cancer Prevention Study-3.<br><br>METHODS: Cancer Prevention Study-3 is a prospective cohort of approximately 250,000 US adults aged 30-65years. At baseline (2006-2013), participants were asked to report their average daily sleep duration over the past year for weekdays and weekends separately. Using the midpoint of each sleep duration category, a 5:2 weekday:weekend weighted average was created. Weekend catch-up sleep was calculated using the difference of weekend and weekday sleep duration category midpoints and categorized as -4 or -2, 0, 2, and 4&#xa0;hours. Cancer incidence (overall and female breast) was determined via linkage to state registries; follow-up time ended at the time of cancer diagnosis, time of death, or end of follow-up (12/31/2018). We used multivariable Cox proportional hazards models to estimate adjusted hazard ratios and 95% confidence intervals for the associations of sleep duration and weekend catch-up sleep with cancer risk adjusted for sociodemographics, socioeconomic status, comorbidities, and lifestyle behaviors.<br><br>RESULTS: A total of 10,256 incident cancer cases were reported among the 248,086 participants included in the study. We found no statistically significant associations between the examined sleep characteristics with overall or breast cancer-specific risk.<br><br>CONCLUSION: Our research strengthens the existing null findings of the association between sleep duration and cancer risk. This was the first study to investigate the relationship of weekend catch-up sleep with cancer risk and more research is necessary to further elucidate this relationship.}, }
@article {pmid39709975, year = {2024}, author = {Pelzer, PT and Stuck, L and Martinez, L and Richards, AS and Acuña-Villaorduña, C and Aronson, NE and Bonnet, M and Carvalho, AC and Chan, PC and Huang, LM and Fang, CT and Churchyard, G and Corral-Londoño, HD and Datta, M and Espinal, MA and Fielding, K and Fiore-Gartland, AJ and Garcia-Basteiro, A and Hanekom, W and Hatherill, M and Hill, PC and Huerga, H and Jones-López, EC and Kritski, A and Mandalakas, AM and Mangtani, P and Martins Netto, E and Mayanja, H and Mazahir, R and Murray, M and Rangaka, M and Scriba, T and Singh, J and Singh, S and Stein, CM and Vekemans, J and Verhagen, LM and Villalba, JA and Wajja, A and Watson, B and White, RG and Cobelens, FGJ}, title = {Effectiveness of the primary Bacillus Calmette-Guérin vaccine against the risk of Mycobacterium tuberculosis infection and tuberculosis disease: a meta-analysis of individual participant data.}, journal = {The Lancet. Microbe}, volume = {}, number = {}, pages = {100961}, doi = {10.1016/j.lanmic.2024.100961}, pmid = {39709975}, issn = {2666-5247}, abstract = {BACKGROUND: Tuberculosis vaccine trials using disease as the primary endpoint are large, time consuming, and expensive. An earlier immunological measure of the protection against disease would accelerate tuberculosis vaccine development. We aimed to assess whether the effectiveness of the Bacillus Calmette-Guérin (BCG) vaccine for prevention of Mycobacterium tuberculosis infection was consistent with that for prevention of tuberculosis disease.<br><br>METHODS: We conducted an individual participant data (IPD) meta-analysis on experimental and observational longitudinal studies before April 6, 2018, identified through systematic reviews, known to us through expert knowledge in the field, reporting on BCG vaccination status, M&#xa0;tuberculosis infection test (QuantiFERON IFN-&#x3b3; release assay [IGRA] and tuberculin skin test [TST]), and tuberculosis incidence. Cohort studies were included only for countries with a mandatory neonatal BCG vaccination policy. Exclusion criteria were previous or current tuberculosis disease, HIV infection, tuberculosis preventive treatment usage, and for household contacts, a positive baseline IGRA or TST test and young children aged 0-2 years; for randomised controlled trials, TST results within 2&#xa0;years after random assignation were excluded. We contacted the investigators of the identified studies to provide IPD. We compared the protective efficacy of the BCG vaccine against M&#xa0;tuberculosis infection with that against tuberculosis disease using mixed-effects, multivariable proportional hazards modelling, by study type, M&#xa0;tuberculosis infection test (IGRA and TST), cutoff for defining test positivity, age, sex, and latitude.<br><br>FINDINGS: We identified 79&#xa0;studies eligible for full screening and of these, IPD datasets from 14&#xa0;studies were included in our analysis: 11&#xa0;household contact studies (29&#x2009;147&#xa0;participants), two adolescent cohort studies (11&#x2009;368&#xa0;participants), and one randomised controlled trial (2963 participants). Among 28&#x2009;188&#xa0;participants we found no protection by the BCG vaccine against TST conversion regardless of cutoff in any type of study. Among 1491&#xa0;household contacts, but not among 5644&#xa0;adolescents, the BCG vaccine protected against QuantiFERON conversion at the primary cutoff of 0&#xb7;7&#xa0;IU/mL or more with the adjusted hazard ratio (0&#xb7;65, 95% CI 0&#xb7;51-0&#xb7;82) being consistent with that for protection against disease (0&#xb7;68, 0&#xb7;18-2&#xb7;59). Protection against QuantiFERON conversion at cutoff of 0&#xb7;35&#xa0;IU/mL or more (0&#xb7;64,&#xa0;0&#xb7;51-0&#xb7;81) was similar.<br><br>INTERPRETATION: Protection from the BCG vaccination against M&#xa0;tuberculosis infection, measured as QuantiFERON conversion, is inconsistent across different groups. Among groups with recent household exposure, QuantiFERON conversion is consistent with protection against disease and could be evaluated as a proxy for disease in tuberculosis vaccine trials. We found that TST lacks value for prevention in phase 2b proof-of-concept trials.<br><br>FUNDING: Bill &amp; Melinda Gates Foundation.}, }
@article {pmid39709604, year = {2024}, author = {Poluben, L and Nouri, M and Liang, J and Chen, S and Varkaris, A and Ersoy-Fazlioglu, B and Voznesensky, O and Lee, II and Qiu, X and Cato, L and Seo, JH and Freedman, ML and Sowalsky, AG and Lack, NA and Corey, E and Nelson, PS and Brown, M and Long, HW and Russo, JW and Balk, SP}, title = {Increased nuclear factor I-mediated chromatin access drives transition to androgen receptor splice variant dependence in prostate cancer.}, journal = {Cell reports}, volume = {44}, number = {1}, pages = {115089}, doi = {10.1016/j.celrep.2024.115089}, pmid = {39709604}, issn = {2211-1247}, abstract = {Androgen receptor (AR) splice variants, of which ARv7 is the most common, are increased in castration-resistant prostate cancer, but the extent to which they drive AR activity is unclear. We generated a subline of VCaP cells (VCaP16) that is resistant to the AR inhibitor enzalutamide (ENZ). AR activity in VCaP16 is driven by ARv7, independently of full-length AR (ARfl), and its cistrome and transcriptome mirror those of ARfl in VCaP cells. ARv7 expression increases rapidly in response to ENZ, but there is a delay in gaining chromatin binding and transcriptional activity, which is associated with increased chromatin accessibility. AR and nuclear factor I (NFI) motifs are most enriched at more accessible sites, and NFIB/X knockdown greatly diminishes ARv7 function. These findings indicate that ARv7 can drive the AR program but that its activity is dependent on adaptations that increase chromatin accessibility to enhance its intrinsically weak chromatin binding.}, }
@article {pmid39709257, year = {2024}, author = {Jindal, T and Jiang, C and Alhalabi, O and Nizam, A and Nguyen, C and Talukder, R and Bakaloudi, D and Davidsohn, M and Freeman, D and Glover, M and Khaki, AR and Evans, S and Lemke, E and Bose, R and Sim, W and Pywell, C and Basu, A and Kilari, D and Barata, PC and Bilen, MA and Zakharia, Y and Milowsky, MI and Shah, SA and Bellmunt, J and Grivas, P and Emamekhoo, H and Davis, NB and Gupta, S and Hoimes, C and Campbell, MT and Alva, A and Koshkin, VS}, title = {Genomic Biomarkers Associated with Enfortumab Vedotin Outcomes for Patients with Advanced Urothelial Carcinoma: Analysis of UNITE Study Data.}, journal = {European urology oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.euo.2024.12.006}, pmid = {39709257}, issn = {2588-9311}, abstract = {Enfortumab vedotin (EV) is used as monotherapy or combined with pembrolizumab in advanced urothelial carcinoma (aUC), but biomarker data associated with EV outcomes are limited. We identified 170 patients in the UNITE study who received EV monotherapy and had molecular biomarker data available. Outcomes for groups with and without a particular biomarker were compared using logistic regression (unadjusted) for the objective response rate (ORR), and a log-rank test and Cox proportional-hazard models (CPHMs) for progression-free survival (PFS) and overall survival (OS) from EV initiation. Molecular biomarkers were also evaluated in separate multivariable analyses using CPHMs that accounted for clinical characteristics. Median patient age was 70 yr; 78% of the cohort were male and 65% had pure UC histology. Median PFS was shorter for patients with CDKN2A alterations (4.6 vs 6 mo; p = 0.024) and for patients with CDKN2B alterations (4.4 vs 6 mo; p = 0.008). Median OS was longer for patients with high tumor mutational burden (13.6 vs 8.3 mo; p = 0.014). ORR was higher for patients with TSC1 alterations (87% vs 51%; p = 0.018). In multivariable analyses, CDKN2A and CDKN2B alterations were associated with inferior median PFS. This multi-institutional retrospective study of patients with aUC identified potential biomarkers associated with EV monotherapy outcomes that should be further investigated. PATIENT SUMMARY: We investigated genetic changes in urinary tract tumors that might be associated with response to enfortumab vedotin (EV) treatment in patients with advanced disease. Survival after EV treatment was longer for tumors with a higher number of mutations than for tumors with fewer mutations. However, mutations in two genes (CDKN2A and CDKN2B) were associated with worse outcomes after EV treatment. These findings will not affect current clinical practice, but should be investigated further in future studies.}, }
@article {pmid39708145, year = {2024}, author = {Klein-Murrey, L and Tirschwell, DL and Hippe, DS and Kharaji, M and Sanchez-Vizcaino, C and Haines, B and Balu, N and Hatsukami, TS and Yuan, C and Akoum, NW and Lila, E and Mossa-Basha, M}, title = {Using clinical data to reclassify ESUS patients to large artery atherosclerotic or cardioembolic stroke mechanisms.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {87}, pmid = {39708145}, issn = {1432-1459}, support = {R01NS125635/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; *Embolic Stroke/etiology/diagnostic imaging/blood ; Aged ; Middle Aged ; Retrospective Studies ; *Atherosclerosis/complications ; *Machine Learning ; Ischemic Stroke/classification/blood ; Aged, 80 and over ; }, abstract = {PURPOSE: Embolic stroke of unidentified source (ESUS) represents 10-25% of all ischemic strokes. Our goal was to determine whether ESUS could be reclassified to cardioembolic (CE) or large-artery atherosclerosis (LAA) with machine learning (ML) using conventional clinical data.<br><br>METHODS: We retrospectively collected conventional clinical features, including patient, imaging (MRI, CT/CTA), cardiac, and serum data from established cases of CE and LAA stroke, and factors with p&#x2009;<&#x2009;0.2 in univariable analysis were used for creating a ML predictive tool. We then applied this tool to ESUS cases, with&#x2009;&#x2265;&#x2009;75% likelihood serving as the threshold for reclassification to CE or LAA. In patients with longitudinal data, we evaluated future cardiovascular events.<br><br>RESULTS: 191 ischemic stroke patients (80 CE, 61 LAA, 50 ESUS) were included. Seven and 6 predictors positively associated with CE and LAA etiology, respectively. The c-statistic for discrimination between CE and LAA was 0.88. The strongest predictors for CE were left atrial volume index (OR&#x2009;=&#x2009;2.17 per 1 SD increase) and BNP (OR&#x2009;=&#x2009;1.83 per 1 SD increase), while the number of non-calcified stenoses&#x2009;&#x2265;&#x2009;30% upstream (OR&#x2009;=&#x2009;0.34 per 1 SD increase) and not upstream (OR&#x2009;=&#x2009;0.74 per 1 SD increase) from the infarct were for LAA. When applied to ESUS cases, the model reclassified 40% (20/50), with 11/50 reclassified to CE and 9/50 reclassified to LAA. In 21/50 ESUS with 30-day cardiac monitoring, 1/4 in CE and 3/16 equivocal reclassifications registered cardiac events, while 0/1 LAA reclassifications showed events.<br><br>CONCLUSION: ML tools built using standard ischemic stroke workup clinical biomarkers can potentially reclassify ESUS stroke patients into cardioembolic or atherosclerotic etiology categories.}, }
@article {pmid39707483, year = {2024}, author = {Byrne, A and Diener, C and Brown, BP and Maust, BS and Feng, C and Alinde, BL and Gibbons, SM and Koch, M and Gray, CM and Jaspan, HB and Nyangahu, DD}, title = {Neonates exposed to HIV but uninfected exhibit an altered gut microbiota and inflammation associated with impaired breast milk antibody function.}, journal = {Microbiome}, volume = {12}, number = {1}, pages = {261}, pmid = {39707483}, issn = {2049-2618}, mesh = {Humans ; *Milk, Human/immunology ; *Gastrointestinal Microbiome ; *HIV Infections/immunology/microbiology ; Female ; Infant, Newborn ; *Inflammation ; *Immunoglobulin A/blood ; Feces/microbiology/virology ; Pregnancy ; Bacteria/classification/isolation &amp; purification ; Adult ; Male ; Virome ; C-Reactive Protein/analysis ; }, abstract = {BACKGROUND: Infants exposed to HIV but uninfected have altered immune profiles which include heightened systemic inflammation. The mechanism(s) underlying this phenomenon is unknown. Here, we investigated differences in neonatal gut bacterial and viral microbiome and associations with inflammatory biomarkers in plasma. Further, we tested whether HIV exposure impacts antibody-microbiota binding in neonatal gut and whether antibodies in breast milk impact the growth of commensal bacteria.<br><br>RESULTS: Neonates exposed to HIV but uninfected (nHEU) exhibited altered gut bacteriome and virome compared to unexposed neonates (nHU). In addition, HIV exposure differentially impacted IgA-microbiota binding in neonates. The relative abundance of Blautia spp. in the whole stool or IgA-bound microbiota was positively associated with plasma concentrations of C-reactive protein. Finally, IgA from the breast milk of mothers living with HIV displayed a significantly lower ability to inhibit the growth of Blautia coccoides which was associated with inflammation in nHEU.<br><br>CONCLUSION: nHEU exhibits profound alterations in gut bacterial microbiota with a mild impact on the enteric DNA virome. Elevated inflammation in nHEU could be due to a lower capacity of breast milk IgA from mothers living with HIV to limit growth the of gut bacteria associated with inflammation. Video Abstract.}, }
@article {pmid39706832, year = {2024}, author = {Jaberi-Douraki, M and Xu, X and Dima, D and Ailawadhi, S and Anwer, F and Mazzoni, S and Valent, J and Habib, MH and Riviere, JE and Raza, S}, title = {Global disparities in drug-related adverse events of patients with multiple myeloma: a pharmacovigilance study.}, journal = {Blood cancer journal}, volume = {14}, number = {1}, pages = {223}, pmid = {39706832}, issn = {2044-5385}, mesh = {Humans ; *Multiple Myeloma/drug therapy/epidemiology ; Male ; Female ; *Pharmacovigilance ; *Drug-Related Side Effects and Adverse Reactions/epidemiology/etiology ; Middle Aged ; Aged ; Adult ; Antineoplastic Agents/adverse effects/therapeutic use ; }, abstract = {Multiple myeloma (MM) is a complex hematological malignancy of clonal plasma cells driven by alterations to the chromosomal material leading to uncontrolled proliferation in the bone marrow. Ethnic and racial disparities persist in the prevalence, diagnosis, management, and outcomes of MM. These disparities are multifaceted and intersect with various factors, including demographics, geography, socioeconomic status, genetics, and access to healthcare. This study utilized the openFDA human drug adverse events (AEs) to analyze global data pertaining to MM patients and patterns of treatment-related AEs. We identified ten most frequently used drugs and drug regimens in six distinct regions, including North America (NA), Europe (EU), Asia (AS), Africa (AF), Oceania (OC), and Latin America &amp; the Caribbean (LA). AE patterns were evaluated using the reporting odds ratio combined with a 95% confidence interval. AE reports were more prevalent in men than in women across all regions. Cardiotoxicities were more likely observed in AS and EU, while secondary neoplasms were more frequently reported in the EU. Nephropathies were prominent in OC, AF (in males), and AS (in females), while vascular toxicity, including embolism and thrombosis, was more common in NA (in males). A notable improvement in survival, particularly in AS, EU, and NA, with a significant decline in death rates was observed. Hospitalization rates displayed less variation in AS and EU but exhibited more pronounced fluctuations in AF, LA, and OC. In conclusion, this comprehensive analysis offers valuable insights into the demographic, geographic, and AE patterns of MM patients across the globe.}, }
@article {pmid39706786, year = {2024}, author = {St-Laurent, MP and Bochner, B and Catto, J and Davies, BJ and Fankhauser, CD and Garg, T and Hamilton-Reeves, J and Master, V and Jensen, BT and Lauridsen, SV and Wulff-Burchfield, E and Psutka, SP}, title = {Increasing Life Expectancy in Patients with Genitourinary Malignancies: Impact of Treatment Burden on Disease Management and Quality of Life.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2024.11.026}, pmid = {39706786}, issn = {1873-7560}, abstract = {BACKGROUND AND OBJECTIVE: Treatment burden refers to the overall impact of medical treatments on a patient's well-being and daily life. Our objective is to evaluate the impact of treatment burden on quality of life (QoL) in patients with genitourinary (GU) malignancies, highlighting the importance of patient-reported outcomes (PROs) in clinical trials to inform treatment decisions and improve patient care.<br><br>METHODS: We conducted a narrative review of clinical trials focused on GU malignancy (prostate, bladder, and kidney) between January 2000 and June 2024, analyzing related PROs and findings regarding treatment burden.<br><br>KEY FINDINGS AND LIMITATIONS: Recent landmark clinical trials demonstrate significant improvements in overall survival across GU malignancies with novel therapies. However, the reporting of QoL outcomes in these trials is often inadequate, with many lacking comprehensive data or long-term impact. Current publications are increasingly evaluating treatment burden and its impact on patient well-being as a critical outcome, but most clinical trials to date have failed to assess treatment burden across key domains including financial, time and travel, and medication management.<br><br>While advancements in treatment have extended longevity in patients with GU malignancies, the treatment burden associated with the receipt of novel agents and its implications for QoL remain inadequately uncharacterized.}, }
@article {pmid39706336, year = {2024}, author = {Goyal, L and DiToro, D and Facchinetti, F and Martin, EE and Peng, P and Baiev, I and Iyer, R and Maurer, J and Reyes, S and Zhang, K and Majeed, U and Berchuck, JE and Chen, CT and Walmsley, C and Pinto, C and Vasseur, D and Gordan, JD and Mody, K and Borad, M and Karasic, T and Damjanov, N and Danysh, BP and Wehrenberg-Klee, E and Kambadakone, AR and Saha, SK and Hoffman, ID and Nelson, KJ and Iyer, S and Qiang, X and Sun, C and Wang, H and Li, L and Javle, M and Lin, B and Harris, W and Zhu, AX and Cleary, JM and Flaherty, KT and Harris, T and Shroff, RT and Leshchiner, I and Parida, L and Kelley, RK and Fan, J and Stone, JR and Uboha, NV and Hirai, H and Sootome, H and Wu, F and Bensen, DC and Hollebecque, A and Friboulet, L and Lennerz, JK and Getz, G and Juric, D}, title = {A Model for Decoding Resistance in Precision Oncology: Acquired Resistance to FGFR inhibitors in Cholangiocarcinoma.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.annonc.2024.12.011}, pmid = {39706336}, issn = {1569-8041}, abstract = {BACKGROUND: Fibroblast growth factor receptor (FGFR) inhibitors have significantly improved outcomes for patients with FGFR-altered cholangiocarcinoma, leading to their regulatory approval in multiple countries. However, as with many targeted therapies, acquired resistance limits their efficacy. A comprehensive, multimodal approach is crucial to characterizing resistance patterns to FGFR inhibitors.<br><br>PATIENTS AND METHODS: This study integrated data from six investigative strategies: cell-free DNA, tissue biopsy, rapid autopsy, statistical genomics, in vitro and in vivo studies, and pharmacology. We characterized the diversity, clonality, frequency, and mechanisms of acquired resistance to FGFR inhibitors in patients with FGFR-altered cholangiocarcinoma. Clinical samples were analyzed longitudinally as part of routine care across 10 institutions.<br><br>RESULTS: Among 138 patients evaluated, 77 met eligibility, yielding a total of 486 clinical samples. Patients with clinical benefit exhibited a significantly higher rate of FGFR2 kinase domain mutations compared to those without clinical benefit (65% vs 10%, p<0.0001). We identified 26 distinct FGFR2 kinase domain mutations, with 63% of patients harboring multiple. While IC50 assessments indicated strong potency of pan-FGFR inhibitors against common resistance mutations, pharmacokinetic studies revealed that low clinically achievable drug concentrations may underly polyclonal resistance. Molecular brake and gatekeeper mutations predominated, with 94% of patients with FGFR2 mutations exhibiting one or both, whereas mutations at the cysteine residue targeted by covalent inhibitors were rare. Statistical genomics and functional studies demonstrated that mutation frequencies were driven by their combined effects on drug binding and kinase activity rather than intrinsic mutational processes.<br><br>CONCLUSION: Our multimodal analysis led to a model characterizing the biology of acquired resistance, informing the rational design of next-generation FGFR inhibitors. FGFR inhibitors should be small, high-affinity, and selective for specific FGFR family members. Tinengotinib, a novel small molecule inhibitor with these characteristics, exhibited preclinical and clinical activity against key resistance mutations. This integrated approach offers a blueprint for advancing drug resistance research across cancer types.}, }
@article {pmid39705656, year = {2024}, author = {Olivieri, DJ and Banerjee, R}, title = {Impatient for Outpatient: Operationalizing Bispecific Antibodies for Multiple Myeloma in the Ambulatory Setting.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2400921}, doi = {10.1200/OP-24-00921}, pmid = {39705656}, issn = {2688-1535}, }
@article {pmid39705106, year = {2024}, author = {Lee, J and Wein, PY and Heffner, JL and Weinberger, AH and Hinds, JT and , }, title = {Practicing inclusive language related to people who are lesbian, gay, bisexual, transgender, queer, intersex, asexual and other sexual and gender identities (LGBTQIA+) in nicotine and tobacco research.}, journal = {Nicotine &amp; tobacco research : official journal of the Society for Research on Nicotine and Tobacco}, volume = {}, number = {}, pages = {}, doi = {10.1093/ntr/ntae305}, pmid = {39705106}, issn = {1469-994X}, }
@article {pmid39704522, year = {2024}, author = {Kader, T and Lin, JR and Hug, CB and Coy, S and Chen, YA and de Bruijn, I and Shih, N and Jung, E and Pelletier, RJ and Lopez Leon, M and Mingo, G and Omran, DK and Lee, JS and Yapp, C and Satravada, BA and Kundra, R and Xu, Y and Chan, S and Tefft, JB and Muhlich, JL and Kim, SH and Gysler, SM and Agudo, J and Heath, JR and Schultz, N and Drescher, CW and Sorger, PK and Drapkin, R and Santagata, S}, title = {Multimodal Spatial Profiling Reveals Immune Suppression and Microenvironment Remodeling in Fallopian Tube Precursors to High-Grade Serous Ovarian Carcinoma.}, journal = {Cancer discovery}, volume = {}, number = {}, pages = {}, doi = {10.1158/2159-8290.CD-24-1366}, pmid = {39704522}, issn = {2159-8290}, abstract = {High-Grade Serous Ovarian Cancer (HGSOC) originates from fallopian tube (FT) precursors. However, the molecular changes that occur as precancerous lesions progress to HGSOC are not well understood. To address this, we integrated high-plex imaging and spatial transcriptomics to analyze human tissue samples at different stages of HGSOC development, including p53 signatures, serous tubal intraepithelial carcinomas (STIC), and invasive HGSOC. Our findings reveal immune modulating mechanisms within precursor epithelium, characterized by chromosomal instability, persistent interferon (IFN) signaling, and dysregulated innate and adaptive immunity. FT precursors display elevated expression of MHC-class I, including HLA-E, and IFN-stimulated genes, typically linked to later-stage tumorigenesis. These molecular alterations coincide with progressive shifts in the tumor microenvironment, transitioning from immune surveillance in early STICs to immune suppression in advanced STICs and cancer. These insights identify potential biomarkers and therapeutic targets for HGSOC interception and clarify the molecular transitions from precancer to cancer.}, }
@article {pmid39703032, year = {2024}, author = {Zhang, Y and Lindström, S and Kraft, P and Liu, Y}, title = {Response to zhang and Lv.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djae323}, pmid = {39703032}, issn = {1460-2105}, }
@article {pmid39701546, year = {2024}, author = {Perlow, HK and Raleigh, DR and Wang, TJC and Pollom, EL and Milano, MT and Breen, WG and Detsky, J and Chang, EL and Tom, MC and Shiue, KR and Lehrer, EJ and Saeed, H and Pike, LRG and Lo, SS and Mishra, MV and Knisely, JPS and Chao, ST and Sahgal, A and Palmer, JD}, title = {Consensus Radiation Treatment Planning Guidelines Utilizing (68)Ga-DOTATATE PET/CT for Resected Meningiomas.}, journal = {International journal of radiation oncology, biology, physics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ijrobp.2024.12.003}, pmid = {39701546}, issn = {1879-355X}, abstract = {BACKGROUND: Meningiomas are the most common primary intracranial tumor. Somatostatin receptor 2 (SSTR 2) is almost universally expressed in meningioma tissue. For patients who require adjuvant radiation, SSTR based (68)Ga-DOTATATE positron emission tomography (PET) imaging can detect additional or residual disease not discernible on magnetic resonance imaging (MRI). PET-guided radiation treatments may improve local control, minimize toxicity by allowing for more precise radiotherapy plans, and allow for more precise dose escalation to maximize local control. The aim of this study was to develop consensus PET-guided treatment planning guidelines for common meningioma presentations.<br><br>METHODS: Five post-operative clinically relevant meningioma cases were selected from a prospective single-institutional registry of patients. Each patient had a preoperative and post-operative contrast enhanced T1-weighted volumetric MRI, and a post-operative (68)Ga-DOTATATE PET/CT, to assist with target delineation. The full treatment scenario including clinical history, histology, surgical history, and imaging were provided for each patient. Nineteen international experts who have published on the treatment and management of meningiomas, and who utilize (68)Ga-DOTATATE PET/CT in their practice, evaluated each case. Individual prescription recommendations were created, pooled, and discussed to create consensus recommendations.<br><br>RESULTS: Consensus recommendations were created for each case. In most cases, PET-based contouring allowed for more precise-dose escalation to 66-70Gy targeting residual disease. When compared to RTOG 0539 and modern clinical trial contouring guidelines, a smaller CTV expansion from the surgical cavity was recommended using PET-guided radiation plans in the absence of radiographic or pathologic evidence of brain or bone invasion.<br><br>CONCLUSION: This report provides consensus target volume delineation guidelines for meningiomas receiving postoperative radiation in common clinical situations. Integration of these guidelines into clinical practice may allow for more precise biomarker-guided radiation treatments and standardize radiotherapy on future meningioma clinical trials.}, }
@article {pmid39701289, year = {2024}, author = {Bhatt, NS and Harris, AC and Gorfinkel, L and Ibanez, K and Tkaczyk, ER and Mitchell, SA and Albuquerque, S and Schechter, T and Pavletic, S and Duncan, CN and Rotz, SJ and Williams, K and Carpenter, PA and Cuvelier, GDE}, title = {Pediatric Transplant and Cellular Therapy Consortium RESILIENT Conference on Pediatric Chronic Graft-Versus-Host Disease Survivorship After Hematopoietic Cell Transplantation: Part I. Phases of Chronic GVHD, Supportive Care, and Systemic Therapy Discontinuation.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2024.12.011}, pmid = {39701289}, issn = {2666-6367}, abstract = {Current literature lacks details on the impact of pediatric chronic graft-versus-host disease (cGVHD) on long-term survivorship after allogeneic hematopoietic cell transplantation (HCT). Nonetheless, cGVHD remains a leading cause of post-transplant morbidity and mortality in children and adolescents, which is particularly relevant given the longer life-expectancy after HCT (measured in decades) compared to older adults. To address this knowledge gap, leaders of the Pediatric Transplant and Cellular Therapy Consortium convened a multidisciplinary taskforce of experts in pediatric cGVHD and HCT late effects known as RESILIENT after Chronic GVHD (Research and Education towards Solutions for Late effects to Innovate, Excel, and Nurture after cGVHD). Our goals were to define: (1) the current state of understanding about how cGVHD impacts long-term survivorship in children transplanted <18 years of age; (2) practical aspects of care to help clinicians managing long-term pediatric cGVHD survivors; and (3) develop a research framework for the next decade to further our knowledge. Four working groups were formed, each tasked with addressing a unique theme: (1) cGVHD natural history (phases of cGVHD) and its impact on clinicians' ability to taper and durably discontinue systemic therapy; (2) organ dysfunction and immune reconstitution in relation to survivorship; (3) how cGVHD and its treatment impact growth, metabolism, and development in children; and (4) psychosocial health and patient reported outcomes. The four groups met before the 2024 BMT Tandem Meeting in San Antonio, Texas, and then convened a larger in-person RESILIENT conference held on February 20, 2024, at the Tandem meeting to put forth recommendations from their respective working groups and garner feedback. These recommendations are now presented in a series of 4 manuscripts. This current manuscript focuses on the first theme and discusses the phases of cGVHD, challenges in differentiating clinically active from quiescent cGVHD in clinical practice, and the resultant difficulties in determining when and if to taper systemic therapy. To overcome these challenges, we propose revised categorization of long-term cGVHD outcomes and practical recommendations for clinicians and researchers around the long-term follow-up for these patients, including determining when and if to taper systemic therapy, along with the integration of non-immunosuppressive supportive care interventions.}, }
@article {pmid39701282, year = {2024}, author = {Daoudlarian, D and Segot, A and Latifyan, S and Bartolini, R and Joo, V and Mederos, N and Bouchaab, H and Demicheli, R and Abdelhamid, K and Ferahta, N and Doms, J and Stalder, G and Noto, A and Mencarelli, L and Mosimann, V and Berthold, D and Stravodimou, A and Sartori, C and Shabafrouz, K and Thompson, JA and Wang, Y and Peters, S and Pantaleo, G and Obeid, M}, title = {Tocilizumab and immune signatures for targeted management of cytokine release syndrome in immune checkpoint therapy.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.annonc.2024.12.004}, pmid = {39701282}, issn = {1569-8041}, abstract = {BACKGROUND: This study aimed to identify specific biomarkers in oncology patients experiencing immune-related cytokine release syndrome (irCRS)-like symptoms during immune checkpoint inhibitor (ICI) therapy, including severe cases like hemophagocytic lymphohistiocytosis (irHLH), and to distinguish these from sepsis. A secondary objective was to retrospectively analyze the efficacy of tocilizumab (TCZ) in treating corticosteroid (CS)-refractory high-grade irCRS.<br><br>PATIENTS AND METHODS: A cohort of 35 patients presenting with irCRS-like symptoms was studied, including 9 with irHLH-like manifestations and 8 with sepsis. Immune profiling was performed using 48 mass cytometry markers, along with an analysis of 45 serum biomarkers, including 27 cytokines and 18 additional markers from the HScore. Twelve patients with high-grade irCRS refractory to CS were treated with TCZ.<br><br>RESULTS: 24 biomarkers significantly distinguished between irHLH and Grade 3 irCRS (P=0.0027-0.0455). Hepatocyte growth factor (HGF) and ferritin had superior predictive values compared to the traditional HScore, both with a positive predictive value (PPV) and negative predictive value (NPV) of 100%. CXCL9 differentiated irHLH from Grade 3 irCRS and predicted the need for TCZ treatment intensification (PPV=90%, NPV=100%). Additional biomarkers, including leukocyte count, neutrophils, ferritin, IL-6, IL-7, EGF, fibrinogen, and GM-CSF, discriminated sepsis from high-grade irCRS (PPV=75-80%, NPV=100%). Elevated frequencies of CXCR5+ or CCR4+ CD8 memory cells, CD38+ intermediate monocytes, and CD62L+ neutrophils were observed in high-grade irCRS compared to sepsis. All 12 patients with high-grade irCRS refractory to CS treated with TCZ experienced complete resolution.<br><br>CONCLUSIONS: This study highlights the importance of specific immunologic biomarkers in determining irCRS severity, predicting outcomes, and distinguishing between irHLH, irCRS, and sepsis. It also demonstrates the efficacy of TCZ in managing high-grade irCRS, underscoring the need for personalized therapeutic strategies based on these biomarkers.}, }
@article {pmid39699239, year = {2024}, author = {Weiss, NS}, title = {Reducing-a little-the high price of randomized trials of the efficacy of multicancer early detection.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djae292}, pmid = {39699239}, issn = {1460-2105}, support = {/CA/NCI NIH HHS/United States ; }, }
@article {pmid39677467, year = {2024}, author = {Figgins, MD and Bedford, T}, title = {Frequency dynamics predict viral fitness, antigenic relationships and epidemic growth.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39677467}, abstract = {During the COVID-19 pandemic, SARS-CoV-2 variants drove large waves of infections, fueled by increased transmissibility and immune escape. Current models focus on changes in variant frequencies without linking them to underlying transmission mechanisms of intrinsic transmissibility and immune escape. We introduce a framework connecting variant dynamics to these mechanisms, showing how host population immunity interacts with viral transmissibility and immune escape to determine relative variant fitness. We advance a selective pressure metric that provides an early signal of epidemic growth using genetic data alone, crucial with current underreporting of cases. Additionally, we show that a latent immunity space model approximates immunological distances, offering insights into population susceptibility and immune evasion. These insights refine real-time forecasting and lay the groundwork for research into the interplay between viral genetics, immunity, and epidemic growth.}, }
@article {pmid39699103, year = {2025}, author = {Choe, M and Campbell, M and Albert, CM}, title = {Advances in cellular therapies for children and young adults with solid tumors.}, journal = {Current opinion in pediatrics}, volume = {37}, number = {1}, pages = {67-74}, pmid = {39699103}, issn = {1531-698X}, mesh = {Humans ; *Neoplasms/therapy/immunology ; Child ; *Immunotherapy, Adoptive/methods ; *Tumor Microenvironment/immunology ; Young Adult ; Adolescent ; Receptors, Chimeric Antigen/immunology ; }, abstract = {PURPOSE OF REVIEW: Adoptive immunotherapy brings hope to children and young adults diagnosed with high-risk solid tumors. Cellular (cell) therapies such as chimeric antigen receptor (CAR) T cell, CAR natural killer (NK) cell, and T cell receptor (TCR) T cell therapy are potential avenues of targeted therapy with limited long-term toxicities. However, development of cell therapies for solid tumors is in its nascent stages. Here, we will review the current clinical experience, barriers to efficacy, and strategies to improve clinical response and patient access.<br><br>RECENT FINDINGS: Cell therapies are shown to be generally safe and well tolerated. Strategies to optimize antitumor activity have now moved into early-phase trials. The immunosuppressive tumor microenvironment remains a major barrier to efficacy, and efforts are underway to gain better understanding. This will inform future treatment strategies to enhance the antitumor activity of cell therapies.<br><br>SUMMARY: Clinical experiences to date provide important insights on how to leverage cell therapies against solid tumors. Key factors in advancing the field include a better understanding of immune cell biology, tumor cell behavior, and the tumor microenvironment. Lastly, improving access to novel cell therapies remains an important consideration in the conduct of clinical trials and for future implementation into standard practice.}, }
@article {pmid39698781, year = {2024}, author = {Ghosh, N and Eyre, TA and Brown, JR and Lamanna, N and Manzoor, BS and Coombs, CC and Tuncer, HH and Ujjani, C and Leslie, LA and Roeker, LE and Davids, MS and Rhodes, JM and Skarbnik, AP and Sinai, W and Fleury, I and Hill, BT and Martinez-Calle, N and Barr, PM and Jawaid, D and Emechebe, N and Pearson, L and Lansigan, F and Choi, Y and Jensen, CE and Fakhri, B and Stephens, DM and Marx, SE and Schuster, SJ and Coyle, M and Pivneva, I and Watson, T and Guerin, A and Shadman, M}, title = {Treatment Effectiveness of Venetoclax-Based Therapy After Bruton Tyrosine Kinase Inhibitors in Chronic Lymphocytic Leukemia: An International Real-World Study.}, journal = {American journal of hematology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ajh.27563}, pmid = {39698781}, issn = {1096-8652}, support = {//AbbVie/ ; }, }
@article {pmid39695226, year = {2024}, author = {Lee, S and Kibler, RD and Ahn, G and Hsia, Y and Borst, AJ and Philomin, A and Kennedy, MA and Huang, B and Stoddard, B and Baker, D}, title = {Four-component protein nanocages designed by programmed symmetry breaking.}, journal = {Nature}, volume = {}, number = {}, pages = {}, pmid = {39695226}, issn = {1476-4687}, abstract = {Four, eight or twenty C3 symmetric protein trimers can be arranged with tetrahedral, octahedral or icosahedral point group symmetry to generate closed cage-like structures[1,2]. Viruses access more complex higher triangulation number icosahedral architectures by breaking perfect point group symmetry[3-9], but nature appears not to have explored similar symmetry breaking for tetrahedral or octahedral symmetries. Here we describe a general design strategy for building higher triangulation number architectures starting from regular polyhedra through pseudosymmetrization of trimeric building blocks. Electron microscopy confirms the structures of T = 4 cages with 48 (tetrahedral), 96 (octahedral) and 240 (icosahedral) subunits, each with 4 distinct chains and 6 different protein-protein interfaces, and diameters of 33 nm, 43 nm and 75 nm, respectively. Higher triangulation number viruses possess very sophisticated functionalities; our general route to higher triangulation number nanocages should similarly enable a next generation of multiple antigen-displaying vaccine candidates[10,11] and targeted delivery vehicles[12,13].}, }
@article {pmid39695145, year = {2024}, author = {Kibler, RD and Lee, S and Kennedy, MA and Wicky, BIM and Lai, SM and Kostelic, MM and Carr, A and Li, X and Chow, CM and Nguyen, TK and Carter, L and Wysocki, VH and Stoddard, BL and Baker, D}, title = {Design of pseudosymmetric protein hetero-oligomers.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {10684}, pmid = {39695145}, issn = {2041-1723}, support = {DGE-1762114//National Science Foundation (NSF)/ ; ALTF 139-2018//European Molecular Biology Organization (EMBO)/ ; P41 GM128577/GM/NIGMS NIH HHS/United States ; P41 GM128577/GM/NIGMS NIH HHS/United States ; P41 GM128577/GM/NIGMS NIH HHS/United States ; R35 GM148166/GM/NIGMS NIH HHS/United States ; shared instrumentation grant S10OD021832//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; #OPP1156262//Bill and Melinda Gates Foundation (Bill &amp; Melinda Gates Foundation)/ ; #OPP1156262//Bill and Melinda Gates Foundation (Bill &amp; Melinda Gates Foundation)/ ; R01 GM139752/GM/NIGMS NIH HHS/United States ; }, mesh = {*Protein Multimerization ; Models, Molecular ; Protein Engineering/methods ; Protein Subunits/chemistry/metabolism ; Proteins/chemistry/metabolism ; }, abstract = {Pseudosymmetric hetero-oligomers with three or more unique subunits with overall structural (but not sequence) symmetry play key roles in biology, and systematic approaches for generating such proteins de novo would provide new routes to controlling cell signaling and designing complex protein materials. However, the de novo design of protein hetero-oligomers with three or more distinct chains with nearly identical structures is a challenging unsolved problem because it requires the accurate design of multiple protein-protein interfaces simultaneously. Here, we describe a divide-and-conquer approach that breaks the multiple-interface design challenge into a set of more tractable symmetric single-interface redesign tasks, followed by structural recombination of the validated homo-oligomers into pseudosymmetric hetero-oligomers. Starting from de novo designed circular homo-oligomers composed of 9 or 24 tandemly repeated units, we redesigned the inter-subunit interfaces to generate 19 new homo-oligomers and structurally recombined them to make 24 new hetero-oligomers, including ABC heterotrimers, A2B2 heterotetramers, and A3B3 and A2B2C2 heterohexamers which assemble with high structural specificity. The symmetric homo-oligomers and pseudosymmetric hetero-oligomers generated for each system have identical or nearly identical backbones, and hence are ideal building blocks for generating and functionalizing larger symmetric and pseudosymmetric assemblies.}, }
@article {pmid39693737, year = {2024}, author = {Zhang, Y and Spitzer, BW and Zhang, Y and Wallace, DA and Yu, B and Qi, Q and Argos, M and Avilés-Santa, ML and Boerwinkle, E and Daviglus, ML and Kaplan, R and Cai, J and Redline, S and Sofer, T}, title = {Untargeted metabolome atlas for sleep-related phenotypes in the Hispanic community health study/study of Latinos.}, journal = {EBioMedicine}, volume = {111}, number = {}, pages = {105507}, doi = {10.1016/j.ebiom.2024.105507}, pmid = {39693737}, issn = {2352-3964}, abstract = {BACKGROUND: Sleep is essential to maintaining health and wellbeing of individuals, influencing a variety of outcomes from mental health to cardiometabolic disease. This study aims to assess the relationships between various sleep-related phenotypes and blood metabolites.<br><br>METHODS: Utilising data from the Hispanic Community Health Study/Study of Latinos, we performed association analyses between 40 sleep-related phenotypes, grouped in several domains (sleep disordered breathing (SDB), sleep duration, sleep timing, self-reported insomnia symptoms, excessive daytime sleepiness (EDS), and heart rate during sleep), and 768 metabolites measured via untargeted metabolomics profiling. Network analysis was employed to visualise and interpret the associations between sleep phenotypes and metabolites.<br><br>FINDINGS: The patterns of statistically significant associations between sleep phenotypes and metabolites differed by superpathways, and highlighted subpathways of interest for future studies. For example, primary bile acid metabolism showed the highest cumulative percentage of statistically significant associations across all sleep phenotype domains except for SDB and EDS phenotypes. Several metabolites were associated with multiple sleep phenotypes, from a few domains. Glycochenodeoxycholate, vanillyl mandelate (VMA) and 1-stearoyl-2-oleoyl-GPE (18:0/18:1) were associated with the highest number of sleep phenotypes, while pregnenolone sulfate was associated with all sleep phenotype domains except for sleep duration. N-lactoyl amino acids such as N-lactoyl phenylalanine (lac-Phe), were associated with sleep duration, SDB, sleep timing and heart rate during sleep.<br><br>INTERPRETATION: This atlas of sleep-metabolite associations will facilitate hypothesis generation and further study of the metabolic underpinnings of sleep health.<br><br>FUNDING: R01HL161012, R35HL135818, R01AG80598.}, }
@article {pmid39693591, year = {2024}, author = {Kalinsky, K and Bianchini, G and Hamilton, E and Graff, SL and Park, KH and Jeselsohn, R and Martin, M and Layman, RM and Hurvitz, SA and Sammons, S and Kaufman, PA and Muñoz, M and Lai, JI and Knoderer, H and Sandoval, C and Chawla, AR and Nguyen, B and Zhou, Y and Ravenberg, E and Litchfield, LM and Smyth, L and Wander, SA}, title = {Abemaciclib Plus Fulvestrant in Advanced Breast Cancer Following Progression on CDK4/6 Inhibition: Results from the Phase III postMONARCH Trial.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2402086}, doi = {10.1200/JCO-24-02086}, pmid = {39693591}, issn = {1527-7755}, abstract = {PURPOSE: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) are the standard first-line treatment for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC); however, disease progression occurs in almost all patients and additional treatment options are needed. Herein we report outcomes of the postMONARCH trial investigating a switch in ET with/without CDK4/6 inhibition with abemaciclib after disease progression on CDK4/6i.<br><br>METHODS: This double-blind, randomized Phase III study enrolled patients with disease progression on prior CDK4/6i plus aromatase inhibitor as initial therapy for advanced disease or recurrence on/after adjuvant CDK4/6i+ET. Patients were randomly assigned (1:1) to abemaciclib+fulvestrant or placebo+fulvestrant. The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included PFS by blinded independent central review (BICR), objective response rate (ORR), and safety.<br><br>RESULTS: This study randomized 368 patients (abemaciclib+fulvestrant, n=182 placebo+fulvestrant, n=186). At the primary analysis (258 events), the hazard ratio (HR) was 0.73 (95% CI, 0.57-0.95; nominal P=0.017), with median PFS 6.0 (95% CI, 5.6-8.6) vs 5.3 (95% CI, 3.7-5.6) months and 6-month PFS rates of 50% and 37% in the abemaciclib+fulvestrant and placebo+fulvestrant arms, respectively. These results were supported by BICR-assessed PFS (HR, 0.55; 95% CI, 0.39-0.77; nominal P<0.001). A consistent treatment effect was seen across major clinical and genomic subgroups, including with/without ESR1 or PIK3CA mutations. Among patients with measurable disease, investigator-assessed ORR was improved with abemaciclib+fulvestrant versus placebo+fulvestrant (17% vs 7%; nominal P=0.015). No new safety signals were observed, with findings consistent with the known safety profile of abemaciclib.<br><br>CONCLUSIONS: Abemaciclib+fulvestrant significantly improved PFS after disease progression on prior CDK4/6i+ET in patients with HR+, HER2- ABC, offering an additional targeted therapy option for these patients.}, }
@article {pmid39693117, year = {2024}, author = {Kresovich, JK and Richards, AR and Ergas, IJ and Cannioto, R and Thomsen, C and Laurent, CA and Shariff-Marco, S and Rillamas-Sun, E and Kolevska, T and Yao, S and Ambrosone, C and Kushi, L and Greenlee, H and Kwan, ML}, title = {Physical activity and incident cardiovascular disease in breast cancer survivors: the pathways study.}, journal = {JNCI cancer spectrum}, volume = {}, number = {}, pages = {}, doi = {10.1093/jncics/pkae123}, pmid = {39693117}, issn = {2515-5091}, abstract = {PURPOSE: Breast cancer survivors experience higher rates of cardiovascular disease (CVD) than women without breast cancer, due in part to cardiotoxic cancer treatments and shared lifestyle risk factors. Physical activity is associated with lower mortality risk in breast cancer survivors, but associations with CVD have not been examined in detail.<br><br>METHODS: The Pathways Study is a prospective cohort study of 4,504 women diagnosed with invasive breast cancer between 2005 and 2013. At enrollment, women self-reported their physical activities during the previous six months, which were dichotomized as meeting the CDC's Physical Activity Guidelines for Americans (&#x2265;150&#x2009;minutes of moderate-intensity or&#x2009;&#x2265;&#x2009;75&#x2009;minutes of vigorous-intensity activity per week) vs not. Incident CVD events (heart failure, cardiomyopathy, cardiac arrest, ischemic heart disease, stroke) occurring between enrollment and December 2021 were identified from electronic health records. Covariate-adjusted, competing risks Cox regression models estimated associations between meeting physical activity guidelines and CVD risk.<br><br>RESULTS: Compared with women who did not meet physical activity guidelines at their diagnosis, those who did had a 25% lower risk of CVD (HR: 0.75, 95% CI: 0.60, 0.94). Among the individual CVD outcomes, meeting physical activity guidelines was protective against incident cardiomyopathy (HR: 0.54, 95% CI: 0.31, 0.95), heart failure (HR: 0.66, 95% CI: 0.50, 0.87), and cardiac arrest (HR: 0.68, 95% CI: 0.49, 0.99).<br><br>CONCLUSIONS: Meeting physical activity guidelines at breast cancer diagnosis was associated with lower risk of CVD after diagnosis. Studies investigating changes in physical activity after a breast cancer diagnosis and CVD risk are warranted.}, }
@article {pmid39691260, year = {2024}, author = {Ho, C and Zhu, S and Gooley, T and Gujral, TS and Lynch, RC and Poh, C and Shadman, M and Smith, SD and Tseng, Y and Gopal, AK}, title = {A phase 2 study of frontline pembrolizumab in follicular lymphoma.}, journal = {EJHaem}, volume = {5}, number = {6}, pages = {1173-1181}, pmid = {39691260}, issn = {2688-6146}, abstract = {BACKGROUND: The tumor microenvironment (TME), including infiltrating T-cells, is thought to play a major role in the pathogenesis and prognosis of follicular lymphoma (FL) and may contribute to its widely varied disease course. We hypothesized that programmed death-1 inhibition may be most effective in untreated, immunocompetent FL patients. Thus, we developed a phase 2 study to evaluate the efficacy of pembrolizumab as the initial treatment for indolent B-cell lymphoma.<br><br>METHODS: Adults with FL or marginal zone lymphoma and an indication for treatment were eligible. Patients received pembrolizumab 200&#xa0;mg IV in 21-day cycles for up to 18 cycles, until progression or unacceptable toxicity. Early response assessment was obtained after cycle 3 with computed tomography (CT), and a fluorodeoxyglucose (FDG)-positron emission tomography-computed tomography (PET-CT) was obtained after cycle 6 to determine candidacy for continuation in the study. Immunosecretome profiling was performed at baseline and on cycle 2 day 1.<br><br>RESULTS: Nine patients with FL were enrolled between February 2019 and April 2021, including eight (89%) with advanced stage, seven (78%) with intermediate/high Follicular Lymphoma International Prognostic Index, and six (67%) with high-tumor burden by Groupe d'Etude des Lymphomes Folliculaires. The best overall response rate by FDG PET-CT was 33% (three partial metabolic responses). Three patients (33%) had stable disease, and three (33%) had progressive disease (including one patient who only had a follow-up CT). By CT four (44%) experienced a reduction in target lesions, but all were less than partial responses. Grade 3 or higher immune-related adverse events (IRAEs) were seen in two (22%) patients, both with transaminitis and one of whom had concurrent hypophysitis. Another patient had grade 1 pneumonitis, requiring treatment with steroids. No associations between the immunosecretome profile and clinical outcomes could be detected.<br><br>CONCLUSION: Frontline pembrolizumab for FL is associated with limited responses and a clinically significant rate of IRAEs. Alternative strategies for targeting the TME in FL should be explored.}, }
@article {pmid39691254, year = {2024}, author = {Naru, J and Othus, M and Lin, C and Biernacki, MA and Bleakley, M and Chauncey, TR and Erba, HP and Fang, M and Fitzgibbon, MP and Gafken, PR and Ivey, RG and Kennedy, JJ and Lorentzen, TD and Meshinchi, S and Moseley, A and Pogosova-Agadjanyan, EL and Liu, VM and Radich, JP and Voytovich, UJ and Wang, P and Whiteaker, JR and Willman, CL and Wu, F and Paulovich, AG and Stirewalt, DL}, title = {Proteogenomic characterization of highly enriched viable leukemic blasts in acute myeloid leukemia: A SWOG report.}, journal = {EJHaem}, volume = {5}, number = {6}, pages = {1243-1251}, pmid = {39691254}, issn = {2688-6146}, abstract = {INTRODUCTION: Acute myeloid leukemia (AML) remains one of the deadliest hematopoietic malignancies. A better understanding of the molecular biology governing AML may lead to improved risk stratification and facilitate the development of novel therapies. Proteins are responsible for much of the biology of cells. Several studies have examined the global proteome in bulk mononuclear cells (MNCs) from AML specimens, which are comprised a heterogenous population of cells at various stages of differentiation.<br><br>METHODS: Given the potential impact of the nonleukemic cells on protein expression profiles, we applied an integrative proteogenomic approach utilizing next-generation sequencing and mass spectrometry-based proteomics to identify novel protein biomarkers in unsorted MNCs and viable leukemic blasts (VLBs) isolated from blood and bone marrow specimens obtained at the time of AML diagnosis.<br><br>RESULTS: We identified significant differences in protein expression between VLBs and MNCs. Subsequent studies (N&#xa0;=&#xa0;27) focused on proteomic profiling of VLBs that identified novel candidate biomarkers associated with mutational genotypes and clinical outcome, some of which were recapitulated in an independent cohort of patients. Using mass spectrometry, we also detected mutated protein products, some of which were predicted via in silico analyses to be potential neoantigens amenable to adoptive immunotherapy. As previously described, analyses comparing transcript and protein expression showed an overall modest correlation between mRNA and protein dataset, but enriching for genes associated with mutations significantly improved the protein-RNA correlation.<br><br>CONCLUSION: Together, the results provide insight into the biology of VLBs and demonstrate the gains derived from examining the proteome in addition to genome and transcriptome.}, }
@article {pmid39691239, year = {2024}, author = {Teymouri, F and Sebastian, G and Gem, H and Minot, SS and Rashidi, A}, title = {Oral acute graft-versus-host disease.}, journal = {EJHaem}, volume = {5}, number = {6}, pages = {1290-1294}, pmid = {39691239}, issn = {2688-6146}, abstract = {Oral acute graft-versus-host disease (aGVHD) is rare and with no diagnostic criteria. We report a case of oral aGVHD with three clinical phases. A self-limited prodrome of largely subjective oral symptoms was followed by concurrent oral and upper gastrointestinal aGVHD. Six months after transplantation, the patient was diagnosed with severe oral and upper gastrointestinal chronic GVHD. We compared the salivary microbiota of our patient at the time of diagnosis of aGVHD with 50 contemporaneous transplant recipients and found no evidence for oral microbiota involvement in pathogenesis. This in-depth N-of-1 analysis reveals novel aspects of oral aGVHD pathogenesis.}, }
@article {pmid39690453, year = {2024}, author = {Do, OA and Ohlsen, TJD and Shipman, KJ and Ballard, SA and Jenssen, KM and Baker, KS and Rosenberg, AR and Barton, KS and Bhatt, NS}, title = {Return-to-School Experiences of Adolescents After Allogeneic Hematopoietic Cell Transplant: A Qualitative Interview Study of Transplant Recipients.}, journal = {Pediatric blood &amp; cancer}, volume = {}, number = {}, pages = {e31481}, doi = {10.1002/pbc.31481}, pmid = {39690453}, issn = {1545-5017}, support = {//Ben Towne Center for Childhood Cancer and Blood Disorders Research Pilot Award program/ ; //Seattle Children's Research Institute and Rally Foundation for Childhood Cancer Research/ ; //Independent Investigator Award/ ; }, abstract = {BACKGROUND: Returning to school after allogeneic hematopoietic cell transplant (HCT) can improve quality of life and promote positive adjustment. However, this process may be challenging, and there is a limited understanding of school-aged children and adolescents' perspectives on this process.<br><br>METHODS: We conducted semi-structured interviews over video with pediatric recipients of HCT (10-18&#xa0;years of age at HCT; 1-7&#xa0;years post HCT) who were treated at our institution and had returned to in-person school post HCT. We performed a thematic network analysis focused on exploring salient challenges regarding the return-to-school process post HCT and potential areas for improvement.<br><br>RESULTS: We interviewed 16 participants (mean age 13.8&#xa0;years at HCT). Four themes emerged: (i) challenges of returning to school, (ii) keys for a successful return-to-school experience, (iii) overall perceptions of the process, and (iv) recommendations for improvement. HCT recipients described several social/emotional, physical, and academic challenges while returning to school and cited strong sources of support as critical to a successful transition. Recommendations for a better transition process included the following: (a) fostering peer support, (b) establishing social connections, (c) providing mental health support, (d) identifying a go-to point of contact for issues, and (e) maintaining academic support.<br><br>CONCLUSIONS: Our findings highlight perspectives from school-aged recipients of HCT regarding gaps in support and areas for improvement to facilitate successful return to school after HCT. Additional assistance throughout the process may optimize academic and social reintegration and support recovery after HCT.}, }
@article {pmid39689462, year = {2024}, author = {Biesma, NC and Graus, MUJE and Cirkel, GA and Besselink, MG and de Groot, JWB and Koerkamp, BG and Herbschleb, KH and Los, M and Verdonk, RC and Wilmink, JW and Cervantes, A and Valle, JW and Valkenburg-van Iersel, LBJ and Froeling, FEM and Molenaar, IQ and Daamen, LA and de Vos-Geelen, J and van Santvoort, HC and , }, title = {Perspectives of the medical oncologist regarding adjuvant chemotherapy for pancreatic cancer: An international expert survey and case vignette study.}, journal = {European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology}, volume = {51}, number = {3}, pages = {109544}, doi = {10.1016/j.ejso.2024.109544}, pmid = {39689462}, issn = {1532-2157}, abstract = {INTRODUCTION: Adjuvant chemotherapy improves survival in patients with resected pancreatic ductal adenocarcinoma (PDAC). The decision to initiate chemotherapy involves both patient and physician factors, decision-specific criteria, and contextual considerations. This study aimed to assess medical oncologists' views on adjuvant chemotherapy following pancreatic resection for PDAC.<br><br>METHODS: An online survey and case vignette study were distributed to medical oncologists via the Dutch Pancreatic Cancer Group (DPCG), International Hepato-Pancreato-Biliary Association (IHPBA) and related networks.<br><br>RESULTS: A total of 91 oncologists from 14 countries participated, 46&#xa0;% of whom treated more than 40 new PDAC patients annually, with a median experience of 15 years. Significant discrepancies were noted in their recommendations for adjuvant chemotherapy across case vignettes. In patients over 70, 17&#xa0;% advised against chemotherapy, while 31&#xa0;% said age was not a factor. Oncologists with less than 10 years of experience and those in non-academic settings were less likely to recommend adjuvant therapy. While 87&#xa0;% agreed mFOLFIRINOX is the preferred adjuvant treatment, consensus on individual cases was lacking. The recommended interval between surgery and chemotherapy ranged from 3 to 26 weeks, with varying reasons for withholding treatment, primarily due to postoperative recovery and performance status.<br><br>CONCLUSIONS: Our study revealed substantial variation among oncologists in counseling on adjuvant chemotherapy after PDAC resection. This emphasizes the need for more patient involvement in decision-making and improving shared decision-making.}, }
@article {pmid39689429, year = {2024}, author = {Hodan, R and Gupta, S and Weiss, JM and Axell, L and Burke, CA and Chen, LM and Chung, DC and Clayback, KM and Felder, S and Foda, Z and Giardiello, FM and Grady, W and Gustafson, S and Hagemann, A and Hall, MJ and Hampel, H and Idos, G and Joseph, N and Kassem, N and Katona, B and Kelly, K and Kieber-Emmons, A and Kupfer, S and Lang, K and Llor, X and Markowitz, AJ and Prats, MM and Niell-Swiller, M and Outlaw, D and Pirzadeh-Miller, S and Samadder, NJ and Shibata, D and Stanich, PP and Swanson, BJ and Szymaniak, BM and Welborn, J and Wiesner, GL and Yurgelun, MB and Dwyer, M and Darlow, S and Diwan, Z}, title = {Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric, Version 3.2024, NCCN Clinical Practice Guidelines In Oncology.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {10}, pages = {695-711}, doi = {10.6004/jnccn.2024.0061}, pmid = {39689429}, issn = {1540-1413}, mesh = {Humans ; Female ; *Endometrial Neoplasms/genetics/diagnosis ; *Genetic Testing/standards/methods ; Risk Assessment/methods ; *Genetic Predisposition to Disease ; Colorectal Neoplasms/genetics/diagnosis ; Stomach Neoplasms/genetics/diagnosis/therapy ; Neoplastic Syndromes, Hereditary/diagnosis/genetics/therapy ; Medical Oncology/standards/methods ; Male ; }, abstract = {Multigene panel testing has allowed for the detection of a growing number of inherited pathogenic/likely pathogenic variants in people at high risk of cancer, including endometrial cancer (EC). Hereditary syndromes associated with EC include Lynch syndrome, PTEN hamartoma tumor syndrome, and Peutz-Jeghers syndrome. This manuscript provides the latest recommendations from the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric on the screening and management of EC in patients at high risk for these syndromes, as well as the advantages and limitations of multigene panel testing. This manuscript also describes recent updates to these guidelines regarding de-implementation of colon cancer screening in individuals with CHEK2 pathogenic/likely pathogenic variants, based on the most up-to-date evidence regarding the association between CHEK2 pathogenic/likely pathogenic variants and colon cancer risk.}, }
@article {pmid39689426, year = {2024}, author = {Sanft, T and Day, AT and Goldman, M and Ansbaugh, S and Armenian, S and Baker, KS and Ballinger, TJ and Demark-Wahnefried, W and Fairman, NP and Feliciano, J and Flores, TF and Friedman, DL and Gabel, N and Hill-Kayser, C and Koura, D and Lee, K and Lee, N and McDonough, AL and Melisko, M and Mooney, K and Moore, HCF and Moryl, N and Neuman, H and Overholser, L and Patel, C and Peterson, L and Pirl, W and Porpiglia, A and Schapira, L and Schwartz, A and Smith, S and Tevaarwerk, A and Von Ah, D and Wake, R and Yang, E and Zee, P and McMillian, N and Freedman-Cass, D}, title = {NCCN Guidelines® Insights: Survivorship, Version 2.2024.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {10}, pages = {648-658}, doi = {10.6004/jnccn.2024.0062}, pmid = {39689426}, issn = {1540-1413}, mesh = {Humans ; *Survivorship ; *Neoplasms/therapy/psychology ; *Cancer Survivors/psychology ; }, abstract = {The NCCN Guidelines for Survivorship include recommendations for screening, evaluation, and treatment of psychosocial and physical problems resulting from adult-onset cancer and its treatment. They also include recommendations to promote healthy behaviors and immunizations in survivors and provide a framework for care coordination. These NCCN Guidelines Insights summarize the panel's current recommendations regarding sexual health and fertility.}, }
@article {pmid39689352, year = {2024}, author = {Vutien, P and Barnard Giustini, A and Kim, NJ and Moon, AM and Hsu, CN and Mezzacappa, C and Borgerding, JA and Johnson, KM and VoPham, T and Berry, K and Beste, LA and Kaplan, DE and Taddei, TH and Ioannou, GN}, title = {Validation and expansion of Baveno VII criteria for cACLD and CSPH based on liver stiffness and platelet count: Correlation with risk of hepatic decompensation and death.}, journal = {Hepatology (Baltimore, Md.)}, volume = {}, number = {}, pages = {}, doi = {10.1097/HEP.0000000000001183}, pmid = {39689352}, issn = {1527-3350}, abstract = {BACKGROUND AND AIMS: Recently proposed "Rule-of-Five" criteria define compensated advanced chronic liver disease (cACLD) and clinically significant portal hypertension (CSPH) using liver stiffness (LS) and platelet count. We aimed to validate these criteria by determining whether they are associated with risk of adverse outcomes.<br><br>METHODS AND RESULTS: Patients without prior hepatic decompensation or hepatocellular carcinoma (HCC) who underwent LS and platelet measurements (n=17,076), were categorized as follows: no cACLD (LS 2.5-9.9 kPa); probable cACLD (LS 10-14.9 kPa); certain cACLD-no CSPH (LS 15-19.9 kPa and platelets &#x2265;110,000/&#xb5;L or LS 20-24.9 kPa and platelets &#x2265;150,000/&#xb5;L); probable CSPH (LS 15-19.9 kPa and platelets <110,000/&#xb5;L or LS 20-24.9 and platelets <150,000/&#xb5;L); and certain CSPH (LS &#x2265;25 Kpa), which we further sub-divided into 25-49.9 kPa and 50-75 kPa.During a median follow-up of 2.82 years, each increase in "Rule-of-Five" category was associated linearly with higher risks of death (hazard ratio [HR] 1.22, 95% CI 1.18-1.25) and decompensation (HR 1.52, 95% CI 1.46-1.58). Compared to patients with LS 25-49.9 kPa, those with LS 50-75 kPa ("critical" CSPH) had approximately double the risk of decompensation (11.24 vs. 4.20 per 100 patient-years) and death (9.85 vs. 6.98 per 100 patient-years).<br><br>CONCLUSIONS: The Baveno VII "Rule-of-Five" criteria provide a valid system for stratifying risks of death and hepatic decompensation and should be used routinely in patients with chronic liver disease. Among patients with CSPH (LS &#x2265;25 kPa), the subgroup with LS 50-75 kPa ("critical" CSPH) has approximately double the risk of death and hepatic decompensation than LS 25-49.9 kPa.}, }
@article {pmid39688693, year = {2024}, author = {Ohlsen, TJD and Hale, MR and Larson, AJ and Jones, SMW and Wilkinson, F and Chow, EJ and Ko, LK and Desai, AD}, title = {Financial toxicity among pediatric oncology families during therapy and early survivorship: a qualitative analysis.}, journal = {Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer}, volume = {33}, number = {1}, pages = {36}, pmid = {39688693}, issn = {1433-7339}, mesh = {Humans ; Female ; Male ; *Qualitative Research ; *Neoplasms/psychology/therapy/economics ; Child ; Adult ; *Caregivers/psychology/economics ; Adolescent ; Middle Aged ; Child, Preschool ; Interviews as Topic ; Cost of Illness ; Survivorship ; Family/psychology ; Young Adult ; Cancer Survivors/psychology ; }, abstract = {PURPOSE: Cancer treatment often results in adverse financial consequences-also termed financial toxicity. To build upon limited research in pediatric oncology, we conducted a qualitative study exploring families' lived experiences with financial toxicity and their perspectives on potential mitigation strategies.<br><br>METHODS: We conducted in-depth semi-structured interviews with a purposive sample of English- and Spanish-speaking family caregivers, 3-24&#xa0;months following diagnosis. We performed a thematic analysis focused on elucidating relationships between components/domains of financial toxicity, identifying mitigating and exacerbating factors, eliciting latent constructs for measurement, and querying caregivers' perspectives on interventions. We organized relationships between themes into a framework to compare with prior theoretically derived models.<br><br>RESULTS: We interviewed 21 caregivers, diverse with respect to income, age, race and ethnicity, family structure/composition, and patient characteristics. We identified four themes relating to financial toxicity: increased spending on providing care to patients/siblings, reduced income due to challenges in maintaining employment, new or worsened material hardship, and heightened psychological distress regarding finances. We also identified an additional theme pertaining to response behaviors directed at managing financial toxicity, with helpful or harmful downstream effects. Factors that exacerbated or lessened financial toxicity included awareness of resources, geography, and community. Caregivers suggested potential mitigation strategies, including proactive education and resource provision.<br><br>CONCLUSION: Pediatric patients and families can experience substantial financial impacts, which may differ from experiences of adults with cancer. These findings suggest a need for careful screening and measurement, as well as family-centered interventions and policies to reduce long-term consequences.}, }
@article {pmid39677796, year = {2024}, author = {Nicoletti, C and Massenet, J and Pintado-Urbanc, AP and Connor, LJ and Nicolau, M and Sundar, S and Xu, M and Schmitt, A and Zhang, W and Fang, Z and Chan, TCI and Tapscott, SJ and Cheung, TH and Simon, MD and Caputo, L and Puri, PL}, title = {E-box independent chromatin recruitment turns MYOD into a transcriptional repressor.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39677796}, issn = {2692-8205}, abstract = {MYOD is an E-box sequence-specific basic Helix-Loop-Helix (bHLH) transcriptional activator that, when expressed in non-muscle cells, induces nuclear reprogramming toward skeletal myogenesis by promoting chromatin accessibility at previously silent loci. Here, we report on the identification of a previously unrecognized property of MYOD as repressor of gene expression, via E-box-independent chromatin binding within accessible genomic elements, which invariably leads to reduced chromatin accessibility. MYOD-mediated repression requires the integrity of functional domains previously implicated in MYOD-mediated activation of gene expression. Repression of mitogen- and growth factor-responsive genes occurs through promoter binding and requires a highly conserved domain within the first helix. Repression of cell-of-origin/alternative lineage genes occurs via binding and decommissioning of distal regulatory elements, such as super-enhancers (SE), which requires the N-terminal activation domain as well as two chromatin-remodeling domains and leads to reduced strength of CTCF-mediated chromatin interactions. Surprisingly, MYOD-mediated chromatin compaction and repression of transcription do not associate with reduction of H3K27ac, the conventional histone mark of enhancer or promoter activation, but with reduced levels of the recently discovered histone H4 acetyl-methyl lysine modification (Kacme). These results extend MYOD biological properties beyond the current dogma that restricts MYOD function to a monotone transcriptional activator and reveal a previously unrecognized functional versatility arising from an alternative chromatin recruitment through E-box or non-E-box sequences. The E-box independent repression of gene expression by MYOD might provide a promiscuous mechanism to reduce chromatin accessibility and repress cell-of-origin/alternative lineage and growth factor/mitogen-responsive genes to safeguard the integrity of cell identity during muscle progenitor commitment toward the myogenic lineage.}, }
@article {pmid39687983, year = {2024}, author = {Williams, JT and Goodpaster, TA and Haraguchi, M}, title = {Optimizing tissue adherence on glass slides using polyurethane glue: a new slide preparation method.}, journal = {Journal of histotechnology}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/01478885.2024.2440679}, pmid = {39687983}, issn = {2046-0236}, abstract = {The application of Clear Gorilla Glue® household adhesive to microscope slides has been found to enhance the mounting and retention of traditionally difficult tissue types, notably bone and tooth specimens. Improvement in end results were observed across H&amp;E staining, immunohistochemistry, and in situ hybridization.}, }
@article {pmid39682018, year = {2024}, author = {Boiko, JR and Hill, GR}, title = {Chronic Graft-versus-host Disease: Immune Insights, Therapeutic Advances, and Parallels for Solid Organ Transplantation.}, journal = {Transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1097/TP.0000000000005298}, pmid = {39682018}, issn = {1534-6080}, abstract = {Chronic graft-versus-host disease remains a frequent and morbid outcome of allogeneic hematopoietic cell transplantation, in which the donor-derived immune system attacks healthy recipient tissue. Preceding tissue damage mediated by chemoradiotherapy and alloreactive T cells compromise central and peripheral tolerance mechanisms, leading to aberrant donor T cell and germinal center B cell differentiation, culminating in pathogenic macrophage infiltration and differentiation in a target tissue, with ensuant fibrosis. This process results in a heterogeneous clinical syndrome with significant morbidity and mortality, frequently requiring prolonged therapy. In this review, we discuss the processes that interrupt immune tolerance, the subsequent clinical manifestations, and new Food and Drug Administration-approved therapeutic approaches that have been born from a greater understanding of disease pathogenesis in preclinical systems, linking to parallel processes following solid organ transplantation.}, }
@article {pmid39681126, year = {2024}, author = {Velloza, J and Poovan, N and Meisner, A and Ndlovu, N and Ndimande-Khoza, N and Grabow, C and Zwane, P and Mbele, S and Molefe, M and Donnell, D and Baeten, JM and Hosek, S and Celum, C and Delany-Moretlwe, S}, title = {Adaptive HIV pre-exposure prophylaxis adherence interventions for young women in Johannesburg, South Africa: a sequential multiple-assignment randomised trial.}, journal = {The lancet. HIV}, volume = {}, number = {}, pages = {}, doi = {10.1016/S2352-3018(24)00268-6}, pmid = {39681126}, issn = {2352-3018}, abstract = {BACKGROUND: Adherence to daily oral pre-exposure prophylaxis (PrEP) is low among African young women, and layered support strategies are needed to improve PrEP adherence in this population. We aimed to evaluate potentially scalable adherence-support strategies for young women aged 18-25 years who initiated PrEP in Johannesburg, South Africa.<br><br>METHODS: We conducted a sequential multiple-assignment randomised trial at Ward 21 of the Wits Reproductive Health and HIV Institute clinical research site, affiliated with University of the Witwatersrand, Johannesburg, South Africa. Participants were eligible if they were assigned female sex at birth, aged 18-25 years, not living with HIV, sexually active, newly initiating PrEP, had regular access to a mobile telephone, and could read. Using sequentially numbered, sealed, opaque envelopes containing group allocation, a staff member assigned enrolled participants (1:1) to receive one of two adherence-support interventions: once per week two-way SMS communication or participation in a WhatsApp peer-support group. Participants assigned to WhatsApp were put into groups with approximately 25 participants, during which they were prompted by staff facilitators to discuss any challenges with PrEP use or other events happening in their lives. The allocation sequence was generated by the data manager using random numbers with variable block sizes between 10 and 14. Only trial investigators were masked to participant intervention assignments; participants, people giving interventions, people assessing outcomes, and people analysing data were not masked to group assignment. All enrolled participants were offered PrEP (ie, co-formulated, once per day oral emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg). The primary outcome was high PrEP adherence at month 9, defined as concentration of tenofovir diphosphate on dried blood sample of 700 fmol per punch or more. At month 3, participants with low PrEP adherence were randomly assigned to a secondary, intensified intervention of issue-focused counselling once per month or drug-level feedback counselling based on PrEP drug concentrations at months 3 and 6. The protocol was registered at ClinicalTrials.gov (NCT04038060) and the trial is complete.<br><br>FINDINGS: Participants were enrolled and followed up between May 16, 2019, and Jan 25, 2022. From May 16, 2019, to Jan 29, 2021, 401 participants were screened and 360 were enrolled and initiated PrEP. 180 (50%) were randomly assigned to two-way SMS and 180 (50%) were randomly assigned to WhatsApp support groups. At month 9, 34 (20%) of 174 participants in the two-way SMS arm had tenofovir diphosphate 700 fmol per punch or more, compared with 32 (18%) of 174 in the WhatsApp arm (relative risk 1&#xb7;06, 95% CI 0&#xb7;69-1&#xb7;64; p=0&#xb7;78). At month 9, four (5%) of 76 participants in the drug-level feedback arm had tenofovir diphosphate 700 fmol per punch or more, compared with three (4%) of 76 participants in the monthly counselling arm (1&#xb7;33, 0&#xb7;31-5&#xb7;76; p=0&#xb7;70). 22 serious adverse events were reported during the trial, but were all deemed unrelated to the trial.<br><br>INTERPRETATION: PrEP adherence did not differ across interventions among young women in Johannesburg, South Africa. Future research is needed on whether and how to scale-up PrEP support for young women in resource-constrained settings.<br><br>FUNDING: US National Institutes of Health.}, }
@article {pmid39680601, year = {2024}, author = {Grinde, KE and Browning, BL and Reiner, AP and Thornton, TA and Browning, SR}, title = {Adjusting for principal components can induce collider bias in genome-wide association studies.}, journal = {PLoS genetics}, volume = {20}, number = {12}, pages = {e1011242}, doi = {10.1371/journal.pgen.1011242}, pmid = {39680601}, issn = {1553-7404}, abstract = {Principal component analysis (PCA) is widely used to control for population structure in genome-wide association studies (GWAS). Top principal components (PCs) typically reflect population structure, but challenges arise in deciding how many PCs are needed and ensuring that PCs do not capture other artifacts such as regions with atypical linkage disequilibrium (LD). In response to the latter, many groups suggest performing LD pruning or excluding known high LD regions prior to PCA. However, these suggestions are not universally implemented and the implications for GWAS are not fully understood, especially in the context of admixed populations. In this paper, we investigate the impact of pre-processing and the number of PCs included in GWAS models in African American samples from the Women's Health Initiative SNP Health Association Resource and two Trans-Omics for Precision Medicine Whole Genome Sequencing Project contributing studies (Jackson Heart Study and Genetic Epidemiology of Chronic Obstructive Pulmonary Disease Study). In all three samples, we find the first PC is highly correlated with genome-wide ancestry whereas later PCs often capture local genomic features. The pattern of which, and how many, genetic variants are highly correlated with individual PCs differs from what has been observed in prior studies focused on European populations and leads to distinct downstream consequences: adjusting for such PCs yields biased effect size estimates and elevated rates of spurious associations due to the phenomenon of collider bias. Excluding high LD regions identified in previous studies does not resolve these issues. LD pruning proves more effective, but the optimal choice of thresholds varies across datasets. Altogether, our work highlights unique issues that arise when using PCA to control for ancestral heterogeneity in admixed populations and demonstrates the importance of careful pre-processing and diagnostics to ensure that PCs capturing multiple local genomic features are not included in GWAS models.}, }
@article {pmid39680021, year = {2024}, author = {Yamamoto, N and Dobersch, S and Loveless, I and Samraj, AN and Jang, GH and Haraguchi, M and Kang, LI and Ruzinova, MB and Vij, KR and Mudd, JL and Walsh, T and Safyan, RA and Chiorean, EG and Hingorani, SR and Bolton, NM and Li, L and Fields, RC and DeNardo, DG and Notta, F and Crawford, HC and Steele, NG and Kugel, S}, title = {HMGA2 Expression Predicts Subtype, Survival, and Treatment Outcome in Pancreatic Ductal Adenocarcinoma.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-24-2200}, pmid = {39680021}, issn = {1557-3265}, abstract = {PURPOSE: To establish HMGA2 as a marker of basal-like disease in pancreatic ductal adenocarcinoma (PDAC) and explore its use as a biomarker for prognosis and treatment resistance.<br><br>EXPERIMENTAL DESIGN: We identified high expression of HMGA2 in basal PDAC cells in a scRNAseq Atlas of 172 patient samples. We then analyzed HMGA2 expression, along with expression of the classical marker GATA6, in a cohort of 580 PDAC samples with multiplex immunohistochemistry. We further supplemented these data with an additional 30 diverse patient samples and multiple independent single-cell RNAseq databases.<br><br>RESULTS: We found that expression of HMGA2, but not previously described basal markers CK5 or CK17, predicted overall survival in our cohort. Combining HMGA2 and GATA6 status allowed for identification of two key study groups: an HMGA2+/GATA6- cohort with worse survival, low tumor-infiltrating CD8+ T cells, increased FAP+ fibroblasts, and poorer response to gemcitabine-based chemotherapies (n=94, median survival=11.2 months post-surgery); and an HMGA2-/GATA6+ cohort with improved survival, increased CD8+ T-cell infiltrate, decreased FAP+ fibroblasts, and improved survival with gemcitabine-based chemotherapy (n=198, median survival=21.7 months post-surgery). HMGA2 was also prognostic for overall survival in RNA sequencing from an independent cohort.<br><br>CONCLUSIONS: IHC stratification of primary tumors by HMGA2 and GATA6 status in pancreatic cancer is associated with differential outcomes, survival following chemotherapy, and tumor microenvironments. As a nuclear marker for basal disease, HMGA2 complements GATA6 to identify disease subtypes in PDAC.}, }
@article {pmid39679349, year = {2024}, author = {Follmann, D and Wang, X and Baden, LR and El Sahly, HM and Essink, B and Gilbert, P and Janes, HE and Kelley, CF and Berman, MA and Frank, I and Chu, E and Deng, W and Priddy, F and Dixit, A and Tomassini, JE and Das, R and Miller, J and Zhou, H}, title = {Who to Boost When: The Effect of Age and Dosing Interval on Delta and Omicron COVID-19 Incidence in the Open-label Phase of the COVE Trial.}, journal = {Open forum infectious diseases}, volume = {11}, number = {12}, pages = {ofae689}, pmid = {39679349}, issn = {2328-8957}, abstract = {BACKGROUND: To help inform COVID-19 vaccination recommendations, we evaluated the impact of age and dosing interval on clinical benefit of a third dose of mRNA-1273.<br><br>METHODS: Approximately 17 000 participants from the phase 3 Coronavirus Efficacy trial who previously received 2 doses of 100&#x2005;&#xb5;g mRNA-1273 were evaluated for COVID-19 between September 2021 and April 2022 during uptake of a third booster dose of 50&#x2005;&#xb5;g of mRNA-1273. Cox models assessed booster relative efficacy of a third dose.<br><br>RESULTS: Initial booster relative efficacy against Delta COVID-19 was 83% (95% confidence interval, 60-93) 14 days postdose and 83% (67-91) 60 days later. Initial booster efficacy against Omicron COVID-19 was 56% (44-65) at 14 days postdose and 4% (-27 to 28) 120 days later. For those aged &#x2265;65 years, initial booster efficacy against Omicron COVID-19 was 86% (69-93) compared with 50% (36-61) for those <65 years. Placebo crossover to 2 doses of mRNA-1273 induced a median 5-month difference from the second to third dose between the original randomized arms. Postboost, the mRNA-1273 arm had a 24% (16%, 32%) lower risk of Omicron COVID-19 compared to the placebo-mRNA-1273 arm. Modeling predicted a 41% postboost reduction in Omicron COVID-19 for a 15- versus 7-month interval between the second and third doses.<br><br>CONCLUSIONS: Boosting reduced Delta COVID-19 risk by 83% through 2 months and reduced Omicron COVID-19 risk by 56% but declined by 4 months. A 15- versus 7-month dosing interval predicted a 41% postboost reduction in Omicron COVID-19 but increased preboost risk.<br><br>PRIMARY FUNDING SOURCE: The National Institutes of Health/National Institute of Allergy and Infectious Diseases. Registration for the COVE Trial.&#x2003; ClinicalTrials.gov ID# NCT04470427.}, }
@article {pmid39678499, year = {2024}, author = {Moloney, B and Li, X and Hirano, M and Saad Eddin, A and Lim, JY and Biswas, D and Kazerouni, AS and Tudorica, A and Li, I and Bryant, ML and Wille, C and Pyle, C and Rahbar, H and Hsieh, SK and Rice-Stitt, TL and Dintzis, SM and Bashir, A and Hobbs, E and Zimmer, A and Specht, JM and Phadke, S and Fleege, N and Holmes, JH and Partridge, SC and Huang, W}, title = {Initial experience in implementing quantitative DCE-MRI to predict breast cancer therapy response in a multi-center and multi-vendor platform setting.}, journal = {Frontiers in oncology}, volume = {14}, number = {}, pages = {1395502}, pmid = {39678499}, issn = {2234-943X}, abstract = {Quantitative dynamic contrast-enhanced (DCE) MRI as a promising method for the prediction of breast cancer response to neoadjuvant chemotherapy (NAC) has been demonstrated mostly in single-center and single-vendor platform studies. This preliminary study reports the initial experience in implementing quantitative breast DCE-MRI in multi-center (MC) and multi-vendor platform (MP) settings to predict NAC response. MRI data, including B1 mapping, variable flip angle (VFA) measurements of native tissue R1 (R1,0), and DCE-MRI, were acquired during NAC at three sites using 3T systems with Siemens, Philips, and GE platforms, respectively. High spatiotemporal resolution DCE-MRI was performed using similar vendor product sequences with k-space undersampling during acquisition and view sharing during reconstruction. A breast phantom was used for quality assurance/quality control (QA/QC) across sites. The Tofts model (TM) and shutter-speed model (SSM) were used for pharmacokinetic (PK) analysis of the DCE data. Additionally, tumor region of interest (ROI)- vs. voxel-based analyses in combination with the use of VFA-measured R1,0 vs. fixed, literature-reported R1,0 were investigated to determine the optimal analysis approach. Results from 15 patients who completed the study are reported. Voxel-based PK analysis using fixed R1,0 was deemed the optimal approach, which allowed the inclusion of data from one vendor platform where VFA measurements produced ≥100% overestimation of R1,0. The semi-quantitative signal enhancement ratio (SER) and quantitative PK parameters outperformed the tumor longest diameter (LD) in the prediction of pathologic complete response (pCR) vs. non-pCR after the first NAC cycle, whereas K[trans] consistently provided more accurate predictions than both SER and LD after the first NAC cycle and at the NAC midpoint. Both TM and SSM K[trans] and kep were excellent predictors of response at the NAC midpoint with ROC AUC >0.90, while the SSM parameters (AUC ≥0.80) performed better than their TM counterparts (AUC <0.80) after the first NAC cycle. The initial experience of this ongoing study indicates the importance of QA/QC using a phantom and suggests that deploying voxel-based PK analysis using a fixed R1,0 may mitigate random errors from R1,0 measurements across platforms and potentially eliminate the need for B1 and VFA acquisitions in MC and MP trials.}, }
@article {pmid39678495, year = {2024}, author = {Saini, J and Erickson, DPJ and Vander Stappen, F and Ruth, M and Cui, S and Gorman, V and Rossomme, S and Cao, N and Ford, EC and Meyer, J and Bloch, C and Wong, T and Grassberger, C and Rengan, R and Zeng, J and Schwarz, M}, title = {Commissioning a clinical proton pencil beam scanning beamline for pre-clinical ultra-high dose rate irradiations on a cyclotron-based system.}, journal = {Frontiers in oncology}, volume = {14}, number = {}, pages = {1460288}, pmid = {39678495}, issn = {2234-943X}, abstract = {BACKGROUND: This manuscript describes modifications to a pencil beam scanning (PBS) proton gantry that enables ultra-high dose rates (UHDR) irradiation, including treatment planning and validation.<br><br>METHODS: Beamline modifications consisted of opening the energy slits and setting the degrader to pass-through mode to maximize the dose rate. A range shifter was inserted upstream from the isocenter to enlarge the spot size and make it rotationally symmetric. We measured the beamline transport efficiency and investigated the variation in output due to the recombination of charge in the dose monitoring chamber. The output calibration was performed through a parallel plate chamber (PPC05), and an intercomparison was performed for various detectors. The pre-clinical field for mice irradiation consisted of different dose levels to deliver uniform doses in transmission mode. The field dose rates were determined through log files while scripting in TPS was used to estimate PBS dose rates. The survival experiments consisted of irradiating the full pelvis of the mice at UHDR and conventional dose rates.<br><br>RESULTS: The spot size was constant with beam current and had a sigma of 8.5 mm at the isocenter. The beam output increased by 35% at 720 nA compared to 5.6 nA, primarily due to recombination in the dose-monitoring ion chambers. The Faraday Cup and PPC05 agreed within 2%, while other detectors were within 3% of FC for dose rates <60 Gy/s. The pre-clinical fields' PBS dose rate is above 45 Gy/sec for all voxels within the target volume. The average and PBS dose rates decrease as field size increases and approaches 40 Gy/s for a field size of 7x7 cm[2]. All UHDR arms showed better survival than the corresponding conventional dose rate arms.<br><br>CONCLUSIONS: We successfully modified a clinical system to perform UHDR pre-clinical experiments. As part of our pre-clinical experiments, we observed the FLASH effect concerning mice survival.}, }
@article {pmid39651227, year = {2024}, author = {Liu, B and Greenwood, NF and Bonzanini, JE and Motmaen, A and Sharp, J and Wang, C and Visani, GM and Vafeados, DK and Roullier, N and Nourmohammad, A and Garcia, KC and Baker, D}, title = {Design of high specificity binders for peptide-MHC-I complexes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39651227}, issn = {2692-8205}, support = {R01 AI103867/AI/NIAID NIH HHS/United States ; R35 GM142795/GM/NIGMS NIH HHS/United States ; }, abstract = {Class I MHC molecules present peptides derived from intracellular antigens on the cell surface for immune surveillance, and specific targeting of these peptide-MHC (pMHC) complexes could have considerable utility for treating diseases. Such targeting is challenging as it requires readout of the few outward facing peptide antigen residues and the avoidance of extensive contacts with the MHC carrier which is present on almost all cells. Here we describe the use of deep learning-based protein design tools to denovo design small proteins that arc above the peptide binding groove of pMHC complexes and make extensive contacts with the peptide. We identify specific binders for ten target pMHCs which when displayed on yeast bind the on-target pMHC tetramer but not closely related peptides. For five targets, incorporation of designs into chimeric antigen receptors leads to T-cell activation by the cognate pMHC complexes well above the background from complexes with peptides derived from proteome. Our approach can generate high specificity binders starting from either experimental or predicted structures of the target pMHC complexes, and should be widely useful for both protein and cell based pMHC targeting.}, }
@article {pmid39649604, year = {2024}, author = {Unsworth, M and Fabens, I and Setswe, G and Moyo, K and Pienaar, J and Makhele, C and Phohole, M and Igaba, N and Hlongwane, S and Sardini, M and Dong, T and Sharma, M and Tweya, H and Ndebele, F and Holec, M and Feldacker, C}, title = {What does it cost to expand two-way texting for post-operative follow-up? A cost analysis in routine voluntary medical male circumcision settings in South Africa.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39649604}, support = {P30 AI027757/AI/NIAID NIH HHS/United States ; R01 NR019229/NR/NINR NIH HHS/United States ; }, abstract = {Up to 98% of adult voluntary medical male circumcision (VMMC) clients heal without adverse events (AEs) in South Africa and in the sub-Saharan Africa (SSA) region, yet all clients in South Africa (SA) are still required to attend in-person reviews, creating added work for providers and barriers for clients. A randomized controlled trial (RCT) using our fee-free, open-source, two-way texting (2wT) approach showed that males could independently monitor their healing with support from VMMC nurse-led telehealth and that 2wT was more cost-effective than routine visits for quality post-operative monitoring. The objectives of this costing activity were to assess the additive cost of 2wT vs. SoC during a stepped wedge design (SWD) expansion trial; costing an augmentation of 2wT with dedicated personnel during peak VMMC periods; and estimate the cost savings of 2wT from the payer perspective if scaled in routine VMMC settings. Data was collected from routine financial reports and complemented by previous RCT time-motion estimates. We conducted activity-based costing of SWD and peak season periods; sensitivity analysis estimated 2wT costs at scale. We included data from 6,842 males, with 2,586 (38%) opting for 2wT. 2wT participants attended an average of zero visits; SoC males had an average of 2 visits. Under 2wT, quality care markers improved and AE ascertainment increased while loss to follow-up (LTFU) decreased. Given a VMMC population of 10,000 adults, scenario analysis suggests that: 1) 2wT becomes cost neutral with 45% 2wT enrollment; 2) 2wT saves $0.29/client with 60% 2wT enrollment; and 3) 2wT saves $0.46/client with 80% 2wT enrollment. When implemented at scale, 2wT appears to significantly reduce costs to the healthcare system while improving the quality of post-operative care and requiring no additional client costs. 2wT should be expanded for eligible males across VMMC and other post-operative contexts in South Africa.}, }
@article {pmid39656951, year = {2024}, author = {Abdou, Y and Barlow, WE and Gralow, JR and Meric-Bernstam, F and Albain, KS and Hayes, DF and Lin, NU and Perez, EA and Goldstein, LJ and Chia, SKL and Dhesy-Thind, S and Rastogi, P and Alba, E and Delaloge, S and Schott, AF and Shak, S and Sharma, P and Lew, DL and Miao, J and Unger, JM and Tripathy, D and Hortobagyi, GN and Pusztai, L and Kalinsky, K}, title = {Race and Clinical Outcomes in Hormone Receptor-Positive, HER2-Negative, Node-Positive Breast Cancer in the Randomized RxPONDER Trial.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djae314}, pmid = {39656951}, issn = {1460-2105}, abstract = {BACKGROUND: The phase III RxPONDER trial has impacted treatment for node-positive(1-3), hormone receptor-positive, HER2-negative breast cancer with 21-gene recurrence score (RS) ≤ 25. We investigated how these findings apply to different racial and ethnic groups within the trial.<br><br>METHODS: The trial randomized women to endocrine therapy (ET) or to chemotherapy plus ET. The primary clinical outcome was invasive disease-free survival (IDFS) with distant relapse-free survival (DRFS) as a secondary outcome. Multivariable Cox models were used to evaluate the association between race/ethnicity and survival outcomes, adjusting for clinicopathologic characteristics, RS, and treatment.<br><br>RESULTS: A total of 4,048 women with self-reported race/ethnicity were included: Hispanic (15.1%), non-Hispanic Black (NHB)(6.1%), Native American/Pacific Islander (0.8%), Asian (8.0%), and non-Hispanic White (NHW)(70%). No differences in RS distribution, tumor size, or number of positive nodes were observed by race/ethnicity. Relative to NHWs, IDFS was worse for NHBs (5-year IDFS 91.6% vs 87.1%, HR&#x2009;=&#x2009;1.37; 95% CI 1.03-1.81) and better for Asians (91.6% vs 93.9%, HR&#x2009;=&#x2009;0.64; 95% CI 0.46-0.91). Relative to NHW, DRFS was worse for NHBs (5-year DRFS 95.8% vs 91.0%, HR&#x2009;=&#x2009;1.65; 95% CI 1.17-2.32) and better for Asians (95.8% vs 96.7%, HR&#x2009;=&#x2009;0.59; 95% CI 0.37-0.95). Adjusting for clinical characteristics, particularly body mass index, diminished the effect of race on outcomes. Chemotherapy treatment efficacy did not differ by race/ethnicity.<br><br>CONCLUSIONS: NHB women had worse clinical outcomes compared to NHWs in the RxPONDER trial despite similar RS and comparable treatment. Our study emphasizes the persistent racial disparities in breast cancer outcomes while highlighting complex interactions among contributing factors.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov: NCT01272037.}, }
@article {pmid39674548, year = {2024}, author = {Duarte, FB and Garcia, YDO and Hamerschlak, N and Funke, VAM and Moreira, MCR and Paz, AA and Filho, JS and Astigarraga, CC and da Silva, RL and de Molla, VC and Silvério, A and Rocha, VG and Feliciano, JVP and Barros, GMN and Colturato, VAR and Nabhan, SK and Farias, JSH and Maia, ACA and Atalla, &#xc2; and Chiattone, R and Macedo, MCMA and Aranha, MAF and Zogbi, YAN and Lener, D and Soares, RDA and Scheinberg, P and Calixto, RF and Teixeira, GM and Colella, MP and Rodrigues, CA and Simione, AJ and da Silva, CC and Martin, PJ and Flowers, ME}, title = {Allogeneic Hematopoietic Cell Transplantation in Elderly Patients in a Latin American Country: Analysis of 11 Years of Data from the Brazilian Registry SBTMO/CIBMTR.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2024.12.003}, pmid = {39674548}, issn = {2666-6367}, abstract = {This study analyzed recent changes in the utilization of allogeneic HCT for treatment of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative diseases (MPD) and the survival of HCT recipients ≥60 years of age in Brazil. This retrospective registry study included patients who received a first allogeneic HCT from any donor between 2012 and 2023. Of the 6657 patients, 444 (7%) were 60 years of age or older who received grafts from HLA-matched related (42%) or unrelated (20%) donors or HLA-haploidentical donors (32%). The proportion of HCT recipients 60 years of age or older increased gradually from 3.2% in 2012 to 16% in 2023 mostly due to the increased use of HLA-haploidentical donors since 2018. Overall survival (OS) at day 100 was 77%, and estimated OS at 12 months was 53% (95% CI, 48-58). OS at 12-months was higher for transplants during 2015-2017 (58%) and 2018-2020 (68%) compared to 2012-2014 (45%), but it did not differ for those during 2021-2023 (49%). Mortality with HLA-haploidentical donors (HR 2.35; 95%CI; 1.65-3.34 [p <0.001]) and cord blood donors (HR 4.68; 95%CI,1.29-16.9 [p= 0.01]) was higher than with HLA-matched related donors. Mortality was lower for transplants during the 2015-2020 period (HR 0.57; 95%CI, 0.34-0.96 [0.037]) than for those during 2012-2014.This study revealed a gradual increase in the use of allogeneic HCT in individuals aged 60 years and older in Brazil. While use of haploidentical donor has increased worldwide, its association with increased mortality in elderly population deserves caution.}, }
@article {pmid39673790, year = {2024}, author = {Chiu, AP and Gowda, GAN and Zhu, W and Arendt-Nielsen, L and Raftery, D and Curatolo, M}, title = {Cerebrospinal Fluid Metabolomics of Pain in Patients with Spinal Muscle Atrophy.}, journal = {Pain medicine (Malden, Mass.)}, volume = {}, number = {}, pages = {}, doi = {10.1093/pm/pnae129}, pmid = {39673790}, issn = {1526-4637}, }
@article {pmid39673461, year = {2024}, author = {Macinnis, RJ and Jenkins, MA and Milne, RL and John, EM and Daly, MB and Andrulis, IL and Colonna, SV and Phillips, KA and ,  and Le Marchand, L and Newcomb, PA and Phipps, A and Schmit, S and Macrae, F and Buchanan, D and Gallinger, S and Pai, RK and Samadder, NJ and Giles, GG and Southey, MC and Hopper, JL and Terry, MB}, title = {Menopausal hormone therapy: assessing associations with breast and colorectal cancers by familial risk.}, journal = {JNCI cancer spectrum}, volume = {}, number = {}, pages = {}, doi = {10.1093/jncics/pkae121}, pmid = {39673461}, issn = {2515-5091}, abstract = {Menopausal hormone therapy (MHT) users are at increased breast cancer (BC) risk and decreased colorectal cancer (CRC) risk compared with never users, but these opposing associations might differ by familial risk of BC and CRC. We harmonized data from three cohorts and generated separate BC and CRC familial risk scores (FRS) based on cancer family history. We defined moderate/strong family history as FRS ≥ 0.4, where 0.4 was equivalent to a 50-year-old woman with one parent diagnosed with either cancer at age 55 years. Of 24,486 women, 1,243 and 405 were diagnosed with incident BC and CRC, respectively. For BC, MHT hazard ratios (HRs) were 1.27 (95%CI = 1.11-1.45) for FRSBC<0.4, 1.01 (95%CI = 0.82-1.25) for FRSBC≥0.4 (P-difference = 0.08). For CRC, MHT HRs were 0.63 (95%CI = 0.50-0.78) for FRSCRC<0.4, 1.21 (95%CI = 0.73-2.00) for FRSCRC≥0.4 (P-difference = 0.03). Associations with MHT that apply to the general population might not hold for women at moderate/strong familial risk of these cancers.}, }
@article {pmid39672634, year = {2025}, author = {Tseng, YD and Mikhaeel, NG}, title = {The seemingly contradictory roles of radiation as focal to systemic therapy in hematologic malignancies.}, journal = {Seminars in radiation oncology}, volume = {35}, number = {1}, pages = {1-3}, doi = {10.1016/j.semradonc.2024.12.001}, pmid = {39672634}, issn = {1532-9461}, }
@article {pmid39672162, year = {2024}, author = {Pasquesi, GIM and Allen, H and Ivancevic, A and Barbachano-Guerrero, A and Joyner, O and Guo, K and Simpson, DM and Gapin, K and Horton, I and Nguyen, LL and Yang, Q and Warren, CJ and Florea, LD and Bitler, BG and Santiago, ML and Sawyer, SL and Chuong, EB}, title = {Regulation of human interferon signaling by transposon exonization.}, journal = {Cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cell.2024.11.016}, pmid = {39672162}, issn = {1097-4172}, abstract = {Innate immune signaling is essential for clearing pathogens and damaged cells and must be tightly regulated to avoid excessive inflammation or autoimmunity. Here, we found that the alternative splicing of exons derived from transposable elements is a key mechanism controlling immune signaling in human cells. By analyzing long-read transcriptome datasets, we identified numerous transposon exonization events predicted to generate functional protein variants of immune genes, including the type I interferon receptor IFNAR2. We demonstrated that the transposon-derived isoform of IFNAR2 is more highly expressed than the canonical isoform in almost all tissues and functions as a decoy receptor that potently inhibits interferon signaling, including in cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our findings uncover a primate-specific axis controlling interferon signaling and show how a transposon exonization event can be co-opted for immune regulation.}, }
@article {pmid39671534, year = {2024}, author = {Shroff, RT and King, G and Colby, S and Scott, AJ and Borad, MJ and Goff, L and Matin, K and Mahipal, A and Kalyan, A and Javle, MM and El Dika, I and Tan, B and Cheema, P and Patel, A and Iyer, R and Kelley, RK and Thumar, J and El-Khoueiry, A and Guthrie, KA and Chiorean, EG and Hochster, H and Philip, PA}, title = {SWOG S1815: A Phase III Randomized Trial of Gemcitabine, Cisplatin, and Nab-Paclitaxel Versus Gemcitabine and Cisplatin in Newly Diagnosed, Advanced Biliary Tract Cancers.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2401383}, doi = {10.1200/JCO-24-01383}, pmid = {39671534}, issn = {1527-7755}, abstract = {PURPOSE: SWOG S1815 was a randomized, open label phase III trial, evaluating gemcitabine, nab-paclitaxel, and cisplatin (GAP) versus gemcitabine and cisplatin (GC) in patients with newly diagnosed advanced biliary tract cancers (BTCs).<br><br>METHODS: Patients with newly diagnosed locally advanced unresectable or metastatic BTC, including intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) and gallbladder carcinoma (GBC), were randomly assigned 2:1 to either GAP (gemcitabine 800 mg/m[2], cisplatin 25 mg/m[2], and nab-paclitaxel 100 mg/m[2] intravenously once per day on days 1 and 8 of a 21-day cycle) or GC (gemcitabine 1,000 mg/m[2] and cisplatin 25 mg/m[2] intravenously once per day on days 1 and 8 of a 21-day cycle).<br><br>RESULTS: Among 452 randomly assigned participants, 441 were eligible and analyzable, 67% with ICC, 16% with GBC, and 17% with ECC. There was no significant difference in overall survival (OS) between GAP versus GC. Median OS with GAP was 14.0 months (95% CI, 12.4 to 16.1) and 13.6 months with GC (95% CI, 9.7 to 16.6); hazard ratio (HR), 0.91 (95% CI, 0.72 to 1.14); P = .41. Median progression-free survival (PFS) was similar between groups with median PFS for GAP being 7.5 months (95% CI, 6.4 to 8.5) versus 6.3 months for GC (95% CI, 4.4 to 8.2); HR, 0.89 (95% CI, 0.71 to 1.12); P = .32. In exploratory subset analyses, the OS and PFS benefits of GAP versus GC treatment were greater in locally advanced disease compared with metastatic disease, although not statistically significant (interaction P = .14 for OS and P = .17 for PFS). Moreover, GAP versus GC showed greater improvement in PFS among participants with GBC than those with ICC or ECC (interaction P = .01), but not OS (interaction P = .28).<br><br>CONCLUSION: The addition of a taxane in the GAP regimen to the standard gemcitabine-cisplatin regimen did not improve OS in newly diagnosed BTC. More toxicity was encountered with GAP versus GC.}, }
@article {pmid39671174, year = {2024}, author = {Wilson, GJ and Church, LWP and Kelley, CF and Robinson, ST and Lu, Y and Furch, BD and Fong, Y and Paez, CA and Yacovone, M and Jacobsen, T and Maughan, M and Martik, D and Heptinstall, JR and Zhang, L and Montefiori, DC and Tomaras, GD and Kublin, JG and Corey, L}, title = {HVTN 123: A Phase 1, Randomized Trial Comparing Safety and Immunogenicity of CH505TF gp120 Produced by Stably and Transiently Transfected Cell Lines.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiae558}, pmid = {39671174}, issn = {1537-6613}, support = {//National Institute of Allergy and Infectious Diseases/ ; UM1 AI068614/NH/NIH HHS/United States ; }, abstract = {Utilizing transiently transfected cell lines could significantly reduce manufacturing timelines for protein subunit vaccines. This trial compared safety and immunogenicity of human immunodeficiency virus (HIV) envelope CH505TF gp120 vaccines produced by upstream stable and transient transfection (each admixed with GLA-SE adjuvant, a TL4 agonist). Both vaccines were safe and well tolerated. Serum IgG binding antibody response rates 2 weeks after final injection were 92% in the stable group and 93% in the transient group (P = 1.000). Neutralization response rates against CH505.w4.3 were also equivalent (92% vs 100%, P = .291). These data support transient transfection as an available tool for accelerating HIV vaccine testing and iteration. Clinical Trials Registration. NCT03856996.}, }
@article {pmid39669607, year = {2024}, author = {Tumulak, MJR and Padilla, CD and Ongchangco, JCE and Laurino, MY and Lagarde, JBB and Regalado, ES and Legaspi, AV and Ventura, ER}, title = {Living with a child with MSUD: Psychosocial issues of Filipino parents with a child with maple syrup urine disease.}, journal = {Genetics in medicine open}, volume = {2}, number = {}, pages = {101847}, pmid = {39669607}, issn = {2949-7744}, abstract = {PURPOSE: Maple syrup urine disease (MSUD) is a common inborn error of metabolism diagnosed in the Philippines. A family may experience stress, anxiety, sorrow, or feelings of helplessness when a child is diagnosed to have a genetic disorder, which can lead to chronic care and disability. This study aims to explore the psychosocial issues experienced by Filipino parents with children having MSUD.<br><br>METHODS: This is a descriptive and qualitative study. One-to-one interviews using a semi-structured set of questions were done between the months of November 2015 to March 2016. A total of 12 parents were interviewed. Thematic analysis was used.<br><br>RESULTS: The diagnosis of MSUD in a child is, indeed, a stressful event for the family. Parents experienced fear, confusion, and hurt, among other emotions. Having a child with MSUD had a negative impact on their families, especially in terms of financial burden, dietary restriction, and marital conflicts leading to separation. However, some parents reported positive effects, such as increased confidence in one's abilities to care for the affected child and closer relationships among family members.<br><br>CONCLUSION: A diagnosis of MSUD on the child places considerable caregiver burden on the parents. Findings have important implications for genetic counselors.}, }
@article {pmid39669077, year = {2024}, author = {Schnuck, JO and Chauhan, SSB and Sham, JG}, title = {Surrogate endpoints in clinical trials: when is good...good enough?.}, journal = {Hepatobiliary surgery and nutrition}, volume = {13}, number = {6}, pages = {1062-1064}, pmid = {39669077}, issn = {2304-3881}, }
@article {pmid39668236, year = {2024}, author = {Orvain, C and Milano, F and Rodríguez-Arbolí, E and Othus, M and Petersdorf, EW and Sandmaier, BM and Appelbaum, FR and Walter, RB}, title = {Relationship between donor source, pre-transplant measurable residual disease, and outcome after allografting for adults with acute myeloid leukemia.}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, pmid = {39668236}, issn = {1476-5551}, abstract = {Lack of HLA-matched related/unrelated donor remains a barrier to allogeneic hematopoietic cell transplantation (HCT) for adult acute myeloid leukemia (AML), with ongoing uncertainty about optimal donor type if more than one alternative donor is available. To assess the relationship between donor type, pre-HCT measurable residual disease (MRD), and post-HCT outcomes, we retrospectively analyzed 1265 myelodysplastic neoplasm (MDS)/AML and AML patients allografted in first or second remission with an HLA-matched sibling (MSD) or unrelated donor (MUD), HLA-mismatched unrelated donor (MMD), an HLA-haploidentical donor, or umbilical cord blood (UCB) at a single institution. Relapse risk was non-significantly higher after HLA-haploidentical and lower after UCB HCT. Non-relapse mortality (NRM) was significantly higher in patients undergoing MMD HCT, HLA-haploidentical HCT, and UCB, translating into significantly lower relapse-free survival (RFS) and overall survival for MMD and HLA-haploidentical HCT. There was a significant interaction between conditioning intensity and post-HCT outcomes for UCB HCT with better RFS for UCB HCT after MAC but higher NRM after non-MAC. In patients with pre-HCT MRD receiving MAC, relapse risk was significantly lower and RFS higher in those who underwent UCB HCT in comparison to MSD/MUD. Together, UCB HCT is a valuable alternative for MAC HCT, particularly in patients with pre-HCT MRD.}, }
@article {pmid39668099, year = {2024}, author = {Robichaux, K and Billings, T and Termini, CM}, title = {Inventories invite independence.}, journal = {Trends in biochemical sciences}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.tibs.2024.11.003}, pmid = {39668099}, issn = {0968-0004}, abstract = {In this piece, we use an antibody inventory system to exemplify the potential benefits of laboratory organization in research environments. We highlight how inventories can support resource accessibility and strengthen a sense of independence for scientists, especially those new to research environments.}, }
@article {pmid39667756, year = {2024}, author = {Biernacki, MA and Bleakley, M}, title = {Clinical trials, challenges, and changes in tcr-based therapeutics for hematologic malignancies.}, journal = {Expert review of hematology}, volume = {}, number = {}, pages = {}, doi = {10.1080/17474086.2024.2441962}, pmid = {39667756}, issn = {1747-4094}, abstract = {INTRODUCTION: T cells engineered to express antigen-specific T cell receptors (TCR; TCR-T) are a promising class of immunotherapeutic for patients with hematologic malignancies. Like chimeric antigen receptor-engineered T cells (CAR-T), TCR-T are cell products with defined specificity and composition. Unlike CAR-T, TCR-T can recognize targets arising both from intracellular and cell surface proteins and leverage the sensitivity of natural TCR signaling machinery. A growing number of TCR-T targeting various antigens in different hematologic malignancies are in early-phase clinical trials, and more are in preclinical development.<br><br>AREAS COVERED: This review covers results from early-phase TCR-T clinical trials for hematologic malignancies. Challenges in the field are reviewed, including identifying optimal targets, engaging CD4[+] help for CD8[+] T cells, and overcoming tumor-induced suppression; recent innovations to overcome these challenges are also highlighted.<br><br>EXPERT OPINION: In the future, TCR-T's promise for hematologic malignancies will be borne out in later-phase clinical trials and approvals for clinical use. Improved antigen discovery methods will help build the toolbox of targets needed for broadly applicable TCR-T. Rationally designed TCR-T modifications including incorporation of accessory receptors and gene editing will enhance TCR-T function. New hybrid receptors combining features of TCR and CAR will enter the clinic.}, }
@article {pmid39667379, year = {2024}, author = {Edupuganti, S and Hurt, CB and Stephenson, KE and Huang, Y and Paez, CA and Yu, C and Yen, C and Hanscom, B and He, Z and Miner, MD and Gamble, T and Heptinstall, J and Seaton, KE and Domin, E and Lin, BC and McKee, K and Doria-Rose, N and Regenold, S and Spiegel, H and Anderson, M and McClosky, N and Zhang, L and Piwowar-Manning, E and Ackerman, ME and Pensiero, M and Dye, BJ and Landovitz, RJ and Mayer, K and Siegel, M and Sobieszczyk, M and Walsh, SR and Gama, L and Barouch, DH and Montefiori, DC and Tomaras, GD and , }, title = {Safety, tolerability, pharmacokinetics, and neutralisation activities of the anti-HIV-1 monoclonal antibody PGT121.414.LS administered alone and in combination with VRC07-523LS in adults without HIV in the USA (HVTN 136/HPTN 092): a first-in-human, open-label, randomised controlled phase 1 trial.}, journal = {The lancet. HIV}, volume = {}, number = {}, pages = {}, doi = {10.1016/S2352-3018(24)00247-9}, pmid = {39667379}, issn = {2352-3018}, abstract = {BACKGROUND: Multiple broadly neutralising monoclonal antibodies (mAbs) are in development for HIV-1 prevention. The aim of this trial was to test the PGT121.414.LS and VRC07-523LS mAbs for safety and pharmacokinetics in adults.<br><br>METHODS: In this first-in-human phase 1 trial (HVTN 136/HPTN 092), adults without HIV were enrolled at six university-affiliated clinical research sites in the USA. Part A evaluated escalating single intravenous doses or subcutaneous infusion of PGT121.414.LS, in four groups: 3 mg/kg intravenous (treatment group 1; n=3), 10 mg/kg intravenous (treatment group 2; n=4), 30 mg/kg intravenous (treatment group 3; n=3), and 5 mg/kg subcutaneous (treatment group 4; n=3). Part B evaluated repeated sequential intravenous administrations of 20 mg/kg PGT121.414.LS plus 20 mg/kg VRC07-523LS (treatment group 5; n=10) and sequential subcutaneous administrations of 5 mg/kg PGT121.414.LS plus 5 mg/kg VRC07-523LS (treatment group 6; n=10) on days 0, 112, and 224. Participants in treatment groups 1 and 2 were enrolled sequentially, with participants enrolled and randomly assigned to treatment groups 3 and 4 after a review of safety data. Participants in treatment groups 5 and 6 were randomly assigned in blocks after a review of safety data from treatment groups 1-4. The primary endpoints were safety and tolerability of mAbs, serum concentrations and pharmacokinetics of mAbs, and serum neutralising activity, assessed in participants who received all scheduled product administrations. Serum concentrations of each mAb were measured via a multiplex assay, and neutralisation activity against multiple HIV viruses was measured via the TZM-bl assay. Serum concentrations were estimated via an open, two-compartment model with first-order elimination from the central compartment. This study was registered with ClinicalTrials.gov (NCT04212091) and has been completed.<br><br>FINDINGS: Between Nov 10, 2020, and Oct 5, 2021, we enrolled 33 participants without HIV: median age was 31 years (range 22-48); 19 were assigned female sex at birth and 11 were assigned male sex at birth. Three participants and four participants were sequentially assigned to treatment groups 1 and 2, respectively, and, after safety review, six participants were randomly assigned to treatment groups 3 (n=3) and 4 (n=3); after safety review, 20 participants were randomly assigned to treatment groups 5 (n=10) and 6 (n=10). Intravenous and subcutaneous infusions were safe and well tolerated, without serious adverse events or dose-limiting toxicities. Dose escalation of PGT121.414.LS from 3 mg/kg to 30 mg/kg (intravenous) resulted in a dose-proportional increase in serum concentration of PGT121.414.LS, whether administered alone or in combination with VRC07-523LS. The estimated elimination half-life of PGT121.414.LS was 71 days (95% CI 66-75), three times that of its parental form, PGT121. The estimated subcutaneous (vs intravenous) bioavailability of PGT121.414.LS was 86&#xb7;1% (95% CI 64&#xb7;0-95&#xb7;5). Neutralisation activities were greater in the higher-dose and dual combination intravenous groups than in the subcutaneous administration groups.<br><br>INTERPRETATION: These findings support further evaluation of PGT121.414.LS in combination with other mAbs for HIV-1 prevention.<br><br>FUNDING: US National Institute of Allergy and Infectious Diseases and US National Institutes of Health.}, }
@article {pmid39666929, year = {2024}, author = {Gien, LT and Song, Z and Poklepovic, A and Collisson, EA and Zwiebel, JA and Gray, RJ and Wang, V and McShane, LM and Rubinstein, LV and Patton, DR and Williams, PM and Hamilton, SR and Tricoli, JV and Conley, BA and Arteaga, CL and Harris, LN and O'Dwyer, PJ and Chen, AP and Flaherty, KT}, title = {Phase II Study of Sunitinib in Tumors With c-KIT Mutations: Results From the NCI MATCH ECOG-ACRIN Trial (EAY131) Subprotocol V.}, journal = {JCO precision oncology}, volume = {8}, number = {}, pages = {e2400514}, doi = {10.1200/PO-24-00514}, pmid = {39666929}, issn = {2473-4284}, mesh = {Humans ; *Sunitinib/therapeutic use ; Middle Aged ; *Proto-Oncogene Proteins c-kit/genetics ; Male ; Female ; Adult ; Aged ; *Mutation ; *Antineoplastic Agents/therapeutic use/adverse effects ; Neoplasms/drug therapy/genetics ; }, abstract = {PURPOSE: The NCI-MATCH study is a tumor-agnostic platform trial enrolling patients to targeted therapies on the basis of genomic alterations. Subprotocol V investigated sunitinib in patients with tumors harboring c-KIT mutations.<br><br>METHODS: EAY131-V, is an open-label, single-arm, phase II study. Eligible patients had malignancies containing somatic c-KIT mutation on exons 9, 11, 13, or 14. Exclusions were mutations on exons 17 and 18, gastrointestinal stromal tumors, renal cell carcinoma, and pancreatic neuroendocrine tumors. Patients received sunitinib 50 mg orally once daily for 4 weeks with 2-week rest per cycle, until disease progression or unacceptable toxicity. Primary end point was objective response rate (ORR); secondary end points were progression-free survival (PFS) at 6 months, PFS, overall survival, and toxicities.<br><br>RESULTS: Between November 1, 2016, and May 21, 2020, 10 patients were enrolled and nine were eligible and started treatment. The median age was 62 years (range, 30-76), 77.8% received two previous lines of systemic therapy, and 22.2% received >3 lines. The most common histology was melanoma (44%) and then squamous cell carcinoma of the lung or thymus (33%). There were two partial responses with an ORR of 22.2% (90% CI, 4.1 to 55) and stable disease in 44%. All patients demonstrated tumor shrinkage of target lesions. The estimated 6-month PFS was 33.3% (90% CI, 15.4 to 72.4). Grade 3-4 toxicities occurred in five patients (55.6%). This arm was closed in 2022 on the basis of low accrual. Prevalence of eligible c-KIT mutations after screening 5,540 patients was 0.45%.<br><br>CONCLUSION: Sunitinib for c-KIT mutations did not meet the primary end point, but in this small sample size, a potential signal cannot be ruled out. Rate of eligible c-KIT mutations was low, affecting accrual to this arm.}, }
@article {pmid39666464, year = {2024}, author = {Landy, R and Katki, HA and Huang, WY and Wang, D and Thomas, M and Qu, F and Freedman, ND and Loftfield, E and Shi, J and Peters, U and Hsu, L and Schoen, RE and Berndt, SI}, title = {Evaluating the Use of Environmental and Polygenic Risk Scores to Inform Colorectal Cancer Risk-Based Surveillance Intervals.}, journal = {Clinical and translational gastroenterology}, volume = {}, number = {}, pages = {}, doi = {10.14309/ctg.0000000000000782}, pmid = {39666464}, issn = {2155-384X}, support = {//Division of Cancer Epidemiology and Genetics, National Cancer Institute/ ; }, abstract = {INTRODUCTION: United States Multi-Society Task Force colonoscopy surveillance intervals are based solely on adenoma characteristics, without accounting for other risk factors. We investigated whether a risk model including demographic, environmental, and genetic risk factors could individualize surveillance intervals under an "equal management of equal risks" framework.<br><br>METHODS: Using 14,069 individuals from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial who had a diagnostic colonoscopy following an abnormal flexible sigmoidoscopy, we modeled the risk of colorectal cancer, considering the diagnostic colonoscopy finding, baseline risk factors (e.g., age and sex), 19 lifestyle and environmental risk factors, and a polygenic risk score for colorectal cancer. Ten-year absolute cancer risks for each diagnostic colonoscopy finding (advanced adenomas [N = 2,446], &#x2265;3 non-advanced adenomas [N = 483], 1-2 non-advanced adenomas [N = 4,400], and no adenoma [N = 7,183]) were used as implicit risk thresholds for recommended surveillance intervals.<br><br>RESULTS: The area under the curve for the model including colonoscopy findings, baseline characteristics, and polygenic risk score was 0.658. Applying the equal management of equal risks framework, 28.2% of individuals with no adenoma and 42.7% of those with 1-2 non-advanced adenomas would be considered high risk and assigned a significantly shorter surveillance interval than currently recommended. Among individuals who developed cancer within 10 years, 52.4% with no adenoma and 48.3% with 1-2 non-advanced adenomas would have been considered high risk and assigned a shorter surveillance interval.<br><br>DISCUSSION: Using a personalized risk-based model has the potential to identify individuals with no adenoma or 1-2 non-advanced adenomas, who are higher risk and may benefit from shorter surveillance intervals.}, }
@article {pmid39666350, year = {2024}, author = {Goss, LB and Liu, M and Zheng, Y and Guo, B and Conti, DV and Haiman, CA and Kachuri, L and Catalona, WJ and Witte, JS and Lin, DW and Newcomb, LF and Darst, BF}, title = {Polygenic Risk Score and Upgrading in Patients With Prostate Cancer Receiving Active Surveillance.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaoncol.2024.5398}, pmid = {39666350}, issn = {2374-2445}, abstract = {IMPORTANCE: Active surveillance is the preferred management strategy for patients with low- or favorable intermediate-risk prostate cancer (PCa); however, frequent health care visits can be costly and burdensome to patients. Identifying patients who may benefit from intensive vs passive surveillance could reduce these burdens.<br><br>OBJECTIVE: To investigate associations between a polygenic risk score (PRS) and risk of upgrading and other prostate tumor features in patients receiving active surveillance.<br><br>This prospective multicenter cohort study across 10 US sites included 1220 patients from the Canary Prostate Active Surveillance Study (PASS) enrolled from July 2008 to November 2017, with follow-up (median, 5.3 years) through August 2022. Participants were those with clinically localized PCa (cT1-T2) receiving active surveillance. Analyses took place from January 2023 to April 2024.<br><br>EXPOSURE: Multi-ancestry PRS of 451 PCa risk variants (PRS-451) and 400 PCa risk variants (PRS-400) after excluding prostate-specific antigen (PSA)-associated variants.<br><br>MAIN OUTCOMES AND MEASURES: The primary outcome was PCa upgrading (any Gleason grade increase) vs no upgrading. Secondary outcomes included prostate volume, PSA, PSA density, percentage of biopsy cores with cancer, and Gleason grade group at diagnosis.<br><br>RESULTS: The median (IQR) age at diagnosis of the 1220 patients receiving active surveillance was 63 (58-67) years. During follow-up, 470 patients upgraded; the 2- and 5-year risks of upgrading were 17.7% (95% CI, 15.5%-19.9%) and 33.3% (95% CI, 30.5%-36.3%), respectively. Each 1-SD unit increase in PRS-451 was associated with 23% increased hazard of upgrading (95% CI, 1.11-1.35; P&#x2009;<&#x2009;.001), whereas PRS-400 was associated with 27% increased hazard (95% CI, 1.15-1.39; P&#x2009;<&#x2009;.001) at any point in time during follow-up. Except for PSA, associations with remaining outcomes were similar or stronger using PRS-400. Higher PRS-400 was associated with smaller prostate volume, a higher percentage of biopsy cores with cancer, and higher PSA density. A model with clinical risk factors had a C-index of 0.64 (95% CI, 0.62-0.67); adding PRS-400 led to a C-index of 0.65 (95% CI, 0.63-0.68).<br><br>CONCLUSIONS AND RELEVANCE: In this cohort study, among patients receiving active surveillance, high PRS was associated with risk of upgrading and possibly tumor multifocality. Excluding PSA variants from the PRS revealed an association with smaller prostate size, which has been previously associated with more aggressive tumors. Although PRS may inform active surveillance, it is yet to be seen whether they improve clinical decisions.}, }
@article {pmid39660025, year = {2024}, author = {Lubwama, M and Holte, SE and Zhang, Y and Mubiru, KR and Katende, G and Orem, J and Kateete, DP and Bwanga, F and Phipps, W}, title = {Etiology, Risk Factors, and Outcomes of Bacteremia in Patients With Hematologic Malignancies and Febrile Neutropenia in Uganda.}, journal = {Open forum infectious diseases}, volume = {11}, number = {12}, pages = {ofae682}, doi = {10.1093/ofid/ofae682}, pmid = {39660025}, issn = {2328-8957}, abstract = {BACKGROUND: We determined the etiology, risk factors, and outcomes associated with bacteremia in patients with hematologic malignancies and febrile neutropenia (FN) at the Uganda Cancer Institute (UCI).<br><br>METHODS: UCI adult and pediatric inpatients with hematologic malignancies and FN were prospectively enrolled and followed up to determine 30-day mortality. Blood drawn from participants with FN was cultured in the BACTEC 9120 blood culture system. Antimicrobial susceptibility testing was performed with the disk diffusion method on identified bacteria. Logistic regression and Cox proportional hazards regression were applied to estimate associations between participant characteristics and FN, bacteremia, and mortality.<br><br>RESULTS: Of 495 participants, the majority (n = 306 [62%]) were male. Median age was 23 years (interquartile range, 11-42 years). Of the 132 participants who experienced FN, 43 (33%) had bacteremia. Participants with younger age (odds ratio [OR], 0.98; P = .05), severe neutropenia (OR, 2.9; P = .01), hypotension (OR, 2.46; P = .04), mucositis (OR, 2.77; P = .01), and receipt of chemotherapy (OR, 2.25; P = .03) were more likely to have bacteremia. Fifty (78%) bacteria isolated were gram negative. Escherichia coli (n = 25 [50%]) was predominant. Thirty-seven of 43 (86%) episodes were caused by multidrug-resistant (MDR) bacteria. Thirty-day overall survival for participants with bacteremia was significantly lower than that for participants with no bacteremia (P = .05). MDR bacteremia (hazard ratio, 1.84; P = .05) was associated with increased risk of death.<br><br>CONCLUSIONS: Bacteremia was frequent in patients with hematologic cancer and FN and was associated with poor survival. MDR bacteria were the main cause of bacteremia and mortality. There is a need for robust infection control and antimicrobial stewardship programs in cancer centers in sub-Saharan Africa.}, }
@article {pmid39653676, year = {2024}, author = {Gati Mirembe, B and Donnell, D and Krows, M and Zwane, Z and Bukusi, E and Panchia, R and Louw, C and Mwelase, N and Selepe, P and Senne, M and Naidoo, L and Chihana, R and Kasaro, M and Nuwagaba-Biribonwoha, H and Kotze, P and Gill, K and MacDonald, P and vanHeerden, A and Bosman, S and Jaggernath, M and du Preez, P and Ward, A and Peters, RPH and Delany-Moretlwe, S and Peacock, S and Johnson, R and Caucutt, J and Morrison, S and Wang, G and Gandhi, M and Velloza, J and Heffron, R and Celum, C and , }, title = {High recent PrEP adherence with point-of-care urine tenofovir testing and adherence counselling among young African women: results from the INSIGHT cohort.}, journal = {Journal of the International AIDS Society}, volume = {27}, number = {12}, pages = {e26389}, doi = {10.1002/jia2.26389}, pmid = {39653676}, issn = {1758-2652}, support = {INV-004743/GATES/Bill &amp; Melinda Gates Foundation/United States ; }, mesh = {Humans ; Female ; *HIV Infections/prevention &amp; control/drug therapy ; *Pre-Exposure Prophylaxis/methods/statistics &amp; numerical data ; *Tenofovir/therapeutic use/urine ; Adolescent ; Young Adult ; *Medication Adherence/statistics &amp; numerical data ; Adult ; *Anti-HIV Agents/therapeutic use ; *Counseling ; Point-of-Care Testing ; Point-of-Care Systems ; Cohort Studies ; }, abstract = {INTRODUCTION: Adolescent girls and young women (AGYW) account for two-thirds of new HIV infections in Africa. African AGYW have had high uptake of oral HIV pre-exposure prophylaxis (PrEP) but low adherence, which might be improved by point-of-care adherence monitoring with tailored counselling.<br><br>METHODS: From August 2022 to July 2023, we conducted a PrEP demonstration project with sexually active AGYW ages 16-30 years from 20 sites in South Africa, Eswatini, Kenya, Malawi, Uganda and Zambia. Participants were offered oral tenofovir-based PrEP at enrolment and followed up at 1, 3 and 6 months. PrEP adherence was assessed by a point-of-care qualitative lateral flow urine tenofovir (TFV) assay indicating PrEP use in the prior 4 days, which accompanied real-time adherence counselling that incorporated urine TFV results when testing was available (70.8% of month 1, 35.3% of month 3 and 83.9% of month 6 visits). We estimated overall adherence, correcting for missing test results, and analysed the association of having received urine TFV results at month 1 or 3 with subsequent urine TFV test positivity, using modified Poisson regression.<br><br>RESULTS: Of the 3087 AGYW enrolled, the median age was 24 years (interquartile range 21-27), 75.7% were from South Africa, 2878 (93.2%) initiated PrEP at enrolment and 107 (3.5%) after enrolment. Visit retention was 92.0-96.2% for months 1, 3 and 6, and 2518 (90.1%) exited the study with a PrEP refill. Adherence, based on the point-of-care urine tenofovir test positivity rate, was estimated as 72%, 71% and 65% at months 1, 3 and 6, respectively. Women who received one prior urine TFV test had a 42% higher likelihood of a subsequent positive urine TFV test (adjusted odds ratio, OR = 1.42, 95% confidence interval, CI 1.27-1.60), and those having received two prior tests had a 67% higher likelihood (adjusted OR = 1.67; 95% CI 1.41-1.98). Observed HIV incidence was 1.38/100 person-years (95% CI 0.97-2.08).<br><br>CONCLUSIONS: Oral PrEP uptake, recent adherence and persistence were high in a multisite cohort of young African women over 6 months of follow-up. The use of a novel point-of-care tenofovir assay with tailored real-time adherence counselling was associated with increased adherence to PrEP at subsequent visits, warranting further study.<br><br>CLINICAL TRIALS REGISTRATION: clinicaltrials.gov NCT05746065.}, }
@article {pmid39653279, year = {2024}, author = {Santos, PMG and Silverwood, S and Suneja, G and Ford, E and Thaker, NG and Ostroff, JS and Weiner, BJ and Gillespie, EF}, title = {Dissemination and Implementation - A Primer for Accelerating "Time to Translation" in Radiation Oncology.}, journal = {International journal of radiation oncology, biology, physics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ijrobp.2024.11.101}, pmid = {39653279}, issn = {1879-355X}, abstract = {The field of radiation oncology has achieved significant technological and scientific advancements in the 21[st] century. Yet uptake of new evidence-based practices has been heterogeneous, even in the presence of national and international guidelines. Addressing barriers to practice change requires a deliberate focus on developing and testing strategies tailored to improving care delivery and quality, especially for vulnerable patient populations. Implementation science provides a systematic approach to developing and testing strategies, though applications in radiation oncology remain limited. In this critical review, we aim to 1) assess the time from first evidence to widespread adoption, or "time to translation," across multiple evidence-based practices involving radiation therapy, and 2) provide a primer on the application of implementation science to radiation oncology. Specifically, we discuss potential targets for implementation research in radiation oncology, including both evidence-based practices and quality metrics, and highlight examples of studies evaluating implementation strategies. We also define key concepts and frameworks in the field of implementation science, review common study designs including hybrid trials and cluster randomization, and discuss the interaction with related disciplines such as quality improvement and behavioral economics. Ultimately, this review aims to illustrate how a comprehensive understanding of implementation science could be used to promote equity and quality in cancer care through the development of effective, scalable, and sustainable care delivery solutions.}, }
@article {pmid39652675, year = {2024}, author = {Dimopoulos, MA and Voorhees, PM and Schjesvold, F and Cohen, YC and Hungria, V and Sandhu, I and Lindsay, J and Baker, RI and Suzuki, K and Kosugi, H and Levin, MD and Beksac, M and Stockerl-Goldstein, K and Oriol, A and Mikala, G and Garate, G and Theunissen, K and Spicka, I and Mylin, AK and Bringhen, S and Uttervall, K and Pula, B and Medvedova, E and Cowan, AJ and Moreau, P and Mateos, MV and Goldschmidt, H and Ahmadi, T and Sha, L and Cortoos, A and Katz, EG and Rousseau, E and Li, L and Dennis, RM and Carson, R and Rajkumar, SV and , }, title = {Daratumumab or Active Monitoring for High-Risk Smoldering Multiple Myeloma.}, journal = {The New England journal of medicine}, volume = {}, number = {}, pages = {}, doi = {10.1056/NEJMoa2409029}, pmid = {39652675}, issn = {1533-4406}, abstract = {BACKGROUND: Daratumumab, an anti-CD38 monoclonal antibody, has been approved for the treatment of multiple myeloma. Data are needed regarding the use of daratumumab for high-risk smoldering multiple myeloma, a precursor disease of active multiple myeloma for which no treatments have been approved.<br><br>METHODS: In this phase 3 trial, we randomly assigned patients with high-risk smoldering multiple myeloma to receive either subcutaneous daratumumab monotherapy or active monitoring. Treatment was continued for 39 cycles, for 36 months, or until confirmation of disease progression, whichever occurred first. The primary end point was progression-free survival; progression to active multiple myeloma was assessed by an independent review committee in accordance with International Myeloma Working Group diagnostic criteria.<br><br>RESULTS: Among the 390 enrolled patients, 194 were assigned to the daratumumab group and 196 to the active-monitoring group. With a median follow-up of 65.2 months, the risk of disease progression or death was 51% lower with daratumumab than with active monitoring (hazard ratio, 0.49; 95% confidence interval [CI], 0.36 to 0.67; P<0.001). Progression-free survival at 5 years was 63.1% with daratumumab and 40.8% with active monitoring. A total of 15 patients (7.7%) in the daratumumab group and 26 patients (13.3%) in the active-monitoring group died (hazard ratio, 0.52; 95% CI, 0.27 to 0.98). Overall survival at 5 years was 93.0% with daratumumab and 86.9% with active monitoring. The most common grade 3 or 4 adverse event was hypertension, which occurred in 5.7% and 4.6% of the patients in the daratumumab group and the active-monitoring group, respectively. Adverse events led to treatment discontinuation in 5.7% of the patients in the daratumumab group, and no new safety concerns were identified.<br><br>CONCLUSIONS: Among patients with high-risk smoldering multiple myeloma, subcutaneous daratumumab monotherapy was associated with a significantly lower risk of progression to active multiple myeloma or death and with higher overall survival than active monitoring. No unexpected safety concerns were identified. (Funded by Janssen Research and Development; AQUILA ClinicalTrials.gov number, NCT03301220.).}, }
@article {pmid39652470, year = {2024}, author = {Chesner, LN and Polesso, F and Graff, JN and Hawley, JE and Smith, AK and Lundberg, A and Das, R and Shenoy, T and Sjöström, M and Zhao, F and Hu, YM and Linder, S and Chen, WS and Hawkins, RM and Shrestha, R and Zhu, X and Foye, A and Li, H and Kim, LM and Bhalla, M and O'loughlin, T and Kuzuoglu-Ozturk, D and Hua, JT and Badura, ML and Wilkinson, S and Trostel, SY and Bergman, AM and Ruggero, D and Drake, CG and Sowalsky, AG and Fong, L and Cooperberg, MR and Zwart, W and Guan, X and Ashworth, A and Xia, Z and Quigley, DA and Gilbert, LA and Feng, FY and Moran, AE}, title = {Androgen receptor inhibition increases MHC Class I expression and improves immune response in prostate cancer.}, journal = {Cancer discovery}, volume = {}, number = {}, pages = {}, doi = {10.1158/2159-8290.CD-24-0559}, pmid = {39652470}, issn = {2159-8290}, abstract = {Tumors escape immune detection and elimination through a variety of mechanisms. Here, we used prostate cancer as a model to examine how androgen-dependent tumors undergo immune evasion through downregulation of the major histocompatibility complex class I (MHCI). We report that response to immunotherapy in late-stage prostate cancer is associated with elevated MHC expression. To uncover the mechanism, we performed a whole genome CRISPRi screen and identified AR as a repressor of the MHCI pathway. Syngeneic mouse models of aggressive prostate cancer deficient in AR also demonstrated increased tumor immunogenicity and promoted T cell mediated tumor-control. Notably, the increase in MHCI expression upon androgen receptor blockade is transient and correlates with resistance to AR inhibition. Mechanistic studies identified androgen response elements upstream of MHCI transcription start sites which increased MHCI expression when deleted. Together, this body of work highlights another mechanism by which hormones can promote immune escape.}, }
@article {pmid39652116, year = {2024}, author = {Azhideh, A and Pouramini, A and Haseli, S and Abbaspour, E and Karande, G and Kafi, F and Chalian, M}, title = {Radiological assessment of extremity bone involvement in Erdheim-Chester disease: a systematic review of case reports.}, journal = {Skeletal radiology}, volume = {}, number = {}, pages = {}, pmid = {39652116}, issn = {1432-2161}, abstract = {OBJECTIVE: To describe the clinical presentations and radiological manifestations of Erdheim-Chester disease (ECD) in the extremities, with particular emphasis on radiologic findings, as radiographs are typically the initial imaging modality used in clinical practice.<br><br>METHODS: Following the PRISMA guidelines, a comprehensive systematic search was performed across Scopus, PubMed, Web of Science, and Embase databases, covering case reports from inception until August 1, 2024. Included were studies with pathologically confirmed ECD (CD68 positive and CD1a negative) that were evaluated with at least one imaging modality and provided detailed descriptions of radiological findings.<br><br>RESULTS: Out of 401 identified articles, 20 articles comprising 20 histologically confirmed cases of ECD met the inclusion criteria following screening and full-text review. Pathological reports were assessed for the presence of lipid-laden cells and Touton giant cells, which were identified in 84.2% and 75% of cases, respectively. Upper extremities were affected in 65% of cases and lower extremities in all cases. Symmetric involvement was observed in 84.6% of upper extremity cases and 84.2% of lower extremity cases. Radiological findings were categorized as pure sclerosis (53.3%) and cortical thickening (42.8%) identified as the most common findings. Clinical manifestations were assessed, with pain and swelling in the extremities being the most common symptoms, occurring in 70% of cases.<br><br>CONCLUSION: The hallmark of ECD is bilateral, symmetric diaphyseal and/or metaphyseal osteosclerosis in the long tubular bones of the lower extremities. Epiphyseal sparing is observed in more than half of the patients.}, }
@article {pmid39651955, year = {2024}, author = {von Itzstein, MS and Burns, TF and Dowell, JE and Horn, L and Camidge, DR and York, SJ and Eaton, KD and Kyle, K and Fattah, FJ and Liu, J and Mu-Mosley, H and Gupta, A and Nadeem, U and Gao, A and Zhang, S and Gerber, DE}, title = {Phase 1/2 trial of XPO1 inhibitor selinexor plus docetaxel in previously treated, advanced KRAS mutant non-small cell lung cancer.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-24-1722}, pmid = {39651955}, issn = {1557-3265}, abstract = {PURPOSE: Patients with KRAS mutant non-small cell lung cancer (NSCLC) have limited therapeutic options. Based on activity of nuclear export inhibition in preclinical models, we evaluated this strategy in previously treated advanced KRAS mutant NSCLC.<br><br>PATIENTS AND METHODS: The primary outcome of this multi-center phase 1/2 dose escalation trial of selinexor plus docetaxel was safety and tolerability. Selinexor was started one week before docetaxel to permit monotherapy pharmacodynamic assessment.<br><br>RESULTS: Among 40 enrolled patients, median age was 66 years, 55% were female, and 85% were white. Maximum tolerated dose was selinexor 60 mg orally weekly plus docetaxel 75 mg/m2 every three weeks. The most common adverse events were nausea (73%, 8% Gr &#x2265;3), fatigue (70%, 5% Gr &#x2265;3), neutropenia (65%, 60% Gr &#x2265;3), and diarrhea (58%, 10% Gr &#x2265;3). Of 32 efficacy evaluable patients, 7 (22%) had partial responses and 18 (56%) had stable disease. Outcomes were not associated with KRAS mutation type but were significantly better in cases with wild type TP53 (42%), including disease control and response rates (27% and 80%, vs. 9% and 27%, respectively; P=0.03) and progression-free survival (median 7.4 vs. 1.8 months; HR, 0.2; 95% CI, 0.07-0.67; P=0.003). Post-selinexor / pre-docetaxel, serum LDH levels increased an average 51 U/L in TP53 altered and decreased an average 48 U/L in TP53 wild type cases (P=0.06).<br><br>CONCLUSIONS: Selinexor plus docetaxel was relatively well tolerated in patients with advanced KRAS mutant NSCLC. The regimen has promising efficacy in TP53 wild type cases, where selinexor monotherapy may also have activity.}, }
@article {pmid39651886, year = {2024}, author = {Painter, H and Larsen, SE and Williams, BD and Abdelaal, HFM and Baldwin, SL and Fletcher, HA and Fiore-Gartland, A and Coler, RN}, title = {Backtranslation of human RNA biosignatures of tuberculosis disease risk into the preclinical pipeline is condition dependent.}, journal = {mSphere}, volume = {}, number = {}, pages = {e0086424}, doi = {10.1128/msphere.00864-24}, pmid = {39651886}, issn = {2379-5042}, abstract = {UNLABELLED: It is unclear whether human progression to active tuberculosis disease (TB) risk signatures are viable endpoint criteria for evaluations of treatments in development. TB is the deadliest infectious disease globally and more efficacious vaccines are needed to reduce this mortality. However, the immune correlates of protection for either preventing infection with Mycobacterium tuberculosis or preventing TB disease have yet to be completely defined, making the advancement of candidate vaccines through the pipeline slow, costly, and fraught with risk. Human-derived correlate of risk (COR) gene signatures, which identify an individual's risk of progressing to active TB disease, provide an opportunity for evaluating new therapies for TB with clear and defined endpoints. Though prospective clinical trials with longitudinal sampling are prohibitively expensive, the characterization of COR gene signatures is practical with preclinical models. Using a 3Rs (replacement, reduction, and refinement) approach we reanalyzed heterogeneous publicly available transcriptional data sets to determine whether a specific set of COR signatures are viable endpoints in the preclinical pipeline. We selected RISK6, Sweeney3, and BATF2 human-derived blood-based RNA biosignatures because they require relatively few genes and have been carefully evaluated across several clinical cohorts. These data suggest that in certain experimental designs and in several tissue types, human COR signatures correlate with disease progression as measured by the bacterial burden in the preclinical TB model pipeline. We observed the best performance when the model most closely reflected human infection or disease conditions. Human-derived COR signatures offer an opportunity for high-throughput preclinical endpoint criteria of vaccine and drug therapy evaluations.<br><br>IMPORTANCE: Understanding the strengths or limitations of back-translating human-derived correlate of risk (COR) RNA signatures into the preclinical pipeline may help streamline down-selection of therapeutic vaccine and drug candidates and better align preclinical models with proposed clinical trial efficacy endpoints.}, }
@article {pmid39651791, year = {2024}, author = {Gupta, S and Rau, RE and Kairalla, JA and Rabin, KR and Wang, C and Angiolillo, AL and Alexander, S and Carroll, AJ and Conway, S and Gore, L and Kirsch, I and Kubaney, HR and Li, AM and McNeer, JL and Militano, O and Miller, TP and Moyer, Y and O'Brien, MM and Okada, M and Reshmi, SC and Shago, M and Wagner, E and Winick, N and Wood, BL and Haworth-Wright, T and Zaman, F and Zugmaier, G and Zupanec, S and Devidas, M and Hunger, SP and Teachey, DT and Raetz, EA and Loh, ML}, title = {Blinatumomab in Standard-Risk B-Cell Acute Lymphoblastic Leukemia in Children.}, journal = {The New England journal of medicine}, volume = {}, number = {}, pages = {}, doi = {10.1056/NEJMoa2411680}, pmid = {39651791}, issn = {1533-4406}, support = {U10CA180899/CA/NCI NIH HHS/United States ; U20CA180886/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: B-cell acute lymphoblastic leukemia (B-cell ALL) is the most common childhood cancer. Despite a high overall cure rate, relapsed B-cell ALL remains a leading cause of cancer-related death among children. The addition of the bispecific T-cell engager molecule blinatumomab (an anti-CD19 and anti-CD3 single-chain molecule) to therapy for newly diagnosed standard-risk (as defined by the National Cancer Institute) B-cell ALL in children may improve outcomes.<br><br>METHODS: We conducted a phase 3 trial involving children with newly diagnosed standard-risk B-cell ALL who had an average or high risk of relapse. Patients were randomly assigned to receive chemotherapy alone or chemotherapy plus two nonsequential 28-day cycles of blinatumomab. The primary end point was disease-free survival.<br><br>RESULTS: The data and safety monitoring committee reviewed the results from the first interim efficacy analysis, which included 1440 patients who had undergone randomization (722 to chemotherapy alone and 718 to blinatumomab and chemotherapy) and recommended early termination of randomization. At a median follow-up of 2.5 years, the estimated 3-year disease-free survival (&#xb1;SE) was 96.0&#xb1;1.2% with blinatumomab and chemotherapy and 87.9&#xb1;2.1% with chemotherapy alone (difference in restricted mean survival time, 72 days; 95% confidence interval, 36 to 108; P<0.001 by stratified log-rank test). The estimated 3-year disease-free survival among patients with an average relapse risk was 97.5&#xb1;1.3% with blinatumomab and chemotherapy and 90.2&#xb1;2.3% with chemotherapy alone; among those with a high relapse risk, the corresponding values were 94.1&#xb1;2.5% and 84.8&#xb1;3.8%. Cytokine release syndrome, seizures, and sepsis of grade 3 or higher were rare during blinatumomab cycles, but the overall incidence of nonfatal sepsis and catheter-related infections was significantly higher among patients with an average relapse risk who had been assigned to receive blinatumomab and chemotherapy than among those assigned to receive chemotherapy alone.<br><br>CONCLUSIONS: Adding blinatumomab to combination chemotherapy in patients with newly diagnosed childhood standard-risk B-cell ALL of average or high risk of relapse significantly improved disease-free survival. (Funded by the National Institutes of Health and others; AALL1731 ClinicalTrials.gov number, NCT03914625.).}, }
@article {pmid39647999, year = {2024}, author = {Shadman, M and Munir, T and Robak, T and Brown, JR and Kahl, BS and Ghia, P and Giannopoulos, K and Šimkovič, M and Österborg, A and Laurenti, L and Walker, PA and Opat, SS and Ciepluch, H and Greil, R and Hanna, M and Tani, M and Trněný, M and Brander, D and Flinn, IW and Grosicki, S and Verner, E and Tedeschi, A and de Guibert, S and Tumyan, G and Laribi, K and García-Marco, JA and Li, JY and Tian, T and Liu, Y and Korolkiewicz, R and Szeto, A and Tam, CS and Jurczak, W}, title = {Zanubrutinib Versus Bendamustine and Rituximab in Patients With Treatment-Naïve Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Median 5-Year Follow-Up of SEQUOIA.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2402265}, doi = {10.1200/JCO-24-02265}, pmid = {39647999}, issn = {1527-7755}, abstract = {Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.SEQUOIA (ClinicalTrials.gov identifier: NCT03336333) is a phase III, randomized, open-label trial that compared the oral Bruton tyrosine kinase inhibitor zanubrutinib to bendamustine plus rituximab (BR) in treatment-naïve patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The initial prespecified analysis (median follow-up, 26.2 months) and subsequent analysis (43.7 months) found superior progression-free survival (PFS; the primary end point) in patients who received zanubrutinib compared with BR. At a median follow-up of 61.2 months, median PFS was not reached in zanubrutinib-treated patients; median PFS was 44.1 months in BR-treated patients (hazard ratio [HR], 0.29; one-sided P = .0001). Prolonged PFS was seen with zanubrutinib versus BR in patients with mutated immunoglobulin heavy-chain variable region (IGHV) genes (HR, 0.40; one-sided P = .0003) and unmutated IGHV genes (HR, 0.21 [95% CI, 0.14 to 0.33]; one-sided P < .0001). Median overall survival (OS) was not reached in either treatment arm; estimated 60-month OS rates were 85.8% and 85.0% in zanubrutinib- and BR-treated patients, respectively. No new safety signals were detected. Adverse events were as expected with zanubrutinib; rate of atrial fibrillation was 7.1%. At a median follow-up of 61.2 months, the results supported the initial SEQUOIA findings and suggested that zanubrutinib was a favorable treatment option for untreated patients with CLL/SLL.}, }
@article {pmid39645377, year = {2024}, author = {, }, title = {Burden of disease scenarios by state in the USA, 2022-50: a forecasting analysis for the Global Burden of Disease Study 2021.}, journal = {Lancet (London, England)}, volume = {404}, number = {10469}, pages = {2341-2370}, doi = {10.1016/S0140-6736(24)02246-3}, pmid = {39645377}, issn = {1474-547X}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Cause of Death/trends ; Disability-Adjusted Life Years/trends ; *Forecasting ; *Life Expectancy/trends ; Risk Factors ; United States/epidemiology ; *Cost of Illness ; *Population Health ; }, abstract = {BACKGROUND: The capacity to anticipate future health issues is important for both policy makers and practitioners in the USA, as such insights can facilitate effective planning, investment, and implementation strategies. Forecasting trends in disease and injury burden is not only crucial for policy makers but also garners substantial interest from the general populace and leads to a better-informed public. Through the integration of new data sources, the refinement of methodologies, and the inclusion of additional causes, we have improved our previous forecasting efforts within the scope of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) to produce forecasts at the state and national levels for the USA under various possible scenarios.<br><br>METHODS: We developed a comprehensive framework for forecasting life expectancy, healthy life expectancy (HALE), cause-specific mortality, and disability-adjusted life-years (DALYs) due to 359 causes of disease and injury burden from 2022 to 2050 for the USA and all 50 states and Washington, DC. Using the GBD 2021 Future Health Scenarios modelling framework, we forecasted drivers of disease, demographic drivers, risk factors, temperature and particulate matter, mortality and years of life lost (YLL), population, and non-fatal burden. In addition to a reference scenario (representing the most probable future trajectory), we explored various future scenarios and their potential impacts over the next several decades on human health. These alternative scenarios comprised four risk elimination scenarios (including safer environment, improved behavioural and metabolic risks, improved childhood nutrition and vaccination, and a combined scenario) and three USA-specific scenarios based on risk exposure or attributable burden in the best-performing US states (improved high adult BMI and high fasting plasma glucose [FPG], improved smoking, and improved drug use [encompassing opioids, cocaine, amphetamine, and others]).<br><br>FINDINGS: Life expectancy in the USA is projected to increase from 78&#xb7;3 years (95% uncertainty interval 78&#xb7;1-78&#xb7;5) in 2022 to 79&#xb7;9 years (79&#xb7;5-80&#xb7;2) in 2035, and to 80&#xb7;4 years (79&#xb7;8-81&#xb7;0) in 2050 for all sexes combined. This increase is forecasted to be modest compared with that in other countries around the world, resulting in the USA declining in global rank over the 2022-50 forecasted period among the 204 countries and territories in GBD, from 49th to 66th. There is projected to be a decline in female life expectancy in West Virginia between 1990 and 2050, and little change in Arkansas and Oklahoma. Additionally, after 2023, we projected almost no change in female life expectancy in many states, notably in Oklahoma, South Dakota, Utah, Iowa, Maine, and Wisconsin. Female HALE is projected to decline between 1990 and 2050 in 20 states and to remain unchanged in three others. Drug use disorders and low back pain are projected to be the leading Level 3 causes of age-standardised DALYs in 2050. The age-standardised DALY rate due to drug use disorders is projected to increase considerably between 2022 and 2050 (19&#xb7;5% [6&#xb7;9-34&#xb7;1]). Our combined risk elimination scenario shows that the USA could gain 3&#xb7;8 additional years (3&#xb7;6-4&#xb7;0) of life expectancy and 4&#xb7;1 additional years (3&#xb7;9-4&#xb7;3) of HALE in 2050 versus the reference scenario. Using our USA-specific scenarios, we forecasted that the USA could gain 0&#xb7;4 additional years (0&#xb7;3-0&#xb7;6) of life expectancy and 0&#xb7;6 additional years (0&#xb7;5-0&#xb7;8) of HALE in 2050 under the improved drug use scenario relative to the reference scenario. Life expectancy and HALE are likewise projected to be 0&#xb7;4-0&#xb7;5 years higher in 2050 under the improved adult BMI and FPG and improved smoking scenarios compared with the reference scenario. However, the increases in these scenarios would not substantially improve the USA's global ranking in 2050 (from 66th of 204 in life expectancy in the reference scenario to 63rd-64th in each of the three USA-specific scenarios), indicating that the USA's best-performing states are still lagging behind other countries in their rank throughout the forecasted period. Regardless, an estimated 12&#xb7;4 million (11&#xb7;3-13&#xb7;5) deaths could be averted between 2022 and 2050 if the USA were to follow the combined scenario trajectory rather than the reference scenario. There would also be 1&#xb7;4 million (0&#xb7;7-2&#xb7;2) fewer deaths over the 28-year forecasted period with improved adult BMI and FPG, 2&#xb7;1 million (1&#xb7;3-2&#xb7;9) fewer deaths with improved exposure to smoking, and 1&#xb7;2 million (0&#xb7;9-1&#xb7;5) fewer deaths with lower rates of drug use deaths.<br><br>INTERPRETATION: Our findings highlight the alarming trajectory of health challenges in the USA, which, if left unaddressed, could lead to a reversal of the health progress made over the past three decades for some US states and a decline in global health standing for all states. The evidence from our alternative scenarios along with other published studies suggests that through collaborative, evidence-based strategies, there are opportunities to change the trajectory of health outcomes in the USA, such as by investing in scientific innovation, health-care access, preventive health care, risk exposure reduction, and education. Our forecasts clearly show that the time to act is now, as the future of the country's health and wellbeing-as well as its prosperity and leadership position in science and innovation-are at stake.<br><br>FUNDING: Bill &amp; Melinda Gates Foundation.}, }
@article {pmid39644910, year = {2024}, author = {Goya, S and Greninger, AL}, title = {Pneumovirus genome misassemblies associated with duplications in glycoprotein genes.}, journal = {The Lancet. Infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1016/S1473-3099(24)00801-6}, pmid = {39644910}, issn = {1474-4457}, }
@article {pmid39644492, year = {2024}, author = {Chao, CW and Sprouse, KR and Miranda, MC and Catanzaro, NJ and Hubbard, ML and Addetia, A and Stewart, C and Brown, JT and Dosey, A and Valdez, A and Ravichandran, R and Hendricks, GG and Ahlrichs, M and Dobbins, C and Hand, A and McGowan, J and Simmons, B and Treichel, C and Willoughby, I and Walls, AC and McGuire, AT and Leaf, EM and Baric, RS and Schäfer, A and Veesler, D and King, NP}, title = {Protein nanoparticle vaccines induce potent neutralizing antibody responses against MERS-CoV.}, journal = {Cell reports}, volume = {43}, number = {12}, pages = {115036}, doi = {10.1016/j.celrep.2024.115036}, pmid = {39644492}, issn = {2211-1247}, abstract = {Middle East respiratory syndrome coronavirus (MERS-CoV) is a betacoronavirus that causes severe respiratory illness in humans. There are no licensed vaccines against MERS-CoV and only a few candidates in phase I clinical trials. Here, we develop MERS-CoV vaccines utilizing a computationally designed protein nanoparticle platform that has generated safe and immunogenic vaccines against various enveloped viruses, including a licensed vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Two-component nanoparticles displaying spike (S)-derived antigens induce neutralizing responses and protect mice against challenge with mouse-adapted MERS-CoV. Epitope mapping reveals the dominant responses elicited by immunogens displaying the prefusion-stabilized S-2P trimer, receptor binding domain (RBD), or N-terminal domain (NTD). An RBD nanoparticle elicits antibodies targeting multiple non-overlapping epitopes in the RBD. Our findings demonstrate the potential of two-component nanoparticle vaccine candidates for MERS-CoV and suggest that this platform technology could be broadly applicable to betacoronavirus vaccine development.}, }
@article {pmid39644022, year = {2024}, author = {Radich, J}, title = {Mutations and MRD: clinical implications of clonal ontogeny.}, journal = {Hematology. American Society of Hematology. Education Program}, volume = {2024}, number = {1}, pages = {150-157}, doi = {10.1182/hematology.2024000541}, pmid = {39644022}, issn = {1520-4383}, mesh = {Humans ; *Neoplasm, Residual ; *Leukemia, Myeloid, Acute/genetics/pathology ; *Mutation ; Recurrence ; }, abstract = {Measurable residual disease (MRD) is a strong but imprecise predictor of relapse in acute myeloid leukemia. Many patients fall into the outlier categories of MRD positivity without relapse or MRD negativity with relapse. Why? We will discuss these states in the context of "clonal ontogeny" examining how mutations, clonal structure, and Darwinian rules impact response, resistance, and relapse.}, }
@article {pmid39643988, year = {2024}, author = {Kuczmarski, TM and Lynch, RC}, title = {Has PD-1 blockade changed the standard of care for cHL?.}, journal = {Hematology. American Society of Hematology. Education Program}, volume = {2024}, number = {1}, pages = {505-510}, doi = {10.1182/hematology.2024000574}, pmid = {39643988}, issn = {1520-4383}, mesh = {Humans ; *Hodgkin Disease/drug therapy/therapy ; *Programmed Cell Death 1 Receptor/antagonists &amp; inhibitors ; *Standard of Care ; Immune Checkpoint Inhibitors/therapeutic use ; Antibodies, Monoclonal, Humanized/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Nivolumab/therapeutic use ; }, abstract = {The treatment paradigm for classic Hodgkin lymphoma (CHL) continues to evolve, particularly in light of the incorporation of programmed cell death protein 1 (PD-1) inhibitors into a variety of therapeutic settings. PD-1 inhibitors have demonstrated high efficacy and a favorable toxicity profile when added to a doxorubicin, vinblastine, dacarbazine chemotherapy backbone in patients with untreated CHL. PD-1 inhibitors are also effective treatment options in the relapsed/refractory setting. For patients who are pursuing autologous stem cell transplant (ASCT), pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin has shown marked efficacy and is an effective treatment regimen to administer prior to transplant. For patients who either are not eligible for ASCT or have relapsed after ASCT, pembrolizumab or nivolumab monotherapy have been well studied and demonstrate high efficacy even when patients have been exposed to numerous lines of prior therapy. As data from previous trials continue to mature and new clinical trials are conducted, PD-1 inhibitors will continue to become an integral component for successful management of CHL.}, }
@article {pmid39643004, year = {2024}, author = {El Kalach, N and Julceus, EF and Rudisill, AC and Malik, FS and Flory, K and Frongillo, EA and Sauder, KA and Mendoza, JA and Liese, AD}, title = {Association between Food Insecurity and Inability to Obtain Provider-Recommended Medications, Multidisciplinary Services, and Technology in Youth and Young Adults with Diabetes: A Cross-Sectional Study.}, journal = {Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eprac.2024.11.014}, pmid = {39643004}, issn = {1530-891X}, abstract = {OBJECTIVE: We assessed if food insecurity (FI) is associated with not obtaining recommended diabetes medications, technology, and multidisciplinary services, and explored the most common reasons for not obtaining recommended treatments in youth and young adults (YYA) with diabetes.<br><br>METHODS: In this cross-sectional study, among 911 YYA with type 1 diabetes (T1D) and 144 with type 2 diabetes (T2D) from the SEARCH Food Security Cohort Study Follow-up 1 (2018-2021), FI (&#x2265;3 items affirmed from the 18-item Household Food Security Survey module) and inability to obtain recommended treatments were self-reported.<br><br>RESULTS: Almost 30% of YYA with T1D and FI and 20% of YYA with T2D and FI did not obtain one or more recommended treatments. Participants with T1D who reported FI had higher odds of not obtaining insulin (OR 3.2, 95% CI 1.2-8.4), mental health counseling (OR 3.3, 95% CI 1.3-8.2), diabetes education (OR 3.6, 95% CI 1.4-9.3), an insulin pump (OR 2.2, 95% CI 1.2- 4.4), and a continuous glucose monitor (CGM) (OR 2.5, 95% CI 1.5-4.4) compared to those who reported food security (FS). Among participants with T2D, FI was related to not obtaining dietician services (OR 8.1, 95% CI 1.2-53.8). Participants with T1D and FI reported more financial reasons for not obtaining a CGM compared to FS participants.<br><br>CONCLUSION: YYA with diabetes and FI face constraints in obtaining medications, diabetes technology, and multidisciplinary services, largely due to financial and structural reasons. New strategies are needed to bridge the gap between medical care required versus obtained by YYA with diabetes.}, }
@article {pmid39642888, year = {2024}, author = {Qiu, Y and Su, Y and Xie, E and Cheng, H and Du, J and Xu, Y and Pan, X and Wang, Z and Chen, DG and Zhu, H and Greenberg, PD and Li, G}, title = {Mannose metabolism reshapes T cell differentiation to enhance anti-tumor immunity.}, journal = {Cancer cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ccell.2024.11.003}, pmid = {39642888}, issn = {1878-3686}, abstract = {Cellular metabolic status profoundly influences T cell differentiation, persistence, and anti-tumor efficacy. Our single-cell metabolic analyses of T cells reveal that diminished mannose metabolism is a prominent feature of T cell dysfunction. Conversely, experimental augmentation/restoration of mannose metabolism in adoptively transferred T cells via D-mannose supplementation enhances anti-tumor activity and restricts exhaustion differentiation both in vitro and in vivo. Mechanistically, D-mannose treatment induces intracellular metabolic programming and increases the O-GlcNAc transferase (OGT)-mediated O-GlcNAcylation of β-catenin, which preserves Tcf7 expression and epigenetic stemness, thereby promoting stem-like programs in T cells. Furthermore, in vitro expansion with D-mannose supplementation yields T cell products for adoptive therapy with stemness characteristics, even after extensive long-term expansion, that exhibits enhanced anti-tumor efficacy. These findings reveal cell-intrinsic mannose metabolism as a physiological regulator of CD8[+] T cell fate, decoupling proliferation/expansion from differentiation, and underscoring the therapeutic potential of mannose modulation in cancer immunotherapy.}, }
@article {pmid39642637, year = {2024}, author = {Rosenberg, JE and Galsky, MD and Powles, T and Petrylak, DP and Bellmunt, J and Loriot, Y and Necchi, A and Hoffman-Censits, J and Perez-Gracia, JL and van der Heijden, MS and Dreicer, R and Durán, I and Castellano, D and Drakaki, A and Retz, M and Sridhar, SS and Grivas, P and Yu, EY and O'Donnell, PH and Burris, HA and Mariathasan, S and Shi, Y and Goluboff, E and Bajorin, D}, title = {Atezolizumab monotherapy for metastatic urothelial carcinoma: final analysis from the phase II IMvigor210 trial.}, journal = {ESMO open}, volume = {9}, number = {12}, pages = {103972}, doi = {10.1016/j.esmoop.2024.103972}, pmid = {39642637}, issn = {2059-7029}, abstract = {BACKGROUND: The IMvigor210 trial demonstrated clinical benefit and manageable toxicity with atezolizumab monotherapy [anti-programmed death-ligand 1 (PD-L1)] in patients with metastatic urothelial carcinoma (UC) in primary analyses. Final efficacy and safety results after long-term follow-up are reported.<br><br>PATIENTS AND METHODS: This phase II single-arm trial of atezolizumab monotherapy in patients with advanced UC included two cohorts: untreated patients ineligible for cisplatin-based chemotherapy (cohort 1; n&#xa0;= 119) and those previously treated with platinum-based chemotherapy (cohort 2; n&#xa0;= 310). Atezolizumab was administered i.v. (1200 mg every 21 days) until progression or unacceptable toxicity. Primary endpoints were independent review facility-assessed confirmed objective response rate (ORR) per RECIST 1.1 in cohort 1 and independent review facility-assessed ORR per RECIST 1.1 and investigator-assessed modified (m)RECIST in cohort 2. Overall survival (OS), efficacy by PD-L1 status, and safety were also assessed.<br><br>RESULTS: At data cut-off (1 June 2023), the median survival follow-up was 96.4 months (range, 0.2-103.4 months) in cohort 1 and 46.2 months [0.2 (censored)-54.9 months] in cohort 2. In cohort 1, the ORR [95% confidence interval (CI)] was 23.5% (16.2% to 32.2%) in all patients and 28.1% (13.8% to 46.8%) in the PD-L1 tumor-infiltrating immune cell (IC)2/3 subgroup. Median OS (95% CI) was 16.3 months (10.4-24.5 months) overall and 12.3 months (6.0-49.8 months) in the PD-L1 IC2/3 subgroup. In cohort 2, the ORR (95% CI) was 16.5% (12.5% to 21.1%) per RECIST 1.1 and 19.7% (95% CI 15.4% to 24.6%) per mRECIST in all patients and 27.0% (18.6% to 36.8%) and 28.0% (19.5% to 37.9%), respectively, in the PD-L1 IC2/3 subgroup. Median OS (95% CI) was 7.9 months (6.7-9.3 months) in all patients and 11.9 months (9.0-22.8 months) in the IC2/3 subgroup. Treatment-related grade 3/4 adverse events occurred in 21.8% (cohort 1) and 18.7% (cohort 2); one treatment-related death occurred in cohort&#xa0;1.<br><br>CONCLUSIONS: With long-term follow-up, atezolizumab monotherapy demonstrated clinically meaningful efficacy with durable responses in a subset of patients with metastatic UC; there were no new safety signals.}, }
@article {pmid39642635, year = {2024}, author = {Choueiri, TK and Kuzel, TM and Tykodi, SS and Verzoni, E and Kluger, H and Nair, S and Perets, R and George, S and Gurney, H and Pachynski, RK and Folefac, E and Castonguay, V and Lee, CH and Vaishampayan, U and Miller, WH and Bhagavatheeswaran, P and Wang, Y and Gupta, S and DeSilva, H and Lee, CW and Escudier, B and Motzer, RJ}, title = {Nivolumab plus relatlimab and nivolumab plus ipilimumab for patients with advanced renal cell carcinoma: results from the open-label, randomised, phase II FRACTION-RCC trial.}, journal = {ESMO open}, volume = {9}, number = {12}, pages = {104073}, doi = {10.1016/j.esmoop.2024.104073}, pmid = {39642635}, issn = {2059-7029}, abstract = {BACKGROUND: The Fast Real-time Assessment of Combination Therapies in Immuno-ONcology study in patients with aRCC (FRACTION-RCC) was designed to assess new immuno-oncology (IO) combinations in patients with advanced renal cell carcinoma (aRCC). We present results in IO-naive patients treated with nivolumab (NIVO) + relatlimab (RELA) or NIVO + ipilimumab (IPI) in track 1.<br><br>METHODS: The open-label, randomised, phase II FRACTION-RCC trial enrolled patients with aRCC from 32 hospitals and cancer centres across six countries. Patients were enrolled in track 1 (IO-naive) or track 2 (IO-experienced). IO-naive patients were stratified by previous tyrosine kinase inhibitor therapy and randomised to NIVO (240 mg)&#xa0;+ RELA (80&#xa0;mg) intravenously once every 2 weeks or NIVO (3 mg/kg)&#xa0;+ IPI (1 mg/kg) intravenously once every 3 weeks for four doses, followed by NIVO (480 mg) once every 4 weeks, each up to &#x223c;2 years. The&#xa0;primary endpoints were objective response by investigator (RECIST version 1.1), duration of response (DOR), and progression-free survival (PFS) rate at 24 weeks. Safety was a secondary endpoint; biomarker analyses were exploratory.<br><br>RESULTS: FRACTION-RCC enrolled patients between 2 February 2017 and 23 January 2020. In track 1, 30 patients each were treated with NIVO&#xa0;+ RELA or NIVO&#xa0;+ IPI (clinical database lock, 1 November 2021). With NIVO&#xa0;+ RELA [median follow-up, 48.6 months; interquartile range (IQR) 46.9-51.7 months], objective response was 30% [95% confidence interval (CI) 15% to 49%], with 33 weeks (95% CI 16-53 weeks) median DOR. The PFS rate at 24 weeks was 43% (95% CI 25% to 60%). With NIVO&#xa0;+ IPI (median follow-up, 48.7 months; IQR 47.1-52.0 months), the objective response was 20% (95% CI 8% to 39%), with the median DOR not reached (95% CI 33 weeks-not estimable). The PFS rate at 24 weeks was 49% (95% CI 29% to 66%). Higher baseline lymphocyte activation gene 3 (LAG-3) and programmed death-ligand 1 (PD-L1) expression levels were detected among track 1 NIVO&#xa0;+ RELA responders. Grade 3-4 treatment-related adverse events were reported in 4/30 (13%) patients treated with NIVO&#xa0;+ RELA and 10/30 (33%) patients treated with NIVO&#xa0;+ IPI. No deaths were attributed to study treatments.<br><br>CONCLUSIONS: Results showed antitumour activity and manageable safety with NIVO&#xa0;+ RELA. Findings also support NIVO&#xa0;+ IPI as an effective combination regimen in IO-naive patients with aRCC.}, }
@article {pmid39640936, year = {2024}, author = {Hawwash, NK and Sperrin, M and Martin, GP and Sinha, R and Matthews, CE and Ricceri, F and Tjønneland, A and Heath, AK and Neuhouser, ML and Joshu, CE and Platz, EA and Freisling, H and Gunter, MJ and Renehan, AG}, title = {Excess weight by degree and duration and cancer risk (ABACus2 consortium): a cohort study and individual participant data meta-analysis.}, journal = {EClinicalMedicine}, volume = {78}, number = {}, pages = {102921}, pmid = {39640936}, issn = {2589-5370}, abstract = {BACKGROUND: Elevated body mass index (BMI) ≥25 kg/m[2] is a major preventable cause of cancer. A single BMI measure does not capture the degree and duration of exposure to excess BMI. We investigate associations between adulthood overweight-years, incorporating exposure time to BMI ≥25 kg/m[2,] and cancer incidence, and compare this with single BMI.<br><br>METHODS: In this cohort study and individual participant data meta-analysis, we obtained data from the ABACus 2 Consortium, consisting of four US cohorts: Atherosclerosis Risk in Communities (ARIC) study (1987-2015), Women's Health Initiative (WHI; 1991 to 2005 [main study], to 2010 [Extension 1], and to 2020 [Extension 2]), Prostate, Lung, Colorectal, Ovarian Cancer Screening (PLCO) Trial (1993-2009), NIH-AARP Diet and Health Study (1996-2011), and one European cohort, the European Prospective Investigation into Cancer and Nutrition (EPIC; participants enrolled in 1990 and administrative censoring was centre-specific). Participants with at least 3 BMI measurements and complete cancer follow-up data were included. We calculated overweight-years: degree of overweight (BMI &#x2265;25&#xa0;kg/m[2]) multiplied by the duration of overweight (years). Using random effects two-stage individual participant data meta-analyses, associations between cancer and overweight-years, single BMI, cumulative overweight degree and duration, measured at the same time and captured over a median of 41 years in men and 39 years in women, were evaluated with Cox proportional hazards models. Models were age-adjusted or multivariable (MV) adjusted for baseline age, ethnicity, alcohol, smoking and hormone replacement therapy (HRT). Harrell's C-statistic of metrics were compared. This study is registered at PROSPERO, CRD42021238270.<br><br>FINDINGS: 720,210 participants, including 312,132 men and 408,078 women, were followed up for cancer incidence over a median 9.85 years (interquartile range (IQR) 8.03, 11.67) in men and 10.80 years (IQR 6.05, 15.55) in women. 12,959 men (4.15%) and 36,509 women (8.95%) were diagnosed with obesity-related cancer. Hazard ratios for obesity-related cancers in men, per 1 standard deviation (SD) overweight-years were 1.15 (95% CI: 1.14, 1.16, I[2]: 0) age-adjusted and 1.15 (95% CI: 1.13, 1.17, I[2]: 0%) MV-adjusted and per 1SD increment in single BMI were 1.17 (95% CI: 1.16, 1.18, I[2]: 0) age-adjusted and 1.16 (95% CI: 1.15, 1.18, I[2]: 0%) MV-adjusted. The HR for overweight-years in women per 1 SD increment was 1.08 (95% CI: 1.04, 1.13, I[2]: 82%) age-adjusted and 1.08 (95% CI: 1.04, 1.13, I[2]: 83%) MV-adjusted and per 1SD increment in single BMI was 1.10 (95% CI: 1.07, 1.14, I[2]: 72%) age-adjusted and 1.11 (95% CI: 1.07, 1.15, I[2]: 79%) MV-adjusted. C-statistics for overweight-years and single BMI for obesity-related cancers were 0.612 (95% CI: 0.578, 0.646) and 0.611 (95% CI: 0.578, 0.644) respectively for men and 0.566 (95% CI: 0.534, 0.598) and 0.573 (95% CI: 0.546, 0.600) for women.<br><br>INTERPRETATION: Adulthood degree and duration of excess BMI were associated with cancer risk. Both factors should be considered in cancer prevention strategies and policies. This study only focused on adulthood exposure to excess BMI, so the minimal differences in the predictive performance between adiposity metrics may be due to underestimation of cumulative excess BMI exposure.<br><br>FUNDING: Cancer Research UK, the Manchester NIHR Biomedical Research Centre, the National Cancer Institute, the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, U.S. Department of Health and Human Services, the Intramural Research Program of the National Cancer Institute, the International Agency for Research on Cancer, Imperial College London, European Commission (DG-SANCO), the Danish Cancer Society, Ligue Contre le Cancer, Institut Gustave-Roussy, Mutuelle G&#xe9;n&#xe9;rale de l'Education Nationale, Institut National de la Sant&#xe9; et de la Recherche M&#xe9;dicale, Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, German Federal Ministry of Education and Research, the Hellenic Health Foundation, Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council, Dutch Ministry of Public Health, Welfare, and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Dutch Zorg Onderzoek Nederland, World Cancer Research Fund, Statistics Netherlands, Health Research Fund, Instituto de Salud Carlos III, regional Spanish governments of Andaluc&#xed;a, Asturias, Basque Country, Murcia, and Navarra, the Catalan Institute of Oncology, Swedish Cancer Society, Swedish Scientific Council, and Region Sk&#xe5;ne and Region V&#xe4;sterbotten, and the Medical Research Council.}, }
@article {pmid39638730, year = {2024}, author = {Barata, PC and Zarrabi, KK and Bex, A and Grivas, P and Hermann, K and Hofman, MS and Li, R and Lopez-Beltran, A and Padani, AR and Powles, T and Taplin, ME and Loriot, Y}, title = {Novel Methods to Assess Tumor Burden and Minimal Residual Disease in Genitourinary Cancers.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2024.11.011}, pmid = {39638730}, issn = {1873-7560}, abstract = {BACKGROUND AND OBJECTIVE: Advances in molecular diagnostics have ushered in a new era for patients with prostate, renal, and urothelial cancers, with novel radiographic and molecular modalities for the assessment of disease burden and minimal residual disease (MRD). Conventional imaging has a limited threshold for disease detection and is often unable to discern clinically occult disease with varying risks of false-negative or false-positive findings depending on the disease state and type of imaging.<br><br>METHODS: We provide an overview of emerging radiographic and molecular tools in development within the genitourinary (GU) disease space. A literature review of contemporary basic, translational, and clinical research studies was performed, covering the timeframe of 1980-2024 through the MEDLINE (via PubMed) and Scopus databases. We highlight select examples of emerging technologies and biomarker-informed clinical trials, which aim to quantify disease at lower thresholds and have the potential for integrating MRD in clinical practice for GU patients.<br><br>KEY FINDINGS AND LIMITATIONS: The development of novel radiotracers, such as prostate-specific membrane antigen or carbonic anhydrase IX, is being evaluated in both clinical practice and trial setting, aiming to change the management of these tumors. Molecular tools including circulating tumor cells and byproducts such as plasma and urine cell-free circulating tumor DNA provide the opportunity for MRD detection. MRD capture on single-cell or cellular byproducts can serve as a conduit for genomic and transcriptomic analyses, providing insight into the molecular underpinnings and clonal evolution of disease.<br><br>While the full potential for MRD applications has yet to be realized, we are witnessing the emergence of novel techniques aimed at MRD detection and the rapid development of elegantly designed studies implementing iterative detection of MRD as means to provide biological rationale and tailor therapeutic options in GU tumors.}, }
@article {pmid39638687, year = {2024}, author = {Zacchi, F and Abida, W and Antonarakis, ES and Bryce, AH and Castro, E and Cheng, HH and Shandhu, S and Mateo, J}, title = {Recent and Future Developments in the Use of Poly (ADP-ribose) Polymerase Inhibitors for Prostate Cancer.}, journal = {European urology oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.euo.2024.11.011}, pmid = {39638687}, issn = {2588-9311}, abstract = {BACKGROUND AND OBJECTIVE: Advanced prostate cancer (PCa) is enriched for alterations in DNA damage repair genes; poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a class of drugs that have demonstrated effectiveness in PCa, particularly in tumors with alterations in BRCA1/2 and other homologous recombination repair (HRR) genes, acting through a synthetic lethal mechanism. To prevent or delay drug resistance, and to expand the patient population that can benefit from this class of drug, combination treatment strategies have been developed in preclinical and clinical studies.<br><br>METHODS: This review examines the latest developments in clinical trials testing PARPi for advanced PCa and their emerging role in earlier disease settings. Furthermore, it discusses the critical role of careful patient selection and identification of additional biomarkers to enhance treatment efficacy.<br><br>KEY FINDINGS AND LIMITATIONS: Two PARPi (olaparib and rucaparib) have been approved as monotherapy in metastatic castration-resistant PCa, thereby establishing the first biomarker-guided drug indications in PCa. Several combinations of PARPi with androgen receptor pathway inhibitors have now also been approved. Anemia and fatigue are the main adverse events associated with this drug class in clinical trials; gastrointestinal toxicities are common but usually manageble.<br><br>PARPi are active against PCa with HRR mutations, especially in those with germline or somatic&#xa0;BRCA1/2&#xa0;mutations.&#xa0; There is still a need to further optimize patient stratification strategies, particularly for combination approaches. Future research should focus on refining predictive biomarkers, improving treatment delivery strategies, and exploring the potential benefits of PARPi in earlier stages of the disease.<br><br>PATIENT SUMMARY: Here, we summarize the results from clinical trials testing different poly (ADP-ribose) polymerase inhibitors (PARPi), a novel targeted drug class, in prostate cancer. Overall, the data from these trials confirm the efficacy of this drug class in those metastatic prostate cancers that show specific gene alterations, such as mutations in the BRCA1/2 genes. Several studies combining PARPi with other standard drugs for prostate cancer suggest that there may be efficacy in larger patient populations, but some of these data still need validation in longer follow-up analyses.}, }
@article {pmid39636638, year = {2024}, author = {Back, AL and Freeman-Young, TK and Morgan, L and Sethi, T and Baker, KK and Myers, S and McGregor, BA and Harvey, K and Tai, M and Kollefrath, A and Thomas, BJ and Sorta, D and Kaelen, M and Kelmendi, B and Gooley, TA}, title = {Psilocybin Therapy for Clinicians With Symptoms of Depression From Frontline Care During the COVID-19 Pandemic: A Randomized Clinical Trial.}, journal = {JAMA network open}, volume = {7}, number = {12}, pages = {e2449026}, pmid = {39636638}, issn = {2574-3805}, mesh = {Humans ; *Psilocybin/therapeutic use ; *COVID-19/psychology ; Female ; Male ; Adult ; Double-Blind Method ; *Depression/drug therapy ; *Stress Disorders, Post-Traumatic/drug therapy ; *Burnout, Professional/drug therapy ; *SARS-CoV-2 ; Middle Aged ; Pandemics ; Hallucinogens/therapeutic use ; Treatment Outcome ; }, abstract = {IMPORTANCE: The psychological morbidity experienced by physicians, advanced practice practitioners (APPs), and nurses from working during the COVID-19 pandemic includes burnout, depression, and posttraumatic stress disorder (PTSD).<br><br>OBJECTIVE: To investigate whether psilocybin therapy could improve symptoms of depression, burnout, and PTSD in US clinicians who developed these symptoms from frontline clinical work during the pandemic.<br><br>This double-blind randomized clinical trial enrolled participants from February to December 2022. Participants included physicians, APPs, and nurses who provided frontline care for more than 1 month during the pandemic and had no prepandemic mental health diagnoses but had moderate or severe symptoms of depression at enrollment. Participants were randomly assigned to either the psilocybin or niacin arm. Data analysis was conducted between December 2023 and May 2024 and was based on the intention-to-treat principle.<br><br>INTERVENTION: One intervention episode consisted of 2 preparation visits, 1 medication session, and 3 integration visits. At the medication session, participants received psilocybin, 25 mg, or niacin, 100 mg, orally.<br><br>MAIN OUTCOME AND MEASURES: The primary outcome was a change from baseline (preparation 1 session) to day 28 (after medication administration) in symptoms of depression as measured by the clinician-administered Montgomery-Asberg Depression Rating Scale (MADRS) used by blinded raters. The secondary outcomes were a change in symptoms of burnout (measured with the Stanford Professional Fulfillment Index [SPFI]) and symptoms of PTSD (measured with the Posttraumatic Stress Disorder Checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [PCL-5]).<br><br>RESULTS: A total of 30 clinicians (15 females [50%]; mean [range] age, 38 [29-60] years) participated, of whom 15 were randomly assigned to receive psilocybin and 15 to receive niacin. The mean change in symptoms of depression (MADRS scores) from preparation 1 session to day 28 was -21.33 (7.84) in the psilocybin arm compared with -9.33 (7.32) in the niacin arm, with a mean difference between arms of -12.00 (95% CI, -17.67 to -6.33; P&#x2009;<&#x2009;.001), a decrease in MADRS scores indicating improvement. The mean change in SPFI scores from preparation 1 session to day 28 showed a numerically larger improvement in symptoms of burnout in the psilocybin compared with the niacin arm (-6.40 [5.00] vs -2.33 [5.97]; P&#x2009;=&#x2009;.05) but was not statistically significant. Since the SPFI score change did not reach statistical significance, the PCL-5 score change was evaluated descriptively. The mean change in PCL-5 scores showed a numerically larger decrease in symptoms of PTSD from preparation 1 session to day 28 in the psilocybin vs the niacin arm (-16.67 [15.04] vs -6.73 [10.69]), but this difference was not statistically tested.<br><br>CONCLUSIONS AND RELEVANCE: This randomized clinical trial found that psilocybin therapy resulted in a significant, sustained reduction in symptoms of depression experienced by clinicians after frontline work during the COVID-19 pandemic. The findings establish psilocybin therapy as a new paradigm of treatment for this postpandemic condition.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05163496.}, }
@article {pmid39636625, year = {2024}, author = {Goddard, KAB and Feuer, EJ and Mandelblatt, JS and Meza, R and Holford, TR and Jeon, J and Lansdorp-Vogelaar, I and Gulati, R and Stout, NK and Howlader, N and Knudsen, AB and Miller, D and Caswell-Jin, JL and Schechter, CB and Etzioni, R and Trentham-Dietz, A and Kurian, AW and Plevritis, SK and Hampton, JM and Stein, S and Sun, LP and Umar, A and Castle, PE}, title = {Estimation of Cancer Deaths Averted From Prevention, Screening, and Treatment Efforts, 1975-2020.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, pmid = {39636625}, issn = {2374-2445}, abstract = {IMPORTANCE: Cancer mortality has decreased over time, but the contributions of different interventions across the cancer control continuum to averting cancer deaths have not been systematically evaluated across major cancer sites.<br><br>OBJECTIVE: To quantify the contributions of prevention, screening (to remove precursors [interception] or early detection), and treatment to cumulative number of cancer deaths averted from 1975 to 2020 for breast, cervical, colorectal, lung, and prostate cancers.<br><br>In this model-based study using population-level cancer mortality data, outputs from published models developed by the Cancer Intervention and Surveillance Modeling Network were extended to quantify cancer deaths averted through 2020. Model inputs were based on national data on risk factors, cancer incidence, cancer survival, and mortality due to other causes, and dissemination and effects of prevention, screening (for interception and early detection), and treatment. Simulated or modeled data using parameters derived from multiple birth cohorts of the US population were used.<br><br>INTERVENTIONS: Primary prevention via smoking reduction (lung), screening for interception (cervix and colorectal) or early detection (breast, cervix, colorectal, and prostate), and therapy (breast, colorectal, lung, and prostate).<br><br>MAIN OUTCOMES AND MEASURES: The estimated cumulative number of cancer deaths averted with interventions vs no advances.<br><br>RESULTS: An estimated 5.94 million cancer deaths were averted for breast, cervical, colorectal, lung, and prostate cancers combined. Cancer prevention and screening efforts averted 8 of 10 of these deaths (4.75 million averted deaths). The contribution of each intervention varied by cancer site. Screening accounted for 25% of breast cancer deaths averted. Averted cervical cancer deaths were nearly completely averted through screening and removal of cancer precursors as treatment advances were modest during the study period. Averted colorectal cancer deaths were averted because of screening and removal of precancerous polyps or early detection in 79% and treatment advances in 21%. Most lung cancer deaths were avoided by smoking reduction (98%) because screening uptake was low and treatment largely palliative before 2014. Screening contributed to 56% of averted prostate cancer deaths.<br><br>CONCLUSIONS AND RELEVANCE: Over the past 45 years, cancer prevention and screening accounted for most cancer deaths averted for these causes; however, their contribution varied by cancer site according to these models using population-level cancer mortality data. Despite progress, efforts to reduce the US cancer burden will require increased dissemination of effective interventions and new technologies and discoveries.}, }
@article {pmid39634680, year = {2024}, author = {Alamin, T and Lin-Martore, M and Kornblith, AE and O'Donnell, A and Gragalia, S}, title = {Piloting a Diagnostic Foot and Ankle Fracture Sonographic Algorithm with Rural and Adolescent Patients.}, journal = {POCUS journal}, volume = {9}, number = {2}, pages = {102-108}, pmid = {39634680}, issn = {2369-8543}, abstract = {Background: Foot and ankle injuries are a common presenting complaint to the Emergency Department (ED) and are often assessed with plain radiography. Rural environments may not have access to radiography mandating the referral or transfer patients to regional centers for definitive diagnosis. The Ottawa Foot and Ankle Rules (OFAR) is a clinical decision rule that can assist in ruling out fractures. Point of care ultrasound (POCUS) can augment this decision rule. The objective of this study was to assess both the feasibility and test characteristics of a previously described POCUS augmented clinical assessment, OFAR-POCUS, for adolescent and adult patients with foot and ankle pain in a rural environment. Methods: This was a prospective cohort study from June to August 2022 including patients with chief complaint of foot or ankle injury presenting to a rural clinic. Patients were included if they had positive finding(s) on the OFAR Test and required radiographic imaging. Patients were excluded if they did not consent, speak English, were unable to be scanned, had obvious joint deformities, had altered mental status, were not physiologically stable, had other injuries preventing sonography, were pregnant, or had previous injury with internal fixation, osteomyelitis, or rheumatoid arthritis. POCUS was performed before transport for radiography. POCUS examiners were POCUS novices who underwent a one and a half to two-hour, standardized foot and ankle POCUS training session. All POCUS studies were reviewed by two emergency medicine ultrasound fellowship trained faculty for quality assurance. Standard test characteristics were calculated for bedside clinician and expert POCUS interpretations compared to the radiographic control. Results: Thirteen POCUS examiners performed exams on 20 patients included in analysis; four patients had fractures on radiograph (20%). The bedside clinician POCUS interpretation had sensitivity (SN) = 100% (95% Cl, 40%-100%), specificity (SP) =94% (95% Cl, 70%-100%), and negative likelihood ratio (-LR) = 16.00 (95% Cl, 2.40-106.73). Expert POCUS interpretation had SN=75% (95% Cl, 19%-99%), SP=75% (95% Cl, 48%-93%), and -LR=0.33 (95% Cl, 0.06-1.86). Conclusion: A POCUS enhanced clinical strategy for clinically significant foot and ankle fractures in adolescent and adult patients in a rural setting is feasible. Larger studies are required to further characterize test characteristics and use of foot and ankle POCUS where plain radiography is unavailable.}, }
@article {pmid39633050, year = {2024}, author = {Lyu, A and Fan, Z and Clark, M and Lea, A and Luong, D and Setayesh, A and Starzinski, A and Wolters, R and Arias-Badia, M and Allaire, K and Wu, K and Gurunathan, V and Valderrábano, L and Wei, XX and Miller, RA and Van Allen, EM and Fong, L}, title = {Evolution of myeloid-mediated immunotherapy resistance in prostate cancer.}, journal = {Nature}, volume = {}, number = {}, pages = {}, pmid = {39633050}, issn = {1476-4687}, abstract = {Patients with advanced metastatic castration-resistant prostate cancer (mCRPC) are refractory to immune checkpoint inhibitors (ICIs)[1,2], partly because there are immunosuppressive myeloid cells in tumours[3,4]. However, the heterogeneity of myeloid cells has made them difficult to target, making blockade of the colony stimulating factor-1 receptor (CSF1R) clinically ineffective. Here we use single-cell profiling on patient biopsies across the disease continuum and find that a distinct population of tumour-associated macrophages with elevated levels of SPP1 transcripts (SPP1[hi]-TAMs) becomes enriched with the progression of prostate cancer to mCRPC. In syngeneic mouse modelling, an analogous macrophage population suppresses CD8[+] T cell activity in vitro and promotes ICI resistance in vivo. Furthermore, Spp1[hi]-TAMs are not responsive to anti-CSF1R antibody treatment. Pathway analysis identifies adenosine signalling as a potential mechanism for SPP1[hi]-TAM-mediated immunotherapeutic resistance. Indeed, pharmacological inhibition of adenosine A2A receptors (A2ARs) significantly reverses Spp1[hi]-TAM-mediated immunosuppression in CD8[+] T cells in vitro and enhances CRPC responsiveness to programmed cell death protein 1 (PD-1) blockade in vivo. Consistent with preclinical results, inhibition of A2ARs using ciforadenant in combination with programmed death 1 ligand 1 (PD-L1) blockade using atezolizumab induces clinical responses in patients with mCRPC. Moreover, inhibiting A2ARs results in a significant decrease in SPP1[hi]-TAM abundance in CRPC, indicating that this pathway is involved in both induction and downstream immunosuppression. Collectively, these findings establish SPP1[hi]-TAMs as key mediators of ICI resistance in mCRPC through adenosine signalling, emphasizing their importance as both a therapeutic target and a potential biomarker for predicting treatment efficacy.}, }
@article {pmid39632080, year = {2024}, author = {Alamdarloo, SM and Hashemi, A and Hessami, K and Askary, E and Barzegar, H and Haseli, S and Abbaspour, E}, title = {Gross hematuria and placenta percreta: Report of two cases and literature review.}, journal = {The journal of obstetrics and gynaecology research}, volume = {}, number = {}, pages = {}, doi = {10.1111/jog.16177}, pmid = {39632080}, issn = {1447-0756}, abstract = {Placenta percreta, a rare variant of placenta accreta spectrum (PAS) disorders, poses a significant risk of life-threatening hemorrhage associated with the adherent placenta. Bladder involvement signifies an even rarer incidence and may sometimes present solely with gross hematuria. Therefore, it is imperative to consider both microscopic and gross hematuria during pregnancy as alarming signs. Among 342 cases of PAS admitted to our hospital between 2016 and 2023, 48 patients were diagnosed with placenta percreta. Two patients, one at 18 weeks and the other at 25 weeks of pregnancy, were referred to our tertiary care center due to severe gross hematuria. Following thorough preoperative evaluation, both pregnancies were terminated due to their unstable conditions. The first case underwent an elective supracervical cesarean hysterectomy at the 19th week of gestation, while the second case underwent an emergency total cesarean hysterectomy due to lack of response to blood transfusions. Both procedures included bilateral internal iliac artery ligation. Postoperatively, patients recovered without any complications; however, the fetuses did not survive. Placenta percreta, protruding into the bladder, can lead to severe hematuria at any stage of pregnancy, increasing the risk of life-threatening hemorrhage. Therefore, both microscopic and macroscopic hematuria during pregnancy should be considered alarming signs that require immediate attention. Early involvement of a urologist and a multidisciplinary medical team is also essential in suspected or confirmed cases of placenta percreta, as immediate surgical intervention may be necessary to ensure patient safety.}, }
@article {pmid39626349, year = {2024}, author = {Liang, EC and Huang, JJ and Portuguese, AJ and Ortiz-Maldonado, V and Albittar, A and Wuliji, N and Basom, R and Jeon, Y and Wu, QV and Torkelson, A and Kirchmeier, DR and Chutnik, A and Pender, BS and Sorror, ML and Hill, JA and Kopmar, NE and Banerjee, R and Cowan, AJ and Green, DJ and Gopal, AK and Poh, C and Shadman, M and Hirayama, AV and Till, BG and Kimble, EL and Iovino, L and Chapuis, AG and Otegbeye, F and Cassaday, RD and Milano, F and Turtle, CJ and Maloney, DG and Gauthier, J}, title = {Development and validation of predictive models of early immune effector cell-associated hematotoxicity (eIPMs).}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024014455}, pmid = {39626349}, issn = {2473-9537}, abstract = {Immune effector cell-associated hematotoxicity (ICAHT) is associated with morbidity and mortality after chimeric antigen receptor (CAR) T-cell therapy. To date, the factors associated with ICAHT are poorly characterized, and there is no validated predictive model of ICAHT specifically. Therefore, we performed comprehensive univariate analyses to identify factors associated with severe (grade 3-4) early ICAHT (eICAHT) in 691 patients who received commercial or investigational CAR T-cell therapy for hematologic malignancies. In univariate logistic regression, pre-infusion factors associated with severe eICAHT included disease type (acute lymphoblastic leukemia), pre-lymphodepletion (LD) blood counts including absolute neutrophil count (ANC), lactate dehydrogenase (LDH), and inflammatory (C-reactive protein [CRP]; ferritin, interleukin-6 [IL-6]), and coagulopathy biomarkers (D-dimer). Post-infusion laboratory markers associated with severe eICAHT included early and peak levels of inflammatory biomarkers (CRP, ferritin, IL-6), coagulopathy biomarkers (D-dimer), peak cytokine release syndrome (CRS) grade, and peak neurotoxicity grade. We trained (n = 483) and validated (n = 208) two Early ICAHT Prediction Models (eIPM): eIPMPre including pre-infusion factors only (disease type and pre-LD ANC, platelet count, LDH, and ferritin) and eIPMPost containing both pre- (disease type and pre-LD ANC, platelet count, and LDH) and post-infusion (day +3 ferritin) factors. Both models generated calibrated predictions and high discrimination (area under the receiver operating characteristic curve [AUROC] in test set: 0.87 for eIPMPre and 0.88 for eIPMPost), with higher net benefit in decision curve analysis for eIPMPost. Individualized predictions of severe eICAHT can be generated from both eIPMs utilizing our online tool (available at https://eipm.fredhutch.org).}, }
@article {pmid39626158, year = {2024}, author = {Crupi, E and Costa de Padua, T and Marandino, L and Fallara, G and Pederzoli, F and Cimadamore, A and Goetz, EC and Cigliola, A and Patané, DA and Mercinelli, C and Tateo, V and Salonia, A and Briganti, A and Montorsi, F and Meeks, JJ and Spiess, PE and Alhalabi, O and Gao, J and Kamat, AM and Grivas, P and Necchi, A and Raggi, D}, title = {Nectin-4 Positivity in Genitourinary Malignancies: A Systematic Review.}, journal = {JCO precision oncology}, volume = {8}, number = {}, pages = {e2400470}, doi = {10.1200/PO-24-00470}, pmid = {39626158}, issn = {2473-4284}, mesh = {Humans ; *Urogenital Neoplasms/pathology/metabolism ; *Cell Adhesion Molecules/analysis ; Urinary Bladder Neoplasms/pathology/metabolism ; Male ; Nectins ; }, abstract = {PURPOSE: Aberrant expression of nectin-4 (N4) has been observed in several malignancies emerging as new target for antibody-drug conjugates, especially in urothelial carcinoma of the bladder (UBC). Limited data on N4 positivity in nonurothelial genitourinary (GU) cancers are available. This systematic-review aimed to investigate N4 positivity among GU malignancies.<br><br>METHODS: A systematic literature review was performed on March 2023 using PubMed, MEDLINE, and Embase databases according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Protocol was amended to incorporate a new updated search on March 2024.<br><br>RESULTS: Twenty-five studies evaluating N4 positivity in GU tumors were included, 14 on UBC, three on upper tract urothelial carcinoma (UTUC), six on histologic subtypes (HS) and divergent histology of the bladder, one on papillary renal cell carcinoma (pRCC), one in chromophobe RCC (chRCC), two on penile cancer, one in prostate cancer (PCa). Among UBC, stratifying per stage N4 positivity was higher in metastatic (weighted mean [WM], 90.8; range, 59.6-100) and in non-muscle-invasive (WM, 87.4; range, 86.7-88.3) than in muscle-invasive UC (WM, 83.1; range, 68.2-100). The N4 positivity of UBC was higher than UTUC (WM, 62.9; range, 44.4-65.7). Immunohistochemistry N4 positivity was reported to be lower in non-UC malignancies, including pRCC (WM, 44.1; range, 44.1-44.1), HS (WM, 63.5; range, 0-100), PCa (WM0; range, 0-0), chRCC (WM, 18.5; range, 18.5-18.5), and penile cancer (WM, 86.5; range, 61.4-98.3), compared with UBC overall (WM, 87.1; range, 59.6-100).<br><br>CONCLUSION: Non-UC malignancies seem to have a lower N4 positivity rate than UC. N4 positivity in bladder cancer appears to vary according to stage and presence of HS. The predictive and prognostic role of N4 must be further characterized in larger and prospective studies.}, }
@article {pmid39625477, year = {2024}, author = {Sinnott-Armstrong, N and Fields, S and Roth, F and Starita, LM and Trapnell, C and Villen, J and Fowler, DM and Queitsch, C}, title = {Understanding genetic variants in context.}, journal = {eLife}, volume = {13}, number = {}, pages = {}, pmid = {39625477}, issn = {2050-084X}, support = {5RM1HG010461/NH/NIH HHS/United States ; RM1 HG010461/HG/NHGRI NIH HHS/United States ; NIGMS R35GM139532/NH/NIH HHS/United States ; Creativity Award//Bruce G. Cochener Foundation/ ; R35 GM139532/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Genetic Variation ; Genomics/methods ; Genetic Predisposition to Disease ; Animals ; Phenotype ; }, abstract = {Over the last three decades, human genetics has gone from dissecting high-penetrance Mendelian diseases to discovering the vast and complex genetic etiology of common human diseases. In tackling this complexity, scientists have discovered the importance of numerous genetic processes - most notably functional regulatory elements - in the development and progression of these diseases. Simultaneously, scientists have increasingly used multiplex assays of variant effect to systematically phenotype the cellular consequences of millions of genetic variants. In this article, we argue that the context of genetic variants - at all scales, from other genetic variants and gene regulation to cell biology to organismal environment - are critical components of how we can employ genomics to interpret these variants, and ultimately treat these diseases. We describe approaches to extend existing experimental assays and computational approaches to examine and quantify the importance of this context, including through causal analytic approaches. Having a unified understanding of the molecular, physiological, and environmental processes governing the interpretation of genetic variants is sorely needed for the field, and this perspective argues for feasible approaches by which the combined interpretation of cellular, animal, and epidemiological data can yield that knowledge.}, }
@article {pmid39624798, year = {2024}, author = {Liu, WL and Kampouri, E and Bui, JK and Sekhon, MK and Tercero, A and Finlay, D and Asghedom, LH and Romasanta, GR and Rice, NT and Ranjbaran, F and Stoltzman, C and Cook, J and Blake, J and Delaney, CS and Hill, JA}, title = {Off-the-shelf allogeneic natural killer cells for the treatment of COVID-19.}, journal = {Molecular therapy. Methods &amp; clinical development}, volume = {32}, number = {4}, pages = {101361}, pmid = {39624798}, issn = {2329-0501}, abstract = {Low levels and function of natural killer (NK) cells are associated with increased coronavirus disease 2019 (COVID-19) severity. NK cell immunotherapy may improve immune function to reduce infection severity. We conducted a first-in-human, open-label, phase 1, dose-escalating (100 × 10[6], 300 × 10[6], or 900 × 10[6] cells) study of a single dose of DVX201, a cord-blood-derived allogeneic NK cell therapy, in hospitalized patients with COVID-19. Participants were followed for 28 days. The maximum allowed steroid dose for eligibility was up to 0.5 mg/kg prednisone (or equivalent) daily. We enrolled nine participants, 3 per dose level. Eight participants had ≥1 comorbidity associated with increased COVID-19 severity, three of whom had a hematologic malignancy. Infusions were well tolerated, with no treatment-related adverse events. There was no evidence of inflammatory complications related to infusions. Peripheral blood NK cells generally increased after infusion, peaking by day 7. The median time from infusion to discharge was 2 days (range: 1-13). Two patients (both with acute lymphoblastic leukemia) were readmitted with recurrent COVID-19. This trial demonstrates the safety of allogeneic NK cell immunotherapy as a potential antiviral. Larger controlled trials are needed to establish efficacy.}, }
@article {pmid39624744, year = {2024}, author = {Mittal, V and So, JY and Li, S and Swetter, SM and Linos, E and Van Horn, L and Neuhouser, ML and Stefanick, ML and Tang, JY}, title = {Associations between dietary and supplemental vitamin A intake and melanoma and non-melanoma skin cancer.}, journal = {Skin health and disease}, volume = {4}, number = {6}, pages = {e462}, pmid = {39624744}, issn = {2690-442X}, abstract = {BACKGROUND: Cutaneous melanoma (CM) and non-melanoma skin cancer (NMSC) are rising in postmenopausal women. Although high doses of oral vitamin A reduce NMSC risk in high-risk patients, the role of vitamin A in preventing skin cancer in this group remains unexplored.<br><br>OBJECTIVES: To determine the association between total (dietary and supplemental) vitamin A and risk of CM and NMSC in postmenopausal women.<br><br>METHODS: This retrospective cohort study included 52&#xa0;877 White women from the Women's Health Initiative cohort, spanning from 1993 to 2019. Exposures were intake of total vitamin A, retinol and provitamin A carotenoids. Cox proportional hazard models estimated hazard ratios for overall CM incidence, whereas logistic regression determined odds ratios (ORs) for melanoma subtypes and NMSC.<br><br>RESULTS: 1154 cases of CM and 9085 cases of NMSC were identified over an average follow-up period of 17.8&#xa0;years (SD 6.7). No associations were identified between total vitamin A intake and melanoma risk. Higher dietary vitamin A intake was associated with higher risk of NMSC (OR of 3rd vs. 1st tertile of dietary intake&#xa0;=&#xa0;1.12, 95% confidence interval [CI] [1.06, 1.18]), as was dietary beta-cryptoxanthin, a provitamin A carotenoid (OR of 3rd vs. 1st tertile of dietary intake&#xa0;=&#xa0;1.22, 95% CI [1.15, 1.29]); these results were consistent across both age- and fully adjusted regression models.<br><br>CONCLUSIONS: Total vitamin A intake was not associated with lower risk of CM or NMSC. Dietary vitamin A and beta-cryptoxanthin intake were associated with a slightly higher risk of NMSC in postmenopausal women.}, }
@article {pmid39624634, year = {2024}, author = {Huang, Y and Dasgupta, S}, title = {Biomarker Panel Development Using Logic Regression in the Presence of Missing Data.}, journal = {The New England Journal of Statistics in Data Science}, volume = {2}, number = {1}, pages = {3-14}, pmid = {39624634}, issn = {2693-7166}, support = {R01 CA277133/CA/NCI NIH HHS/United States ; R37 AI054165/AI/NIAID NIH HHS/United States ; U24 CA086368/CA/NCI NIH HHS/United States ; }, abstract = {We consider the problem of developing flexible and parsimonious biomarker combinations for cancer early detection in the presence of variable missingness at random. Motivated by the need to develop biomarker panels in a cross-institute pancreatic cyst biomarker validation study, we propose logic-regression based methods for feature selection and construction of logic rules under a multiple imputation framework. We generate ensemble trees for classification decision, and further select a single decision tree for simplicity and interpretability. We demonstrate superior performance of the proposed methods compared to alternative methods based on complete-case data or single imputation. The methods are applied to the pancreatic cyst data to estimate biomarker panels for pancreatic cysts subtype classification and malignant potential prediction.}, }
@article {pmid39624016, year = {2024}, author = {Georges, GE and Khanna, D and Wener, MH and Mei, MG and Mayes, MD and Simms, RW and Sanchorawala, V and Hosing, C and Kafaja, S and Pawarode, A and Holmberg, LA and Kolfenbach, J and Furst, DE and Sullivan, KM and Huang, S and Gooley, T and Nash, RA}, title = {Autologous non-myeloablative hematopoietic stem cell transplantation for diffuse cutaneous systemic sclerosis: identifying disease risk factors for toxicity and long-term outcomes in a prospective, single-arm trial.}, journal = {Arthritis &amp; rheumatology (Hoboken, N.J.)}, volume = {}, number = {}, pages = {}, doi = {10.1002/art.43072}, pmid = {39624016}, issn = {2326-5205}, abstract = {OBJECTIVE: Two randomized trials for patients with diffuse systemic sclerosis (SSc) demonstrated an overall survival (OS) and event-free survival (EFS) advantage of autologous hematopoietic stem cell transplantation (AHSCT) using CD34+ selected peripheral blood stem cells (PBSC) compared to monthly cyclophosphamide. We asked if an unmodified PBSC graft followed by maintenance mycophenolate mofetil (MMF) after AHSCT, instead of CD34+ selected graft, could provide comparable AHSCT outcomes.<br><br>METHODS: 20 patients with high-risk SSc were enrolled in a prospective, single-arm trial with cyclophosphamide 200 mg/kg and horse anti-thymocyte globulin (CY200/ATG), followed by unmanipulated autologous PBSC, then MMF maintenance starting at 2 months after AHSCT.<br><br>RESULTS: Point estimates of OS and EFS at 5 years after AHSCT were 85% (95% CI, 60.4%-94.9%) and 75% (95% CI, 50%-88.7%), respectively. Median follow-up was 7.5 years (range, 5.6-11.6) after transplant for living patients. Eight patients (40%) required intensive care unit treatment early after transplant. Early transplant-related mortality occurred in 2 patients (10%). Five patients developed relapse/progression of SSc after AHSCT. Four of 9 patients with anti-RNA polymerase-III antibody had both prior scleroderma renal crisis and the lowest quartile of estimated glomerular filtration rate (eGFR) upon study entry; all 4 patients developed prolonged organ failure/death early post-transplant.<br><br>CONCLUSION: We observed favorable OS and EFS after AHSCT for SSc patients, using CY200/ATG, unmanipulated PBSC and MMF post-transplant maintenance, that was comparable to trials with CD34+ graft selection. We identified a possible risk factor, pretransplant low eGFR, for adverse outcome after AHSCT.}, }
@article {pmid39621969, year = {2024}, author = {Tregnago, C and Benetton, M and Ries, RE and Peplinski, JH and Alonzo, TA and Stirewalt, D and Othus, M and Duployez, N and Sonneveld, E and Abrahamsson, J and Fogelstrand, L and von Neuhoff, N and Hasle, H and Reinhardt, D and Meshinchi, S and Locatelli, F and Pigazzi, M}, title = {Influence of Nucleophosmin (NPM1) Genotypes on Outcome of Patients With AML: An AIEOP-BFM and COG-SWOG Intergroup Collaboration.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2401715}, doi = {10.1200/JCO-24-01715}, pmid = {39621969}, issn = {1527-7755}, abstract = {PURPOSE: Several genomic subsets of NPM1 mutations with varying sequences (type A, B, D, etc) have been identified. Despite molecular heterogeneity, NPM1 mutations cumulatively portend a more favorable outcome, but biology and prognostic implications of different genomic subsets have not been extensively studied. In this multicentric study, we investigated the impact of NPM1 genotypes on patient's outcomes and interrogated the underlying biology of the different subtypes.<br><br>MATERIALS AND METHODS: Of more than 4,000 patients enrolled in multiple pediatric cooperative (AIEOP, BFM, ELAM02, NOPHO, DCOG, and COG trials), or adult (SWOG) trials, 348 pediatric and 75 adult AML patients with known NPM1 genotype and available outcome were selected for this study. Diverse NPM1 variants were correlated with the probabilities of overall survival (OS) and event-free survival. Nuclear localization and translational efficiency of the NPM1 variants was studied.<br><br>RESULTS: Evaluation of clinical outcome on the basis of NPM1 genotypes showed that patients with type A, B, and other rare variants had similarly favorable outcomes, whereas those with type D had a significantly worse outcome (OS of 63% for type D v 86% for type non-D, P = .005). Multivariate analysis confirmed type D as an independent prognostic factor associated with inferior OS (hazard ratio, 3; P = .005). In vitro, we demonstrated that in type D versus type A synonymous variants, codon optimality plays major roles in determining gene expression levels, and translation efficiency, which resulted in a more expressed NPM1-D mRNA and protein, mediating peculiar mitochondrial gene expression.<br><br>CONCLUSION: The evaluation of specific NPM1 genotypes identified AML patients with type D mutations being significantly associated with inferior outcomes, suggesting a reclassification of D cases to higher-risk groups.}, }
@article {pmid39621968, year = {2024}, author = {Pusztai, L and Hoag, JR and Albain, KS and Barlow, WE and Stemmer, SM and Meisner, A and Hortobagyi, GN and Shak, S and Rae, JM and Baehner, R and Sharma, P and Kalinsky, KM}, title = {Development and Validation of the RSClinN+ Tool to Predict Prognosis and Chemotherapy Benefit for Hormone Receptor-Positive, Node-Positive Breast Cancer.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2401507}, doi = {10.1200/JCO-24-01507}, pmid = {39621968}, issn = {1527-7755}, abstract = {PURPOSE: Clinicopathological factors and the 21-gene Oncotype DX Breast Recurrence Score (RS) test both influence prognosis. Our goal was to develop a new tool, RSClinN+, to individualize recurrence risk and chemotherapy benefit predictions by menopausal status for patients with HR+/human epidermal growth factor receptor 2-negative, lymph node-positive breast cancer by integrating the RS result with clinicopathological factors (grade, tumor size, age).<br><br>METHODS: We used patient-level data from 5,283 patients treated with chemoendocrine therapy (CET) versus endocrine therapy alone (ET) in the S1007 (N = 4,916) and S8814 (N = 367) trials to develop the tool. Cox proportional hazards regression models stratified by trial were used to estimate 5-year invasive disease-free survival for pre- and postmenopausal woman, respectively. The integrated RSClinN+ model was compared with RS alone and clinicopathological models using likelihood ratio tests. Absolute CET benefit was estimated as the difference between ET and CET risk estimates. Validation of RSClinN+ was performed in 592 patients with node-positive disease in the Clalit Health Services registry.<br><br>RESULTS: RSClinN+ provides better prognostic information than RS model alone (premenopausal P = .034; postmenopausal P < .001) or clinicopathological model alone (premenopausal P = .002; postmenopausal, P < .001). In postmenopausal women, RS showed interaction with CET benefit (P = .016), with RSClinN+ absolute CET benefit ranging from <0.1% to 21.5% over RS ranges 0-50. In premenopausal patients with RS &#x2264;25, there was no significant interaction between RS and CET benefit. In external validation, RSClinN+ risk estimates were prognostic (hazard ratio, 1.75 [95% CI, 1.38 to 2.20]) and concordant with observed risk (Lin's concordance, 0.92).<br><br>CONCLUSION: RSClinN+ provides improved estimates of prognosis and absolute CET benefit for individual patients compared with RS or with clinical data alone and could be used in patient counseling.}, }
@article {pmid39621930, year = {2024}, author = {Zanders, SE and Smith, GR}, title = {Killer meiotic drive executed by two alternative conformations of a single protein.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {50}, pages = {e2420620121}, doi = {10.1073/pnas.2420620121}, pmid = {39621930}, issn = {1091-6490}, support = {R35 GM151982/GM/NIGMS NIH HHS/United States ; GM118120//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; }, }
@article {pmid39621322, year = {2024}, author = {Terry, KL and Harris, HR and Missmer, SA}, title = {Endometriosis and Ovarian Cancer.}, journal = {JAMA}, volume = {}, number = {}, pages = {}, doi = {10.1001/jama.2024.21905}, pmid = {39621322}, issn = {1538-3598}, }
@article {pmid39619675, year = {2024}, author = {Little, A and Deek, RA and Zhang, A and Zhao, N and Ling, W and Wu, MC}, title = {Enhanced visualization of microbiome data in repeated measures designs.}, journal = {Frontiers in genetics}, volume = {15}, number = {}, pages = {1480972}, pmid = {39619675}, issn = {1664-8021}, abstract = {INTRODUCTION: Repeated measures microbiome studies, including longitudinal and clustered designs, offer valuable insights into the dynamics of microbial communities and their associations with various health outcomes. However, visualizing such multivariate data poses significant challenges, particularly in distinguishing meaningful biological patterns from noise introduced by covariates and the complexities of repeated measures.<br><br>METHODS: In this study, we propose a framework to enhance the visualization of repeated measures microbiome data using Principal Coordinates Analysis (PCoA) adjusted for covariates through linear mixed models (LMM). Our method adjusts for confounding variables and accounts for the repeated measures structure of the data, enabling clearer identification of microbial community variations across time points or clusters.<br><br>RESULTS: We demonstrate the utility of our approach through simulated scenarios and real datasets, showing that it effectively mitigates the influence of nuisance covariates and highlights key axes of microbiome variation.<br><br>DISCUSSION: This refined visualization technique provides a robust tool for researchers to explore and understand microbial community dynamics in repeated measures microbiome studies.}, }
@article {pmid39619274, year = {2024}, author = {Tsao, AS and Hsieh, MH and Koczywas, M and Tu, J and Riess, J and Tanvetyanon, T and Ma, BT and Zhao, YQ and Redman, MW and Edelman, MJ and Gandara, DR and Gray, JE and Kelly, KL}, title = {S1701, A Randomized Phase 2 Trial of Carboplatin-Paclitaxel With and Without Ramucirumab in Patients With Locally Advanced, Recurrent, or Metastatic Thymic Carcinoma.}, journal = {JTO clinical and research reports}, volume = {5}, number = {12}, pages = {100738}, pmid = {39619274}, issn = {2666-3643}, abstract = {INTRODUCTION: Thymic carcinoma is a rare and aggressive malignancy with few treatment options. Preclinical studies suggested that targeting the angiogenic pathway may be beneficial in this disease.<br><br>METHODS: This randomized phase 2 trial enrolled patients with unresectable, locally advanced, recurrent, or metastatic thymic carcinoma. Patients were randomized to receive carboplatin-paclitaxel with or without ramucirumab. The primary end point was progression-free survival (PFS) and secondary end points included response by Response Evaluation Criteria in Solid Tumors, disease control, toxicity, and overall survival. The primary analysis was done using a one-sided 10%-level log-rank test. Target sample size was 66 patients.<br><br>RESULTS: Between 2018 and 2022, 21 patients enrolled to ramucirumab plus carboplatin-paclitaxel (RCP, n&#xa0;= 8) and to the control arm (carboplatin-paclitaxel [CP], n&#xa0;= 13) with one patient on CP not meeting eligibility criteria. Owing to slow accrual, the study was terminated early by the Data and Safety Monitoring Board. Of the 20 eligible patients, eight on RCP and nine on CP received protocol treatment. PFS was not statistically different (hazard ratio&#xa0;= 0.51, 80% confidence interval [CI]: 0.24-1.09, p&#xa0;= 0.13). There were no grade 4 or higher treatment-related adverse events with RCP, although 50% experienced grade 3 adverse events, in which one patient had a grade 3 thromboembolic event. Among nine assessable patients for toxicity on CP, one patient (11%) encountered grade 4 neutropenia and one patient (11%) reported grade 3 thromboembolic events. Response rates favored the RCP arm, with an 88% (seven of eight, 80% CI: 59%-99%) response rate compared with 40% (four of 10, 80% CI: 19%-65%) on CP arm (p&#xa0;= 0.04). Disease control rate was higher in the RCP arm (100% versus 70%, p&#xa0;= 0.09). At the time of analysis, as only one death has been reported, overall survival remains immature.<br><br>CONCLUSIONS: Accrual to this population is challenging, and the study was closed early because of feasibility. Although PFS was not statistically better with RCP, the hazard ratio was 0.51 and the lack of significance was likely due to small sample sizes. Notably, addition of ramucirumab to CP led to higher response rates than CP alone. Future research should consider exploring larger multicenter trials and other combinations to improve outcomes. Challenges in enrollment emphasize the need for innovative strategies and larger collaborations in rare malignancies such as thymic carcinoma.}, }
@article {pmid39617269, year = {2024}, author = {Franić, D and Pravica, M and Zubčić, K and Miles, S and Bedalov, A and Boban, M}, title = {Quiescent cells maintain active degradation-mediated protein quality control requiring proteasome, autophagy and nucleus-vacuole junctions.}, journal = {The Journal of biological chemistry}, volume = {}, number = {}, pages = {108045}, doi = {10.1016/j.jbc.2024.108045}, pmid = {39617269}, issn = {1083-351X}, abstract = {Many cells spend a major part of their life in quiescence, a reversible state characterized by a distinct cellular organization and metabolism. In glucose-depleted quiescent yeast cells, there is a metabolic shift from glycolysis to mitochondrial respiration, and a large fraction of proteasomes are reorganized into cytoplasmic granules containing disassembled particles. Given these changes, the operation of protein quality control (PQC) in quiescent cells, in particular the reliance on degradation-mediated PQC and the specific pathways involved, remains unclear. By examining model misfolded proteins expressed in glucose-depleted quiescent yeast cells, we found that misfolded proteins are targeted for selective degradation requiring functional 26S proteasomes. This indicates that a significant pool of proteasomes remains active in degrading quality control substrates. Misfolded proteins were degraded in a manner dependent on the E3 ubiquitin ligases Ubr1 and San1, with Ubr1 playing a dominant role. In contrast to exponentially growing cells, the efficient clearance of certain misfolded proteins additionally required intact nucleus-vacuole junctions (NVJ) and Cue5-independent selective autophagy. Our findings suggest that proteasome activity, autophagy, and NVJ-dependent degradation operate in parallel. Together the data demonstrate that quiescent cells maintain active PQC that relies primarily on selective protein degradation. The necessity of multiple degradation pathways for the removal of misfolded proteins during quiescence underscores the importance of misfolded protein clearance in this cellular state.}, }
@article {pmid39617028, year = {2024}, author = {Bender Ignacio, RA and Shapiro, AE and Montaño, MA and Titanji, BK}, title = {An urgent call to address the intersection of mpox and HIV in Africa.}, journal = {Lancet (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.1016/S0140-6736(24)02542-X}, pmid = {39617028}, issn = {1474-547X}, support = {K23 AI140918/AI/NIAID NIH HHS/United States ; R24 AI067039/AI/NIAID NIH HHS/United States ; }, }
@article {pmid39616600, year = {2024}, author = {Hatlen, TJ and Bender Ignacio, R and Daar, ES}, title = {Advances in Treatment and Prevention of HIV.}, journal = {JAMA}, volume = {}, number = {}, pages = {}, doi = {10.1001/jama.2024.24027}, pmid = {39616600}, issn = {1538-3598}, }
@article {pmid39616467, year = {2024}, author = {Bryce, AH and Agarwal, N and Beltran, H and Hussain, MH and Sartor, O and Shore, N and Antonarakis, ES and Armstrong, AJ and Calais, J and Carducci, MA and Dorff, TB and Efstathiou, JA and Gleave, M and Gomella, LG and Higano, C and Hope, TA and Iagaru, A and Morgans, AK and Morris, DS and Morris, MJ and Petrylak, DP and Reiter, RE and Rettig, MB and Ryan, CJ and Sellinger, SB and Spratt, DE and Srinivas, S and Tagawa, ST and Taplin, ME and Yu, EY and Zhang, T and McKay, RR and Koo, PJ and Crawford, ED}, title = {Implementing evidence-based strategies for men with biochemically recurrent and advanced prostate cancer: Consensus recommendations from the US Prostate Cancer Conference 2024.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.35612}, pmid = {39616467}, issn = {1097-0142}, abstract = {Current US clinical practice guidelines for advanced prostate cancer management contain recommendations based on high-level evidence from randomized controlled trials; however, these guidelines do not address the nuanced clinical questions that are unanswered by prospective trials but nonetheless encountered in day-to-day practice. To address these practical questions, the 2024 US Prostate Cancer Conference (USPCC 2024) was created to generate US-focused expert clinical decision-making guidance for circumstances in which level 1 evidence is lacking. At the second annual USPCC meeting (USPCC 2024), a multidisciplinary panel of experts convened to discuss ongoing clinical challenges related to 5 topic areas: biochemical recurrence; metastatic, castration-resistant prostate cancer; poly [ADP-ribose] polymerase inhibitors; prostate-specific membrane antigen radioligand therapy; and metastatic, castration-resistant prostate cancer. Through a modified Delphi process, 34 consensus recommendations were developed and are intended to provide clinicians who manage prostate cancer with guidance related to the implementation of novel treatments and technologies. In this report, the authors review the areas of consensus identified by the USPCC 2024 experts and evaluate ongoing unmet needs regarding translational application of the current clinical evidence.}, }
@article {pmid39616411, year = {2024}, author = {Newton, H and Colla, CH and Busch, SH and Tomaino, M and Hardy, B and Brunette, MF and Agravat, D and Meara, E}, title = {Medicare Accountable Care Organization Treatment of Serious Mental Illness: Associations Between Behavioral Health Integration Activities and Outcomes.}, journal = {Medical care}, volume = {}, number = {}, pages = {}, pmid = {39616411}, issn = {1537-1948}, abstract = {OBJECTIVE: Characterize the association between Medicare Accountable Care Organizations' (ACOs) behavioral health integration capability and quality and utilization among adults with serious mental illness (SMI).<br><br>BACKGROUND: Controlled research supports the efficacy of integrating physical and mental health care for adults with SMI, yet little is known about the organizations integrating care and associations between integration capability and quality.<br><br>METHODS: We surveyed Medicare ACOs (2017-2018 National Survey of ACOs, response rate 69%) and linked responses to 2016-2017 fee-for-service Medicare claims for beneficiaries with SMI. We examined the cross-sectional association between ACO-reported integration capability (tertiles of a 14-item index) and 7 patient-level quality and utilization outcomes. We fit generalized linear models for each outcome as a function of ACO integration capability, adjusting for ACO and beneficiary characteristics.<br><br>RESULTS: Study sample included 274,928 beneficiary years (199,910 unique beneficiaries) attributed to 265 Medicare ACOs. ACOs with high behavioral health integration capability (top-tertile) served more dual-eligible beneficiaries (67.8%) than bottom-tertile (63.7%) and middle-tertile ACOs (63.3%). Most beneficiaries received follow-up 30 days after mental health hospitalization and chronic disease monitoring-exceeding national quality benchmarks-but beneficiaries receiving care from top-tertile (vs bottom-tertile) ACOs were modestly less likely to receive follow-up [-2.17 percentage points (pp), P < 0.05], diabetes monitoring (-2.19 pp, P < 0.05), and cardiovascular disease monitoring (-6.07 pp, P < 0.05). Integration capability was not correlated with utilization.<br><br>CONCLUSIONS: ACOs serving adults with substantial physical and mental health needs were more likely to report comprehensive integration capability but were not yet meeting the primary care needs of many adults with SMI.}, }
@article {pmid39616199, year = {2024}, author = {Vadathya, AK and Garza, T and Alam, U and Ho, A and Musaad, SMA and Beltran, A and Moreno, JP and Baranowski, T and Haidar, N and Hughes, SO and Mendoza, JA and Veeraraghavan, A and Young, J and Sano, A and O'Connor, TM}, title = {Validation studies of the FLASH-TV system to passively measure children's TV viewing.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {29805}, pmid = {39616199}, issn = {2045-2322}, support = {R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; }, mesh = {Humans ; *Television ; Female ; Male ; Child ; Screen Time ; Machine Learning ; Child, Preschool ; }, abstract = {TV viewing is associated with health risks, but existing measures of TV viewing are imprecise due to relying on self-report. We developed the Family Level Assessment of Screen use in the Home (FLASH)-TV, a machine learning pipeline with state-of-the-art computer vision methods to measure children's TV viewing. In three studies, lab pilot (n = 10), lab validation (n = 30), and home validation (n = 20), we tested the validity of FLASH-TV 3.0 in task-based protocols which included video observations of children for 60 min. To establish a gold-standard to compare FLASH-TV output, the videos were labeled by trained staff at 5-second epochs for whenever the child watched TV. For the combined sample with valid data (n = 59), FLASH-TV 3.0 provided a mean 85% (SD 8%) accuracy, 80% (SD 17%) sensitivity, 86% (SD 8%) specificity, and 0.71 (SD 0.15) kappa, compared to gold-standard. The mean intra-class correlation (ICC) of child's TV viewing durations of FLASH-TV 3.0 to gold-standard was 0.86. Overall, FLASH-TV 3.0 correlated well with the gold standard across a diverse sample of children, but with higher variability among Black children than others. FLASH-TV provides a tool to estimate children's TV viewing and increase the precision of research on TV viewing's impact on children's health.}, }
@article {pmid39612623, year = {2024}, author = {Lee, MJ and Litchford, ML and Vendrame, E and Vergara, R and Ranganath, T and Fish, CS and Chebet, D and Langat, A and Mburu, C and Neary, J and Benki, S and Wamalwa, D and John-Stewart, G and Lehman, DA and Blish, CA}, title = {Distinct immune profiles in children living with HIV based on timing and duration of suppressive antiretroviral treatment.}, journal = {Virology}, volume = {602}, number = {}, pages = {110318}, doi = {10.1016/j.virol.2024.110318}, pmid = {39612623}, issn = {1096-0341}, abstract = {Timely initiation of antiretroviral therapy (ART) remains a major challenge in the effort to treat children living with HIV ("CLH") and little is known regarding the dynamics of immune normalization following ART in CLH with varying times to and durations of ART. Here, we leveraged two cohorts of virally-suppressed CLH from Nairobi, Kenya to examine differences in the peripheral immune systems between two cohorts of age-matched children (to control for immune changes with age): one group which initiated ART during early HIV infection and had been on ART for 5-6 years at evaluation (early, long-term treated; "ELT" cohort), and one group which initiated ART later and had been on ART for approximately 9 months at evaluation (delayed, short-term treated; "DST" cohort). We profiled PBMC and purified NK cells from these two cohorts by mass cytometry time-of-flight (CyTOF). Although both groups of CLH had undetectable viral RNA load at evaluation, there were marked differences in both immune composition and immune phenotype between the ELT cohort and the DST cohort. DST donors had reduced CD4 T cell percentages, decreased naive to effector memory T cell ratios, and markedly higher expression of stress-induced markers. Conversely, ELT donors had higher naive to effector memory T cell ratios, low expression of stress-induced markers, and increased expression of markers associated with an effective antiviral response and resolution of inflammation. Collectively, our results demonstrate key differences in the immune systems of virally-suppressed CLH with different ages at ART initiation and durations of treatment and provide further rationale for emphasizing early onset of ART.}, }
@article {pmid39612163, year = {2024}, author = {Swensen, SN and Figuracion, KCF and Venur, VA and Emerson, S and Tseng, YD and Lo, SS and Ermoian, RP and Halasz, LM}, title = {Treatment Options for IDH-Mutant Malignant Gliomas.}, journal = {Current treatment options in oncology}, volume = {}, number = {}, pages = {}, pmid = {39612163}, issn = {1534-6277}, abstract = {As the peak incidence of isocitrate dehydrogenase (IDH)-mutant gliomas is amongst young adults, there is a need to balance tumor control with long term side effects of therapy. Following initial clinical presentation and acquisition of contrasted diagnostic imaging, tissue diagnosis is essential in suspected diffuse glioma. Depending on the location and extent of disease, maximal surgical resection is preferred both for histologic diagnosis and initial therapy. Partial resection or biopsy alone is considered when the tumor cannot be completely resected or if there are clinical reservations regarding a more significant operation. The classification of diffuse glioma has evolved over time, with histopathology and molecular marker status guiding discussions of prognosis and postoperative management. In patients with IDH-mutant grade 2 glioma and low-risk features, observation with active surveillance is generally recommended following a gross total resection. For those with high-risk features, which historically included age > 40 years or subtotal resection, adjuvant chemotherapy and radiation therapy are generally recommended, however decisions for adjuvant therapy pose challenges as many of the landmark historical trials guiding adjuvant therapy were performed prior to the molecularly defined era. This is an area where multiple clinical trials are ongoing and hold promise to inform treatment paradigms, including recent data on the use of IDH-mutant inhibitors in grade 2 tumors with recurrent or residual disease. For IDH-mutant grade 3 and 4 glioma, adjuvant chemotherapy and radiation are recommended for all patients after initial resection.}, }
@article {pmid39610699, year = {2024}, author = {Wu, P and Barros-Becker, F and Ogelman, R and Camci, ED and Linbo, TH and Simon, JA and Rubel, EW and Raible, DW}, title = {Multiple mechanisms of aminoglycoside ototoxicity are distinguished by subcellular localization of action.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1480435}, pmid = {39610699}, issn = {1664-2295}, support = {R01 DC005987/DC/NIDCD NIH HHS/United States ; }, abstract = {Mechanosensory hair cells of the inner ears and lateral line of vertebrates display heightened vulnerability to environmental insult, with damage resulting in hearing and balance disorders. An important example is hair cell loss due to exposure to toxic agents including therapeutic drugs such as the aminoglycoside antibiotics neomycin and gentamicin and antineoplastic agents. We describe two distinct cellular pathways for aminoglycoside-induced hair cell death in zebrafish lateral line hair cells. Neomycin exposure results in death from acute exposure with most cells dying within 1 h of exposure. By contrast, exposure to gentamicin results primarily in delayed hair cell death, taking up to 24 h for maximal effect. Washout experiments demonstrate that delayed death does not require continuous exposure, demonstrating two mechanisms where downstream responses differ in their timing. Acute damage is associated with mitochondrial calcium fluxes and can be alleviated by the mitochondrially-targeted antioxidant mitoTEMPO, while delayed death is independent of these factors. Conversely delayed death is associated with lysosomal accumulation and is reduced by altering endolysosomal function, while acute death is not sensitive to lysosomal manipulations. These experiments reveal the complexity of responses of hair cells to closely related compounds, suggesting that intervention focusing on early events rather than specific death pathways may be a successful therapeutic strategy.}, }
@article {pmid39610652, year = {2024}, author = {Nanduri, S and Black, A and Bedford, T and Huddleston, J}, title = {Dimensionality reduction distills complex evolutionary relationships in seasonal influenza and SARS-CoV-2.}, journal = {Virus evolution}, volume = {10}, number = {1}, pages = {veae087}, pmid = {39610652}, issn = {2057-1577}, abstract = {Public health researchers and practitioners commonly infer phylogenies from viral genome sequences to understand transmission dynamics and identify clusters of genetically-related samples. However, viruses that reassort or recombine violate phylogenetic assumptions and require more sophisticated methods. Even when phylogenies are appropriate, they can be unnecessary or difficult to interpret without specialty knowledge. For example, pairwise distances between sequences can be enough to identify clusters of related samples or assign new samples to existing phylogenetic clusters. In this work, we tested whether dimensionality reduction methods could capture known genetic groups within two human pathogenic viruses that cause substantial human morbidity and mortality and frequently reassort or recombine, respectively: seasonal influenza A/H3N2 and SARS-CoV-2. We applied principal component analysis, multidimensional scaling (MDS), t-distributed stochastic neighbor embedding (t-SNE), and uniform manifold approximation and projection to sequences with well-defined phylogenetic clades and either reassortment (H3N2) or recombination (SARS-CoV-2). For each low-dimensional embedding of sequences, we calculated the correlation between pairwise genetic and Euclidean distances in the embedding and applied a hierarchical clustering method to identify clusters in the embedding. We measured the accuracy of clusters compared to previously defined phylogenetic clades, reassortment clusters, or recombinant lineages. We found that MDS embeddings accurately represented pairwise genetic distances including the intermediate placement of recombinant SARS-CoV-2 lineages between parental lineages. Clusters from t-SNE embeddings accurately recapitulated known phylogenetic clades, H3N2 reassortment groups, and SARS-CoV-2 recombinant lineages. We show that simple statistical methods without a biological model can accurately represent known genetic relationships for relevant human pathogenic viruses. Our open source implementation of these methods for analysis of viral genome sequences can be easily applied when phylogenetic methods are either unnecessary or inappropriate.}, }
@article {pmid39609636, year = {2024}, author = {Thomas, CE and Peters, U}, title = {Genomic landscape of cancer in racially and ethnically diverse populations.}, journal = {Nature reviews. Genetics}, volume = {}, number = {}, pages = {}, pmid = {39609636}, issn = {1471-0064}, abstract = {Cancer incidence and mortality rates can vary widely among different racial and ethnic groups, attributed to a complex interplay of genetic, environmental and social factors. Recently, substantial progress has been made in investigating hereditary genetic risk factors and in characterizing tumour genomes. However, most research has been conducted in individuals of European ancestries and, increasingly, in individuals of Asian ancestries. The study of germline and somatic genetics in cancer across racial and ethnic groups using omics technologies offers opportunities to identify similarities and differences in both heritable traits and the molecular features of cancer genomes. An improved understanding of population-specific cancer genomics, as well as translation of those findings across populations, will help reduce cancer disparities and ensure that personalized medicine and public health approaches are equitable across racial and ethnic groups.}, }
@article {pmid39609400, year = {2024}, author = {Lemos, MP and Astronomo, RD and Huang, Y and Narpala, S and Prabhakaran, M and Mann, P and Paez, CA and Lu, Y and Mize, GJ and Glantz, H and Westerberg, K and Colegrove, H and Smythe, KS and Lin, M and Pierce, RH and Hutter, J and Frank, I and Mascola, JR and McDermott, AB and Bekker, LG and McElrath, MJ}, title = {Enhanced and sustained biodistribution of HIV-1 neutralizing antibody VRC01LS in human genital and rectal mucosa.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {10332}, pmid = {39609400}, issn = {2041-1723}, support = {UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI069481/AI/NIAID NIH HHS/United States ; UM1 AI069501/AI/NIAID NIH HHS/United States ; UM1 AI069534/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *HIV-1/immunology ; *Rectum/virology ; *HIV Antibodies/immunology ; Adult ; Male ; *HIV Infections/immunology/prevention &amp; control/virology ; *Broadly Neutralizing Antibodies/immunology ; *Antibodies, Monoclonal/pharmacokinetics/immunology/administration &amp; dosage ; Tissue Distribution ; Mucous Membrane/immunology/virology/metabolism ; Antibodies, Neutralizing/immunology ; Middle Aged ; Vagina/virology/immunology ; Young Adult ; Half-Life ; Intestinal Mucosa/metabolism/immunology ; }, abstract = {To prevent sexually-acquired HIV-1 infection by immunoprophylaxis, effective concentrations of broadly neutralizing antibodies are likely needed at mucosal sites of exposure. Here, we examine the biodistribution of monoclonal antibody VRC01 and its extended half-life variant, VRC01LS, in colorectal and genitourinary tracts of healthy adults 1-52 weeks after intravenous infusion. At 1-2 weeks, VRC01LS levels are ~3-4 times higher than VRC01 in serum (p = 0.048), rectal (p = 0.067), vaginal (p = 0.003) and cervical tissues (p = 0.003); these differences increase over time. Both antibodies primarily localize within rectal lamina propria and cervicovaginal stroma, with limited and variable epithelial distribution. Although 8-28% of serum mAb levels reach mucosal tissues, <3% are in seminal and rectal secretions. Elimination half-lives in mucosal tissues are 20-28 days for VRC01 and 51-68 days for VRC01LS. Thus, VRC01LS infusion achieves higher, sustained concentrations in human mucosal tissues than VRC01, supporting the future investigation of potent, long-acting LS-modified antibodies to prevent HIV-1.}, }
@article {pmid39607987, year = {2024}, author = {Weiss, NS}, title = {Gauging the efficacy of multicancer screening: the road ahead may be long and bumpy.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djae267}, pmid = {39607987}, issn = {1460-2105}, support = {/CA/NCI NIH HHS/United States ; }, }
@article {pmid39607599, year = {2024}, author = {Ondeng'e, K and Guo, X and Mbeda, C and Schnabel, D and Panchia, R and Dominguez, K and Dadabhai, S and Hamilton, EL and Sandfort, TGM}, title = {Bisexuality among Men who have Sex with Men in Sub-Saharan Africa: Findings from the HPTN 075 Study.}, journal = {AIDS and behavior}, volume = {}, number = {}, pages = {}, pmid = {39607599}, issn = {1573-3254}, support = {R21-MH130217//National Institute of Mental Health and Neurosciences/ ; UM1-AI068613//Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ ; UM1-AI068617//Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ ; P30-MH43520/MH/NIMH NIH HHS/United States ; UM1 AI068619/AI/NIAID NIH HHS/United States ; UM1-AI068619//Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ ; UM1 AI068617/AI/NIAID NIH HHS/United States ; }, abstract = {Studies among men who have sex with men (MSM) in sub-Saharan Africa (SSA) focus mainly on HIV epidemiology, revealing little about the diversity within this population. We utilized data from the HIV Prevention Trials Network (HPTN) 075 study, to explore demographic and psychosexual characteristics of MSM in SSA who also have sex with women. Persons included in the analyses were aged 18-44 years and assigned male sex at birth and identified as male, reported anal sex with a man in the past 3 months, and had enrolled at one of four study sites (Kisumu, Kenya; Blantyre, Malawi; Cape Town and Soweto, South Africa). Nearly a quarter of the participants had recently engaged in sex with both men and women (MSMW). These men differed in terms of demographic and psychosexual characteristics, and sexual behavior from men who only had had sex with men (MSME). Compared to the latter, MSMW were more likely to prefer the insertive sexual role, reported more sexual partners in the past three months, and had more instances of condomless insertive anal intercourse with a man. These findings suggest that men who have sex with both men and women have specific characteristics and need tailored interventions that take their specific needs into account.}, }
@article {pmid39606729, year = {2024}, author = {Jennings-Shaffer, C and Rich, DH and Macaulay, M and Karcher, MD and Ganapathy, T and Kiami, S and Kooperberg, A and Zhang, C and Suchard, MA and Matsen, FA}, title = {Finding high posterior density phylogenies by systematically extending a directed acyclic graph.}, journal = {ArXiv}, volume = {}, number = {}, pages = {}, pmid = {39606729}, issn = {2331-8422}, support = {R01 AI162611/AI/NIAID NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, abstract = {Bayesian phylogenetics typically estimates a posterior distribution, or aspects thereof, using Markov chain Monte Carlo methods. These methods integrate over tree space by applying local rearrangements to move a tree through its space as a random walk. Previous work explored the possibility of replacing this random walk with a systematic search, but was quickly overwhelmed by the large number of probable trees in the posterior distribution. In this paper we develop methods to sidestep this problem using a recently introduced structure called the subsplit directed acyclic graph (sDAG). This structure can represent many trees at once, and local rearrangements of trees translate to methods of enlarging the sDAG. Here we propose two methods of introducing, ranking, and selecting local rearrangements on sDAGs to produce a collection of trees with high posterior density. One of these methods successfully recovers the set of high posterior density trees across a range of data sets. However, we find that a simpler strategy of aggregating trees into an sDAG in fact is computationally faster and returns a higher fraction of probable trees.}, }
@article {pmid39606437, year = {2024}, author = {Vo, P and Sandmaier, B and Othus, M and Ali, N and Rodríguez-Arbolí, E and Orvain, C and Davis, C and Basom, R and Storb, R and Walter, R}, title = {Relationship Between Age, Conditioning Intensity, and Outcome After Allografting in Adults Age ≥60 Years with AML.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39606437}, issn = {2693-5015}, support = {P01 CA018029/CA/NCI NIH HHS/United States ; P01 CA078902/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {Methodological advancements now allow older adults with AML to receive allografts although conflicting data exist regarding relative outcomes across age groups and benefits of different conditioning intensities. We retrospectively analyzed 495 adults aged 60-64 (n = 184), 65-69 (n = 189), or ≥ 70 (n = 122) who underwent allogeneic HCT for AML in remission at our institution from 2006 to 2023. There were no significant differences in relapse or relapse-free survival (RFS) among the 3 age cohorts after multivariable adjustment. Patients aged ≥ 70 years had a higher risk of non-relapse mortality (NRM) than those aged ≥ 60-64 (P = 0.022) but their overall survival (OS) was only statistically non-significantly shorter (P = 0.11). There was an important interplay between age, conditioning intensity, and outcomes. Age ≥ 70 years was associated with a higher risk of relapse (hazard ratio [HR] = 3.47; P = 0.012) and NRM (HR = 3.88; P = 0.001) with reduced intensity conditioning (RIC), leading to shorter RFS (HR = 3.79; P < 0.001) and OS (HR = 3.46; P < 0.001), while no association was found with nonmyeloablative conditioning. Conversely, patients aged 60-64 and 65-69, not those aged ≥ 70, had a significantly lower risk of relapse with RIC, but NRM risk increased with age. Our findings support allogeneic HCT for adults with AML in remission even if aged beyond 70, especially with nonmyeloablative conditioning.}, }
@article {pmid39605726, year = {2024}, author = {Rominger, MC and Gupta, S and Moorthi, S and McSharry, M and Kamlapurkar, S and O'Brien, S and Waldum, A and Lo, A and Duke, F and Lowe, AR and Cromwell, E and Glabman, R and Koehne, A and Berger, AH}, title = {Mutant RIT1 cooperates with YAP to drive an EMT-like lung cancer state.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39605726}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P50 CA228944/CA/NCI NIH HHS/United States ; R00 CA197762/CA/NCI NIH HHS/United States ; R37 CA252050/CA/NCI NIH HHS/United States ; }, abstract = {The discovery of oncogene addiction in cancer has led to the development of over a dozen FDA-approved biomarker-driven therapies in lung adenocarcinoma. Somatic mutations of the "Ras-like in all tissues" (RIT1) gene are non-canonical driver events in lung cancer, occurring in ~2% of lung adenocarcinomas in a mutually exclusive fashion with KRAS and EGFR mutations. Patients with RIT1-mutant lung cancer lack targeted therapy treatment options, and a lack of pre-clinical models has hindered the development of therapeutic strategies for RIT1-mutant lung cancer. Here we report a new mouse model of RIT1-driven lung cancer in which the human RIT1[M90I] variant can be induced in a Cre-regulated manner. We show that autochthonous expression of RIT1[M90I] in the lung weakly promotes cancer alone or in combination with loss of the p53 tumor suppressor. However, potent synergy between RIT1[M90I] and inactivation of Nf2 drives an aggressive epithelial-to-mesenchymal (EMT) lung cancer with 100% penetrance and short latency. We show this oncogenic cooperation is driven by synergistic activation of cJUN, a component of the AP-1 complex. Therapeutic inhibition of MEK and YAP/TEAD suppressed RIT1-driven lung cancer in vivo. These data identify YAP/TEAD as an important mediator of RIT1's oncogenic potential and nominate TEAD as an important drug target in RIT1-mutant lung cancer.}, }
@article {pmid39605711, year = {2024}, author = {Wu, E and Bieniosek, M and Wu, Z and Thakkar, N and Charville, GW and Makky, A and Schürch, C and Huyghe, JR and Peters, U and Li, CI and Li, L and Giba, H and Behera, V and Raman, A and Trevino, AE and Mayer, AT and Zou, J}, title = {ROSIE: AI generation of multiplex immunofluorescence staining from histopathology images.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39605711}, issn = {2692-8205}, support = {P20 CA252733/CA/NCI NIH HHS/United States ; P50 CA285275/CA/NCI NIH HHS/United States ; R01 CA280639/CA/NCI NIH HHS/United States ; }, abstract = {Hematoxylin and eosin (H&amp;E) is a common and inexpensive histopathology assay. Though widely used and information-rich, it cannot directly inform about specific molecular markers, which require additional experiments to assess. To address this gap, we present ROSIE, a deep-learning framework that computationally imputes the expression and localization of dozens of proteins from H&amp;E images. Our model is trained on a dataset of over 1000 paired and aligned H&amp;E and multiplex immunofluorescence (mIF) samples from 20 tissues and disease conditions, spanning over 16 million cells. Validation of our in silico mIF staining method on held-out H&amp;E samples demonstrates that the predicted biomarkers are effective in identifying cell phenotypes, particularly distinguishing lymphocytes such as B cells and T cells, which are not readily discernible with H&amp;E staining alone. Additionally, ROSIE facilitates the robust identification of stromal and epithelial microenvironments and immune cell subtypes like tumor-infiltrating lymphocytes (TILs), which are important for understanding tumor-immune interactions and can help inform treatment strategies in cancer research.}, }
@article {pmid39605495, year = {2024}, author = {Slein, MD and Backes, IM and Kelkar, NS and Garland, CR and Khanwalkar, US and Sholukh, AM and Johnston, CM and Leib, DA and Ackerman, ME}, title = {Improving antibody-mediated protection against HSV infection by eliminating interactions with the viral Fc receptor gE/gI.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39605495}, issn = {2692-8205}, support = {R01 AI178284/AI/NIAID NIH HHS/United States ; R01 EY009083/EY/NEI NIH HHS/United States ; P01 AI098681/AI/NIAID NIH HHS/United States ; U19 AI145825/AI/NIAID NIH HHS/United States ; R21 AI147714/AI/NIAID NIH HHS/United States ; R01 AI176646/AI/NIAID NIH HHS/United States ; T32 AI007363/AI/NIAID NIH HHS/United States ; }, abstract = {Herpes simplex virus (HSV) encodes surface glycoproteins that are host defense evasion molecules, allowing the virus to escape immune clearance. In addition to their role in neuropathogenesis and cell-cell spread, glycoproteins E and I (gE/gI) form a viral Fc receptor (vFcR) for most subclasses and allotypes of human IgG and promote evasion of humoral immune responses. While monoclonal antibodies (mAbs) protect mice from neonatal HSV (nHSV) infections, the impact of the vFcR on mAb-mediated protection by binding to IgG is unknown. Using HSV-1 with intact and ablated gE-mediated IgG Fc binding, and Fc-engineered antibodies with modified ability to interact with gE/gI, we investigated the role of the vFcR in viral pathogenesis and mAb-mediated protection from nHSV. The gD-specific human mAb HSV8 modified to lack binding to gE exhibited enhanced neutralization and in vivo protection compared to its native IgG1 form. This improved protection by the engineered mAbs was dependent on the presence of the vFcR. Human IgG3 allotypes lacking vFcR binding also exhibited enhanced antiviral activity in vivo, suggesting that vaccines that robustly induce IgG3 responses could show enhanced protection. suggesting the value of vaccination strategies that robustly induce this subclass. Lastly, analysis of longitudinal responses to acute primary genital infection in humans raised the possibility that unlike most viruses, HSV may exhibited slow induction of IgG3. In summary, this study demonstrates that mAbs lacking the ability to interact with the vFcR can exhibit improved protection from HSV-offering new prospects for antibody-based interventions.}, }
@article {pmid39605329, year = {2024}, author = {Nolan, CT and Campbell, I and Farrell-Sherman, A and Ortiz, BAB and Naish, KA and Stilio, VD and Kaldy, JE and Donoghue, C and Ruesink, JL and Imaizumi, T}, title = {Florigen and antiflorigen gene expression correlates with reproductive state in a marine angiosperm, Zostera marina.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39605329}, issn = {2692-8205}, support = {R01 GM079712/GM/NIGMS NIH HHS/United States ; }, abstract = {• Florigen and antiflorigen genes within the phosphatidylethanolamine-binding protein (PEBP) family regulate flowering in angiosperms. In eelgrass (Zostera marina), a marine foundation species threatened by climate change, flowering and seed production are crucial for population resilience. Yet, the molecular mechanism underpinning flowering remains unknown. • Using phylogenetic analysis and functional assays in Arabidopsis, we identified thirteen PEBP genes in Z. marina (ZmaPEBP) and showed that four genes altered flowering phenotypes when overexpressed. We used quantitative RT-PCR on Z. marina shoots from perennial and annual populations in Willapa Bay, USA to assess expression of these four genes in different tissue and expression changes throughout the growth season. • We demonstrated that ZmaFT2 and ZmaFT4 promote flowering, and ZmaFT9 and ZmaTFL1a repress flowering in Arabidopsis. Across five natural sites exhibiting different degrees of population genetic structure, ZmaFT2 and ZmaFT4 were expressed in leaves of vegetative and reproductive shoots and in stems and rhizomes of reproductive shoots. ZmaFT9 was distinctively expressed in leaves of vegetative and juvenile shoots, while ZmaTFL1a levels increased after flowering shoots emerged. • Our results suggest that ZmaFT2 and ZmaFT4 may promote flowering, while ZmaFT9 may inhibit a floral transition in eelgrass. We speculate that ZmaTFL1a may be involved in flowering shoot architecture.}, }
@article {pmid39605281, year = {2024}, author = {Zheng, C and Furukawa, C and Liu, J and Sankaran, S and Lin, H and Munugeti, N and Wang, M and Smith, GR}, title = {Debunking the dogma that RecBCD nuclease destroys phage.}, journal = {Genetics}, volume = {}, number = {}, pages = {}, doi = {10.1093/genetics/iyae199}, pmid = {39605281}, issn = {1943-2631}, abstract = {For decades, it has been repeatedly claimed that the potent bacterial helicase-nuclease RecBCD (exonuclease V) destroys foreign (non-self) DNA, such as that of phages, but repairs and recombines cellular (self) DNA. While this would constitute a strong host-survival mechanism, no phage destroyed by RecBCD is ever specified in those claims. To determine which phages are destroyed by RecBCD, we searched for phage isolates that grow on Escherichia coli ΔrecBCD but not on recBCD+. In contrast to the prevailing claim, we found none among >80 new isolates from nature and >80 from previous collections. Based on these and previous observations, we conclude that RecBCD repairs broken DNA that can recombine but destroys DNA that cannot recombine and recycles the nucleotides.}, }
@article {pmid39604409, year = {2024}, author = {Holmes, S and Li, H and Shen, X and Martin, M and Tuck, R and Chen, Y and Giorgi, EE and Kirshner, HF and Berry, M and Van Italie, E and Venkatayogi, S and Martin Beem, JS and Edwards, RJ and Mansouri, K and Singh, A and Kuykendall, C and Gurley, T and Anthony Moody, M and DeNayer, N and Demarco, T and Denny, TN and Wang, Y and Evangelous, TD and Clinton, JT and Hora, B and Wagh, K and Seaman, MS and Saunders, KO and Solomotis, N and Misamore, J and Lewis, MG and Wiehe, K and Montefiori, DC and Shaw, GM and Williams, WB}, title = {Neonatal immunity associated with heterologous HIV-1 neutralizing antibody induction in SHIV-infected Rhesus Macaques.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {10302}, pmid = {39604409}, issn = {2041-1723}, support = {HHSN272201800004C/AI/NIAID NIH HHS/United States ; AI140897//Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)/ ; AI160607//Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)/ ; R01 AI160607/AI/NIAID NIH HHS/United States ; R01 AI140897/AI/NIAID NIH HHS/United States ; P30 AI064518/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; *Macaca mulatta/immunology ; *HIV-1/immunology ; *Simian Acquired Immunodeficiency Syndrome/immunology/virology ; *Simian Immunodeficiency Virus/immunology ; *Antibodies, Neutralizing/immunology ; *HIV Antibodies/immunology/blood ; *Animals, Newborn ; Female ; Humans ; Male ; B-Lymphocytes/immunology ; HIV Infections/immunology/virology ; T-Lymphocytes, Regulatory/immunology ; Germinal Center/immunology ; Disease Models, Animal ; Epitopes/immunology ; }, abstract = {The details of the pediatric immune system that supports induction of antibodies capable of neutralizing geographically-diverse or heterologous HIV-1 is currently unclear. Here we explore the pediatric immune environment in neonatal macaque undergoing Simian-HIV infection. Simian-HIV infection of 11 pairs of therapy-naive dams and infant rhesus macaques for 24 months results in heterologous HIV-1 neutralizing antibodies in 64% of young macaques compared to 18% of adult macaques. Heterologous HIV-1 neutralizing antibodies emerge by 12 months post-infection in young macaques, in association with lower expression of immunosuppressive genes, fewer germinal center CD4 + T regulatory cells, and a lower ratio of CD4 + T follicular regulatory to helper cells. Antibodies from peripheral blood B cells in two young macaques following SHIV infection neutralize 13% of 119 heterologous HIV-1 strains and map to regions of canonical broadly neutralizing antibody epitopes on the envelope surface protein. Here we show that pediatric immunity to SHIV infection in a macaque model may inform vaccine strategies to induce effective HIV-1 neutralizing antibodies in infants and children prior to viral exposure.}, }
@article {pmid39604364, year = {2024}, author = {Gem, H and Ebadi, M and Sebastian, G and Abasaeed, R and Lloid, M and Minot, SS and Dean, DR and Rashidi, A}, title = {A sex-dependent salivary bacterium influences oral mucositis severity after allogeneic hematopoietic cell transplantation.}, journal = {NPJ biofilms and microbiomes}, volume = {10}, number = {1}, pages = {140}, pmid = {39604364}, issn = {2055-5008}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P30 CA015704/NH/NIH HHS/United States ; resident research award//American Academy of Oral Medicine Research Advancement Committee/ ; Dr. Douglass L. Morell Dentistry Research Fund//Research Advisory Committee of the University of Washington School of Dentistry/ ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Male ; Female ; *Stomatitis/etiology/microbiology ; *Saliva/microbiology ; Middle Aged ; Adult ; *Transplantation, Homologous/adverse effects ; Sex Factors ; Microbiota ; Severity of Illness Index ; Uric Acid/analysis ; Aged ; }, abstract = {The success of allogeneic hematopoietic cell transplantation (alloHCT) in curing hematologic disorders is limited by its short- and long-term toxicities. One such toxicity is oral mucositis (OM), causing pain, speech/swallowing difficulty, and prolonged hospitalization. Although conditioning chemoradiotherapy is the direct cause of OM, potential host-intrinsic mediators of mucosal injury remain elusive. We hypothesized that the oral microbiota may influence OM severity. We used a validated comprehensive scoring system based on specialized Oral Medicine examinations to longitudinally quantify OM severity in alloHCT recipients. High-throughput multi-site profiling of the oral microbiota was performed in parallel. We identify a sex-dependent commensal bacterium, Oribacterium asaccharolyticum, whose presence in saliva before transplantation is associated with more severe OM 14 days after transplantation. The sex predilection of this species correlated with higher uric acid levels in men. Our findings represent the first sex-dependent microbiota-mediated pathway in OM pathogenesis and introduce novel targets for preventative interventions.}, }
@article {pmid39603592, year = {2024}, author = {Thomson, CA and Arnold, KB and Anderson, G and Sun, V and Secord, AA and Yung, A and Al-Kasspooles, M and Nfonsam, VN and Grant, M and Deutsch, GB and Deneve, JL and Krouse, RS}, title = {Intake and Nutritional Adequacy in Patients with Cancer Diagnosed with Malignant Bowel Obstruction: A secondary analysis of a randomized trial.}, journal = {Journal of the Academy of Nutrition and Dietetics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jand.2024.11.011}, pmid = {39603592}, issn = {2212-2672}, abstract = {BACKGROUND: Malignant bowel obstruction (MBO) is experienced by many with advanced cancer. Patients with MBO cannot eat and may have reduced ability to eat once the acute process has resolved. Sparse data exist to describe oral intake capacity and adequacy of nutrition in MBO patients. These data are critical to developing effective supportive care nutrition therapy for patients with MBO.<br><br>OBJECTIVE: To describe the ability to consume food/liquids orally estimating nutritional adequacy of diet in a sample of patients who received surgical or non-surgical treatment for MBO.<br><br>DESIGN: A descriptive secondary data analysis of repeated dietary intake measures from S1316, a pragmatic comparative effectiveness trial of surgical and non-surgical treatment for MBO. Participant enrollment occurred between 2015 and 2020. Ability to eat was assessed through self-reported telephone survey and intake was estimated using telephone-based 24-hour recalls, applying USDA multi-pass methodology.<br><br>PARTICIPANTS/SETTING: The primary trial was conducted within the SWOG Cancer Research Network and included recruitment sites across the U.S. and Latin America. Eligible participants were diagnosed with, and hospitalized for, MBO.<br><br>MAIN OUTCOME MEASURES: The main outcomes measures were self- or caregiver reported ability to eat, as well as overall nutrient intake.<br><br>STATISTICAL ANALYSIS: Descriptive statistics were used to report patient characteristics, intake, and nutrient adequacy. Nutrient intake was presented by tertiles of gastrointestinal symptom severity and assessed.<br><br>RESULTS: 221 participants were registered; 199 were eligible and included. At Week 1, 51% of patients with MBO reported consuming some solid food orally; 34% reported no oral intake; 13% were on enteral feeding only. For patients alive and responsive to recalls at 13 weeks (n=57), 82% (n=47) reported consuming solid food. Compared to recommendations, mean reported intake was inadequate for most nutrients.<br><br>CONCLUSIONS: Oral intake is reported in more than half of patients diagnosed with MBO. Medical nutrition therapy should be tailored to patients' tolerance for eating and with consideration or patient's desire to address nutritional inadequacies.}, }
@article {pmid39600206, year = {2024}, author = {Antin, T and Cartujano-Barrera, F and De Genna, NM and Hinds, JT and Kaner, E and Lee, J and Patterson, JG and Ruiz, RA and Stimatze, T and Tan, ASL and Heffner, JL}, title = {Structural stigma and inequities in tobacco use among sexual and gender minoritized people: Accounting for context and intersectionality.}, journal = {Nicotine &amp; tobacco research : official journal of the Society for Research on Nicotine and Tobacco}, volume = {}, number = {}, pages = {}, doi = {10.1093/ntr/ntae280}, pmid = {39600206}, issn = {1469-994X}, }
@article {pmid39599646, year = {2024}, author = {Smith, KS and Gudenkauf, LM and Hoogland, AI and Li, X and Hoobler, R and Playdon, MC and Gigic, B and Small, BJ and Gonzalez, BD and Oswald, LB and Byrd, DA and Greathouse, KL and Ulrich, CM and Li, CI and Shibata, D and Toriola, AT and Peoples, AR and Siegel, EM and Figueiredo, JC and Jim, HSL and Crowder, SL}, title = {Associations Between Dietary Patterns and Quality of Life in a Longitudinal Cohort of Colorectal Cancer Survivors.}, journal = {Nutrients}, volume = {16}, number = {22}, pages = {}, pmid = {39599646}, issn = {2072-6643}, support = {R01NR018762/NR/NINR NIH HHS/United States ; T32CA009168, R2 U01CA206110, 1A1 R01CA189184, R01CA207371, and T32CA090314/CA/NCI NIH HHS/United States ; P30-CA076292//Cancer Center Support Grant/ ; }, mesh = {Humans ; *Quality of Life ; Female ; Male ; Middle Aged ; *Colorectal Neoplasms/psychology ; *Cancer Survivors/psychology/statistics &amp; numerical data ; Aged ; Longitudinal Studies ; Prospective Studies ; *Diet ; Adult ; Cross-Sectional Studies ; Feeding Behavior/psychology ; United States/epidemiology ; Dietary Patterns ; }, abstract = {PURPOSE: To characterize dietary patterns and examine associations with cross-sectional and longitudinal changes in quality of life (QOL) over approximately one year after colorectal cancer (CRC) diagnosis.<br><br>METHODS: The ColoCare Study is an international, multi-center, prospective cohort study of newly diagnosed CRC survivors of any stage. A subset of participants with CRC in the United States completed patient-reported outcome measures at 6- and 12-months post-enrollment, including the Food Frequency Questionnaire (FFQ) and European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Dietary patterns at 6 months (around the time of treatment completion) were identified using Principal Component Analysis (PCA) with varimax rotation. Adherence scores were calculated for participants within each dietary pattern, with higher scores indicating higher adherence. Mixed models were used to examine the effect of each dietary pattern on changes in QOL at 6- and 12-month follow-ups, controlling for cancer stage, biological sex, body mass index (BMI), smoking status, and age.<br><br>RESULTS: Participants (N = 174) were, on average, 56 &#xb1; 14 years old and were mostly female (51.5%), stage III or IV (51.7%), never smokers (60.2%), non-Hispanic (97.1%), and White (83.3%) with a BMI of 27.9 &#xb1; 6.1 kg/m[2]. PCA revealed two emerging dietary patterns: "Western diet", characterized by processed meats, refined grains, and sugars, and "Prudent diet" characterized by lean proteins, fruits, and vegetables. Higher adherence to a Western diet was associated with worse social functioning at 6-month follow-up (FE = -12.6, p = 0.010). Loss of appetite from 6 to 12 months was associated with higher adherence to both the Western and Prudent dietary patterns (FE = 1.5, p = 0.044; FE = 1.3, p = 0.046, respectively). Neither dietary pattern was associated with global QOL score at 6- or 12-month follow-up (p's > 0.05).<br><br>CONCLUSIONS: Among CRC survivors in the United States, the Western diet was concurrently associated with worse social functioning. Loss of appetite was reported by CRC survivors following both dietary patterns, suggesting that loss of appetite may be a global experience for CRC survivors during this timeframe. Further research is needed to understand specific social challenges experienced by CRC survivors and develop supportive care interventions to address appetite and nutritional concerns.}, }
@article {pmid39596582, year = {2024}, author = {Ha, ET and Haessler, J and Taylor, KD and Tuftin, B and Briggs, M and Parikh, MA and Peterson, SJ and Gerszten, RE and Wilson, JG and Kelsey, K and Tahir, UA and Seeman, T and Rich, SS and Carson, AP and Post, WS and Kooperberg, C and Rotter, JI and Raffield, LM and Auer, P and Reiner, AP}, title = {The Relationship of Duffy Gene Polymorphism with High-Sensitivity C-Reactive Protein, Mortality, and Cardiovascular Outcomes in Black Individuals.}, journal = {Genes}, volume = {15}, number = {11}, pages = {}, pmid = {39596582}, issn = {2073-4425}, support = {N01HC95163/HL/NHLBI NIH HHS/United States ; N01HC95164/HL/NHLBI NIH HHS/United States ; P30 DK063491/DK/NIDDK NIH HHS/United States ; N01HC95165/HL/NHLBI NIH HHS/United States ; N01HC95167/HL/NHLBI NIH HHS/United States ; HHSN268201800015I/HB/NHLBI NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; HHSN268201800010I/HB/NHLBI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; N01WH22110/WH/WHI NIH HHS/United States ; U01 HG004801/HG/NHGRI NIH HHS/United States ; 75N92020D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; HHSN268201500003C/HL/NHLBI NIH HHS/United States ; HHSN268201800012C/HL/NHLBI NIH HHS/United States ; 75N92020D00005/HL/NHLBI NIH HHS/United States ; N01HC95160/HL/NHLBI NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; U54 HG003067/HG/NHGRI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; U01 HG004790/HG/NHGRI NIH HHS/United States ; UL1 TR001079/TR/NCATS NIH HHS/United States ; HHSN268201800014I/HB/NHLBI NIH HHS/United States ; 75N92020D00001/HL/NHLBI NIH HHS/United States ; N01HC95169/HL/NHLBI NIH HHS/United States ; N02HL64278/HL/NHLBI NIH HHS/United States ; HHSN268201800014C/HL/NHLBI NIH HHS/United States ; N01HC95162/HL/NHLBI NIH HHS/United States ; 75N92020D00003/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; N01HC95168/HL/NHLBI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; U01 HG011720/HG/NHGRI NIH HHS/United States ; HHSN268201800013I/MD/NIMHD NIH HHS/United States ; N01HC95159/HL/NHLBI NIH HHS/United States ; HHSN268201800012I/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; N01HC95161/HL/NHLBI NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; 75N92020D00004/HL/NHLBI NIH HHS/United States ; HHSN268201800011C/HL/NHLBI NIH HHS/United States ; 75N92020D00007/HL/NHLBI NIH HHS/United States ; R01 HL146500/HL/NHLBI NIH HHS/United States ; HHSN268201500003I/HL/NHLBI NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; 75N92020D00006/HL/NHLBI NIH HHS/United States ; N01HC95166/HL/NHLBI NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; HHSN268201800011I/HB/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Duffy Blood-Group System/genetics ; Female ; *C-Reactive Protein/genetics/metabolism ; Male ; *Polymorphism, Single Nucleotide ; *Cardiovascular Diseases/genetics/mortality ; Aged ; Middle Aged ; Receptors, Cell Surface/genetics ; Black or African American/genetics ; White ; }, abstract = {Background: Black adults have higher incidence of all-cause mortality and worse cardiovascular disease (CVD) outcomes when compared to other U.S. populations. The Duffy chemokine receptor is not expressed on erythrocytes in a large majority of Black adults, but the clinical implications of this are unclear. Methods: Here, we investigated the relationship of Duffy receptor status, high-sensitivity C-reactive protein (hs-CRP), and mortality and incident CVD events (coronary heart disease, stroke, and heart failure) in self-identified Black members of three contemporary, longitudinal cohort studies (the Women's Health Initiative, Jackson Heart Study, and Multi-Ethnic Study of Atherosclerosis). Data on 14,358 Black participants (9023 Duffy-null and 5335 Duffy-receptor-positive, as defined using single-nucleotide polymorphism (SNP) rs2814778) were included in this analysis. Results: Duffy null was strongly associated with higher hs-CRP (meta-analysis p = 2.62 × 10[-9]), but the association was largely attenuated, though still marginally significant (p = 0.005), after conditioning on known CRP locus alleles in linkage disequilibrium with the Duffy gene. In our discovery cohorts, Duffy-null status appeared to be associated with a higher risk of all-cause mortality and incident stroke, though these associations were attenuated and non-significant following adjustment for traditional risk factors including hs-CRP. Moreover, the association of Duffy-null status with mortality could not be replicated in an independent sample of Black adults from the UK Biobank. Conclusions: These findings suggest that the higher levels of hs-CRP found in Duffy-null individuals may be in part independent of CRP alleles known to influence circulating levels of hs-CRP. During the follow-up of this community-based sample of Black participants, Duffy-null status was not associated with mortality or incident CVD events independently of traditional risk factors including hs-CRP.}, }
@article {pmid39596404, year = {2024}, author = {Wang, Z and Kaplan, RC and Burk, RD and Qi, Q}, title = {The Oral Microbiota, Microbial Metabolites, and Immuno-Inflammatory Mechanisms in Cardiovascular Disease.}, journal = {International journal of molecular sciences}, volume = {25}, number = {22}, pages = {}, pmid = {39596404}, issn = {1422-0067}, support = {K01 HL169019/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Cardiovascular Diseases/microbiology/immunology/metabolism ; *Mouth/microbiology ; Inflammation/microbiology/metabolism/immunology ; Gastrointestinal Microbiome ; Microbiota ; Animals ; }, abstract = {Cardiovascular diseases (CVDs) remain a leading cause of global morbidity and mortality. Recent advancements in high-throughput omics techniques have enhanced our understanding of the human microbiome's role in the development of CVDs. Although the relationship between the gut microbiome and CVDs has attracted considerable research attention and has been rapidly evolving in recent years, the role of the oral microbiome remains less understood, with most prior studies focusing on periodontitis-related pathogens. In this review, we summarized previously reported associations between the oral microbiome and CVD, highlighting known CVD-associated taxa such as Porphyromonas gingivalis, Fusobacterium nucleatum, and Aggregatibacter actinomycetemcomitans. We also discussed the interactions between the oral and gut microbes. The potential mechanisms by which the oral microbiota can influence CVD development include oral and systemic inflammation, immune responses, cytokine release, translocation of oral bacteria into the bloodstream, and the impact of microbial-related products such as microbial metabolites (e.g., short-chain fatty acids [SCFAs], trimethylamine oxide [TMAO], hydrogen sulfide [H2S], nitric oxide [NO]) and specific toxins (e.g., lipopolysaccharide [LPS], leukotoxin [LtxA]). The processes driven by these mechanisms may contribute to atherosclerosis, endothelial dysfunction, and other cardiovascular pathologies. Integrated multi-omics methodologies, along with large-scale longitudinal population studies and intervention studies, will facilitate a deeper understanding of the metabolic and functional roles of the oral microbiome in cardiovascular health. This fundamental knowledge will support the development of targeted interventions and effective therapies to prevent or reduce the progression from cardiovascular risk to clinical CVD events.}, }
@article {pmid39594840, year = {2024}, author = {Dekker, SE and Deng, L}, title = {Clinical Advances and Challenges in Targeting KRAS Mutations in Non-Small Cell Lung Cancer.}, journal = {Cancers}, volume = {16}, number = {22}, pages = {}, pmid = {39594840}, issn = {2072-6694}, abstract = {KRAS mutation is one of the most common oncogenic drivers in non-small cell lung cancer. Since its discovery about four decades ago, drug development targeting KRAS has been met with countless failures. Recently, KRAS G12C, a subvariant of KRAS, became the first druggable KRAS mutation. The efficacy of the first-generation KRAS inhibitor is modest, but with scientific advancement, KRAS G12C inhibitors with higher potency are on the horizon. Additionally, novel therapeutic approaches targeting other KRAS subvariants are also being explored in clinical trials with encouraging early data. We will review the clinical advances and challenges for patients with KRAS-mutated non-small cell lung cancer, with a focus on small molecule inhibitors.}, }
@article {pmid39594810, year = {2024}, author = {Ally, F and Chen, X}, title = {Acute Myeloid Leukemia: Diagnosis and Evaluation by Flow Cytometry.}, journal = {Cancers}, volume = {16}, number = {22}, pages = {}, pmid = {39594810}, issn = {2072-6694}, abstract = {With recent technological advances and significant progress in understanding the pathogenesis of acute myeloid leukemia (AML), the updated fifth edition WHO Classification (WHO-HAEM5) and the newly introduced International Consensus Classification (ICC), as well as the European LeukemiaNet (ELN) recommendations in 2022, require the integration of immunophenotypic, cytogenetic, and molecular data, alongside clinical and morphologic findings, for accurate diagnosis, prognostication, and guiding therapeutic strategies in AML. Flow cytometry offers rapid and sensitive immunophenotyping through a multiparametric approach and is a pivotal laboratory tool for the classification of AML, identification of therapeutic targets, and monitoring of measurable residual disease (MRD) post therapy. The association of immunophenotypic features and recurrent genetic abnormalities has been recognized and applied in informing further diagnostic evaluation and immediate therapeutic decision-making. Recently, the evolving role of machine learning models in assisting flow cytometric data analysis for the automated diagnosis and prediction of underlying genetic alterations has been illustrated.}, }
@article {pmid39591433, year = {2024}, author = {Peebles, K and Matrajt, L and Baeten, JM and Palanee-Phillips, T and Brown, ER and , }, title = {Understanding the sources of efficacy dilution in a trial of a monthly dapivirine vaginal ring for HIV-1 prevention.}, journal = {International journal of STD &amp; AIDS}, volume = {}, number = {}, pages = {9564624241300199}, doi = {10.1177/09564624241300199}, pmid = {39591433}, issn = {1758-1052}, abstract = {INTRODUCTION: Women-initiated HIV - 1 prevention products are key to reducing women's HIV-1 risk. Clinical trials of vaginal microbicides have shown limited to no efficacy in intention-to-treat (ITT) analyses. It is hypothesized that these negative results are partly due to efficacy dilution.<br><br>METHODS: We developed a microsimulation model of MTN-020/ASPIRE, a phase 3 trial that evaluated monthly use of a dapivirine vaginal ring for HIV-1 prevention. We evaluated four sources of efficacy dilution: trial-level factors: (i) an imbalance in the number of monthly sex acts between study arms and (ii) heterogeneity in risk emergent over time; and individual-level factors: (iii) product non-adherence and (iv) receptive anal intercourse.<br><br>RESULTS: Assuming 70% per-vaginal exposure efficacy (consistent with the ITT estimate of 27%), heterogeneity in risk accounted for the largest proportion of efficacy dilution, at 42% (90% CrI: 38, 45), followed by non-adherence (33%; 90% CrI: 27, 39), an imbalance in arms (18%; 90% CrI: 16, 21) and lastly, anal intercourse with less than 10% of efficacy dilution.<br><br>CONCLUSION: Our results suggest that heterogeneity in risk was the most important source of efficacy dilution in the ASPIRE trial. Future trials of HIV-1 prevention products for women should consider alternative trial designs and analytic approaches that minimize bias introduced by heterogeneity in risk.}, }
@article {pmid39589879, year = {2024}, author = {Varuzhanyan, G and Chen, CC and Freeland, J and He, T and Tran, W and Song, K and Wang, L and Cheng, D and Xu, S and Dibernardo, GA and Esedebe, FN and Bhatia, V and Han, M and Abt, ER and Park, JW and Memarzadeh, S and Shackelford, DB and Lee, JK and Graeber, TG and Shirihai, OS and Witte, ON}, title = {PGC-1α drives small cell neuroendocrine cancer progression toward an ASCL1-expressing subtype with increased mitochondrial capacity.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {49}, pages = {e2416882121}, pmid = {39589879}, issn = {1091-6490}, support = {01//G. Harold and Leila Y. Mathers Foundation (Mathers Foundation)/ ; P50CA092131&#xc2;//NIH UCLA SPORE in Prostate Cancer/ ; R01CA222877&#xc2;//NIH R01 Grant/ ; 01//UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research Hal Gaba Director's Fund for Cancer Stem Cell Research/ ; 01//Parker Institute for Cancer Immunotherapy (PICI)/ ; NIH T32 CA-009056//UCLA Tumor Cell Biology Training Program (USHHS) Ruth L. Kirschstein Institutional national Research Service Award/ ; 01//UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research predoctoral fellowship/ ; 01//UCLA Dissertation Year Fellowship/ ; I01BX006019//Veteran Affairs funds/ ; I01BX006019//Veteran Affairs funds/ ; 01//UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research Award/ ; 01//University of California-Historically Black Colleges and Universities (UC-HBCU) Initiative Fellowship provided by University of California Office of the President (UCOP)./ ; DP2 CA271301/CA/NCI NIH HHS/United States ; 2 P30 CA016042-44//NIH (NIH)/ ; 1 S10 OD026917-01A1//NIH (NIH)/ ; }, mesh = {Humans ; *Basic Helix-Loop-Helix Transcription Factors/metabolism/genetics ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism/genetics ; *Mitochondria/metabolism ; Male ; *Oxidative Phosphorylation ; Animals ; Cell Line, Tumor ; *Disease Progression ; Mice ; Prostatic Neoplasms/metabolism/pathology/genetics ; Gene Expression Regulation, Neoplastic ; Neuroendocrine Tumors/metabolism/pathology/genetics ; Cell Proliferation ; }, abstract = {Adenocarcinomas from multiple tissues can converge to treatment-resistant small cell neuroendocrine (SCN) cancers composed of ASCL1, POU2F3, NEUROD1, and YAP1 subtypes. We investigated how mitochondrial metabolism influences SCN cancer (SCNC) progression. Extensive bioinformatics analyses encompassing thousands of patient tumors and human cancer cell lines uncovered enhanced expression of proliferator-activatedreceptor gamma coactivator 1-alpha (PGC-1α), a potent regulator of mitochondrial oxidative phosphorylation (OXPHOS), across several SCNCs. PGC-1α correlated tightly with increased expression of the lineage marker Achaete-scute homolog 1, (ASCL1) through a positive feedback mechanism. Analyses using a human prostate tissue-based SCN transformation system showed that the ASCL1 subtype has heightened PGC-1α expression and OXPHOS activity. PGC-1α inhibition diminished OXPHOS, reduced SCNC cell proliferation, and blocked SCN prostate tumor formation. Conversely, PGC-1α overexpression enhanced OXPHOS, validated by small-animal Positron Emission Tomography mitochondrial imaging, tripled the SCN prostate tumor formation rate, and promoted commitment to the ASCL1 lineage. These results establish PGC-1α as a driver of SCNC progression and subtype determination, highlighting metabolic vulnerabilities in SCNCs across different tissues.}, }
@article {pmid39589470, year = {2024}, author = {Udovicich, C and Lo, SS and Guckenberger, M and Sahgal, A}, title = {Shifting the Landscape of Spine and Non-Spine Bone Metastases: A Review of Stereotactic Body Radiotherapy.}, journal = {Cancer journal (Sudbury, Mass.)}, volume = {30}, number = {6}, pages = {385-392}, pmid = {39589470}, issn = {1540-336X}, mesh = {Humans ; *Radiosurgery/methods ; *Spinal Neoplasms/secondary/radiotherapy ; *Bone Neoplasms/secondary/radiotherapy ; Palliative Care/methods ; Treatment Outcome ; }, abstract = {Both spine and nonspine bone metastases are frequent sites of spread from solid organ malignancies. As bone metastases frequently cause significant morbidity for patients, it is critical to offer a treatment that can achieve rapid and durable symptomatic relief and local control, without being associated with serious risks of toxicity. Conventional palliative radiation therapy has a key treatment component in the multidisciplinary management of these patients; however, over the past decade, it has evolved to routinely deliver high biologically effective doses with precision in the form of stereotactic body radiation therapy. This change in paradigm is a result of the shifting landscape in cancer care, such that short-term pain relief is no longer the sole therapeutic aim for selected patients, and durable symptom relief and local tumor control are the goals. This review discusses the randomized prospective evidence, ongoing trials, approach to surveillance imaging, and treatment delivery for stereotactic body radiation therapy, to both spine and nonspine bone metastases, with a specific section on sacral metastases.}, }
@article {pmid39589370, year = {2024}, author = {Lerner, SP and Tangen, C and Svatek, RS and Daneshmand, S and Pohar, KS and Skinner, E and Schuckman, A and Sagalowsky, AI and Smith, ND and Kamat, AM and Kassouf, W and Plets, M and Bangs, R and Koppie, TM and Alva, A and La Rosa, FG and Pal, SK and Kibel, AS and Canter, DJ and Thompson, IM and , }, title = {Standard or Extended Lymphadenectomy for Muscle-Invasive Bladder Cancer.}, journal = {The New England journal of medicine}, volume = {391}, number = {13}, pages = {1206-1216}, pmid = {39589370}, issn = {1533-4406}, support = {U10 CA180821/CA/NCI NIH HHS/United States ; 707213//Canadian Cancer Society/ ; U10 CA180863/CA/NCI NIH HHS/United States ; U10 CA180820/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; U10 CA180819/CA/NCI NIH HHS/United States ; U10CA180888 U10CA180819, U10CA180820, U10CA180821,/CA/NCI NIH HHS/United States ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; Chemotherapy, Adjuvant ; *Cystectomy/adverse effects/methods ; Disease-Free Survival ; Kaplan-Meier Estimate ; *Lymph Node Excision/adverse effects/methods ; Lymphatic Metastasis/pathology/therapy ; Neoadjuvant Therapy ; Neoplasm Invasiveness ; Neoplasm Staging ; *Urinary Bladder Neoplasms/mortality/pathology/therapy ; Adult ; Aged, 80 and over ; }, abstract = {BACKGROUND: Whether extended lymphadenectomy is associated with improved disease-free and overall survival, as compared with standard lymphadenectomy, among patients with localized muscle-invasive bladder cancer undergoing radical cystectomy is unclear.<br><br>METHODS: We randomly assigned, in a 1:1 ratio, patients with localized muscle-invasive bladder cancer of clinical stage T2 (confined to muscle) to T4a (invading adjacent organs) with two or fewer positive nodes (N0, N1, or N2) to undergo bilateral standard lymphadenectomy (dissection of lymph nodes on both sides of the pelvis) or extended lymphadenectomy involving removal of common iliac, presciatic, and presacral nodes. Randomization was performed during surgery and stratified according to the receipt and type of neoadjuvant chemotherapy, tumor stage (T2 vs. T3 or T4a), and a Zubrod's performance-status score (0 or 1 vs. 2; assessed on a 5-point scale, with higher scores indicating greater disability). The primary outcome was disease-free survival. Overall survival and safety were also assessed.<br><br>RESULTS: Of 658 patients who were enrolled, 592 eligible patients were randomly assigned to undergo extended lymphadenectomy (292 patients) or standard lymphadenectomy (300). Surgery was performed by 36 surgeons at 27 sites in the United States and Canada. Neoadjuvant chemotherapy had been received by 57% of the patients. At a median follow-up of 6.1 years, recurrence or death had occurred in 130 patients (45%) in the extended-lymphadenectomy group and in 127 (42%) in the standard-lymphadenectomy group, and the estimated 5-year disease-free survival was 56% and 60%, respectively (hazard ratio for recurrence or death, 1.10; 95% confidence interval [CI], 0.86 to 1.40; P&#x2009;=&#x2009;0.45). Overall survival at 5 years was 59% in the extended-lymphadenectomy group and 63% in the standard-lymphadenectomy group (hazard ratio for death, 1.13; 95% CI, 0.88 to 1.45). Adverse events of grade 3 to 5 occurred in 157 patients (54%) in the extended-lymphadenectomy group and in 132 (44%) in the standard-lymphadenectomy group; death within 90 days after surgery occurred in 19 patients (7%) and 7 patients (2%), respectively.<br><br>CONCLUSIONS: As compared with standard lymphadenectomy, extended lymphadenectomy did not result in improved disease-free or overall survival among patients with muscle-invasive bladder cancer undergoing radical cystectomy and was associated with higher perioperative morbidity and mortality. (Funded by the National Cancer Institute and the Canadian Cancer Society; SWOG S1011 ClinicalTrials.gov number, NCT01224665.).}, }
@article {pmid39589343, year = {2024}, author = {Haffner, MC and Morris, MJ and Ding, CC and Sayar, E and Mehra, R and Robinson, B and True, LD and Gleave, M and Lotan, TL and Aggarwal, R and Huang, J and Loda, M and Nelson, PS and Rubin, MA and Beltran, H}, title = {Framework for the Pathology Workup of Metastatic Castration-Resistant Prostate Cancer Biopsies.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-24-2061}, pmid = {39589343}, issn = {1557-3265}, abstract = {Lineage plasticity and histologic transformation from prostate adenocarcinoma to neuroendocrine prostate cancer (NEPC) occurs in up to 15-20% of patients with castration-resistant prostate cancer (CRPC) as mechanism of treatment resistance and is associated with aggressive disease and poor prognosis. NEPC tumors typically display small cell carcinoma morphology with loss of androgen receptor (AR) expression and gain of neuroendocrine (NE) lineage markers. However, there is a spectrum of phenotypes that are observed during the lineage plasticity process, and the clinical significance of mixed histologies or those that co-express AR and NE markers or lack all markers is not well defined. Translational research studies investigating NEPC have used variable definitions making clinical trial design challenging. Here we discuss the diagnostic workup of metastatic biopsies to help guide the reproducible classification of phenotypic CRPC subtypes. We recommend classifying CRPC tumors based on histomorphology (adenocarcinoma, small cell carcinoma, poorly differentiated carcinoma, other morphologic variant, or mixed morphology) and immunohistochemical markers with a priority for AR, NKX3.1, INSM1, synaptophysin and cell proliferation based on Ki-67 positivity, with additional markers to be considered based on the clinical context. Ultimately, a unified workup of metastatic CRPC biopsies can improve clinical trial design and eventually practice.}, }
@article {pmid39587707, year = {2024}, author = {Ilozumba, MN and Lin, T and Hardikar, S and Byrd, DA and Round, JL and Stephens, WZ and Holowatyj, AN and Warby, CA and Damerell, V and Li, CI and Figueiredo, JC and Toriola, AT and Shibata, D and Fillmore, GC and Pickron, B and Siegel, EM and Kahlert, C and Florou, V and Gigic, B and Ose, J and Ulrich, CM}, title = {Fusobacterium nucleatum Abundance is Associated with Cachexia in Colorectal Cancer Patients: The ColoCare Study.}, journal = {Cancer medicine}, volume = {13}, number = {22}, pages = {e70431}, pmid = {39587707}, issn = {2045-7634}, support = {//the German Ministry of Education and Research project PerMiCCion (01KD2101D)/ ; //German Cancer Research Center/ ; //the German Consortium of Translational Cancer Research, (DKTK)/ ; R01 CA189184/CA/NCI NIH HHS/United States ; R01 CA207371/CA/NCI NIH HHS/United States ; R01 CA211705/CA/NCI NIH HHS/United States ; R01 CA254108/CA/NCI NIH HHS/United States ; U01 CA206110/CA/NCI NIH HHS/United States ; //University of Utah Immunology, Inflammation, and Infectious Disease Initiative/ ; //Huntsman Cancer Foundation/ ; //Stiftung LebensBlicke, Matthias Lackas Stiftung, Claussen-Simon Stiftung/ ; //the Rahel-Goitein-Straus-Program, Medical Faculty Heidelberg University/ ; //ERA-NET (European Research Area Network) on Translational Cancer Research (TRANSCAN) project/ ; //Cancer Control and Population Health Sciences (CCPS) at the University of Utah/ ; }, mesh = {Humans ; *Colorectal Neoplasms/complications/microbiology ; Male ; *Cachexia/etiology/microbiology ; *Fusobacterium nucleatum/isolation &amp; purification ; Female ; Aged ; Middle Aged ; *Feces/microbiology ; Fusobacterium Infections/complications/microbiology ; Neoplasm Staging ; Risk Factors ; }, abstract = {BACKGROUND: Cachexia accounts for about 20% of all cancer-related deaths and indicates poor prognosis. The impact of Fusobacterium nucleatum (Fn), a microbial risk factor for colorectal cancer (CRC), on the development of cachexia in CRC has not been established.<br><br>METHODS: We evaluated the association between Fn abundance in pre-surgical stool samples and onset of cachexia at 6&#x2009;months post-surgery in n&#x2009;=&#x2009;87 patients with stages I-III CRC in the ColoCare Study.<br><br>RESULTS: High fecal Fn abundance compared to negative/low fecal Fn abundance was associated with 4-fold increased risk of cachexia onset at 6&#x2009;months post-surgery (OR&#x2009;=&#x2009;4.82, 95% CI&#x2009;=&#x2009;1.15, 20.10, p&#x2009;=&#x2009;0.03).<br><br>CONCLUSION: Our findings suggest that high fecal Fn abundance was associated with an increased risk of cachexia at 6&#x2009;months post-surgery in CRC patients. This is the first study to link Fn abundance with cachexia in CRC patients, offering novel insights into biological mechanisms and potential management of cancer cachexia. Due to the small sample size, our results should be interpreted with caution. Future studies with larger sample sizes are needed to validate these findings.}, }
@article {pmid39587448, year = {2024}, author = {Papadimitriou, N and Murphy, N and Jenab, M and Chen, Z and Brenner, H and Kweon, SS and Le Marchand, L and Moreno, V and Platz, EA and van Duijnhoven, FJB and Cheng, I and Pai, RK and Phipps, AI and Peters, U and Zheng, W and Hughes, DJ}, title = {Body mass index at birth and early life and colorectal cancer: A two-sample Mendelian randomization analysis in European and East Asian genetic similarity populations.}, journal = {Pediatric obesity}, volume = {}, number = {}, pages = {e13186}, doi = {10.1111/ijpo.13186}, pmid = {39587448}, issn = {2047-6310}, support = {31312020//International Health Cohorts Consortium/Global Genomic Medicine Collaborative/ ; R01CA188214/NH/NIH HHS/United States ; }, abstract = {BACKGROUND: Varying obesogenic inherited predisposition in early to later life may differentially impact colorectal cancer (CRC) development. Previous Mendelian randomization (MR) studies, conducted in populations of European genetic similarity, have not observed any significant associations between early life body weight with CRC risk. However, it remains unclear whether body mass index (BMI) at different early lifetime points is causally related with CRC risk in both Europeans and East Asian populations.<br><br>OBJECTIVES: We conducted a two-sample MR study to investigate potential causal relationships between genetically predicted BMI during early life (birth to 8&#x2009;years old) and at specific periods (birth, transient, early rise and late rise) and CRC risk.<br><br>METHODS: Summary data were obtained from genome-wide association study (GWAS) of BMI in 28&#x2009;681 children from the Norwegian Mother, Father and Child Cohort Study (MoBa) study and applied to CRC GWAS data from European and East Asian descent populations (102&#x2009;893 cases and 485&#x2009;083 non-cases).<br><br>RESULTS: There were no significant associations observed between early life BMI and CRC risk in European or East Asian populations. The effect estimates were similar in European studies (odds ratio [OR] per a 1-standard deviation [SD] increase: 1.01, 95% confidence interval [CI]: 0.95, 1.07) and in East Asians (OR per a 1-SD increase: 1.02, 95% CI: 0.91, 1.14). Similar nonsignificant associations were found between time of BMI measurement during childhood and cancer-site-specific analyses.<br><br>CONCLUSIONS: We found little evidence of any associations between early life adiposity on later life CRC risk.}, }
@article {pmid39586191, year = {2024}, author = {Dean, NE and Halloran, ME and Zarnitsyna, VI}, title = {Poor vaccine responders mask the true trend in vaccine effectiveness against progression to severe disease.}, journal = {Vaccine}, volume = {43}, number = {Pt 2}, pages = {126516}, doi = {10.1016/j.vaccine.2024.126516}, pmid = {39586191}, issn = {1873-2518}, abstract = {Vaccines can reduce an individual's risk of infection and their risk of progression to severe disease given infection. The latter effect is less commonly estimated but is relevant for vaccine impact modeling and cost-effectiveness calculations. Using a motivating example from the COVID-19 literature, we note how vaccine effectiveness against progression to severe disease can appear to increase from below 0 % to over 70 % within 8 months. With true biological strengthening of this magnitude being unlikely, we use a mathematical modeling framework to identify parameter combinations where this phenomenon can occur. Fundamental features are an immunocompetent population with high initial protection against infection, contrasted with a vulnerable subpopulation with poor vaccine response against infection and progression. As a result, the earliest infections are among those with the weakest protection against severe disease. This work highlights methodological challenges in isolating a vaccine's effect on progression to severe disease after infection, and it signals the need for refined analytical methods to adjust for differences between the vaccinated infected and the unvaccinated infected populations.}, }
@article {pmid39586040, year = {2024}, author = {LeBlanc, ML}, title = {Using Cure Models for Trial Analysis and Design.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2401918}, doi = {10.1200/JCO-24-01918}, pmid = {39586040}, issn = {1527-7755}, }
@article {pmid39584453, year = {2024}, author = {Colasurdo, M and Ferrer-Font, L and Middlebrook, A and Konecny, AJ and Prlic, M and Spidlen, J}, title = {SingletSeeker: an unsupervised clustering approach for automated singlet discrimination in cytometry.}, journal = {Cytometry. Part B, Clinical cytometry}, volume = {}, number = {}, pages = {}, doi = {10.1002/cyto.b.22216}, pmid = {39584453}, issn = {1552-4957}, support = {R01 AI123323/NH/NIH HHS/United States ; R56 DE032009/NH/NIH HHS/United States ; //Emerson Collective/ ; }, abstract = {Flow cytometry is a high-throughput, high-dimensional technique that generates large sets of single-cell data. Prior to analyzing this data, it is common to exclude any events that contain two or more cells, multiplets, to ensure downstream analysis and quantification is of single-cell events, singlets, only. The process of singlet discrimination is critical yet fundamentally subjective and time-consuming; it is performed manually by the user, where the proper exclusion of multiplets depends on the user's expertise and often varies from experiment to experiment. To address this problem, we have developed an algorithm to automatically discriminate singlets from other unwanted events such as multiplets and debris. Using parameters derived from imaging, the algorithm first identifies high-density clusters of events using a density-based clustering algorithm, and then classifies the clusters based on their properties. Multiplets are discarded in the first step, while singlets are distinguished from debris in the second step. The algorithm can use different strategies on imaging feature selection-based user's preferences and imaging features available. In addition, the relative importance of singlets precision vs. sensitivity can be further tweaked via a density coefficient adjustment. Twenty-two datasets from various sites and of various cell types acquired on the BD FACSDiscover™ S8 Cell Sorter with CellView™ Image Technology were used to develop and validate the algorithm across multiple imaging feature sets. A consistent singlets precision >97% with a solid >88% sensitivity has been demonstrated with a LightLoss feature set and the default density coefficient. This work yields a high-precision, high-sensitivity algorithm capable of objective and automated singlet discrimination across multiple cell types using various imaging-derived parameters. A free FlowJo™ Software plugin implementation is available for simple and reproducible singlet discrimination for use at the beginning of any user's workflow.}, }
@article {pmid39582620, year = {2024}, author = {Isacchini, G and Quiniou, V and Barennes, P and Mhanna, V and Vantomme, H and Stys, P and Mariotti-Ferrandiz, E and Klatzmann, D and Walczak, AM and Mora, T and Nourmohammad, A}, title = {Local and Global Variability in Developing Human T-Cell Repertoires.}, journal = {PRX life}, volume = {2}, number = {1}, pages = {}, pmid = {39582620}, issn = {2835-8279}, support = {R35 GM142795/GM/NIGMS NIH HHS/United States ; }, abstract = {The adaptive immune response relies on T cells that combine phenotypic specialization with diversity of T-cell receptors (TCRs) to recognize a wide range of pathogens. TCRs are acquired and selected during T-cell maturation in the thymus. Characterizing TCR repertoires across individuals and T-cell maturation stages is important for better understanding adaptive immune responses and for developing new diagnostics and therapies. Analyzing a dataset of human TCR repertoires from thymocyte subsets, we find that the variability between individuals generated during the TCR V(D)J recombination is maintained through all stages of T-cell maturation and differentiation. The interindividual variability of repertoires of the same cell type is of comparable magnitude to the variability across cell types within the same individual. To zoom in on smaller scales than whole repertoires, we defined a distance measuring the relative overlap of locally similar sequences in repertoires. We find that the whole repertoire models correctly predict local similarity networks, suggesting a lack of forbidden T-cell receptor sequences. The local measure correlates well with distances calculated using whole repertoire traits and carries information about cell types.}, }
@article {pmid39581347, year = {2024}, author = {Wittenauer, R and Bacci, JL and Shah, PD and Stergachis, A}, title = {Vaccination payments in states with provider status for pharmacists: a claims analysis.}, journal = {Journal of the American Pharmacists Association : JAPhA}, volume = {}, number = {}, pages = {102301}, doi = {10.1016/j.japh.2024.102301}, pmid = {39581347}, issn = {1544-3450}, abstract = {BACKGROUND: Federal-level legislation to recognize pharmacists as providers and thus allow insurance reimbursement for health services claims, not just prescription drug claims (known as provider status), has been advocated by the profession but is yet to be passed into federal law. Several state governments have enacted this recognition for commercial insurance and/or Medicaid plans. However, the impact of these laws on reimbursement and access to health services has yet to be explored empirically.<br><br>OBJECTIVE: Compare commercial reimbursements for influenza and herpes zoster vaccinations for adults in provider status vs non-provider status states to determine whether these laws have had an intended effect of increasing reimbursement to pharmacists for provided services.<br><br>METHODS: We used pharmaceutical and outpatient services claims from a national claims database, Marketscan, to examine payments made to pharmacies for all codes billed during vaccination visits. We then used a multivariable logistic regression model to compare the net revenue of vaccination visits in commercial provider status states versus non-provider-status states.<br><br>RESULTS: Our dataset contained 2.3 million vaccination visits for influenza and herpes zoster during 2021-2022. We found that the odds of a vaccination visit having positive net revenue were slightly higher in provider status states (shingles OR: 1.03, p<0.001; influenza OR 1.01:, p<0.001). These findings are limited by the stark lack of health services claims by pharmacies in our dataset; only 0.4% of visits included any outpatient services claims, even among provider status states.<br><br>CONCLUSION: This indicates that pharmacists are not submitting claims for reimbursement to payors for health services they are providing. This absence could be due to several reasons and limits the ability to generate evidence about the effect of these laws on health and economic outcomes for patients and health systems. Further research is needed to identify and address barriers to implementation of provider status laws.}, }
@article {pmid39581232, year = {2024}, author = {Setia, M and Suvas, PK and Rana, M and Chakraborty, A and Suvas, S}, title = {Herpes stromal keratitis erodes the establishment of tissue-resident memory T cell pool in HSV-1 infected corneas.}, journal = {Mucosal immunology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.mucimm.2024.11.003}, pmid = {39581232}, issn = {1935-3456}, abstract = {The recurrent herpes simplex virus-1 (HSV-1) infection of the cornea can cause the development of herpes stromal keratitis (HSK). This chronic immunoinflammatory condition is a major cause of infection-induced vision loss. The previous episodes of HSK increase the risk of future recurrences in the same cornea. However, not all HSV-1 infected corneas that shed infectious virus at the ocular surface develop HSK, suggesting that corneal HSV-1 infection may cause an establishment of protective immunity in HSV-1 infected corneas. However, upon recurrent corneal HSV-1 infection, the established protective immunity can get compromised, resulting in the development of HSK. In this study, we compared the quantity and quality of tissue-resident memory T (TRM) cells in HSV-1 infected corneas that did or did not develop HSK. Our results showed the predominance of TRM cell in the epithelium than in stroma of HSV-1 infected corneas. Furthermore, HSV-1 infected non-HSK corneas exhibited more CD4 and CD8 TRM cells than HSK corneas. The TRM cells in non-HSK than in HSK corneas were more effective in clearing the infectious virus upon secondary corneal HSV-1 infection. Our results demonstrate the differential quantity and quality of TRM cells in HSV-1 infected corneas that did or did not develop HSK.}, }
@article {pmid39580580, year = {2024}, author = {Chan, WC and Liu, L and Bouras, E and Zuber, V and Wen, W and Long, J and Gill, D and Murphy, N and Gunter, MJ and Assimes, TL and Bujanda, L and Gruber, SB and Küry, S and Lynch, BM and Qu, C and Thomas, M and White, E and Woods, MO and Peters, U and Li, CI and Chan, AT and Brenner, H and Tsilidis, KK and Zheng, W}, title = {Associations of blood lipids and LDL cholesterol lowering drug-targets with colorectal cancer risk: a Mendelian randomisation study.}, journal = {British journal of cancer}, volume = {}, number = {}, pages = {}, pmid = {39580580}, issn = {1532-1827}, abstract = {BACKGROUND: Whether blood lipids are causally associated with colorectal cancer (CRC) risk remains unclear.<br><br>METHODS: Using two-sample Mendelian randomisation (MR), our study examined the associations of genetically-predicted blood concentrations of lipids and lipoproteins (primary: LDL-C, HDL-C, triglycerides, and total cholesterol), and genetically-proxied inhibition of HMGCR, NPC1L1, and PCSK9 (which mimic therapeutic effects of LDL-lowering drugs), with risks of CRC and its subsites. Genetic associations with lipids were obtained from the Global Lipids Genetics Consortium (n&#x2009;=&#x2009;1,320,016), while genetic associations with CRC were obtained from the largest existing CRC consortium (n&#x2009;=&#x2009;58,221 cases and 67,694 controls). Our main analysis was a multivariable MR (MVMR) with mutual adjustments for LDL-C, HDL-C, and triglycerides. Secondary analyses, including MVMR additionally-adjusting for BMI or diabetes, were also performed.<br><br>RESULTS: Genetically-predicted LDL-C was positively associated with CRC risk in the MVMR adjusted for HDL-C and triglycerides (OR&#x2009;=&#x2009;1.09; 95%CI 1.02-1.16 per SD increase) and additionally-adjusted for BMI (OR&#x2009;=&#x2009;1.12; 95%CI 1.05-1.21) or diabetes (OR&#x2009;=&#x2009;1.09; 95%CI 1.02-1.17). Associations were generally consistent across anatomical subsites. No clear evidence of association was found for other lipids, lipoproteins, or LDL-lowering drug-targets.<br><br>CONCLUSIONS: We found evidence of a weak positive association between LDL-C and CRC that did not appear to be explained by potential pleiotropic pathways such as via HDL-C, triglycerides, BMI, or diabetes.}, }
@article {pmid39579334, year = {2024}, author = {Clement, ME and Hanscom, B and Haines, D and Bazan, JA and Chotirosniramit, N and Kofron, R and Mannheimer, S and Mayer, KH and Torres Silva, MS and Soto-Torres, L and Rinehart, AR and Rooney, JF and Jennings, A and Gomez-Feliciano, K and McCauley, M and Grinsztejn, B and Landovitz, RJ and , }, title = {Cabotegravir Maintains Protective Efficacy in the Setting of Bacterial STIs: A Secondary Analysis of HPTN 083.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciae572}, pmid = {39579334}, issn = {1537-6591}, abstract = {BACKGROUND: Sexually transmitted infections (STIs) have been shown to facilitate HIV transmission and acquisition. HPTN 083, a global clinical trial, demonstrated superiority of long-acting cabotegravir (CAB-LA) versus daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for HIV prevention among transgender women and cisgender men who have sex with men. This analysis assessed whether CAB-LA maintained protective efficacy when bacterial STIs (syphilis, rectal/urethral gonorrhea and chlamydia) were present.<br><br>METHODS: STI events per 100 person-years (PY) were calculated, including by subgroups (age, race/ethnicity, gender, education, treatment arm, drug use, alcohol use, region/country, condom usage, partner number, marital status, baseline STI). Association between baseline factors and STI incidence was modeled using Poisson regression. Cox proportional hazards modeling with STI status as a time-varying covariate was used to evaluate potential interactions between STI status and the relative efficacy of CAB-LA vs. TDF/FTC.<br><br>FINDINGS: Among 3,859 participants, overall STI incidence rate was 50.7 infections/100PY. STIs were diagnosed in 1,562 (40.5%) participants; 79% of STIs occurred in 25% of the participants. STI incidence was not different by PrEP arm. In the final multivariable model, age, region, race, education level, marital status, and baseline STI were associated with incident STI (p<0.05). HIV incidence was lower with CAB-LA vs. TDF/FTC with or without STIs (hazard ratios 0.37 and 0.31, respectively), with no significant interaction between STIs and the HR for HIV incidence (p = 0.75).<br><br>CONCLUSION: In a large PrEP trial with high STI incidence, CAB-LA maintained robust protective efficacy relative to TDF/FTC in the setting of bacterial STIs.}, }
@article {pmid39577421, year = {2024}, author = {Hamidi, H and Senbabaoglu, Y and Beig, N and Roels, J and Manuel, C and Guan, X and Koeppen, H and Assaf, ZJ and Nabet, BY and Waddell, A and Yuen, K and Maund, S and Sokol, E and Giltnane, JM and Schedlbauer, A and Fuentes, E and Cowan, JD and Kadel, EE and Degaonkar, V and Andreev-Drakhlin, A and Williams, P and Carter, C and Gupta, S and Steinberg, E and Loriot, Y and Bellmunt, J and Grivas, P and Rosenberg, J and van der Heijden, MS and Galsky, MD and Powles, T and Mariathasan, S and Banchereau, R}, title = {Molecular heterogeneity in urothelial carcinoma and determinants of clinical benefit to PD-L1 blockade.}, journal = {Cancer cell}, volume = {42}, number = {12}, pages = {2098-2112.e4}, doi = {10.1016/j.ccell.2024.10.016}, pmid = {39577421}, issn = {1878-3686}, mesh = {Humans ; *Immune Checkpoint Inhibitors/therapeutic use/pharmacology ; *B7-H1 Antigen/antagonists &amp; inhibitors/genetics/metabolism ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Urinary Bladder Neoplasms/drug therapy/genetics/pathology ; Carcinoma, Transitional Cell/drug therapy/genetics/pathology ; Male ; Female ; Biomarkers, Tumor/genetics/metabolism ; Genetic Heterogeneity ; Aged ; }, abstract = {Checkpoint inhibitors targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) have revolutionized cancer therapy across many indications including urothelial carcinoma (UC). Because many patients do not benefit, a better understanding of the molecular mechanisms underlying response and resistance is needed to improve outcomes. We profiled tumors from 2,803 UC patients from four late-stage randomized clinical trials evaluating the PD-L1 inhibitor atezolizumab by RNA sequencing (RNA-seq), a targeted DNA panel, immunohistochemistry, and digital pathology. Machine learning identifies four transcriptional subtypes, representing luminal desert, stromal, immune, and basal tumors. Overall survival benefit from atezolizumab over standard-of-care is observed in immune and basal tumors, through different response mechanisms. A self-supervised digital pathology approach can classify molecular subtypes from H&amp;E slides with high accuracy, which could accelerate tumor molecular profiling. This study represents a large integration of UC molecular and clinical data in randomized trials, paving the way for clinical studies tailoring treatment to specific molecular subtypes in UC and other indications.}, }
@article {pmid39576958, year = {2024}, author = {Adams, RC and MacDonald, KP and Hill, GR}, title = {The Contribution of the Monocyte-Macrophage Lineage to Immunotherapy Outcomes.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024025680}, pmid = {39576958}, issn = {1528-0020}, abstract = {Macrophages execute core functions in maintaining tissue homeostasis, where their extensive plasticity permits a spectrum of functions from tissue remodelling to immune defence. However, perturbations to tissue-resident macrophages during disease, and the subsequent emergence of monocyte-derived macrophages, can hinder tissue recovery and promote further damage through inflammatory and fibrotic programs. Gaining a fundamental understanding of the critical pathways defining pathogenic macrophage populations enables the development of targeted therapeutic approaches to improve disease outcomes. In the setting of chronic graft-versus-host disease (cGVHD), which remains the major complication of allogeneic haematopoietic stem cell transplantation, colony-stimulating factor 1 (CSF1)-dependent donor-derived macrophages have been identified as key pathogenic mediators of fibrotic skin and lung disease. Antibody blockade of the CSF1R to induce macrophage depletion showed remarkable capacity to prevent fibrosis in pre-clinical models and has subsequently demonstrated impressive efficacy for improving fibrotic cGVHD in ongoing clinical trials. Similarly, macrophage depletion approaches are currently under investigation for their potential to augment responses to immune checkpoint inhibition. Moreover, both monocyte and tissue-resident macrophage populations have recently been implicated as mediators of the numerous toxicities associated with CAR T-cell therapy, further highlighting potential avenues of macrophage-based interventions to improve clinical outcomes. Herein, we examine the current literature on basic macrophage biology and contextualise this in the setting of cellular and immunotherapy. Additionally, we highlight mechanisms by which macrophages can be targeted, largely by interfering with the CSF1/CSF1R signalling axis, for therapeutic benefit in the context of both cellular and immunotherapy.}, }
@article {pmid39576815, year = {2024}, author = {Weissman, JL and Chappell, CR and Francesco Rodrigues de Oliveira, B and Evans, N and Fagre, AC and Forsythe, D and Frese, SA and Gregor, R and Ishaq, SL and Johnston, J and K R, B and Matsuda, SB and McCarren, S and Ortiz Alvarez de la Campa, M and Roepke, TA and Sinnott-Armstrong, N and Stobie, CS and Talluto, L and Vargas-Muñiz, JM and , }, title = {Queer- and trans-inclusive faculty hiring-A call for change.}, journal = {PLoS biology}, volume = {22}, number = {11}, pages = {e3002919}, pmid = {39576815}, issn = {1545-7885}, mesh = {*Faculty ; Humans ; *Personnel Selection/methods ; *Sexual and Gender Minorities ; Universities ; }, abstract = {As queer and trans scientists, we face varied and systemic barriers to our professional success, resulting in our relative absence from faculty ranks at many institutions. In this Perspective, we call for a change in faculty hiring practices and present concrete guidance to make it a more inclusive process.}, }
@article {pmid39576760, year = {2024}, author = {Correa-Medero, RL and Pai, R and Ebare, K and Buchanan, DD and Jenkins, MA and Phipps, AI and Newcomb, PA and Gallinger, S and Grant, R and Le Marchand, L and Banerjee, I}, title = {Causal debiasing for unknown bias in histopathology-A colon cancer use case.}, journal = {PloS one}, volume = {19}, number = {11}, pages = {e0303415}, pmid = {39576760}, issn = {1932-6203}, mesh = {Humans ; *Colonic Neoplasms/pathology ; Proportional Hazards Models ; Bias ; Prognosis ; Female ; Male ; Disease-Free Survival ; }, abstract = {Advancement of AI has opened new possibility for accurate diagnosis and prognosis using digital histopathology slides which not only saves hours of expert effort but also makes the estimation more standardized and accurate. However, preserving the AI model performance on the external sites is an extremely challenging problem in the histopathology domain which is primarily due to the difference in data acquisition and/or sampling bias. Although, AI models can also learn spurious correlation, they provide unequal performance across validation population. While it is crucial to detect and remove the bias from the AI model before the clinical application, the cause of the bias is often unknown. We proposed a Causal Survival model that can reduce the effect of unknown bias by leveraging the causal reasoning framework. We use the model to predict recurrence-free survival for the colorectal cancer patients using quantitative histopathology features from seven geographically distributed sites and achieve equalized performance compared to the baseline traditional Cox Proportional Hazards and DeepSurvival model. Through ablation study, we demonstrated benefit of novel addition of latent probability adjustment and auxiliary losses. Although detection of cause of unknown bias is unsolved, we proposed a causal debiasing solution to reduce the bias and improve the AI model generalizibility on the histopathology domain across sites. Open-source codebase for the model training can be accessed from https://github.com/ramon349/fair_survival.git.}, }
@article {pmid39576210, year = {2024}, author = {Sweis, RF and Chatta, GS and Jain, RK and Moon, H and Delacroix, SE and Fang, A and D'Amico, L and Kask, AS and Cheever, MA and Fling, S and Sharon, E and Lacroix, A and Kaiser, JC and Pachynski, RK and Yu, EY}, title = {A phase II open label, randomized clinical trial of atezolizumab with or without human recombinant IL-7 (CYT107) in advanced urothelial cancer.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-24-1728}, pmid = {39576210}, issn = {1557-3265}, abstract = {PURPOSE: Advanced urothelial cancer generally has high mortality despite modern anti-PD-1/L1 antibody-based combinations. Augmenting checkpoint inhibitor-mediated immune responses with lymphocyte growth factors may improve outcomes. We conducted a randomized phase II study (CITN-14) in 47 patients to explore whether human recombinant IL-7 (CYT107) could be safely combined with PD-L1 inhibition to enhance responses.<br><br>PATIENTS AND METHODS: Patients with urothelial cancer following platinum chemotherapy were randomized to atezolizumab alone or with CYT107 weekly for four doses. The primary objective was clinical efficacy by objective response rate (ORR). Secondary objectives included safety, toxicity, and other clinical outcomes. Correlative endpoints included peripheral immunophenotyping and quantification of cytokines.<br><br>RESULTS: CYT107 plus atezolizumab was well-tolerated, without dose-limiting toxicities (DLTs), and lower grade 3-4 treatment-related adverse events (TRAEs) compared to atezolizumab. The ORR was 26.3% for the combination versus 23.8% for atezolizumab alone (p = 0.428). The complete response (CR) rate was 10.5% for the combination versus 4.8% for monotherapy. Three patients on the combination had responses >21 months versus one with monotherapy. CD4+ and CD8+ T lymphocyte expansion occurred in patients with response to combination therapy, with the greatest effect in T memory stem cell (Tscm) cells. Responding patients had elevated baseline CCL4 and decreased VEGF-A and TNF.<br><br>CONCLUSIONS: Combining CYT107 with atezolizumab was safe and resulted in lymphocyte expansion, a doubling of the CR rate, and durable responses exceeding 2 years, however, the ORR was similar to atezolizumab alone. Increased and sustained doses of CYT107 coupled with patient selection strategies should be further investigated.}, }
@article {pmid39575237, year = {2024}, author = {Byrne, C and Schiffer, JT}, title = {Ensemble modeling of SARS-CoV-2 immune dynamics in immunologically naïve rhesus macaques predicts that potent, early innate immune responses drive viral elimination.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1426016}, pmid = {39575237}, issn = {1664-3224}, mesh = {Animals ; *Macaca mulatta ; *SARS-CoV-2/immunology ; *COVID-19/immunology/virology ; *Immunity, Innate ; *Viral Load ; Antibodies, Viral/immunology/blood ; Lung/immunology/virology ; }, abstract = {INTRODUCTION: An unprecedented breadth of longitudinal viral and multi-scale immunological data has been gathered during SARS-CoV-2 infection. However, due to the high complexity, non-linearity, multi-dimensionality, mixed anatomic sampling, and possible autocorrelation of available immune data, it is challenging to identify the components of the innate and adaptive immune response that drive viral elimination. Novel mathematical models and analytical approaches are required to synthesize contemporaneously gathered cytokine, transcriptomic, flow cytometry, antibody response, and viral load data into a coherent story of viral control, and ultimately to discriminate drivers of mild versus severe infection.<br><br>METHODS: We investigated a dataset describing innate, SARS-CoV-2 specific T cell, and antibody responses in the lung during early and late stages of infection in immunologically na&#xef;ve rhesus macaques. We used multi-model inference and ensemble modeling approaches from ecology and weather forecasting to compare and combine various competing models.<br><br>RESULTS AND DISCUSSION: Model outputs suggest that the innate immune response plays a crucial role in controlling early infection, while SARS-CoV-2 specific CD4+ T cells correspond to later viral elimination, and anti-spike IgG antibodies do not impact viral dynamics. Among the numerous genes potentially contributing to the innate response, we identified IFI27 as most closely linked to viral load decline. A 90% knockdown of the innate response from our validated model resulted in a ~10-fold increase in peak viral load during infection. Our approach provides a novel methodological framework for future analyses of similar complex, non-linear multi-component immunologic data sets.}, }
@article {pmid39574839, year = {2024}, author = {Chang, YH and Head, ST and Harrison, T and Yu, Y and Huff, CD and Pasaniuc, B and Lindström, S and Bhattacharya, A}, title = {Isoform-level analyses of 6 cancers uncover extensive genetic risk mechanisms undetected at the gene-level.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39574839}, support = {R01 CA194393/CA/NCI NIH HHS/United States ; R21 CA293419/CA/NCI NIH HHS/United States ; U01 CA194393/CA/NCI NIH HHS/United States ; }, abstract = {Integrating genome-wide association study (GWAS) and transcriptomic datasets can help identify potential mediators for germline genetic risk of cancer. However, traditional methods have been largely unsuccessful because of an overreliance on total gene expression. These approaches overlook alternative splicing, which can produce multiple isoforms from the same gene, each with potentially different effects on cancer risk. Here, we integrate genetic and multi-tissue isoform-level gene expression data from the Genotype Tissue-Expression Project (GTEx, N = 108-574) with publicly available European-ancestry GWAS summary statistics (all N > 20,000 cases) to identify both isoform- and gene-level risk associations with six cancers (breast, endometrial, colorectal, lung, ovarian, prostate) and six related cancer subtype classifications (N = 12 total). Compared to traditional methods leveraging total gene expression, directly modeling isoform expression through transcriptome-wide association studies (isoTWAS) substantially increases discovery of transcriptomic mechanisms underlying genetic associations. Using the same RNA-seq datasets, isoTWAS identified 164% more significant unique gene associations compared to TWAS (6,163 and 2,336, respectively), with isoTWAS-prioritized genes enriched 4-fold for evolutionarily-constrained genes (P = 6.1 × 10[-13]). isoTWAS tags transcriptomic associations at 52% more independent GWAS loci compared to TWAS across the six cancers. Additionally, isoform expression mediates an estimated 63% greater proportion of cancer risk SNP heritability compared to gene expression when evaluating cis-genetic influence on isoform expression. We highlight several notable isoTWAS associations that demonstrate GWAS colocalization at the isoform level but not at the gene level, including, CLPTM1L (lung cancer), LAMC1 (colorectal), and BABAM1 (breast). These results underscore the critical importance of modeling isoform-level expression to maximize discovery of genetic risk mechanisms for cancers.}, }
@article {pmid39574748, year = {2024}, author = {Gupta, S and Martinov, T and Thelen, A and Sunahara, M and Mureli, S and Vazquez, A and Gerdts, J and Dandekar, R and Cortese, I and Fouassier, C and Schanzer, E and Urnov, FD and Marson, A and Shy, BR and Greenberg, PD and Wilson, MR}, title = {Antigen-Specific T Cell Receptor Discovery for Treating Progressive Multifocal Leukoencephalopathy.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39574748}, issn = {2692-8205}, support = {K08 AI174061/AI/NIAID NIH HHS/United States ; K08 CA273529/CA/NCI NIH HHS/United States ; L30 TR002983/TR/NCATS NIH HHS/United States ; T32 GM007232/GM/NIGMS NIH HHS/United States ; }, abstract = {BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a frequently fatal disease of the central nervous system caused by JC virus (JCV). Survival is dependent on early diagnosis and ability to re-establish anti-viral T cell immunity. Adoptive transfer of polyomavirus-specific T cells has shown promise; however, there are no readily available HLA-matched anti-viral T cells to facilitate rapid treatment.<br><br>OBJECTIVE: Identify epitopes of the JCV major capsid protein VP1 that elicit an immune response in the context of human leukocyte antigen allele A*02:01 (HLA-A2) and isolate cognate T cell receptors (TCRs) from healthy donors. Evaluate individual VP1-specific TCRs for their capacity to be expressed in T cells and clear JCV in vitro.<br><br>METHODS: PBMCs from HLA-A2+ healthy donors were stimulated with peptide libraries tiled across the JCV VP1 protein. Multiple rounds of stimulation were performed to identify the antigens that induced the largest expansion and CD8[+] T cell response (measured as INF&#x3b3;, TNF&#x3b1;, CD137, and CD69 expression). High-affinity, antigen-specific CD8[+] T cells were isolated based on intensity of tetramer binding for downstream single-cell TCR sequencing. Candidate TCRs were selected based on tetramer binding affinity and activation assays. Promising TCRs were introduced into the T cell genome via viral transduction for in vitro validation including peptide-pulsed K562 cells and astrocyte cells, and JCV-infected astrocytes.<br><br>RESULTS: Four conserved JCV VP1 epitopes (amino acids 100-108, 251-259, 253-262, and 274-283) presented by HLA-A2 were identified. VP1(100-108) consistently elicited the highest level of IFN-&#x3b3; production from multiple donors and this peptide is in a highly conserved region of VP1. We next identified fourteen high avidity TCRs specific for VP1(100-108). When virally transduced into primary human T cells, seven of these TCRs demonstrated specific binding to VP1(100-108):HLA-A2 tetramers, and four showed increased IFN-&#x3b3; response when incubated with peptide. Primary CD8[+] T cells expressing two of these TCRs cleared both HLA-A2 positive K562 cells and HLA-A2 positive SVG astrocyte cell line presenting exogenously added VP1 peptide at a range of E:T ratios. In addition, both TCR-transduced T cell populations effectively lysed JCV-infected astrocytes.<br><br>CONCLUSIONS: We identified JCV VP1 epitopes that are immunogenic in the context of HLA-A2 MHC-I, including epitopes that have not been previously described. The VP1(100-108) epitope was used to isolate HLA-A2-restricted TCRs. When cloned into primary human CD8[+] T cells, these TCRs recognized VP1 (100-108)-presenting targets, and the transduced T cells conferred cytotoxic activity and eliminated K562 and astrocyte cells displaying the VP1(100-108) peptide and not sham peptide, as well as JCV-infected astrocytes. Taken together, these data suggest that JCV VP1-specific TCRs could be appealing therapeutics for HLA-A2+ individuals with PML in whom intrinsic T cell immunity cannot be rescued.}, }
@article {pmid39574678, year = {2024}, author = {Zhu, L and Beichman, A and Harris, K}, title = {Population size interacts with reproductive longevity to shape the germline mutation rate.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39574678}, issn = {2692-8205}, support = {R35 GM133428/GM/NIGMS NIH HHS/United States ; T32 AG066574/AG/NIA NIH HHS/United States ; }, abstract = {Mutation rates vary across the tree of life by many orders of magnitude, with lower mutation rates in species that reproduce quickly and maintain large effective population sizes. A compelling explanation for this trend is that large effective population sizes facilitate selection against weakly deleterious "mutator alleles" such as variants that interfere with the molecular efficacy of DNA repair. However, in multicellular organisms, the relationship of the mutation rate to DNA repair efficacy is complicated by variation in reproductive age. Long generation times leave more time for mutations to accrue each generation, and late reproduction likely amplifies the fitness consequences of any DNA repair defect that creates extra mutations in the sperm or eggs. Here, we present theoretical and empirical evidence that a long generation time amplifies the strength of selection for low mutation rates in the spermatocytes and oocytes. This leads to the counterintuitive prediction that the species with the highest germline mutation rates per generation are also the species with most effective mechanisms for DNA proofreading and repair in their germ cells. In contrast, species with different generation times accumulate similar mutation loads during embryonic development. Our results parallel recent findings that the longest-lived species have the lowest mutation rates in adult somatic tissues, potentially due to selection to keep the lifetime mutation load below a harmful threshold.}, }
@article {pmid39572695, year = {2024}, author = {Schuermans, A and Pournamdari, AB and Lee, J and Bhukar, R and Ganesh, S and Darosa, N and Small, AM and Yu, Z and Hornsby, W and Koyama, S and Kooperberg, C and Reiner, AP and Januzzi, JL and Honigberg, MC and Natarajan, P}, title = {Integrative proteomic analyses across common cardiac diseases yield mechanistic insights and enhanced prediction.}, journal = {Nature cardiovascular research}, volume = {}, number = {}, pages = {}, pmid = {39572695}, issn = {2731-0590}, support = {K08 HL166687/HL/NHLBI NIH HHS/United States ; R01HL127564//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; 979465//American Heart Association (American Heart Association, Inc.)/ ; 940166//American Heart Association (American Heart Association, Inc.)/ ; K08HL166687//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; Paul &amp; Phyllis Fireman Endowed Chair in Vascular Medicine//Massachusetts General Hospital (MGH)/ ; }, abstract = {Cardiac diseases represent common highly morbid conditions for which molecular mechanisms remain incompletely understood. Here we report the analysis of 1,459 protein measurements in 44,313 UK Biobank participants to characterize the circulating proteome associated with incident coronary artery disease, heart failure, atrial fibrillation and aortic stenosis. Multivariable-adjusted Cox regression identified 820 protein-disease associations-including 441 proteins-at Bonferroni-adjusted P < 8.6 × 10[-6]. Cis-Mendelian randomization suggested causal roles aligning with epidemiological findings for 4% of proteins identified in primary analyses, prioritizing therapeutic targets across cardiac diseases (for example, spondin-1 for atrial fibrillation and the Kunitz-type protease inhibitor 1 for coronary artery disease). Interaction analyses identified seven protein-disease associations that differed Bonferroni-significantly by sex. Models incorporating proteomic data (versus clinical risk factors alone) improved prediction for coronary artery disease, heart failure and atrial fibrillation. These results lay a foundation for future investigations to uncover disease mechanisms and assess the utility of protein-based prevention strategies for cardiac diseases.}, }
@article {pmid39571171, year = {2024}, author = {Chong, EA and Penuel, E and Napier, EB and Lundberg, RK and Budde, LE and Shadman, M and Matasar, MJ and Bartlett, NL and Flinn, IW and Bosch, F and Fay, K and Goy, A and Kumar, A and Nastoupil, LJ and Wei, MC and Wu, M and Yin, S and Fraietta, JA and Chong, ER and Schuster, SJ}, title = {Impact of prior CAR-T cell therapy on mosunetuzumab efficacy in patients with relapsed or refractory B-cell lymphomas.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024013640}, pmid = {39571171}, issn = {2473-9537}, abstract = {Mosunetuzumab and other CD20/CD3 bispecific antibodies (BsAbs) have efficacy in B-cell lymphomas relapsing after or refractory to CD19-directed chimeric antigen receptor-modified T cells (CAR-T). The optimal timing of BsAbs and biomarkers of BsAb response after CAR-T are unknown. We addressed these questions using clinical data and blood samples from patients previously treated with CAR-T treated on a phase I/II study of mosunetuzumab (clinicaltrials.gov; NCT02500407). Thirty patients had paired samples at baseline and after 1 cycle of mosunetuzumab. Median time from CAR-T to mosunetuzumab was significantly longer for responding than for nonresponding patients (p=0.006, unadjusted for multiple comparisons). Most patients (20/30) did not receive intervening therapy between CAR-T administration and mosunetuzumab. The remainder of patients received one intervening therapy after a protocol-mandated drug washout. After mosunetuzumab, responding patients had higher lymphocytes (995 vs 400 cells/µL, p = 0.02) and greater increases in CD4 and CD8 cells (median change, 73 vs -90 cells/µL, p=0.005; 243 vs -103 cells/µL, p=0.004, respectively). Additionally, responding patients had an increase in activated CD8 cells (median 1.7-fold-change, p=0.02). Non-responders had a relative decrease in CAR transgene levels (N=16; p=0.04). This is the first study to assess changes in lymphocytes, T cells, and CAR transgene levels in patients treated with BsAb after CAR-T. These findings suggest an interaction between prior CAR-T and BsAb outcomes, and have implications for optimal timing of BsAb after CAR-T.}, }
@article {pmid39570997, year = {2024}, author = {Courret, C and Hemmer, LW and Wei, X and Patel, PD and Chabot, BJ and Fuda, NJ and Geng, X and Chang, CH and Mellone, BG and Larracuente, AM}, title = {Turnover of retroelements and satellite DNA drives centromere reorganization over short evolutionary timescales in Drosophila.}, journal = {PLoS biology}, volume = {22}, number = {11}, pages = {e3002911}, pmid = {39570997}, issn = {1545-7885}, support = {R35 GM131868/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Centromere/genetics/metabolism ; *DNA, Satellite/genetics ; *Retroelements/genetics ; *Drosophila/genetics ; *Evolution, Molecular ; Female ; In Situ Hybridization, Fluorescence/methods ; Male ; Drosophila melanogaster/genetics ; Meiosis/genetics ; Y Chromosome/genetics ; Drosophila simulans/genetics ; Chromatin/metabolism/genetics ; Biological Evolution ; }, abstract = {Centromeres reside in rapidly evolving, repeat-rich genomic regions, despite their essential function in chromosome segregation. Across organisms, centromeres are rich in selfish genetic elements such as transposable elements and satellite DNAs that can bias their transmission through meiosis. However, these elements still need to cooperate at some level and contribute to, or avoid interfering with, centromere function. To gain insight into the balance between conflict and cooperation at centromeric DNA, we take advantage of the close evolutionary relationships within the Drosophila simulans clade-D. simulans, D. sechellia, and D. mauritiana-and their relative, D. melanogaster. Using chromatin profiling combined with high-resolution fluorescence in situ hybridization on stretched chromatin fibers, we characterize all centromeres across these species. We discovered dramatic centromere reorganization involving recurrent shifts between retroelements and satellite DNAs over short evolutionary timescales. We also reveal the recent origin (<240 Kya) of telocentric chromosomes in D. sechellia, where the X and fourth centromeres now sit on telomere-specific retroelements. Finally, the Y chromosome centromeres, which are the only chromosomes that do not experience female meiosis, do not show dynamic cycling between satDNA and TEs. The patterns of rapid centromere turnover in these species are consistent with genetic conflicts in the female germline and have implications for centromeric DNA function and karyotype evolution. Regardless of the evolutionary forces driving this turnover, the rapid reorganization of centromeric sequences over short evolutionary timescales highlights their potential as hotspots for evolutionary innovation.}, }
@article {pmid39570620, year = {2024}, author = {Jabbour, E and Oehler, VG and Koller, PB and Jamy, O and Lomaia, E and Hunter, AM and Uspenskaya, O and Samarina, S and Mukherjee, S and Cortes, JE and Baer, MR and Zherebtsova, V and Shuvaev, V and Turkina, A and Davydkin, I and Guo, H and Chen, Z and Fu, T and Jiang, L and Wang, C and Wang, H and Yang, D and Zhai, Y and Kantarjian, H}, title = {Olverembatinib After Failure of Tyrosine Kinase Inhibitors, Including Ponatinib or Asciminib: A Phase 1b Randomized Clinical Trial.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, pmid = {39570620}, issn = {2374-2445}, abstract = {IMPORTANCE: Patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) resistant or intolerant to BCR-ABL1 tyrosine kinase inhibitors (TKIs) have limited treatment options. Olverembatinib, which is approved in China, has only been tested in Chinese patients.<br><br>OBJECTIVE: To assess the pharmacokinetics, safety, efficacy, and recommended dose of olverembatinib in patients with CML or Philadelphia chromosome-positive ALL resistant or intolerant to at least 2 TKIs.<br><br>This multicenter phase 1b randomized clinical trial was conducted from January 28, 2020, to January 2, 2024, with a median (range) follow-up of 48 (0-166) weeks. Patients with CML or Philadelphia chromosome-positive ALL were enrolled. This bridging study was performed in part to confirm that there are no racial differences in the pharmacokinetic profile of olverembatinib.<br><br>INTERVENTIONS: Patients were randomly assigned to 30, 40, or 50 mg of olverembatinib orally every other day in 28-day cycles.<br><br>MAIN OUTCOMES AND MEASURES: Pharmacokinetic profile of olverembatinib.<br><br>RESULTS: Of 80 included patients, 46 (58%) were male, and the median (range) age was 54.0 (21-80) years. The pharmacokinetic profile of olverembatinib was compatible with alternate-day dosing and similar to that in Chinese patients. Based on investigators' assessments, 60 patients (75%) experienced at least 1 treatment-related adverse event; 32 (40%) experienced grade 3 or higher treatment-related adverse events; and 12 (15%) experienced treatment-related serious adverse events, none of which were fatal. Frequently reported (10% or more) treatment-emergent adverse events included elevated blood creatine phosphokinase (all grades, 31 [39%]; grade 3 or higher, 10 [13%]) and thrombocytopenia (all grades, 23 [29%]; grade 3 or higher, 14 [18%]). Among evaluable patients with chronic-phase CML, complete cytogenetic response (CCyR) occurred in 31 of 51 patients (61%; 95% CI, 46.1-74.2), and major molecular response (MMR) occurred in 25 of 59 patients (42%; 95% CI, 29.6-55.9). Cytogenetic and molecular responses were similar in patients with or without T315I variants. A total of 15 of 26 patients with prior ponatinib treatment (58%; 95% CI, 36.9-76.6) achieved CCyR, and 11 of 30 (37%; 95% CI, 19.9-56.1) achieved MMR. A total of 4 of 8 patients with asciminib resistance (50%; 95% CI, 15.7-84.3) had CCyR, and 4 of 12 (33%; 95% CI, 9.9-65.1) had MMR. The recommended phase 3 dose of olverembatinib is 30 mg every other day in patients without T315I variants.<br><br>CONCLUSIONS AND RELEVANCE: In this trial, olverembatinib had a favorable pharmacokinetic profile, was generally well tolerated, and showed strong antileukemic activity in patients with heavily pretreated chronic-phase CML with or without T315I variants, including prior ponatinib and/or asciminib failure. Olverembatinib may provide a viable new treatment option for patients after failure of 2 or more TKIs.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04260022.}, }
@article {pmid39570045, year = {2024}, author = {Valint, DJ and Fiedler, TL and Liu, C and Srinivasan, S and Fredricks, DN}, title = {Effect of metronidazole on concentrations of vaginal bacteria associated with risk of HIV acquisition.}, journal = {mBio}, volume = {}, number = {}, pages = {e0111024}, doi = {10.1128/mbio.01110-24}, pmid = {39570045}, issn = {2150-7511}, abstract = {Several bacterial vaginosis (BV)-associated bacteria have been associated with elevated risk of human immunodeficiency virus (HIV) acquisition; however, susceptibility of these bacteria to antibiotics is poorly understood. Vaginal samples were collected from 22 persons daily for 2 weeks following BV diagnosis. Metronidazole treatment was prescribed for 5-7 days. Changes in bacterial concentrations were measured with taxon-specific 16S rRNA gene quantitative PCR (qPCR) assays. A culture-based antimicrobial assay confirmed presence of antibiotics in vaginal swab samples. Bacterial DNA concentrations decreased during antibiotic administration for all 13 bacterial taxa tested. Comparison of bacterial DNA concentrations in samples before administration of antibiotics to samples taken on the last day of antimicrobial assay-confirmed antibiotic presence showed a 2.25-4.78 log10-fold decrease across all taxa. Concentrations were frequently reduced to the qPCR assay's limit of detection, suggesting eradication of bacteria. Mean clearance time varied across taxa (1.2-7.9 days), with several bacteria (e.g., Sneathia spp., Vaginal TM7, and Eggerthella-like sp.) taking >7 days to suppress. Metronidazole reduces quantities of bacterial taxa associated with increased HIV acquisition risk.IMPORTANCEHuman immunodeficiency virus (HIV) transmission through sex remains a major public health challenge despite efforts at risk reduction and use of anti-retroviral pre-exposure prophylaxis. Many bacterial vaginosis (BV)-associated vaginal bacteria have been associated with increased HIV infection risk among women. If these bacteria help mediate HIV infection risk, then eradication of these bacteria is one potential strategy to reduce this risk. However, the best approach to eradicate HIV-high risk bacteria from the vagina is not known. We analyzed vaginal swabs collected daily from women with BV to determine the impact of metronidazole treatment on 13 vaginal bacterial taxa linked to elevated risk of HIV infection through use of taxon-directed quantitative PCR assays. We conclude that eradication of high-risk vaginal bacteria using metronidazole is one promising avenue for reducing HIV acquisition risk, and we provide evidence that a 5-7-day treatment course may not be sufficient to suppress all bacteria.}, }
@article {pmid39569838, year = {2024}, author = {Triplette, M and Snidarich, M and Heffner, JL and Omernik, B and Ahmed, A and Brooks, E and Telew, B and Crothers, K and Brown, M}, title = {A Community-Engaged Research Study to Inform Tailored Programming for Smoking Cessation and Lung Cancer Screening Among At-Risk LGBTQ+ Elders.}, journal = {Health promotion practice}, volume = {}, number = {}, pages = {15248399241296101}, doi = {10.1177/15248399241296101}, pmid = {39569838}, issn = {1524-8399}, abstract = {Purpose. Lung cancer is the leading cause of cancer death, with most cases attributable to cigarette smoking. Many communities within the lesbian, gay, bisexual, transgender and queer/questioning (LGBTQ+) umbrella have high rates of smoking, but focused lung cancer prevention is limited. Our objective was to utilize a community-based participatory research (CBPR) approach to guide the development of a program focused on lung cancer prevention in LGBTQ+ elders. Methods. Through community partnerships, we recruited participants who self-identified as LGBTQ+ and were eligible for lung cancer screening (LCS) to participate in semi-structured qualitative discussions with complementary surveys. Qualitative guides were developed to collect data on determinants of smoking cessation and LCS and to elicit feedback on interventions to support lung cancer prevention through a tailored approach to patient navigation. Qualitative data were analyzed using rapid templated analysis to elucidate themes. Results. The 21 enrolled participants had diverse sexual and gender identities and 57% were of minoritized race/ethnicity. Most (81%) had experience with smoking cessation but few (10%) had undergone LCS. Overall themes suggest interest in personalized (to individuals), tailored (to the LGBTQ+ community) and integrated longitudinal programs to support lung cancer prevention. Themes suggest strong endorsement of focused messaging to LGBTQ+ persons and reducing stigma related to LGBTQ+ identity and smoking. Conclusions. Themes highlight the need for integrated tobacco and LCS programming which can provide longitudinal support, and ideally, center community settings and peer support. This formative work will be utilized to adapt a patient navigation program to assist screen-eligible LGBTQ+ elders.}, }
@article {pmid39567685, year = {2024}, author = {Reyes, RA and Raghavan, SSR and Hurlburt, NK and Introini, V and Bol, S and Kana, IH and Jensen, RW and Martinez-Scholze, E and Gestal-Mato, M and López-Gutiérrez, B and Sanz, S and Bancells, C and Fernández-Quintero, ML and Loeffler, JR and Ferguson, JA and Lee, WH and Martin, GM and Theander, TG and Lusingu, JPA and Minja, DTR and Ssewanyana, I and Feeney, ME and Greenhouse, B and Ward, AB and Bernabeu, M and Pancera, M and Turner, L and Bunnik, EM and Lavstsen, T}, title = {Broadly inhibitory antibodies to severe malaria virulence proteins.}, journal = {Nature}, volume = {636}, number = {8041}, pages = {182-189}, pmid = {39567685}, issn = {1476-4687}, mesh = {Animals ; Humans ; Antibodies, Monoclonal/immunology ; *Antibodies, Protozoan/immunology ; Binding Sites ; Brain/blood supply/parasitology ; Endothelial Protein C Receptor/immunology/metabolism ; Erythrocytes/parasitology/immunology ; *Malaria, Falciparum/immunology/parasitology ; Microvessels/immunology/parasitology ; Models, Molecular ; *Plasmodium falciparum/immunology/pathogenicity ; Protein Binding ; Protein Domains ; *Protozoan Proteins/immunology/chemistry/metabolism ; *Virulence ; *Virulence Factors/chemistry/immunology/metabolism ; *Broadly Neutralizing Antibodies/immunology ; Malaria Vaccines/immunology ; }, abstract = {Malaria pathology is driven by the accumulation of Plasmodium falciparum-infected erythrocytes in microvessels[1]. This process is mediated by the polymorphic erythrocyte membrane protein 1 (PfEMP1) adhesion proteins of the parasite. A subset of PfEMP1 variants that bind to human endothelial protein C receptor (EPCR) through their CIDRα1 domains is responsible for severe malaria pathogenesis[2]. A longstanding question is whether individual antibodies can recognize the large repertoire of circulating PfEMP1 variants. Here we describe two broadly reactive and inhibitory human monoclonal antibodies to CIDRα1. The antibodies isolated from two different individuals exhibited similar and consistent EPCR-binding inhibition of diverse CIDRα1 domains, representing five of the six subclasses of CIDRα1. Both antibodies inhibited EPCR binding of both recombinant full-length and native PfEMP1 proteins, as well as parasite sequestration in bioengineered 3D human brain microvessels under physiologically relevant flow conditions. Structural analyses of the two antibodies in complex with three different CIDRα1 antigen variants reveal similar binding mechanisms that depend on interactions with three highly conserved amino acid residues of the EPCR-binding site in CIDRα1. These broadly reactive antibodies are likely to represent a common mechanism of acquired immunity to severe malaria and offer novel insights for the design of a vaccine or treatment targeting severe malaria.}, }
@article {pmid39567681, year = {2024}, author = {Leyderman, M and Chandrasekar, T and Grivas, P and Li, R and Bhat, S and Basnet, A and Shapiro, O and Jacob, J and Daneshvar, MA and Kord, E and Bratslavsky, G and Goldberg, H}, title = {Metastasis development in non-muscle-invasive bladder cancer.}, journal = {Nature reviews. Urology}, volume = {}, number = {}, pages = {}, pmid = {39567681}, issn = {1759-4820}, abstract = {Non-muscle-invasive bladder cancer (NMIBC) is the most common type of bladder cancer presentation and is characterized by a varying probability of recurrence and progression. Sporadically, patients with NMIBC might also develop tumour metastases without any pathological evidence of muscle-invasive disease within the bladder, a condition known as metastatic NMIBC. In the published literature, this phenomenon is limited to several case reports and small reviews, with few data regarding the possible aetiologies. Several possible factors can be potentially associated with metastatic NMIBC, including tumour understaging, the number of transurethral resection procedures received by the patient, the presence of circulating tumour cells, the modality used for diagnostic cystoscopy and possible gender-associated differences. In this Perspective, our aim was to integrate and report currently available data on this relatively rare entity and provide some potential aetiological explanations.}, }
@article {pmid39567499, year = {2024}, author = {Chatterjee, SS and Linares, JF and Cid-Diaz, T and Duran, A and Khan, MIK and Osrodek, M and Brady, NJ and Reina-Campos, M and Marzio, A and Venkadakrishnan, VB and Bakht, MK and Khani, F and Mosquera, JM and Robinson, BD and Moyer, J and Elemento, O and Hsieh, AC and Goodrich, DW and Rickman, DS and Beltran, H and Moscat, J and Diaz-Meco, MT}, title = {Increased translation driven by non-canonical EZH2 creates a synthetic vulnerability in enzalutamide-resistant prostate cancer.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {9755}, pmid = {39567499}, issn = {2041-1723}, support = {R50 CA265332/CA/NCI NIH HHS/United States ; R01 GM135362/GM/NIGMS NIH HHS/United States ; R01CA246765//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; R50 CA283476/CA/NCI NIH HHS/United States ; R01 CA277857/CA/NCI NIH HHS/United States ; R01 CA234162/CA/NCI NIH HHS/United States ; R01CA277857//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; P50 CA211024/CA/NCI NIH HHS/United States ; R50CA283476//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; R50CA265332//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; R37 CA230617/CA/NCI NIH HHS/United States ; R01 CA250025/CA/NCI NIH HHS/United States ; R01 CA230913/CA/NCI NIH HHS/United States ; R01 CA275846/CA/NCI NIH HHS/United States ; R01 CA265892/CA/NCI NIH HHS/United States ; R01 CA246765/CA/NCI NIH HHS/United States ; R01 CA276308/CA/NCI NIH HHS/United States ; }, mesh = {*Enhancer of Zeste Homolog 2 Protein/metabolism/genetics ; Male ; *Phenylthiohydantoin/pharmacology ; *Benzamides ; Humans ; *Nitriles/pharmacology ; *Prostatic Neoplasms, Castration-Resistant/drug therapy/genetics/metabolism/pathology ; *Drug Resistance, Neoplasm/genetics ; Cell Line, Tumor ; Animals ; Phosphorylation ; Protein Biosynthesis/drug effects ; Mice ; Transforming Growth Factor beta/metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; Protein Kinase C/metabolism/genetics ; }, abstract = {Overcoming resistance to therapy is a major challenge in castration-resistant prostate cancer (CRPC). Lineage plasticity towards a neuroendocrine phenotype enables CRPC to adapt and survive targeted therapies. However, the molecular mechanisms of epigenetic reprogramming during this process are still poorly understood. Here we show that the protein kinase PKCλ/ι-mediated phosphorylation of enhancer of zeste homolog 2 (EZH2) regulates its proteasomal degradation and maintains EZH2 as part of the canonical polycomb repressive complex (PRC2). Loss of PKCλ/ι promotes a switch during enzalutamide treatment to a non-canonical EZH2 cistrome that triggers the transcriptional activation of the translational machinery to induce a transforming growth factor β (TGFβ) resistance program. The increased reliance on protein synthesis creates a synthetic vulnerability in PKCλ/ι-deficient CRPC.}, }
@article {pmid39565920, year = {2024}, author = {Hammarlund, N and Holt, SK and Etzioni, R and Morehead, D and Lee, JR and Wolff, EM and Burrola-Mendez, Y and Sage, L and Gore, JL and Nyame, YA}, title = {The Association of Where Patients with Prostate Cancer Live and Receive Care on Racial Treatment Inequities.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djae302}, pmid = {39565920}, issn = {1460-2105}, abstract = {Black individuals are less likely to be treated for prostate cancer even though they are more than twice as likely to die compared to White individuals. The complex causes of these inequities are influenced by social and structural factors, including racism, which contribute to the differential delivery of care. This study investigates how factors related to the location of where individuals live and receive care affect treatment inequities for prostate cancer between Black and White individuals. We hypothesize that both location and race independently influence treatment inequities. We used data from the Surveillance, Epidemiology, and End Results (SEER) cancer registry linked to Medicare claims to estimate the treatment inequity, as defined by differences in radiation or radical prostatectomy. Fixed effects at the physician, hospital, and patient ZIP code levels were incorporated to adjust for all time-invariant factors at these levels. The results indicate that residential location-related factors explain only half of the treatment inequity, while provider- and hospital-level factors do not significantly account for disparities. Even after accounting for all time-invariant factors, significant differences in treatment rates persist. The study highlights the importance of understanding race as a social construct and racism as a systemic and structural phenomenon in addressing treatment inequities. These findings provide a necessary step toward understanding equitable care and designing interventions to solve this inequity.}, }
@article {pmid39565908, year = {2024}, author = {Othus, M and Patel, SP and Chae, YK and Dietrich, E and Streicher, H and Sharon, E and Kurzrock, R}, title = {First Cycle Toxicity and Survival in Patients with Rare Cancers Treated with Checkpoint Inhibitors.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djae297}, pmid = {39565908}, issn = {1460-2105}, abstract = {BACKGROUND: Associations between immune-related adverse events (irAEs) from checkpoint inhibitor therapy and outcomes have been previously evaluated, with most prior research finding a positive association between toxicity and survival. This prior research has generally reported on more common tumor types. We use a unique data resource of a federally-funded basket trial ((NCT02834013) for patients with rare cancers (N = 684) to evaluate associations between irAEs and overall survival and progression-free survival.<br><br>METHODS: Patients were treated with nivolumab and ipilimumab; the trial was opened at&#x2009;>&#x2009;1000 sites. Landmark Cox regression models were used to assess first cycle irAE associations with progression-free and overall survival.<br><br>RESULTS: We found that grade 1-2 treatment-related irAEs in the first cycle of therapy were associated with longer overall survival (OS) (multivariable hazard ratio, 95% confidence interval, p-value: 0.61, 0.49-0.75, p&#x2009;<&#x2009;.001) compared to no treatment-related irAE, while grade 3-4 irAEs were associated with shorter OS (HR&#x2009;=&#x2009;1.41, 95% CI&#x2009;=&#x2009;1.04-1.90, p&#x2009;=&#x2009;.025). Similar, but weaker, associations were observed with progression-free survival (PFS) and grade 1-2 treatment-related irAEs: HR&#x2009;=&#x2009;0.83, 95% CI&#x2009;=&#x2009;0.67-1.01, p&#x2009;=&#x2009;.067 and grade 3-4: HR&#x2009;=&#x2009;1.35, 95% CI&#x2009;=&#x2009;1.02-1.78, p&#x2009;=&#x2009;.037 compared to no treatment-related irAEs. Grade 1-2 dermatologic toxicity was associated with improved OS compared to other grade 1-2 toxicities (HR&#x2009;=&#x2009;0.67, 95% CI&#x2009;=&#x2009;0.52-0.85, p&#x2009;=&#x2009;.002). There was no significant OS difference between patients with Grade 1-2 fatigue, gastrointestinal, metabolic, hepatic, endocrine, and thyroid toxicities vs other Grade 1-2 toxicities.<br><br>CONCLUSIONS: In this large cohort of patients with rare tumors receiving checkpoint inhibitor therapy, grade of irAE in the first cycle was predictive for survival.}, }
@article {pmid39565901, year = {2024}, author = {Zhao, Y and Gulati, R and Yang, Z and Newcomb, L and Zheng, Y and Zhu, K and Liu, M and Heijnsdijk, EAM and Haffner, MC and Cooperberg, M and Eggener, SE and De Marzo, AM and Kibel, AS and Rizopoulos, D and Hall, IJ and Etzioni, R}, title = {Projected Outcomes of Reduced-Biopsy Management of Grade Group 1 Prostate Cancer: Implications for Relabeling.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djae296}, pmid = {39565901}, issn = {1460-2105}, abstract = {BACKGROUND: Implications of relabeling grade group (GG) 1 prostate cancer as non-cancer will depend on the recommended active surveillance (AS) strategy. Whether relabeling should prompt de-intensifying, PSA-based active monitoring approaches is unclear. We investigated outcomes of biopsy-based AS strategies vs PSA-based active monitoring for GG1 diagnoses under different patient adherence rates.<br><br>METHODS: We analyzed longitudinal PSA levels and time to GG&#x2009;&#x2265;&#x2009;2 reclassification among 850 patients diagnosed with GG1 disease from the Canary Prostate Active Surveillance Study (2008-2013). We then simulated 20,000 patients over 12&#x2009;years, comparing GG&#x2009;&#x2265;&#x2009;2 detection under biennial biopsy against three PSA-based strategies:(1) PSA: biopsy for PSA change &#x2265;20%/year, (2) PSA+MRI: MRI for PSA change &#x2265;20%/year and biopsy for PI-RADS &#x2265;3, and (3) Predicted risk: biopsy for predicted upgrading risk &#x2265;10%.<br><br>RESULTS: Under biennial biopsies and 20% dropout to active treatment, 17% of patients had a&#x2009;>&#x2009;2-year delay in GG&#x2009;&#x2265;&#x2009;2 detection. The PSA strategy reduced biopsies by 39% but delayed detection in 32% of patients. The PSA+MRI strategy cut biopsies by 52%, with a 34% delay. The predicted risk strategy reduced biopsies by 31%, with only an 8% delay. These findings are robust to biopsy sensitivity and confirmatory biopsy.<br><br>CONCLUSIONS: PSA-based active monitoring could substantially reduce biopsy frequency; however, a precision strategy based on an individual upgrading risk is most likely to minimize delays in disease progression detection. This strategy may be preferred if AS is deintensified under relabeling, provided patient adherence remains unaffected.}, }
@article {pmid39565830, year = {2024}, author = {Hannon, PA and Harris, JR and Doody, DR}, title = {Opportunities to Improve Health Equity for Employees in Low-Wage Industries in the United States.}, journal = {Annual review of public health}, volume = {}, number = {}, pages = {}, doi = {10.1146/annurev-publhealth-071723-120104}, pmid = {39565830}, issn = {1545-2093}, abstract = {This review describes employees working in low-wage industries in the United States, their health risks, and their access to health promotion and other health-related resources through their employers. We use publicly available datasets to illustrate how low-wage jobs affect employees' social determinants of health, health risk behaviors, and chronic conditions. We also discuss how the COVID-19 pandemic has shifted these employees' and employers' health-related priorities and work settings. We describe employees' access to health supports through federal programs and their employers and the potential ways in which low-wage employers could support employee health and well-being. We close with a brief research and practice agenda to improve health equity for employees in low-wage industries. The goal of this review is to help practitioners and researchers in workplace health promotion, occupational health, and public health reach employees and employers in low-wage industries with interventions that address employees' health risks and employees' and employers' health priorities.}, }
@article {pmid39565459, year = {2024}, author = {Ziu, M and Halasz, LM and Kumthekar, PU and McGranahan, TM and Lo, SS and Olson, JJ}, title = {Congress of Neurological Surgeons systematic review and evidence-based guidelines for the role of chemotherapy in newly diagnosed WHO Grade II diffuse glioma in adults: update.}, journal = {Journal of neuro-oncology}, volume = {}, number = {}, pages = {}, pmid = {39565459}, issn = {1573-7373}, abstract = {UNLABELLED: Questions and recommendations from the prior version of these guidelines without changeTarget populationAdult patients (older than 18 years of age) with newly diagnosed World Health Organization (WHO) Grade II gliomas (Oligodendroglioma, astrocytoma, mixed oligoastrocytoma).QuestionIs there a role for chemotherapy as adjuvant therapy of choice in treatment of patients with newly diagnosed low-grade gliomas?RecommendationLevel III: Chemotherapy is recommended as a treatment option to postpone the use of radiotherapy, to slow tumor growth and to improve progression free survival (PFS), overall survival (OS) and clinical symptoms in adult patients with newly diagnosed LGG.QuestionWho are the patients with newly diagnosed LGG that would benefit the most from chemotherapy?RecommendationLevel III: Chemotherapy is recommended as an optional component alone or in combination with radiation as the initial adjuvant therapy for all patients who cannot undergo gross total resection (GTR) of a newly diagnosed LGG. Patients with residual tumor >1 cm on post-operative MRI, presenting diameter of 4 cm or older than 40 years of age should be considered for adjuvant therapy as well.QuestionAre there tumor markers that can predict which patients can benefit the most from initial treatment with chemotherapy?RecommendationLevel III: The addition of chemotherapy to standard RT is recommended in LGG patients that carry IDH mutation. In addition, temozolomide (TMZ) is recommended as a treatment option to slow tumor growth in patients who harbor the 1p/19q co-deletion.QuestionHow soon should the chemotherapy be started once the diagnosis of LGG is confirmed?RecommendationThere is insufficient evidence to make a definitive recommendation on the timing of starting chemotherapy after surgical/pathological diagnosis of LGG has been made. However, using the 12 weeks mark as the latest timeframe to start adjuvant chemotherapy is suggested. It is recommended that patients be enrolled in properly designed clinical trials to assess the timing of chemotherapy initiation once diagnosis is confirmed for this target population.QuestionWhat chemotherapeutic agents should be used for treatment of newly diagnosed LGG?RecommendationThere is insufficient evidence to make a recommendation of one particular regimen. Enrollment of subjects in properly designed trials comparing the efficacy of these or other agents is recommended so as to determine which of these regimens is superior.QuestionWhat is the optimal duration and dosing of chemotherapy as initial treatment for LGG?RecommendationInsufficient evidence exists regarding the duration of any specific cytotoxic drug regimen for treatment of newly diagnosed LGG. Enrollment of subjects in properly designed clinical investigations assessing the optimal duration of this therapy is recommended.QuestionShould chemotherapy be given alone or in conjunction with RT as initial therapy for LGG?RecommendationInsufficient evidence exists to make recommendations in this regard. Hence, enrollment of patients in properly designed clinical trials assessing the difference between chemotherapy alone, RT alone or a combination of them is recommended.QuestionShould chemotherapy be given in addition to other type of adjuvant therapy to patients with newly diagnosed LGG?RecommendationLevel II: It is recommended that chemotherapy be added to the RT in patients with unfavorable LGG to improve their progression free survival.Updated Question and Recommendations from the Prior Version of These GuidelinesQuestionIn adult patients with pathologically confirmed WHO Grade II diffuse glioma does chemotherapy alone, combined with radiation therapy or after radiation therapy compared to radiotherapy alone result in better overall survival, progression free survival, local control, fewer complications, neurocognitive preservation, and quality of life?RecommendationLevel I: It is recommended that chemotherapy (PCV) be added to radiation therapy (RT) in all patients with newly diagnosed high-risk WHO Grade II diffuse glioma (Patients younger than 40 unable to get gross total resection and older than 40 regardless of the degree of resection) to improve their overall survival.<br><br>LEVEL II: It is recommended that chemotherapy be added to radiation therapy in all patients with newly diagnosed high-risk WHO Grade II diffuse glioma to improve overall survival without a decline in neurocognitive function.<br><br>LEVEL III: It is suggested that chemotherapy (temozolomide) be added to RT in all patients with newly diagnosed high-risk WHO Grade II diffuse glioma to improve progression free survival and overall survival.<br><br>LEVEL III: It is suggested that chemotherapy alone should be considered in patients with newly diagnosed WHO Grade II diffuse glioma in cases with 1p/19q co-deletion.New questions and recommendationsTarget populationThese recommendations apply to adult patients diagnosed with WHO Grade II diffuse glioma.QuestionIn adult patients with newly diagnosed WHO grade II diffuse glioma does administration of chemotherapy prior to surgical resection improve extent of resection, provide longer progression free survival and overall survival when compared to chemotherapy alone?RecommendationLevel III: Neo-adjuvant temozolomide may be used in patients with WHO Grade II diffuse gliomas deemed unsafe for resection due to infiltration of eloquent areas or with large contralateral extension as an initial step to improve the extent of resection.There is insufficient evidence to support a recommendation regarding the ability of chemotherapy provided prior to surgical resection to improve progression free survival (PFS) and overall survival (OS).QuestionIn adult patients with newly diagnosed WHO grade II diffuse glioma does the administration of temozolomide increase the rate of malignant transformation when compared to no chemotherapy or other chemotherapy regimens?RecommendationThere is insufficient evidence to support a recommendation against the use of temozolomide for WHO Grade II diffuse gliomas due to concern over increasing the rate of malignant transformation.QuestionIn adult patients with newly diagnosed WHO grade II diffuse glioma does administration of multi-agent chemotherapy improve progression free survival and overall survival when compared to administration of single-agent chemotherapy?RecommendationThere is insufficient evidence to support a recommendation for or against the use of multi-agent chemotherapy to improve progression free survival and overall survival when compared to administration of single-agent chemotherapy in patients with newly diagnosed WHO Grade II diffuse glioma.}, }
@article {pmid39563927, year = {2024}, author = {Kassamali-Escobar, Z and Hartlage, W and Chan, JD and Castillo, A and Martinez-Paz, N and Bajenov, M and Jain, R and Lynch, JB and Bryson-Cahn, C}, title = {Antimicrobial stewardship and quality improvement strategies in critical access hospitals: a process evaluation of an intensive quality improvement cohort.}, journal = {Antimicrobial stewardship &amp; healthcare epidemiology : ASHE}, volume = {4}, number = {1}, pages = {e201}, pmid = {39563927}, issn = {2732-494X}, abstract = {We describe our experience implementing an intensive quality improvement cohort pilot focused on managing asymptomatic bacteriuria in 19 critical access hospitals. Participation in the pilot was high, and almost all sites identified an improvement goal and collected clinical data. Barriers to implementation included staffing shortages, turnover, and lack of bandwidth.}, }
@article {pmid39562313, year = {2024}, author = {Bollinger, BJ and Chrisman, SP and Sahlberg, J and Mendoza, JA and Palermo, TM and Zhou, C and Brooks, MA and Rivara, FP and Pedersen, P and Prentice, E and Hansen, C}, title = {Understanding factors influencing exercise program adherence for youth with persistent post-concussive symptoms (PPCS).}, journal = {Brain injury}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/02699052.2024.2428404}, pmid = {39562313}, issn = {1362-301X}, abstract = {BACKGROUND: A significant portion of youth sustain a concussion every year, with around 30% experiencing persistent post-concussion symptoms (PPCS). Research has shown exercising just below the exertion level that provokes symptoms can lead to more rapid recovery. However, youth often struggle to adhere to exercise recommendations following concussion.<br><br>METHODS: We conducted structured qualitative interviews (n&#x2009;=&#x2009;32) with concussed youth and their parents to examine factors influencing motivation to engage in exercise post-concussion. Questions were framed through the lens of Self-Determination Theory (SDT) and Thematic Analysis was used to code and analyze transcripts.<br><br>RESULTS: Four primary factors appeared to motivate youth to exercise after receiving a concussion: 1) social support, 2) accountability, 3) goal setting, and 4) structure. Utilizing the lens of SDT, one could theorize that including social support and accountability helped fulfill the need of relatedness, setting goals helped fulfill the need of autonomy, and providing program structure helped fulfill the need for competence.<br><br>CONCLUSIONS: Our results suggest that Self-Determination Theory may be a useful frame for examining exercise adherence post-concussion. Incorporating social support, accountability, goal setting and structure could increase the effectiveness of exercise prescription post-concussion and should be the focus of further study.}, }
@article {pmid39561920, year = {2024}, author = {Yi, JC and Ballard, S and Walsh, C and Friedman, DN and Ganz, PA and Jacobs, LA and Partridge, AH and Mitchell, SA and Leisenring, WM and Syrjala, KL and Baker, KS}, title = {INteractive survivorship program to improve health care REsources [INSPIRE]: A study protocol testing a digital intervention with stepped care telehealth to improve outcomes for adolescent and young adult survivors.}, journal = {Contemporary clinical trials}, volume = {148}, number = {}, pages = {107745}, doi = {10.1016/j.cct.2024.107745}, pmid = {39561920}, issn = {1559-2030}, abstract = {BACKGROUND: Adolescents and young adults with cancer (AYAs, ages 15-39 at the time of diagnosis) experience significant adverse health and psychosocial outcomes. AYAs live with emotional distress and health care demands that exceed those of their healthy peers but can have difficulty accessing care. Digitally delivered interventions are an attractive option for AYA survivors, a population that routinely utilizes online resources when seeking health information and support.<br><br>AIM: By improving access to survivorship resources and support and strengthening health literacy and self-management skills, the INteractive Survivorship Program to Improve Health care REsources [INSPIRE] is designed to improve adherence to AYA health care guidelines and reduce cancer-related distress. We describe the protocol for a two-arm randomized controlled trial (RCT) testing the AYA-adapted INSPIRE program.<br><br>METHODS/DESIGN: The intervention includes an interactive mobile app, study website, and social media platforms, adding telehealth for those with continued distress, lower survivorship health care literacy, or poor engagement with the digital program at 6&#xa0;weeks. Participants are randomized to INSPIRE or an active control. In the active control arm, survivors receive access to a study website with links to existing AYA survivor resources followed by delayed access to the INSPIRE program. Participants are not blinded; study staff not providing telehealth are blinded. The primary outcomes are cancer-related distress and health care adherence specific to second cancer and cardiometabolic screenings.<br><br>DISCUSSION: If effective, the program is positioned for accelerated implementation to improve care for AYA survivors by using a scalable informatics-based administration and largely digital intervention program.}, }
@article {pmid39561770, year = {2024}, author = {Kullo, IJ and Conomos, MP and Nelson, SC and Adebamowo, SN and Choudhury, A and Conti, D and Fullerton, SM and Gogarten, SM and Heavner, B and Hornsby, WE and Kenny, EE and Khan, A and Khera, AV and Li, Y and Martin, I and Mercader, JM and Ng, M and Raffield, LM and Reiner, A and Rowley, R and Schaid, D and Stilp, A and Wiley, K and Wilson, R and Witte, JS and Natarajan, P and , }, title = {The PRIMED Consortium: Reducing disparities in polygenic risk assessment.}, journal = {American journal of human genetics}, volume = {111}, number = {12}, pages = {2594-2606}, doi = {10.1016/j.ajhg.2024.10.010}, pmid = {39561770}, issn = {1537-6605}, mesh = {Humans ; *Genetic Predisposition to Disease ; *Genome-Wide Association Study ; Genotype ; *Multifactorial Inheritance/genetics ; Neoplasms/genetics ; Phenotype ; Risk Assessment ; Risk Factors ; }, abstract = {By improving disease risk prediction, polygenic risk scores (PRSs) could have a significant impact on health promotion and disease prevention. Due to the historical oversampling of populations with European ancestry for genome-wide association studies, PRSs perform less well in other, understudied populations, leading to concerns that clinical use in their current forms could widen health care disparities. The PRIMED Consortium was established to develop methods to improve the performance of PRSs in global populations and individuals of diverse genetic ancestry. To this end, PRIMED is aggregating and harmonizing multiple phenotype and genotype datasets on AnVIL, an interoperable secure cloud-based platform, to perform individual- and summary-level analyses using population and statistical genetics approaches. Study sites, the coordinating center, and representatives from the NIH work alongside other NHGRI and global consortia to achieve these goals. PRIMED is also evaluating ethical and social implications of PRS implementation and investigating the joint modeling of social determinants of health and PRS in computing disease risk. The phenotypes of interest are primarily cardiometabolic diseases and cancer, the leading causes of death and disability worldwide. Early deliverables of the consortium include methods for data sharing on AnVIL, development of a common data model to harmonize phenotype and genotype data from cohort studies as well as electronic health records, adaptation of recent guidelines for population descriptors to global cohorts, and sharing of PRS methods/tools. As a multisite collaboration, PRIMED aims to foster equity in the development and use of polygenic risk assessment.}, }
@article {pmid39561372, year = {2024}, author = {Luque Paz, D and Gagelmann, N and Benajiba, L and Riou, J and Salit, RB and Orvain, C and Schroeder, T and Bories, C and Gurnari, C and Badbaran, A and Boyer-Perrard, F and Pagliuca, S and Rautenberg, C and Tavitian, S and Panagiota, V and Ianotto, JC and Thol, FR and Cayssials, E and Heuser, M and Rubio, MT and Cassinat, B and Daltro de Oliveira, R and Sauter, CS and Maciejewski, JP and Reinhardt, HC and Scott, BL and Ugo, V and Kröger, N and Kiladjian, JJ and Robin, M}, title = {Role of molecular alterations in transplantation decisions for patients with primary myelofibrosis.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024014368}, pmid = {39561372}, issn = {2473-9537}, abstract = {The aim of our study was to analyze the potential survival benefit associated with HSCT according to clinico-biological scores which incorporate molecular data (MIPSS70 and MIPSS70+V2) to facilitate decision-making in this context. One transplant (n=241) and one non-transplant cohorts (n=239) were used to test the hypothesis that PMF patients with higher risk molecular score benefit from HSCT. A weighted propensity score was applied to balance confounding factors with the transplanted cohort as reference. Weighted Cox proportional hazard models and logistic regression analyses were performed. 105 non-transplanted patients could be matched to the 239 transplanted patients. Mean age in transplanted and non-transplanted matched patients was 55.5 and 57.9 years. Blood cell count and DIPSS score distribution were similar in both groups. HSCT was associated with a higher 6-year OS rate in intermediate-2 (60.1% versus 41.5%) and high-risk DIPSS patients (44.4% versus 6.55%), high-risk MIPSS70 (46.5 versus 23.9%), high-risk (73.2% versus 39.7%) or very high-risk MIPSS70V2 (51.8% versus 24%). Intermediate MIPSS70 patients have an advantage of survival with HSCT only when their MTSS were low or intermediate. Transplanted patients had an increased mortality risk the first year but a significant benefit with HSCT after the one-year landmark was observed in higher risk patients. This study confirms that similar to DIPSS, MIPSS70 and MIPSS70+V2 risk score in addition to MTSS can be used to determine which patients with primary myelofibrosis have survival benefit from HSCT over non-HSCT strategies.}, }
@article {pmid39561273, year = {2024}, author = {Chae, YK and Corthell, L and Patel, SP and Edwards, R and Scalici, JM and Kim, HS and Chung, LI and Othus, M and McLeod, CM and Chen, HX and Sharon, E and Streicher, H and Ryan, CW and Blanke, CD and Kurzrock, R}, title = {A Phase II Basket Trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) SWOG S1609: Vulvar Cancers.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-24-1957}, pmid = {39561273}, issn = {1557-3265}, abstract = {BACKGROUND: Dual PD-1/CTLA-4 inhibition shows promise in various malignancies. The SWOG S1609 DART trial presents initial results of ipilimumab/nivolumab in vulvar cancers.<br><br>METHODS: DART is a prospective/open-label/multicenter (1,016 US sites)/multi-cohort phase II clinical trial of ipilimumab (1mg/kg intravenously every 6 weeks) plus nivolumab (240mg intravenously every 2 weeks). The primary endpoint was objective response rate [ORR, confirmed complete and partial responses (CR and PR, respectively)] per RECISTv1.1; progression-free survival (PFS), overall survival (OS), clinical benefit rate [CBR; overall response plus stable disease (SD) &#x2265;6 months], and toxicity are secondary endpoints.<br><br>RESULTS: Sixteen evaluable patients (median age, 55.5 years; 0-6 prior therapies; no prior immunotherapy) were analyzed, all of whom had squamous cell carcinoma histology. ORR was 18.8% (3/16), CBR was 25% (4/16), and CBR plus unconfirmed PR rate was 31% (5/16); PFS was 34.1, 16.7. 15.5, 7.2 and 7.0 months for these five patients. The median PFS and OS were 2.2 and 7.6 months. The most common adverse events were diarrhea, fatigue, pruritus, anorexia, and nausea (25%, n=4 each). Grade 3-4 adverse events occurred in 25% of patients (n=4). There was 1 grade 1-2 adverse event (6.7%) that led to discontinuation, and 1 (6.7%) grade 5 death adverse event.<br><br>CONCLUSION: Ipilimumab plus nivolumab in vulvar cancers resulted in an objective response in three out of 16 patients, all of whom had durable responses lasting over one year. Notably, two additional patients experienced durable SD and unconfirmed PR. Correlative studies to determine response and resistance markers are ongoing.}, }
@article {pmid39561007, year = {2024}, author = {Schoenfeld, DA and Djureinovic, D and Su, DG and Zhang, L and Lu, BY and Kamga, L and Mann, JE and Huck, JD and Hurwitz, M and Braun, DA and Jilaveanu, L and Ring, AM and Kluger, HM}, title = {Decoy-resistant IL-18 reshapes the tumor microenvironment and enhances rejection by anti-CTLA-4 in renal cell carcinoma.}, journal = {JCI insight}, volume = {}, number = {}, pages = {}, doi = {10.1172/jci.insight.184545}, pmid = {39561007}, issn = {2379-3708}, abstract = {The cytokine interleukin-18 (IL-18) has immunostimulatory effects but is negatively regulated by a secreted binding protein, IL-18BP, that limits IL-18's anti-cancer efficacy. A "decoy-resistant" form of IL-18 (DR-18), that avoids sequestration by IL-18BP while maintaining its immunostimulatory potential, has recently been developed. Here, we investigated the therapeutic potential of DR-18 in renal cell carcinoma (RCC). Using pan-tumor transcriptomic data, we found that clear cell RCC had among the highest expression of IL-18 receptor subunits and IL18BP of tumor types in the database. In samples from RCC patients treated with immune checkpoint inhibitors, IL-18BP protein expression increased in the tumor microenvironment and circulating in plasma in non-responding patients and decreased in the majority of responding patients. We used immunocompetent RCC murine models to assess the efficacy of DR-18 in combination with single- and dual-agent anti-PD-1 and anti-CTLA-4. In contrast to preclinical models of other tumor types, in RCC models DR-18 enhanced the activity of anti-CTLA-4 but not anti-PD-1 treatment. This activity correlated with intra-tumoral enrichment and clonal expansion of effector CD8+ T cells, decreased regulatory T cell levels, and enrichment of pro-inflammatory, anti-tumor myeloid cell populations. Our findings support further clinical investigation of the combination of DR-18 and anti-CTLA-4 in RCC.}, }
@article {pmid39560823, year = {2024}, author = {Vaidya, R and Till, C and Henry, NL and Fisch, MJ and Hershman, DL and Unger, JM}, title = {Neighborhood socioeconomic deprivation and patient-reported outcomes in symptom management trials for women with breast cancer.}, journal = {Breast cancer research and treatment}, volume = {}, number = {}, pages = {}, pmid = {39560823}, issn = {1573-7217}, support = {CA189974//National Cancer Institute at the National Institutes of Health/ ; CA189974//National Cancer Institute at the National Institutes of Health/ ; CA189974//National Cancer Institute at the National Institutes of Health/ ; CA189974//National Cancer Institute at the National Institutes of Health/ ; CA189974//National Cancer Institute at the National Institutes of Health/ ; CA189974//National Cancer Institute at the National Institutes of Health/ ; }, abstract = {PURPOSE: Neighborhood socioeconomic deprivation (NSD) is associated with worse outcomes among patients with cancer, but little is known about NSD-related disparities in patient-reported outcomes (PRO) in clinical trials. We examined the relationship between PROs and NSD in symptom management trials among women with breast cancer.<br><br>METHODS: We pooled data from three SWOG randomized trials to examine four outcomes: physical and functional wellbeing (PWB, FWB), average pain, and pain interference. NSD was measured using participants' zip code linked to the area deprivation index (ADI) score, categorized into tertiles. Multivariable linear regression adjusted for sociodemographic and clinical characteristics was used to analyze baseline PROs. Linear mixed models were used to examine if trajectory of PROs from baseline through 24&#xa0;weeks varied by ADI.<br><br>RESULTS: We examined 761 participants, of whom 51% were from least deprived neighborhoods. Participants in the most deprived neighborhoods had worse average pain at baseline (&#x3b2;&#x2009;=&#x2009;.38, 95% CI&#x2009;=&#x2009;.03 to .72, p&#x2009;=&#x2009;.03) while participants in somewhat deprived areas also had worse FWB (&#x3b2;&#x2009;=&#x2009;-1.07, 95% CI&#x2009;=&#x2009;-1.95 to -.20, p&#x2009;=&#x2009;.02) and pain interference (&#x3b2;&#x2009;=&#x2009;0.42, 95% CI&#x2009;=&#x2009;.09 to .75, p&#x2009;=&#x2009;.01) compared to those from least deprived areas. Hispanic ethnicity and having Medicaid/no insurance were associated with worse outcomes. After adjusting for baseline score, ADI was not associated with any outcome over time.<br><br>CONCLUSIONS: Breast cancer patients living in areas with NSD had worse FWB, joint pain, and pain interference at baseline. Clinical trial participants should be screened for community-level needs. Implementing interventions to address those needs could help mitigate disparities.}, }
@article {pmid39560645, year = {2024}, author = {Kohrt, SE and Novak, EJ and Tapadar, S and Wu, B and Strope, J and Asante, Y and Kim, H and Chang, MS and Gurdak, D and Khalil, A and Rood, M and Raftery, E and Stavreva, D and Nguyen, HM and Brown, LG and Ramser, M and Peer, C and Meyers, WM and Aboreden, N and Chakravortee, M and Sallari, R and Nelson, PS and Kelly, KK and Graham, TGW and Darzacq, X and Figg, WD and Oyelere, AK and Corey, E and Adelaiye-Ogala, R and Gryder, BE}, title = {Small-molecule disruption of androgen receptor-dependent chromatin clusters.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {48}, pages = {e2406239121}, pmid = {39560645}, issn = {1091-6490}, support = {W81XWH-19-1-0715//U.S. Department of Defense (DOD)/ ; P50 CA097186/CA/NCI NIH HHS/United States ; CA097186//Prostate Cancer Foundation (PCF)/ ; 5R01CA291963-02//HHS | National Institutes of Health (NIH)/ ; K22 CA255594/CA/NCI NIH HHS/United States ; P50CA97186//HHS | National Institutes of Health (NIH)/ ; 1K22CA255594//HHS | National Institutes of Health (NIH)/ ; RO1 CA266013//HHS | National Institutes of Health (NIH)/ ; R01 CA266013/CA/NCI NIH HHS/United States ; S10 OD024996/OD/NIH HHS/United States ; R01 CA291963/CA/NCI NIH HHS/United States ; P01 CA163227/CA/NCI NIH HHS/United States ; }, mesh = {*Receptors, Androgen/metabolism/genetics ; Humans ; *Chromatin/metabolism ; Male ; Cell Line, Tumor ; Animals ; *Prostatic Neoplasms, Castration-Resistant/drug therapy/metabolism/genetics/pathology ; *Androgen Receptor Antagonists/pharmacology/metabolism ; Mice ; Gene Expression Regulation, Neoplastic/drug effects ; Promoter Regions, Genetic ; Xenograft Model Antitumor Assays ; Signal Transduction/drug effects ; }, abstract = {Sustained androgen receptor (AR) signaling during relapse is a central driver of metastatic castration-resistant prostate cancer (mCRPC). Current AR antagonists, such as enzalutamide, fail to provide long-term benefit for the mCRPC patients who have dramatic increases in AR expression. Here, we report AR antagonists with efficacy in AR-overexpressing models. These molecules bind to the ligand-binding domain of the AR, promote AR localization to the nucleus, yet potently and selectively down-regulate AR-target genes. The molecules BG-15a and the pharmacokinetically optimized BG-15n elicit a decrease in cell and tumor growth in vitro and in vivo in models of mCRPC. BG-15a/n treatment causes the collapse of chromatin loops between enhancers and promoters at key genes in the AR-driven epigenome. AR binding in the promoter, as well as 3D chromatin clustering, is needed for genes to respond. BG-15a/n represent promising agents for treating patients with relapsed AR-driven mCRPC tumors.}, }
@article {pmid39560376, year = {2024}, author = {Stafford, E and Dimitrov, D and Trinidad, SB and Matrajt, L}, title = {Closing the gap in race-based inequities for seasonal influenza hospitalizations: a modeling study.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciae564}, pmid = {39560376}, issn = {1537-6591}, abstract = {BACKGROUND: BIPOC (Black, Indigenous, and other People of Color) communities bear a disproportional burden of seasonal influenza hospitalizations in the United States.<br><br>METHODS: We developed a race-stratified (5 racial-ethnic groups) agent-based model of seasonal influenza transmission and quantify the effects of 5 idealized interventions aimed at reducing inequities in symptomatic infections and hospitalizations. The interventions assumed (i) equalized vaccination rates, (ii) equalized comorbidities, (iii) work-risk distribution proportional to the distribution of the population, (iv) reduced work contacts for all, or (v) a combination of equalizing vaccination rates and comorbidities and reducing work contacts.<br><br>RESULTS: Our analysis suggests that symptomatic infections could be greatly reduced (by up to 17% in BIPOC adults aged 18-49) by strategies reducing work contacts or equalizing vaccination rates. All tested interventions reduced the inequity in influenza hospitalizations in all racial-ethnic groups, but interventions equalizing comorbidities were the most effective, with over 40% less hospitalizations in BIPOC groups. Inequities in hospitalizations in different racial-ethnic groups responded differently to interventions, pointing to the need of tailored interventions for different populations. Notably, these interventions resulted in better outcomes across all racial-ethnic groups, not only those prioritized by the interventions.<br><br>CONCLUSIONS: In this simulation modeling study, equalizing vaccination rates and reducing number of work contacts (e.g., improving air filtration systems, tailored vaccination campaigns) reduced both inequity and the total number of symptomatic infections and hospitalizations in all age and racial-ethnic groups. Reducing inequity in influenza hospitalizations requires different interventions for different groups.}, }
@article {pmid39559248, year = {2024}, author = {Kopmar, NE and Cassaday, RD}, title = {Clinical Insights on Brexucabtagene Autoleucel for the Treatment of Patients with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia.}, journal = {Cancer management and research}, volume = {16}, number = {}, pages = {1587-1596}, pmid = {39559248}, issn = {1179-1322}, abstract = {Autologous chimeric antigen receptor-modified T-cell therapy (CAR-T) has revolutionized treatment paradigms across multiple lymphoid malignancies, including relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). The introduction of the CD19-directed CAR-T product brexucabtagene autoleucel (brexu-cel; Tecartus) in October 2021 made this treatment approach available for the first time for adults with R/R B-ALL, a historically challenging clinical entity to treat. In this review, we will discuss the pivotal clinical trial data from the ZUMA-3 study that led to the US Food and Drug Administration (FDA) approval of brexu-cel, including clinical outcomes and key toxicity data (most importantly, the incidence and severity of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome). Additionally, we will compare and contrast these data from the ZUMA-3 study with "real-world" data from examinations of patient outcomes with brexu-cel as an FDA-approved therapy in R/R B-ALL, and discuss practical considerations with brexu-cel use in the clinic, including the role of consolidative allografting for patients post-brexu-cel. We finish by discussing future directions for CAR-T use in R/R B-ALL with the anticipated introduction of a new CD19-directed CAR-T product - obecabtagene autoleucel - in the near future.}, }
@article {pmid39556786, year = {2024}, author = {Huang, IJ and Baek, GT and Cohen, J and Khajaviyan, S and Louie, S and Samples, L and Smith, SD and Till, BG and Warren, EH and Gopal, AK and Poh, C and Lynch, RC and Ujjani, CS and Shadman, M}, title = {Clinical Relevance of Intensive Laboratory Monitoring With Standard Venetoclax Ramp-Up for Chronic Lymphocytic Leukemia: A Real-World Experience.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2400416}, doi = {10.1200/OP.24.00416}, pmid = {39556786}, issn = {2688-1535}, abstract = {PURPOSE: Venetoclax is the standard of care for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) but requires intensive monitoring for optimal safety. Clinical relevance of intensive monitoring in practice is unknown, especially for patients with low or intermediate risk for tumor lysis syndrome (TLS).<br><br>PATIENTS AND METHODS: A retrospective review was conducted to determine clinical significance of monitoring for TLS during standard ramp-up for patients with CLL/SLL. Patients receiving abbreviated ramp-up, clinical trials, or concurrent Bruton tyrosine kinase inhibitors were excluded. The primary end point was TLS incidence, with secondary end points describing associated clinical interventions.<br><br>RESULTS: Fifty-five patients met study criteria. The majority of patients received venetoclax as first-line therapy (58%), with anti-CD20 antibody therapy (82%), and were at low risk of TLS (75%). No clinical TLS events occurred, whereas laboratory TLS occurred in only 1.8% of patients. No patients required antihyperuricemic therapy, and few interventions for hyperphosphatemia or hypocalcemia (3.6% of patients) were required. Additional intravenous fluids were uncommonly required (1.8% of patients), and no unplanned hospitalizations were required.<br><br>CONCLUSION: These findings support efforts to reduce intensive monitoring requirements during venetoclax ramp-up for patients with CLL, potentially increasing accessibility of venetoclax.}, }
@article {pmid39555026, year = {2024}, author = {Huang, Y and Feng, Z}, title = {ASSESSING SCREENING EFFICACY IN THE PRESENCE OF CANCER OVERDIAGNOSIS.}, journal = {The annals of applied statistics}, volume = {18}, number = {2}, pages = {1543-1564}, pmid = {39555026}, issn = {1932-6157}, support = {R01 CA277133/CA/NCI NIH HHS/United States ; U24 CA086368/CA/NCI NIH HHS/United States ; }, abstract = {Cancer screening facilitates the early detection of cancer, at a stage when treatment is often most effective. However, it also brings the risk of over-diagnosis, where a diagnosis made through screening would not have led to symptoms or death during the patient's lifetime. In this paper, we tackle a significant unresolved issue in the evaluation of screening efficacy: selecting primary endpoints and inferential procedures that efficiently consider potential overdiagnosis in screening trials. This is motivated by the necessity to design and analyze a phase IV Early Detection Initiative (EDI) trial for evaluating a pancreatic cancer screening strategy. We introduce two novel approaches for assessing screening efficacy, grounded on cancer stage-shift. These methods address potential overdiagnosis by: i) borrowing information about clinical diagnosis from the control arm that hasn't undergone screening (the BR approach), and ii) performing sensitivity analysis, contingent upon a conservative bound of the overdiagnosis magnitude (the SEN-T approach). Analytical methods and extensive simulation studies underscore the superiority of our proposed methods, demonstrating enhanced efficiency in estimating and testing screening efficacy compared to existing methods. The latter either overlook overdiagnosis or adhere to a valid, yet conservative, cumulative incidence endpoint. We illustrate the practical application of these approaches using ovarian cancer data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. The results affirm that our methods bolster an efficient and robust study design for cancer screening trials.}, }
@article {pmid39554199, year = {2024}, author = {Yu, Z and Vromman, A and Nguyen, NQH and Schuermans, A and Rentz, T and Vellarikkal, SK and Uddin, MM and Niroula, A and Griffin, G and Honigberg, MC and Lin, AE and Gibson, CJ and Katz, DH and Tahir, U and Fang, S and Haidermota, S and Ganesh, S and Antoine, T and Weinstock, J and Austin, TR and Ramachandran, VS and Peloso, GM and Hornsby, W and Ganz, P and Manson, JE and Haring, B and Kooperberg, CL and Reiner, AP and Bis, JC and Psaty, BM and Min, YI and Correa, A and Lange, LA and Post, WS and Rotter, JI and Rich, SS and Wilson, JG and Ebert, BL and Yu, B and Ballantyne, CM and Coresh, J and Sankaran, VG and Bick, AG and Jaiswal, S and Gerszten, RE and ,  and Libby, P and Gupta, RM and Natarajan, P}, title = {Human Plasma Proteomic Profile of Clonal Hematopoiesis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39554199}, issn = {2692-8205}, support = {RC2 HL102419/HL/NHLBI NIH HHS/United States ; R01 HL148565/HL/NHLBI NIH HHS/United States ; R01 HL134892/HL/NHLBI NIH HHS/United States ; R01 HL127564/HL/NHLBI NIH HHS/United States ; P30 DK063491/DK/NIDDK NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; HHSN268201800010I/HB/NHLBI NIH HHS/United States ; N01HC85081/HL/NHLBI NIH HHS/United States ; 75N92020D00002/HL/NHLBI NIH HHS/United States ; HHSN268201500003C/HL/NHLBI NIH HHS/United States ; HHSN268201800012C/HL/NHLBI NIH HHS/United States ; 75N92020D00005/HL/NHLBI NIH HHS/United States ; N01HC95160/HL/NHLBI NIH HHS/United States ; DP5 OD029586/OD/NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; U54 HG003067/HG/NHGRI NIH HHS/United States ; U01 DK108809/DK/NIDDK NIH HHS/United States ; HHSN268201600002C/HL/NHLBI NIH HHS/United States ; R01 MH104964/MH/NIMH NIH HHS/United States ; 75N92022D00002/HL/NHLBI NIH HHS/United States ; R01 HL153499/HL/NHLBI NIH HHS/United States ; R01 HL151283/HL/NHLBI NIH HHS/United States ; N01HC95163/HL/NHLBI NIH HHS/United States ; U01 HL080295/HL/NHLBI NIH HHS/United States ; R01 HL163099/HL/NHLBI NIH HHS/United States ; UL1 TR001079/TR/NCATS NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; HHSN268201800014I/HB/NHLBI NIH HHS/United States ; R01 DK125782/DK/NIDDK NIH HHS/United States ; U01 HL130114/HL/NHLBI NIH HHS/United States ; HHSN268200800007C/HL/NHLBI NIH HHS/United States ; 75N92020D00001/HL/NHLBI NIH HHS/United States ; N01HC95169/HL/NHLBI NIH HHS/United States ; U01 HG004402/HG/NHGRI NIH HHS/United States ; N01HC95164/HL/NHLBI NIH HHS/United States ; N01HC55222/HL/NHLBI NIH HHS/United States ; HHSN268201800014C/HL/NHLBI NIH HHS/United States ; N01HC95162/HL/NHLBI NIH HHS/United States ; N01HC85086/HL/NHLBI NIH HHS/United States ; 75N92020D00003/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; N01HC95168/HL/NHLBI NIH HHS/United States ; 75N92022D00004/HL/NHLBI NIH HHS/United States ; R01 HL142711/HL/NHLBI NIH HHS/United States ; HHSN268201200036C/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; HHSN268201800013I/MD/NIMHD NIH HHS/United States ; R01 HL151152/HL/NHLBI NIH HHS/United States ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; R01 HL159081/HL/NHLBI NIH HHS/United States ; N01HC95165/HL/NHLBI NIH HHS/United States ; N01HC95159/HL/NHLBI NIH HHS/United States ; HHSN268201800012I/HL/NHLBI NIH HHS/United States ; N01HC95161/HL/NHLBI NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; 75N92020D00004/HL/NHLBI NIH HHS/United States ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; DP2 HL157540/HL/NHLBI NIH HHS/United States ; HHSN268201800011C/HL/NHLBI NIH HHS/United States ; 75N92020D00007/HL/NHLBI NIH HHS/United States ; R01 MH123451/MH/NIMH NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; 75N92022D00003/HL/NHLBI NIH HHS/United States ; HHSN268201500003I/HL/NHLBI NIH HHS/United States ; 75N92021D00006/HL/NHLBI NIH HHS/United States ; 75N92022D00005/HL/NHLBI NIH HHS/United States ; N01HC85082/HL/NHLBI NIH HHS/United States ; N01HC95167/HL/NHLBI NIH HHS/United States ; N01HC85083/HL/NHLBI NIH HHS/United States ; HHSN268201800015I/HB/NHLBI NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; 75N92020D00006/HL/NHLBI NIH HHS/United States ; N01HC85079/HL/NHLBI NIH HHS/United States ; N01HC95166/HL/NHLBI NIH HHS/United States ; R01 HL135242/HL/NHLBI NIH HHS/United States ; R01 AG023629/AG/NIA NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; HHSN268201800011I/HB/NHLBI NIH HHS/United States ; R01 HL134320/HL/NHLBI NIH HHS/United States ; N01HC85080/HL/NHLBI NIH HHS/United States ; 75N92022D00001/HL/NHLBI NIH HHS/United States ; R01 HL148050/HL/NHLBI NIH HHS/United States ; T32 HL007604/HL/NHLBI NIH HHS/United States ; }, abstract = {Plasma proteomic profiles associated with subclinical somatic mutations in blood cells may offer novel insights into downstream clinical consequences. Here, we explore such patterns in clonal hematopoiesis of indeterminate potential (CHIP), which is linked to several cancer and non-cancer outcomes, including coronary artery disease (CAD). Among 61,833 ancestrally diverse participants (3,881 with CHIP) from NHLBI TOPMed and UK Biobank with blood-based DNA sequencing and proteomic measurements (1,148 proteins by SomaScan in TOPMed and 2,917 proteins by Olink in UK Biobank), we identified 32 and 345 unique proteins from TOPMed and UK Biobank, respectively, associated with the most prevalent driver genes (DNMT3A, TET2, and ASXL1). These associations showed substantial heterogeneity by driver genes, sex, and race, and were enriched for immune response and inflammation pathways. Mendelian randomization in humans, coupled with ELISA in hematopoietic Tet2-/- vs wild-type mice validation, disentangled causal proteomic perturbations from TET2 CHIP. Lastly, we identified plasma proteins shared between CHIP and CAD.}, }
@article {pmid39553428, year = {2024}, author = {Nealy, ES and Reed, SJ and Adelmund, SM and Badeau, BA and Shadish, JA and Girard, EJ and Brasel, K and Pakiam, FJ and Mhyre, AJ and Price, JP and Sarkar, S and Kalia, V and DeForest, CA and Olson, JM}, title = {Versatile tissue-injectable hydrogels capable of the extended hydrolytic release of bioactive protein therapeutics.}, journal = {Bioengineering &amp; translational medicine}, volume = {9}, number = {5}, pages = {e10668}, pmid = {39553428}, issn = {2380-6761}, support = {T32 GM095421/GM/NIGMS NIH HHS/United States ; R01 AI132819/AI/NIAID NIH HHS/United States ; R01 CA114567/CA/NCI NIH HHS/United States ; F32 CA265056/CA/NCI NIH HHS/United States ; R35 GM138036/GM/NIGMS NIH HHS/United States ; T32 CA080416/CA/NCI NIH HHS/United States ; }, abstract = {Hydrogels are extensively employed in healthcare due to their adaptable structures, high water content, and biocompatibility, with FDA-approved applications ranging from spinal cord regeneration to local therapeutic delivery. However, clinical hydrogels encounter challenges related to inconsistent therapeutic exposure, unmodifiable release windows, and difficulties in subsurface polymer insertion. Addressing these issues, we engineered injectable, biocompatible hydrogels as a local therapeutic depot, utilizing poly(ethylene glycol) (PEG)-based hydrogels functionalized with bioorthogonal SPAAC handles for network polymerization and functionalization. Our hydrogel solutions polymerize in situ in a temperature-sensitive manner, persist in tissue, and facilitate the delivery of bioactive therapeutics in subsurface locations. Demonstrating the efficacy of our approach, recombinant anti-CD47 monoclonal antibodies, when incorporated into subsurface-injected hydrogel solutions, exhibited cytotoxic activity against infiltrative high-grade glioma xenografts in the rodent brain. To enhance the gel's versatility, recombinant protein cargos can undergo site-specific modification with hydrolysable "azidoester" adapters, allowing for user-defined release profiles from the hydrogel. Hydrogel-generated gradients of murine CXCL10, linked to intratumorally injected hydrogel solutions via azidoester linkers, resulted in significant recruitment of CD8[+] T-cells and the attenuation of tumor growth in a "cold" syngeneic melanoma model. This study highlights a highly customizable, hydrogel-based delivery system for local protein therapeutic administration to meet diverse clinical needs.}, }
@article {pmid39551677, year = {2024}, author = {Simunic, M and McGraw, K and Pavletic, SZ and Rashidi, A}, title = {Intestinal microbiome and myelodysplastic syndromes: Current state of knowledge and perspectives for future.}, journal = {Seminars in hematology}, volume = {}, number = {}, pages = {}, doi = {10.1053/j.seminhematol.2024.10.006}, pmid = {39551677}, issn = {1532-8686}, abstract = {The intestinal microbiome has been mechanistically linked with health and many disease processes. Cancer is no exception. Both in solid tumors and hematologic malignancies, there is increasing evidence supporting the involvement of the intestinal microbiome in tumor development, disease progression, response to treatment, and treatment toxicity. Consistent with microbiome mediation of the immune system and the potent effect of the immune system on cancer, the most compelling evidence has been obtained in the setting of cancer immunotherapy. Here, we review the current state of knowledge about microbiome effects in myelodysplastic syndromes, identify gaps and challenges in related research, and provide insights for future work.}, }
@article {pmid39550102, year = {2025}, author = {Waghmare, A and Hijano, DR}, title = {SARS-CoV-2 Infection and COVID-19 in Children.}, journal = {Rheumatic diseases clinics of North America}, volume = {51}, number = {1}, pages = {139-156}, doi = {10.1016/j.rdc.2024.09.003}, pmid = {39550102}, issn = {1558-3163}, mesh = {Child ; Humans ; *COVID-19/complications/immunology/physiopathology/therapy ; SARS-CoV-2/immunology/pathogenicity ; *Systemic Inflammatory Response Syndrome/etiology/immunology/physiopathology/therapy ; }, abstract = {Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is common in children, and clinical manifestations can vary depending on age, underlying disease, and vaccination status. Most children will have asymptomatic or mild infection, but certain baseline characteristics can increase the risk of moderate to severe disease. The following article will provide an overview of the clinical manifestations of coronavirus disease 2019 in children, including the post-infectious phenomenon called multisystem inflammatory syndrome in children. Currently available treatment and prophylaxis strategies will be outlined, with the caveat that new therapeutics and clinical efficacy data are constantly on the horizon.}, }
@article {pmid39549763, year = {2024}, author = {Tseng, YD and Stevenson, P and Nguyen, B and Li, DC and Lee, DY and Paydar, I and Nakashima, J and Balogh, A and Ravella, R and Barbour, AB and Post, C and Ababneh, H and Pinnix, CC and Ballas, LK and Binkley, MS and Dedeckova, K and Hoppe, RT and Patel, C and Nabavizadeh, N and Kelsey, CR and Kumar, KA and Landsburg, D and Figura, NB and Lo, AC and Plastaras, JP}, title = {Impact of Myc-Altered Pathology on Radiation Therapy Efficacy Among Patients With Relapsed/Refractory Large-B Cell Lymphoma: A Collaborative Study by ILROG.}, journal = {International journal of radiation oncology, biology, physics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ijrobp.2024.11.072}, pmid = {39549763}, issn = {1879-355X}, abstract = {PURPOSE: The presence of MYC and BCL2 translocations (ie, double-hit lymphoma, DHL) in large B-cell lymphoma (LBCL) is associated with reduced chemosensitivity, but less is known on its impact on radiotherapy (RT) efficacy.<br><br>METHODS AND MATERIALS: Patients with LBCL who received their first course of RT for relapsed/refractory disease between 2008 and 2020 were eligible if there was adequate pathologic evaluation to be categorized as DHL versus non-DHL as per the World Health Organization (fifth edition). Separate analyses were conducted by treatment intent. Predictors for response (complete and partial) and local recurrence (LR) were evaluated using Cox regression analysis. LR analysis was restricted to curative-intent patients to ensure adequate follow-up.<br><br>RESULTS: Three hundred and eighty-three patients (102 DHL, 281 non-DHL, and 44% curative) were treated at 447 sites. Median time from diagnosis to RT was 11.6 months, with 38.7% of patients having primary chemorefractory disease, 37.4% having received >2 lines of systemic therapy, and 24% status post-stem cell transplant. Median biological equivalent dose (alpha/beta: 10) was 28 Gy (range: 3.2-60.0) for palliative and 46.9 Gy (range: 6.4-84.0) for curative-intent patients. With a median follow-up of 41.1 and 41.5 months among curative and palliative patients, respectively, the response was high (81.1% curative, 60.1% palliative). On univariate analysis, DHL pathology was not associated with RT response in either curative or palliative patients. Among curative patients, 2-year LR rate was 38.8%. On multivariable analysis, DHL pathology was associated with a 2 times higher risk of LR (95% CI: 1.05-3.67, P = .03), with a crude LR rate of 42.9% (DHL) versus 28.9% (non-DHL). RT was well tolerated with low rates of grade 3 or higher acute toxicity (1.8% curative, 2.9% palliative).<br><br>CONCLUSIONS: Relapsed/refractory LBCL remains radioresponsive with a 60%-80% response rate to RT. Although DHL pathology does not appear to influence RT response, its presence is associated with higher rates of LR, suggesting that it may be more radioresistant.}, }
@article {pmid39546840, year = {2024}, author = {Bellows, AL and Palmer, AC and Curriero, F and Thorne-Lyman, AL and Shamim, AA and Shaikh, S and Haque, R and Ali, H and Sugimoto, JD and Christian, P and West, KP and Labrique, AB}, title = {Changes in urbanicity and household availability of and proximity to food vendors from 2004 to 2020 in a rural district of northwestern Bangladesh.}, journal = {Health &amp; place}, volume = {90}, number = {}, pages = {103374}, pmid = {39546840}, issn = {1873-2054}, mesh = {Bangladesh ; Humans ; *Rural Population/statistics &amp; numerical data ; *Commerce/statistics &amp; numerical data ; *Food Supply/statistics &amp; numerical data ; *Family Characteristics ; Female ; Male ; Adult ; Residence Characteristics/statistics &amp; numerical data ; Socioeconomic Factors ; Urban Population/statistics &amp; numerical data ; }, abstract = {BACKGROUND: The nutrition transition underway in South Asia is likely mediated by changes to the food environment. Yet, few studies have been conducted in rural areas of South Asia to describe how the food environment has changed.<br><br>OBJECTIVE: This analysis assessed changes in household availability of and proximity to markets, grocery shops, and tea shops over a 16-year time period in Gaibandha, Bangladesh.<br><br>METHODS: We analyzed household demographic and geospatial data collected at 3 time points from 2004 to 2020 in a contiguous rural area (435&#xa0;km[2]). We defined availability as number of food vendors within 400- and 1600-m radius of households and proximity as distance to nearest vendor. We used linear and Poisson models to estimate associations between household socioeconomic status (SES) and food vendor availability and proximity. We used multi-level models to conduct similar analyses for community-level urbanicity.<br><br>RESULTS: From 2004 to 2020, the numbers of markets, grocery shops and tea shops increased by 21%, 66% and 270%, respectively. Food vendor proximity did not change by household SES, but less urban households witnessed larger increases in proximity to markets (p for interaction<0.001) and tea shops (p for interaction<0.001) over time. Grocery shop and tea shop availability was initially higher and increased more over time for households in higher urbanicity areas (p for interaction<0.001).<br><br>CONCLUSION: Over a 16-year period, this rural area of Bangladesh became more urbanized, increasing the availability of and proximity to markets, grocery shops, and tea shops. Further research is needed to see how these changes impact rural residents' intake and nutritional status.}, }
@article {pmid39543541, year = {2024}, author = {Pan, C and Ng, K and Voutsinas, J and Barber, B and Rizvi, ZH and Marchiano, E and Ferrandino, RM and Futran, N and Laramore, GE and Liao, JJ and Parvathaneni, U and Panjwani, N and Martins, RG and Rodriguez, CP and Wu, QV}, title = {Development of a prognostic signature for overall survival using peripheral blood biomarkers in head and neck squamous cell carcinoma treated with immune checkpoint inhibitors.}, journal = {BMC cancer}, volume = {24}, number = {1}, pages = {1406}, pmid = {39543541}, issn = {1471-2407}, support = {T32 DC000018/DC/NIDCD NIH HHS/United States ; T32 DC000018/NH/NIH HHS/United States ; }, mesh = {Humans ; Male ; *Immune Checkpoint Inhibitors/therapeutic use ; *Squamous Cell Carcinoma of Head and Neck/blood/drug therapy/mortality ; Female ; Middle Aged ; Prognosis ; Aged ; *Biomarkers, Tumor/blood ; *Head and Neck Neoplasms/blood/drug therapy/mortality ; *Neutrophils ; Adult ; Aged, 80 and over ; L-Lactate Dehydrogenase/blood ; }, abstract = {BACKGROUND: We previously reported in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) treated with immune checkpoint inhibitors (ICIs), pretreatment higher lactate dehydrogenase (LDH) and absolute (abx) neutrophils as well as lower percent (%) lymphocytes correlated with worse overall survival (OS). In this study we aimed to develop a prognostic signature for HNSCC treated with ICIs using these peripheral blood biomarkers (PBBMs).<br><br>METHODS: Adults with R/M HNSCC treated with ICIs at our institution from 08/2012 to 03/2021 with pretreatment PBBMs were included. Follow-up continued until 02/15/2022. The cohort (n&#x2009;=&#x2009;151) was randomly split into training (n&#x2009;=&#x2009;100) and testing (n&#x2009;=&#x2009;51) datasets. A prognostic score incorporating LDH, % lymphocytes, and abx neutrophils was developed from the training dataset using Cox proportional hazards regression. In the training dataset, a grid search identified the optimal cutpoints classifying patients into high, medium, and low-risk groups (trichotomized signature) as well as high vs. low-risk groups (dichotomized signature). The prognostic score, dichotomized and trichotomized signatures were then validated in the testing dataset.<br><br>RESULTS: Training and testing datasets showed no clinically meaningful differences in clinicodemographic characteristics or PBBMs. An OS prognostic model was developed from the training dataset: Risk score&#x2009;=&#x2009;1.24*log10(LDH) - 1.95*log10(% lymphocytes)&#x2009;+&#x2009;0.47*log10(abx neutrophils). Optimal risk score cutpoints for the dichotomized and trichotomized signatures were defined in the training dataset, and Kaplan-Meier curves for both dichotomized and trichotomized signatures showed good separation between risk groups. Risk scores were calculated in the testing dataset, where the trichotomized signature demonstrated overlap between low and medium-risk groups but good separation from the high-risk group while the dichotomized signature showed clear separation between low and high-risk groups. Higher risk score correlated with worse OS (HR 2.08, [95%CI 1.17-3.68], p&#x2009;=&#x2009;0.012). Progression-free survival Kaplan-Meier curves likewise showed excellent separation between dichotomized risk groups in the training and testing datasets.<br><br>CONCLUSIONS: We developed a prognostic signature for OS based on 3 previously identified PBBMs for HNSCC treated with ICIs and identified a high-risk group of patients least likely to have survival benefit from ICIs. This signature may improve ICI patient selection and warrants validation in an independent cohort as well as correlation with CPS.}, }
@article {pmid39542703, year = {2024}, author = {Demirci, RA and Ghodsi, A and Gulati, R and Behnia, S and Nelson, PS and Cheng, HH and Yezefski, TA and Haffner, MC and Hawley, JE and Montgomery, RB and Yu, EY and Schweizer, MT and Chen, DL and Iravani, A}, title = {PET-Based TheraP Eligibility and Outcomes of VISION-Eligible Patients with Metastatic Castration-Resistant Prostate Cancer Who Received [177]Lu-PSMA-617: Importance of [18]F-FDG-Avid Discordant Findings.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {}, number = {}, pages = {}, doi = {10.2967/jnumed.124.268167}, pmid = {39542703}, issn = {1535-5667}, support = {R37 CA286450/CA/NCI NIH HHS/United States ; }, abstract = {The VISION and TheraP trials introduced different PET-based criteria for patient selection for treatment with [177]Lu-PSMA-617 (LuPSMA). TheraP used a higher prostate-specific membrane antigen (PSMA) uptake threshold than VISION and required [18]F-FDG PET to exclude patients with discordant findings. Although the screen-failed patients had shorter overall survival (OS) than those treated with LuPSMA, it remains unclear whether their outcomes might have been modified if they had been exposed to LuPSMA. In this study, we evaluated associations between the TheraP eligibility criteria and subgroups and the treatment outcomes of patients who were deemed suitable and treated on the basis of VISION criteria. Methods: Consecutive patients who were treated with LuPSMA and who underwent pretreatment PSMA and [18]F-FDG PET were classified as TheraP-eligible (TheraP-E) and TheraP-ineligible (TheraP-I), the latter of which were subclassified as low PSMA or discordant. Odds ratios for an at least 50% decline in prostate-specific antigen (PSA50) were computed using logistic regression, and hazard ratios (HRs) for PSA progression-free survival (PSA-PFS) and OS were computed using Cox regressions. Multivariable analyses were adjusted for baseline imaging and clinical parameters. Results: Of 75 patients, 31 (41%) were deemed TheraP-I; of those, 24 were subclassified as having discordant disease. TheraP-I patients had a lower PSA50 rate than that of TheraP-E patients (28% vs. 67%; odds ratio, 0.19; 95% CI, 0.06-0.52; P = 0.002) and a higher risk of PSA progression (HR, 2.0; 95% CI, 1.2-3.3; P = 0.007). OS in the TheraP-I group was numerically shorter than in the TheraP-E group, but the comparison was only marginally significant (10.4 mo vs. not reached; HR, 1.9; 95% CI, 1.0-3.7; P = 0.054). TheraP-I patients with low PSMA had no significantly different risk of death (P = 0.9) from that of TheraP-E patients, but those with discordant findings had higher risk of death (HR, 2.3; 95% CI, 1.1-4.6; P = 0.02). Discordant disease remained prognostic for OS after adjusting for baseline imaging and clinical parameters (HR, 3.0; 95% CI, 1.3-6.8; P = 0.01). Conclusion: In VISION-eligible patients who were treated with LuPSMA, TheraP-I patients with discordant findings had lower PSA50, PSA-PFS, and OS. Our study suggests that the shorter OS of TheraP-I patients is mainly driven by the presence of discordant disease.}, }
@article {pmid39542654, year = {2024}, author = {Shatila, M and Zhang, HC and Shirwaikar Thomas, A and Machado, AP and Naz, S and Mittal, N and Catinis, C and Varatharajalu, K and Colli Cruz, C and Lu, E and Wu, D and Brahmer, JR and Carbonnel, F and Hanauer, SB and Lashner, B and Schneider, B and Thompson, JA and Obeid, M and Farris, DP and Wang, Y}, title = {Systematic review of immune checkpoint inhibitor-related gastrointestinal, hepatobiliary, and pancreatic adverse events.}, journal = {Journal for immunotherapy of cancer}, volume = {12}, number = {11}, pages = {}, pmid = {39542654}, issn = {2051-1426}, mesh = {Humans ; *Immune Checkpoint Inhibitors/adverse effects ; *Gastrointestinal Diseases/chemically induced ; Immunotherapy/adverse effects/methods ; Pancreatic Diseases/chemically induced ; Neoplasms/drug therapy ; }, abstract = {Gastrointestinal immune-related adverse events (GI irAEs) are common manifestations of immune checkpoint inhibitor (ICI) toxicity. We present a comprehensive systematic review of the incidence, management, and clinical course of irAEs across the entire GI system, including the luminal GI tract, liver, and pancreas. MEDLINE, Embase, Web of Science Core Collection, and Cochrane Library were used to conduct this review. All studies pertaining to GI irAEs were included. Both abstracts and full manuscripts were eligible if they included human subjects and were written in the English language. Articles not available in English, animal studies, or research not specific to GI toxicity of immunotherapy were excluded. We excluded certain article types depending on whether stronger evidence was available in the literature for a specific toxicity, for example, if prospective studies were available on a topic, retrospective studies and case reports were excluded. We extracted a final 166 articles for our review and followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for data reporting. Risk of bias tools were not used to evaluate the extracted studies given the narrative nature of this manuscript, but each study was critically appraised by the manuscript writer. We detail the incidence, presentation, evaluation, management, and outcomes of the various GI toxicities that may arise with ICI therapy. Specifically, we discuss the characteristics of upper GI toxicity (esophagitis and gastroenteritis), lower GI toxicity (colitis), hepatobiliary inflammation, pancreatitis, and rarer forms of GI toxicity. We hope this review serves as a useful and accessible clinical tool that helps physicians familiarize themselves with the nuances of gastrointestinal/hepatic/pancreatic ICI toxicity diagnosis and management.}, }
@article {pmid39542408, year = {2024}, author = {Wechkin, HA and Menzel, PT and Loggers, ET and Macauley, RC and Pope, TM and Reagan, PL and Quill, TE}, title = {"Mr. Smith Has No Mealtimes": Minimal Comfort Feeding for Patients with Advanced Dementia.}, journal = {Journal of pain and symptom management}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jpainsymman.2024.11.001}, pmid = {39542408}, issn = {1873-6513}, abstract = {While Comfort Feeding Only is appropriate for patients with advanced dementia, its emphasis on assiduous hand-feeding that may prolong life for years fails to accommodate the preferences of those who do not want to continue living with this illness. Some have proposed advance directives to completely halt the provision of oral nutrition and hydration once a person has reached an advanced stage of dementia. However, these directives may fail to address patients' discomfort, caregivers' obligations, or current care and regulatory standards when patients reside in facilities. In response to these dilemmas, we introduce Minimal Comfort Feeding (MCF). Rather than offering food and liquids proactively as with Comfort Feeding Only, caregivers provide nutrition and hydration only in response to signs of hunger and thirst. While further study is required to define and negotiate challenges in operationalizing this approach, MCF provides a framework that resolves competing ethical and clinical considerations in caring for those with advanced dementia.}, }
@article {pmid39542140, year = {2024}, author = {Welch, SR and Bilello, JP and Carter, K and Delang, L and Dirr, L and Durantel, D and Feng, JY and Gowen, BB and Herrero, LJ and Janeba, Z and Kleymann, G and Lee, AA and Meier, C and Moffat, J and Schang, LM and Schiffer, JT and Seley-Radtke, KL and Sheahan, TP and Spengler, JR}, title = {Meeting report of the 37th International Conference on Antiviral Research in Gold Coast, Australia, May 20-24, 2024, organized by the International Society for Antiviral Research.}, journal = {Antiviral research}, volume = {232}, number = {}, pages = {106037}, doi = {10.1016/j.antiviral.2024.106037}, pmid = {39542140}, issn = {1872-9096}, mesh = {*Antiviral Agents/therapeutic use/pharmacology ; Humans ; Animals ; Australia ; Drug Discovery ; COVID-19 ; Drug Development ; Vaccine Development ; COVID-19 Drug Treatment ; }, abstract = {The 37th International Conference on Antiviral Research (ICAR) was held in Gold Coast, Australia, May 20-24, 2024. ICAR 2024 featured over 75 presentations along with two poster sessions and special events, including those specifically tailored for trainees and early-career scientists. The meeting served as a platform for the exchange of cutting-edge research, with presentations and discussions covering novel antiviral compounds, vaccine development, clinical trials, and therapeutic advancements. A comprehensive array of topics in antiviral science was covered, from the latest breakthroughs in antiviral drug development to innovative strategies for combating emerging viral threats. The keynote presentations provided fascinating insight into two diverse areas fundamental to medical countermeasure development and use, including virus emergence at the human-animal interface and practical considerations for bringing antivirals to the clinic. Additional sessions addressed a variety of timely post-pandemic topics, such as the hunt for broad spectrum antivirals, combination therapy, pandemic preparedness, application of in silico tools and AI in drug discovery, the virosphere, and more. Here, we summarize all the presentations and special sessions of ICAR 2024 and introduce the 38th ICAR, which will be held in Las Vegas, USA, March 17-21, 2025.}, }
@article {pmid39541580, year = {2024}, author = {Nagarajan, R and Kondo, M and Salas, F and Sezgin, E and Yao, Y and Klotzman, V and Godambe, SA and Khan, N and Limon, A and Stephenson, G and Taraman, S and Walton, N and Ehwerhemuepha, L and Pandit, J and Pandita, D and Weiss, M and Golden, C and Gold, A and Henderson, J and Shippy, A and Celi, LA and Hogan, WR and Oermann, EK and Sanger, T and Martel, S}, title = {Economics and Equity of Large Language Models: Health Care Perspective.}, journal = {Journal of medical Internet research}, volume = {26}, number = {}, pages = {e64226}, pmid = {39541580}, issn = {1438-8871}, mesh = {Humans ; *Delivery of Health Care ; Language ; }, abstract = {Large language models (LLMs) continue to exhibit noteworthy capabilities across a spectrum of areas, including emerging proficiencies across the health care continuum. Successful LLM implementation and adoption depend on digital readiness, modern infrastructure, a trained workforce, privacy, and an ethical regulatory landscape. These factors can vary significantly across health care ecosystems, dictating the choice of a particular LLM implementation pathway. This perspective discusses 3 LLM implementation pathways-training from scratch pathway (TSP), fine-tuned pathway (FTP), and out-of-the-box pathway (OBP)-as potential onboarding points for health systems while facilitating equitable adoption. The choice of a particular pathway is governed by needs as well as affordability. Therefore, the risks, benefits, and economics of these pathways across 4 major cloud service providers (Amazon, Microsoft, Google, and Oracle) are presented. While cost comparisons, such as on-demand and spot pricing across the cloud service providers for the 3 pathways, are presented for completeness, the usefulness of managed services and cloud enterprise tools is elucidated. Managed services can complement the traditional workforce and expertise, while enterprise tools, such as federated learning, can overcome sample size challenges when implementing LLMs using health care data. Of the 3 pathways, TSP is expected to be the most resource-intensive regarding infrastructure and workforce while providing maximum customization, enhanced transparency, and performance. Because TSP trains the LLM using enterprise health care data, it is expected to harness the digital signatures of the population served by the health care system with the potential to impact outcomes. The use of pretrained models in FTP is a limitation. It may impact its performance because the training data used in the pretrained model may have hidden bias and may not necessarily be health care-related. However, FTP provides a balance between customization, cost, and performance. While OBP can be rapidly deployed, it provides minimal customization and transparency without guaranteeing long-term availability. OBP may also present challenges in interfacing seamlessly with downstream applications in health care settings with variations in pricing and use over time. Lack of customization in OBP can significantly limit its ability to impact outcomes. Finally, potential applications of LLMs in health care, including conversational artificial intelligence, chatbots, summarization, and machine translation, are highlighted. While the 3 implementation pathways discussed in this perspective have the potential to facilitate equitable adoption and democratization of LLMs, transitions between them may be necessary as the needs of health systems evolve. Understanding the economics and trade-offs of these onboarding pathways can guide their strategic adoption and demonstrate value while impacting health care outcomes favorably.}, }
@article {pmid39541411, year = {2024}, author = {Lin, L and Spreng, RL and Seaton, KE and Dennison, SM and Dahora, LC and Schuster, DJ and Sawant, S and Gilbert, PB and Fong, Y and Kisalu, N and Pollard, AJ and Tomaras, GD and Li, J}, title = {GeM-LR: Discovering predictive biomarkers for small datasets in vaccine studies.}, journal = {PLoS computational biology}, volume = {20}, number = {11}, pages = {e1012581}, pmid = {39541411}, issn = {1553-7358}, support = {P01 AI162242/AI/NIAID NIH HHS/United States ; P30 AI064518/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Biomarkers ; *Vaccines/immunology ; Logistic Models ; *Computational Biology/methods ; Algorithms ; Vaccination/statistics &amp; numerical data ; }, abstract = {Despite significant progress in vaccine research, the level of protection provided by vaccination can vary significantly across individuals. As a result, understanding immunologic variation across individuals in response to vaccination is important for developing next-generation efficacious vaccines. Accurate outcome prediction and identification of predictive biomarkers would represent a significant step towards this goal. Moreover, in early phase vaccine clinical trials, small datasets are prevalent, raising the need and challenge of building a robust and explainable prediction model that can reveal heterogeneity in small datasets. We propose a new model named Generative Mixture of Logistic Regression (GeM-LR), which combines characteristics of both a generative and a discriminative model. In addition, we propose a set of model selection strategies to enhance the robustness and interpretability of the model. GeM-LR extends a linear classifier to a non-linear classifier without losing interpretability and empowers the notion of predictive clustering for characterizing data heterogeneity in connection with the outcome variable. We demonstrate the strengths and utility of GeM-LR by applying it to data from several studies. GeM-LR achieves better prediction results than other popular methods while providing interpretations at different levels.}, }
@article {pmid39540294, year = {2024}, author = {Karra, P and Hardikar, S and Winn, M and Anderson, GL and Haaland, B and Shadyab, AH and Neuhouser, ML and Seguin-Fowler, RA and Thomson, CA and Coday, M and Wactawski-Wende, J and Stefanick, ML and Zhang, X and Cheng, TD and Karanth, S and Sun, Y and Saquib, N and Pichardo, MS and Jung, SY and Tabung, FK and Summers, SA and Holland, WL and Jalili, T and Gunter, MJ and Playdon, MC}, title = {Metabolic phenotype and risk of obesity-related cancers in the Women's Health Initiative.}, journal = {Cancer prevention research (Philadelphia, Pa.)}, volume = {}, number = {}, pages = {}, doi = {10.1158/1940-6207.CAPR-24-0082}, pmid = {39540294}, issn = {1940-6215}, abstract = {Body mass index (BMI) may misclassify obesity-related cancer (ORC) risk, as metabolic dysfunction can occur across BMI levels. We hypothesized that metabolic dysfunction at any BMI increases ORC risk compared to normal BMI without metabolic dysfunction. Postmenopausal women (n=20,593) in the Women's Health Initiative with baseline metabolic dysfunction biomarkers (blood pressure, fasting triglycerides, high-density lipoprotein-cholesterol, fasting glucose, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and high sensitive C-reactive protein (hs-CRP)) were included. Metabolic phenotype (metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy overweight/obese (MHO), metabolically unhealthy overweight/obese (MUO)) was classified using four definitions of metabolic dysfunction: (1) Wildman criteria, (2) National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III), (3) HOMA-IR, and (4) hs-CRP. Multivariable Cox proportional hazards regression, with death as a competing risk, was used to assess the association between metabolic phenotype and ORC risk. After a median (IQR) follow-up duration of 21 (IQR 15-22) years, 2,367 women developed an ORC. The risk of any ORC was elevated among MUNW (HR 1.12, 95% CI: 0.90-1.39), MHO (HR 1.15, 95% CI: 1.00-1.32), and MUO (HR 1.35, 95% CI: 1.18-1.54) compared with MHNW using Wildman criteria. Results were similar using ATP III criteria, hs-CRP alone, or HOMA-IR alone to define metabolic phenotype. Individuals with overweight or obesity with or without metabolic dysfunction were at higher risk of ORCs compared with metabolically healthy normal weight individuals. The magnitude of risk was greater among those with metabolic dysfunction, although the confidence intervals of each category overlapped.}, }
@article {pmid39540227, year = {2024}, author = {Zelikson, V and Gurumurthi, A and Sawalha, Y and Annunzio, K and Saha, A and Dong, N and Qualls, D and Amoozgar, B and Kahl, B and Baird, J and Challa, P and Huntington, SF and Santos, J and Bair, S and Narkhede, M and Li, S and Frosch, Z and Ho, C and Smith, SD and Winter, A and Landsburg, D and Furqan, F and Hamadani, M and Baird, K and Romancik, J and Alharthy, H and Law, J and Bojanini, L and Advani, R and Hu, B and Johnson, PC and Grover, NS and Merril, M and Crombie, JL and Shafagati, N and Sterling, C and Nastoupil, LJ and Epperla, N and Ayers, EC}, title = {Loncastuximab in high-risk and heavily pretreated relapsed / refractory diffuse large B-cell lymphoma: a real-world analysis from 21 US centers.}, journal = {Haematologica}, volume = {}, number = {}, pages = {0}, doi = {10.3324/haematol.2024.285977}, pmid = {39540227}, issn = {1592-8721}, abstract = {Outcomes in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) are poor. Loncastuximab-teserine (Lonca) is an antibody drug conjugate (ADC) which was FDA approved for R/R DLBCL patients who have received at least 2 prior lines of therapy based on the LOTIS-2 trial. However, there are limited data regarding its efficacy in the real-world setting (RWS). This retrospective study included 21 US centers and evaluated outcomes of patients with R/R DLBCL treated with Lonca. Our analysis includes 187 patients with notably higher risk baseline features compared to LOTIS-2 including a higher proportion of patients with bulky disease (17% vs 0%), high-grade B-cell histology (HGBL) (22% vs 8%), and increased number of prior lines of therapy (median 4 vs 3). The complete response (CR) rate was 14% and overall response rate (ORR) was 32%. Median event free (EFS) and overall survival (OS) were 2.1 and 4.6 months, respectively. Those with bulky disease and HGBL had significantly worse outcomes, and those with non-germinal center cell of origin and CR to most recent line of therapy demonstrated superior outcomes. In summary, in this largest retrospective cohort study of Lonca in the RWS, the response rates, EFS, and OS were lower than those reported in LOTIS-2, which is likely reflective of its use in higher risk and more heavily pre-treated patients within the real world compared to those enrolled on clinical study.}, }
@article {pmid39538264, year = {2024}, author = {Carnegie, L and McCrone, JT and du Plessis, L and Hasan, M and Ali, MZ and Begum, R and Hassan, MZ and Islam, S and Rahman, MH and Uddin, ASM and Sarker, MS and Das, T and Hossain, M and Khan, M and Razu, MH and Akram, A and Arina, S and Hoque, E and Molla, MMA and Nafisaa, T and Angra, P and Rambaut, A and Pullan, ST and Osman, KL and Hoque, MA and Biswas, P and Flora, MS and Raghwani, J and Fournié, G and Samad, MA and Hill, SC}, title = {Genomic epidemiology of early SARS-CoV-2 transmission dynamics in Bangladesh.}, journal = {Virology journal}, volume = {21}, number = {1}, pages = {291}, pmid = {39538264}, issn = {1743-422X}, support = {BB/T008709/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; NU2GGH002077//Combating the threats of antimicrobial resistance and zoonotic diseases to achieve the GHSA in Bangladesh/ ; NU2GGH002077//Combating the threats of antimicrobial resistance and zoonotic diseases to achieve the GHSA in Bangladesh/ ; NU2GGH002077//Combating the threats of antimicrobial resistance and zoonotic diseases to achieve the GHSA in Bangladesh/ ; BB/S011269/1//UK Research and Innovation/ ; BB/S011269/1//UK Research and Innovation/ ; 223038200//Zoonosis and Transboundary Animal Diseases Prevention and Control project/ ; 220414/Z/20/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Bangladesh/epidemiology ; *COVID-19/transmission/epidemiology/virology ; Humans ; *SARS-CoV-2/genetics/classification ; *Genome, Viral ; *Phylogeography ; Phylogeny ; Whole Genome Sequencing ; Genomics ; Molecular Epidemiology ; Male ; Adult ; Female ; Middle Aged ; Young Adult ; Adolescent ; Child ; }, abstract = {BACKGROUND: Genomic epidemiology has helped reconstruct the global and regional movement of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there is still a lack of understanding of SARS-CoV-2 spread in some of the world's least developed countries (LDCs).<br><br>METHODS: To begin to address this disparity, we studied the transmission dynamics of the virus in Bangladesh during the country's first COVID-19 wave by analysing case reports and whole-genome sequences from all eight divisions of the country.<br><br>RESULTS: We detected&#x2009;>&#x2009;50 virus introductions to the country during the period, including during a period of national lockdown. Additionally, through discrete phylogeographic analyses, we identified that geographical distance and population -density and/or -size influenced virus spatial dispersal in Bangladesh.<br><br>CONCLUSIONS: Overall, this study expands our knowledge of SARS-CoV-2 genomic epidemiology in Bangladesh, shedding light on crucial transmission characteristics within the country, while also acknowledging resemblances and differences to patterns observed in other nations.}, }
@article {pmid39538107, year = {2024}, author = {Timperanza, C and Gustafsson-Lutz, A and Bäck, T and Green, DJ and Lindegren, S and Aneheim, E}, title = {Modified poly-L-lysine for use as a clearing agent in pretargeted radioimmunotherapy.}, journal = {EJNMMI radiopharmacy and chemistry}, volume = {9}, number = {1}, pages = {76}, pmid = {39538107}, issn = {2365-421X}, support = {2021:354//Stiftelsen Jubileumsklinikens Forskningsfond mot Cancer/ ; 21 1842 Pj 01 H//Cancerfonden/ ; }, abstract = {BACKGROUND: Pretargeted radioimmunotherapy of cancer has the potential to increase tumor specific uptake of activity when compared with conventional radioimmunotherapy. This is especially true in radioimmunotherapy with nuclides that exhibit a relatively short half-life. When administering antibody-based pretargeting molecules systemically, the antibodies often show a relatively slow clearance from the blood. Therefore, the use of a clearing agent is advantageous to remove unbound pretargeting molecules from the circulation, facilitating a reduction in the nonspecific radiation exposure to normal tissue while maximizing the dose delivered to the tumors.<br><br>RESULTS: In the current study, two types of poly-L-lysine based clearing agents were produced for two different pretargeting systems: (strept)avidin/biotin and Tetrazine/Transcyclooctene. Poly-L-lysine was used as scaffold for production of clearing agents. The polymer is available in multiple sizes and can readily be modified with several functional groups, allowing different pretargeting strategies to be used. In vivo evaluation of the biotin-functionalized poly-L-lysine clearing agent, 110 repeating units, resulted in a decrease in blood concentration of the Iodine-125 labeled pretargeting agent of 50%, circa 23&#xa0;h after injection, compared to controls. Two sizes, 68 and 143 repeating units, of the tetrazine-functionalized poly-L-lysine clearing agent were also evaluated, which at 23&#xa0;h after injection decreased the blood concentration of the Iodine-125 labeled pretargeting agent to 58 and 38% respectively.<br><br>CONCLUSION: The straightforward synthesis of poly-L-lysine based clearing agents makes kit preparation possible and these agents show good potential for further evaluation, especially within the Tetrazine/Transcyclooctene pretargeting system where no liver or kidney accumulation was observed.}, }
@article {pmid39537980, year = {2024}, author = {Sheridan, L and Pocobelli, G and Anderson, M and Li, CI and Kruse, GR and Tiro, JA and Kamineni, A}, title = {Cervical cancer screening rates in females living with HIV at three healthcare settings in the United States, 2010-2019.}, journal = {Cancer causes &amp; control : CCC}, volume = {}, number = {}, pages = {}, pmid = {39537980}, issn = {1573-7225}, support = {UM1CA221940//National Cancer Institute of the National Institutes of Health/ ; }, abstract = {PURPOSE: Females living with human immunodeficiency virus (FLWHIV) are at increased risk of cervical cancer and U.S. guidelines, first published in 2009 and updated since then, recommend more frequent screening in this population. We examined screening rates among FLWHIV in the U.S. during 2010-2019.<br><br>METHODS: This cohort study included 18-89-year-old FLWHIV during 2010-2019 at three U.S. healthcare settings. Sociodemographics, comorbidities, and cervical cancer screening tests were ascertained from administrative and clinical databases. We reported cervical cancer screening rates overall and by modality. Generalized estimating equations with Poisson distribution were used to estimate screening rate ratios (SRRs) and 95% confidence intervals (CIs) for the associations between screening rates and calendar year, age, race and ethnicity, and comorbidity.<br><br>RESULTS: Among 3,556 FLWHIV, a total of 7,704 cervical cancer screening tests were received over 18,605 person-years during 2010-2019 (screening rate&#x2009;=&#x2009;41.4 per 100 person-years). Relatively lower screening rates were associated with later calendar years (SRR&#x2009;=&#x2009;0.71 [95% CI 0.68-0.75] for 2017-2019 versus 2010-2013), older age (SRR&#x2009;=&#x2009;0.82 [95% CI 0.74-0.89] for 50-65-year-olds versus 18-29-year-olds), non-Hispanic white race versus non-Hispanic Black race (SRR&#x2009;=&#x2009;0.89 [95% CI 0.81-0.98]) and greater comorbidity burden (SRR&#x2009;=&#x2009;0.89 [95% CI 0.82-0.98] for&#x2009;&#x2265;&#x2009;9 versus 0-6 comorbidity score).<br><br>CONCLUSION: The decrease in cervical cancer screening rates during 2010-2019 in this large cohort of FLWHIV may be explained at least partly by guideline changes during the study period recommending longer screening intervals. Our findings of relatively lower screening rates in FLWHIV who were non-Hispanic white, older, and with greater comorbidity burden should be confirmed in other U.S.}, }
@article {pmid39536820, year = {2024}, author = {Nilius, H and Naas, S and Studt, JD and Tsakiris, DA and Greinacher, A and Mendez, A and Schmidt, A and Wuillemin, WA and Gerber, B and Vishnu, P and Graf, L and Kremer Hovinga, JA and Bakchoul, T and Nakas, C and Nagler, M}, title = {The dynamic range of immunoassays for heparin-induced thrombocytopenia.}, journal = {Journal of thrombosis and haemostasis : JTH}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtha.2024.10.026}, pmid = {39536820}, issn = {1538-7836}, abstract = {BACKGROUND: Following the current guidelines, immunoassays for the diagnosis of heparin-induced thrombocytopenia (HIT) are interpreted dichotomously, with test results categorized as either positive or negative. However, the extent to which test results hold diagnostic significance across the entire dynamic range remains unclear.<br><br>OBJECTIVES: We utilized data from the prospective towards precise and rapid diagnosis of heparin-induced thrombocytopenia study, comprising 1393 consecutive patients with suspected HIT, to assess the diagnostic significance of 2 heparin/platelet factor 4 immunoassay test results across their respective dynamic ranges: HemoSil Acustar HIT IgG (chemiluminescence immunoassay [CLIA]) and Lifecodes PF4 immunoglobulin G (enzyme-linked immunosorbent assay [ELISA]).<br><br>METHODS: HIT diagnosis was determined by a washed platelet heparin-induced platelet activation assay. For each measurement point in the dataset, we computed likelihood ratios (LRs), sensitivities, and specificities. To provide posttest probabilities for individual test results, we calculated interval-specific LRs and integrated them into a web-based calculator.<br><br>RESULTS: The prevalence of HIT was 8.5% (n&#xa0;= 119). An LR of &#x2265;10 was first achieved at 0.3% of the dynamic range (0.4 U/mL; CLIA) and then at 16% (0.64 optical density; ELISA). An LR of &#x2265;100 was present at 9.4% (12 U/mL; CLIA) and 75.0% (3.0 optical density; ELISA). The slope of the linear regression line (LR &#x223c; dynamic range) was 9.5 (CLIA) and 0.9 (ELISA).<br><br>CONCLUSION: Despite both immunoassays showing an association between results and diagnostic significance, the strength of the association varies by assay. CLIA has a larger increase per measurement unit. Posttest probabilities for individual patients can be estimated using a web-based calculator: https://pcd-research.shinyapps.io/BayesianCalculator/.}, }
@article {pmid39536447, year = {2024}, author = {Oehler, VG and Huang, IJ and Siu, C and Kim, M and Signorelli, J and Bell, CS and Hobbs, GS}, title = {Dose Modifications in the Management of Chronic Phase Chronic Myeloid Leukemia: Who, What, and When.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {9}, pages = {}, doi = {10.6004/jnccn.2024.7044}, pmid = {39536447}, issn = {1540-1413}, mesh = {Humans ; *Protein Kinase Inhibitors/therapeutic use/adverse effects/administration &amp; dosage ; Leukemia, Myeloid, Chronic-Phase/drug therapy ; Antineoplastic Agents/therapeutic use/administration &amp; dosage/adverse effects ; Fusion Proteins, bcr-abl/antagonists &amp; inhibitors/genetics ; Treatment Outcome ; Quality of Life ; Disease Management ; }, abstract = {With the availability of BCR::ABL1 targeted tyrosine kinase inhibitors (TKIs), outcomes for most individuals with chronic phase chronic myeloid leukemia (CP-CML) are outstanding, with life expectancy similar to age-matched peers. Treatment-emergent adverse events (TEAEs) impair quality of life and many patients struggle with low-level chronic AEs, which for some individuals impact emotional well-being as well as social and work functioning. An emerging body of data supports that many TEAEs are related to therapy dose and can improve with dose reduction. However, it is critical that dose reductions do not alter current outcomes, especially in the rare patients who are at greater risk of losing response or transforming to acute leukemia. Organizations including the National Comprehensive Cancer Network have begun to address when dose reductions may be considered in patients with CP-CML. In this manuscript, we review retrospective and prospective data reporting outcomes in patients after dose reduction and review data supporting lower dose preemptive dosing in first-line and later-line therapy. Switching therapy for intolerance can result in improvements in symptoms and limit toxicity, but other TEAEs may occur. Additionally, emerging therapeutics such as the new class of BCR::ABL1 allosteric inhibitors are under evaluation with a goal of improving tolerability. However, with many TKIs on the cusp of becoming generic, dose reduction becomes an appealing and important cost-effective strategy to minimize TEAEs and improve quality of life while preserving outstanding outcomes in CP-CML.}, }
@article {pmid39536442, year = {2024}, author = {Xu, YG and Lim, Y and Bordeaux, JS and Aasi, SZ and Alam, M and Chen, PL and Contreras, CM and DiMaio, D and Donigan, JM and Farma, JM and Grekin, RC and Mark, L and Nehal, KS and Nghiem, P and Olino, K and Patel, T and Scott, J and Shaha, AR and Srivastava, D and Schmults, CD}, title = {Achieving Adherence With NCCN Guidelines for Nonmelanoma Skin Cancer Regarding Peripheral and Deep En Face Margin Assessment (PDEMA).}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {9}, pages = {}, doi = {10.6004/jnccn.2024.7037}, pmid = {39536442}, issn = {1540-1413}, mesh = {Humans ; *Skin Neoplasms/pathology/surgery/therapy/diagnosis ; *Margins of Excision ; *Mohs Surgery/methods/standards ; Guideline Adherence/statistics &amp; numerical data ; Practice Guidelines as Topic ; Carcinoma, Squamous Cell/pathology/surgery/therapy/diagnosis ; }, abstract = {Peripheral and deep en face margin assessment (PDEMA), formerly termed by NCCN as complete circumferential peripheral and deep margin assessment (CCPDMA), has the advantages of histologic visualization of the entire marginal surface, highly accurate resection of involved tissue, and sparing of uninvolved tissue. Owing to its highest reported cure rates, PDEMA is the NCCN-preferred treatment for dermatofibrosarcoma protuberans, high-risk basal cell carcinoma, and very-high-risk cutaneous squamous cell carcinoma. In the United States, Mohs micrographic surgery (Mohs) is the most common method of PDEMA. In Germany and some other countries, non-Mohs methods of PDEMA referred to as the Tubingen torte and muffin techniques are more widely used. The Tubingen methods of PDEMA require close communication between surgeon and pathologist. This article describes the background of both Mohs and Tubingen PDEMA, reviews what constitutes PDEMA, and provides a protocol for Tubingen PDEMA detailing critical components in a stepwise fashion using illustrative photos and diagrams. We hope to broaden understanding of the NCCN Guidelines and their rationale, align practice, and optimize patient outcomes.}, }
@article {pmid39534377, year = {2024}, author = {Brusselmans, M and Carvalho, LM and L Hong, S and Gao, J and Matsen Iv, FA and Rambaut, A and Lemey, P and Suchard, MA and Dudas, G and Baele, G}, title = {On the importance of assessing topological convergence in Bayesian phylogenetic inference.}, journal = {Virus evolution}, volume = {10}, number = {1}, pages = {veae081}, pmid = {39534377}, issn = {2057-1577}, abstract = {Modern phylogenetics research is often performed within a Bayesian framework, using sampling algorithms such as Markov chain Monte Carlo (MCMC) to approximate the posterior distribution. These algorithms require careful evaluation of the quality of the generated samples. Within the field of phylogenetics, one frequently adopted diagnostic approach is to evaluate the effective sample size and to investigate trace graphs of the sampled parameters. A major limitation of these approaches is that they are developed for continuous parameters and therefore incompatible with a crucial parameter in these inferences: the tree topology. Several recent advancements have aimed at extending these diagnostics to topological space. In this reflection paper, we present two case studies-one on Ebola virus and one on HIV-illustrating how these topological diagnostics can contain information not found in standard diagnostics, and how decisions regarding which of these diagnostics to compute can impact inferences regarding MCMC convergence and mixing. Our results show the importance of running multiple replicate analyses and of carefully assessing topological convergence using the output of these replicate analyses. To this end, we illustrate different ways of assessing and visualizing the topological convergence of these replicates. Given the major importance of detecting convergence and mixing issues in Bayesian phylogenetic analyses, the lack of a unified approach to this problem warrants further action, especially now that additional tools are becoming available to researchers.}, }
@article {pmid39529638, year = {2024}, author = {Treekitkarnmongkol, W and Dai, J and Liu, S and Sankaran, D and Nguyen, T and Balasenthil, S and Hurd, MW and Chen, M and Katayama, H and Roy-Chowdhuri, S and Calin, GA and Brand, RE and Lampe, PD and Hu, TY and Maitra, A and Koay, EJ and Killary, AM and Sen, S}, title = {Blood-Based microRNA Biomarker Signature of Early-Stage Pancreatic Ductal Adenocarcinoma With Lead-Time Trajectory in Prediagnostic Samples.}, journal = {Gastro hep advances}, volume = {3}, number = {8}, pages = {1098-1115}, pmid = {39529638}, issn = {2772-5723}, abstract = {BACKGROUND AND AIMS: Clinically validated biomarker of pancreatic ductal adenocarcinoma (PDAC), carbohydrate antigen 19-9 (CA19-9), has limited sensitivity and specificity for early-stage disease. Circulating miRNAs in plasma associated with cancer relevant pathways were developed as early detection biomarkers.<br><br>METHODS: 2083 miRNAs in 15 &#x3bc;l of plasma from multicenter age-matched cohorts (N&#xa0;= 203: healthy controls, n&#xa0;= 46; pancreatitis controls, n&#xa0;= 36; diagnosed cases: n&#xa0;= 121) and a prediagnostic Prostate, Lung, Colorectal, and Ovarian age- and gender-matched cohort (N&#xa0;=&#xa0;96; controls, n&#xa0;= 48; prediagnosed cases, n&#xa0;= 48) were interrogated. A three-miRNA biomarker signature was developed for early-stage PDAC.<br><br>RESULTS: The three-miRNA signature (let-7i-5p, miR-130a-3p and miR-221-3p) detected PDAC from healthy controls independently (area under the curve [AUC] of stage I, II, I-IV&#xa0;= 0.970, 0.975, 0.974) and in combination with CA19-9 (AUC of stage I, II, I-IV&#xa0;= 1.000, 0.992, 0.995). It also discriminated chronic pancreatitis (AUC of stage I, II, I-IV&#xa0;= 0.932, 0.931, 0.929), improving performance of CA19-9 alone (AUC of stage I, II, I-IV&#xa0;= 0.763, 0.701, 0.735) in combination (AUC of stage I, II, I-IV&#xa0;= 0.971, 0.943, 0.951). Blinded validation in prediagnostic Prostate, Lung, Colorectal, and Ovarian cohort revealed lead-time trajectory increase in AUC from 0.702 to 0.729 to 0.757 at twelve-, six-, and three-months before PDAC diagnosis, respectively. The signature also helped stratification of patients with different circulating tumor DNA and imaging subtypes.<br><br>CONCLUSION: Plasma miRNAs associated with oncogenic pathways may serve as PDAC early detection biomarkers.}, }
@article {pmid39533017, year = {2024}, author = {Liang, EC and Rejeski, K and Fei, T and Albittar, A and Huang, JJ and Portuguese, AJ and Wu, Q and Raj, S and Subklewe, M and Shouval, R and Gauthier, J}, title = {Correction: Development and validation of an automated computational approach to grade immune effector cell-associated hematotoxicity.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41409-024-02453-6}, pmid = {39533017}, issn = {1476-5365}, }
@article {pmid39532861, year = {2024}, author = {Carpp, LN and Hyrien, O and Fong, Y and Benkeser, D and Roels, S and Stieh, DJ and Van Dromme, I and Van Roey, GA and Kenny, A and Huang, Y and Carone, M and McDermott, AB and Houchens, CR and Martins, K and Jayashankar, L and Castellino, F and Amoa-Awua, O and Basappa, M and Flach, B and Lin, BC and Moore, C and Naisan, M and Naqvi, M and Narpala, S and O'Connell, S and Mueller, A and Serebryannyy, L and Castro, M and Wang, J and Petropoulos, CJ and Luedtke, A and Lu, Y and Yu, C and Juraska, M and Hejazi, NS and Wolfe, DN and Sadoff, J and Gray, GE and Grinsztejn, B and Goepfert, PA and Bekker, LG and Gaur, AH and Veloso, VG and Randhawa, AK and Andrasik, MP and Hendriks, J and Truyers, C and Vandebosch, A and Struyf, F and Schuitemaker, H and Douoguih, M and Kublin, JG and Corey, L and Neuzil, KM and Follmann, D and Koup, RA and Donis, RO and Gilbert, PB and ,  and ,  and , }, title = {Neutralizing antibody correlate of protection against severe-critical COVID-19 in the ENSEMBLE single-dose Ad26.COV2.S vaccine efficacy trial.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {9785}, pmid = {39532861}, issn = {2041-1723}, mesh = {Humans ; *Antibodies, Neutralizing/immunology/blood ; *COVID-19/immunology/prevention &amp; control/virology ; *SARS-CoV-2/immunology ; *Antibodies, Viral/immunology/blood ; *COVID-19 Vaccines/immunology/administration &amp; dosage ; Female ; Male ; Middle Aged ; Adult ; Vaccine Efficacy ; Spike Glycoprotein, Coronavirus/immunology ; Ad26COVS1/immunology ; Vaccination ; Aged ; }, abstract = {Assessment of immune correlates of severe COVID-19 has been hampered by the low numbers of severe cases in COVID-19 vaccine efficacy (VE) trials. We assess neutralizing and binding antibody levels at 4 weeks post-Ad26.COV2.S vaccination as correlates of risk and of protection against severe-critical COVID-19 through 220 days post-vaccination in the ENSEMBLE trial (NCT04505722), constituting ~4.5 months longer follow-up than our previous correlates analysis and enabling inclusion of 42 severe-critical vaccine-breakthrough cases. Neutralizing antibody titer is a strong inverse correlate of severe-critical COVID-19, with estimated hazard ratio (HR) per 10-fold increase 0.35 (95% CI: 0.13, 0.90). In a multivariable model, HRs are 0.31 (0.11, 0.89) for neutralizing antibody titer and 1.22 (0.49, 3.02) for anti-Spike binding antibody concentration. VE against severe-critical COVID-19 rises with neutralizing antibody titer: 63.1% (95% CI: 40.0%, 77.3%) at unquantifiable [<4.8975 International Units (IU)50/ml], 85.2% (47.2%, 95.3%) at just-quantifiable (5.2 IU50/ml), and 95.1% (81.1%, 96.9%) at 90[th] percentile (30.2 IU50/ml). At the same titers, VE against moderate COVID-19 is 32.5% (11.8%, 48.4%), 33.9% (19.1%, 59.3%), and 60.7% (40.4%, 76.4%). Protection against moderate vs. severe disease may require higher antibody levels, and very low antibody levels and/or other immune responses may associate with protection against severe disease.}, }
@article {pmid39532048, year = {2024}, author = {Grivas, P and Barata, P and Moon, H and Gupta, S and Hutson, T and Sternberg, CN and Brown, JR and Dave, V and Downey, C and Shillington, AC and Katzenstein, HM and Kirker, M and Hanson, S and Liu, FX and Morris, V and Bhanegaonkar, A and Sonpavde, GP}, title = {Avelumab First-Line Maintenance for Locally Advanced or Metastatic Urothelial Carcinoma: Results From the Real-World US PATRIOT-II Study.}, journal = {Clinical genitourinary cancer}, volume = {22}, number = {6}, pages = {102238}, doi = {10.1016/j.clgc.2024.102238}, pmid = {39532048}, issn = {1938-0682}, mesh = {Humans ; Male ; Female ; *Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects ; Aged ; Retrospective Studies ; Middle Aged ; Carcinoma, Transitional Cell/drug therapy/mortality/pathology/secondary ; United States ; Maintenance Chemotherapy ; Antineoplastic Agents, Immunological/therapeutic use/adverse effects ; Urinary Bladder Neoplasms/drug therapy/pathology ; Progression-Free Survival ; Aged, 80 and over ; Urologic Neoplasms/drug therapy/pathology/mortality ; Treatment Outcome ; }, abstract = {INTRODUCTION: In JAVELIN Bladder 100, avelumab first-line maintenance (1LM) improved overall survival (OS) and progression-free survival (PFS) in patients with locally advanced/metastatic urothelial carcinoma (la/mUC) without progression following 1L platinum-based chemotherapy (PBC) versus best supportive care. PATRIOT-II describes real-world outcomes with avelumab 1LM.<br><br>PATIENTS AND METHODS: This observational, retrospective study of avelumab 1LM in US community/academic centers used medical record data collected from avelumab initiation for &#x2265;12 months to assess survival, safety, and healthcare resource utilization; analyses are descriptive.<br><br>RESULTS: The study included 160 patients from 37 centers (median age, 70 years; 77% male). Avelumab 1LM was initiated at a median of 4 weeks (IQR 3-6) after PBC completion. Median follow-up from avelumab 1LM was 16 months (IQR 11-21). At study end, 19.4% of patients continued avelumab; 73.7% had discontinued due to progression, adverse events (AEs), or performance status deterioration. Median PFS and OS from avelumab initiation were 5.4 months (95% CI, 3.8-6.9) and 24.4 months (95% CI, 20.4-28.4), respectively. Grade &#x2265;3 treatment-related AEs (TRAEs) occurred in 15 patients (9.4%); 35 (21.9%) had any-grade immune-related AEs, and 23 (14.3%) received high-dose systemic corticosteroids for AEs. Forty-four patients (27.5%) were hospitalized during the avelumab treatment period, of whom 13 (8.1%) were hospitalized due to TRAEs. Limitations of this study include a small sample size, potential selection bias, and missing/unknown data.<br><br>CONCLUSION: These results align with the JAVELIN Bladder 100 clinical trial and other real-world studies, supporting avelumab 1LM use in patients with la/mUC without progression following 1L PBC.}, }
@article {pmid39531474, year = {2024}, author = {Dadonaite, B and Ahn, JJ and Ort, JT and Yu, J and Furey, C and Dosey, A and Hannon, WW and Vincent Baker, AL and Webby, RJ and King, NP and Liu, Y and Hensley, SE and Peacock, TP and Moncla, LH and Bloom, JD}, title = {Deep mutational scanning of H5 hemagglutinin to inform influenza virus surveillance.}, journal = {PLoS biology}, volume = {22}, number = {11}, pages = {e3002916}, pmid = {39531474}, issn = {1545-7885}, support = {S10 OD028685/OD/NIH HHS/United States ; 75N93021C00015/AI/NIAID NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; R01 AI141707/AI/NIAID NIH HHS/United States ; R01 AI165821/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; *Hemagglutinin Glycoproteins, Influenza Virus/genetics/immunology ; *Ferrets ; Mice ; *Mutation ; Humans ; Influenza, Human/virology/epidemiology/immunology ; Orthomyxoviridae Infections/virology ; Influenza A virus/genetics/immunology ; Female ; Antibodies, Viral/immunology/blood ; }, abstract = {H5 influenza is considered a potential pandemic threat. Recently, H5 viruses belonging to clade 2.3.4.4b have caused large outbreaks in avian and multiple nonhuman mammalian species. Previous studies have identified molecular phenotypes of the viral hemagglutinin (HA) protein that contribute to pandemic potential in humans, including cell entry, receptor preference, HA stability, and reduced neutralization by polyclonal sera. However, prior experimental work has only measured how these phenotypes are affected by a handful of the >10,000 different possible amino-acid mutations to HA. Here, we use pseudovirus deep mutational scanning to measure how all mutations to a 2.3.4.4b H5 HA affect each phenotype. We identify mutations that allow HA to better bind α2-6-linked sialic acids and show that some viruses already carry mutations that stabilize HA. We also measure how all HA mutations affect neutralization by sera from mice and ferrets vaccinated against or infected with 2.3.4.4b H5 viruses. These antigenic maps enable rapid assessment of when new viral strains have acquired mutations that may create mismatches with candidate vaccine virus, and we show that a mutation present in some recent H5 HAs causes a large antigenic change. Overall, the systematic nature of deep mutational scanning combined with the safety of pseudoviruses enables comprehensive measurements of the phenotypic effects of mutations that can inform real-time interpretation of viral variation observed during surveillance of H5 influenza.}, }
@article {pmid39530736, year = {2024}, author = {Shearer, T and Comstock, M and Williams, RL and Johnson, MC and Cendrowicz, E and Leonowens, C and Smith, M and Baughman, TM and Breitbach, CJ and Cheng, S and Green, DJ}, title = {Kinetics of nirogacestat-mediated increases in B-cell maturation antigen on plasma cells inform therapeutic combinations in multiple myeloma.}, journal = {Cancer research communications}, volume = {}, number = {}, pages = {}, doi = {10.1158/2767-9764.CRC-24-0075}, pmid = {39530736}, issn = {2767-9764}, abstract = {B-cell maturation antigen (BCMA) is the target of several investigational and approved drugs for multiple myeloma (MM). BCMA expressed on plasma cells (PCs) and MM cells is cleaved by the enzyme gamma secretase, reducing membrane-bound BCMA (mbBCMA) receptor density. Gamma secretase inhibitors (GSIs) have been shown to increase mbBCMA density and may enhance efficacy of BCMA-targeted therapies. The pharmacodynamic profile of the GSI nirogacestat was evaluated in MM cell lines and a phase 1 study in healthy volunteers. In MM cell lines, mbBCMA density and soluble BCMA (sBCMA) concentrations were measured before and after short-duration nirogacestat exposure and at serial timepoints following washout. In the phase 1 study, 23 participants were administered a single oral dose of nirogacestat 50, 150, or 300 mg or repeated doses of 100 mg every 12h for up to 48h; mbBCMA density on PCs (from whole blood and bone marrow) and nirogacestat plasma concentrations were measured at baseline and postdose. After single-dose administration, serum nirogacestat concentrations rapidly increased (Tmax ~1h), and a two-compartment model with linear absorption and clearance best described nirogacestat pharmacokinetics. In MM cells and healthy volunteers' PCs, nirogacestat resulted in rapid and robust increases in mbBCMA density, with increases up to 20-fold within 4-8h of exposure. Concomitant decreases in sBCMA were observed. Nirogacestat is currently being evaluated in combination with several BCMA-directed therapeutic agents in patients with MM. Elucidating the kinetics of BCMA in response to nirogacestat is key to guiding dosing and therapeutic strategies in MM.}, }
@article {pmid39528599, year = {2024}, author = {Paik, J and Kim, A and Fogassy, K and Snyder, JM and Brabb, T and Dill-McFarland, KA and He, Q and Amory, JK}, title = {Weight loss and metabolic effects of an ALDH1A1-specific inhibitor, FSI-TN42, in a diet induced mouse model of obesity.}, journal = {International journal of obesity (2005)}, volume = {}, number = {}, pages = {}, pmid = {39528599}, issn = {1476-5497}, abstract = {BACKGROUND: Retinoic acid (RA) participates in weight regulation and energy metabolism. Mice lacking ALDH1A1, one of the major enzymes responsible for RA biosynthesis, are resistant to diet-induced obesity. Previously, we identified FSI-TN42 (N42) as an ALDH1A1-specific inhibitor and reported its pharmacokinetics and pharmacodynamics as well as its efficacy in weight suppression.<br><br>METHODS: In the first study, C57BL/6&#x2009;J male mice were fed a high fat diet for 8 weeks to induce obesity. Mice were then divided into three groups and fed (1) moderate fat diet (MFD), (2) MFD&#x2009;+&#x2009;WIN 18,446 (1&#x2009;g/kg diet), or (3) MFD&#x2009;+&#x2009;N42 (1&#x2009;g/kg diet) for 8 weeks. A control group of mice were fed a low-fat diet for the entire period. Mice were weighed weekly and fasting glucose was determined every 4 weeks. Tissues were examined for potential toxicity using histopathology and complete blood counts. In the second study, we examined influences of N42 on energy balance and/or appetite by determining food intake, activity and energy expenditure in mice with obesity treated with MFD or MFD&#x2009;+&#x2009;N42. Lastly, we tested fertility with a mating study.<br><br>RESULTS: N42 significantly accelerated weight loss compared to MFD alone in mice with obesity by reducing fat mass without decreasing lean mass. N42 did not alter food intake or activity levels. While mice treated with N42 lost significantly more weight, they maintained a similar level of energy expenditure compared to mice fed MFD only. Mice fed N42 preferentially used fat postprandially, especially under thermoneutral or mild cold challenge. N42 did not affect male fertility.<br><br>CONCLUSIONS: N42 promotes weight loss when used with MFD in mice with diet-induced obesity without causing significant organ toxicity or male infertility. Future studies will determine if N42 can be used to promote further weight loss if combined with current weight loss drugs.}, }
@article {pmid39528488, year = {2024}, author = {Giaccherini, M and Clay-Gilmour, AI and Liotti, R and Macauda, A and Gentiluomo, M and Brown, EE and Machiela, MJ and Chanock, SJ and Hildebrandt, MAT and Norman, AD and Manasanch, E and Rajkumar, SV and Hofmann, JN and Berndt, SI and Bhatti, P and Giles, GG and Ziv, E and Kumar, SK and Camp, NJ and Cozen, W and Slager, SL and Canzian, F and Gemignani, F and Vachon, CM and Campa, D}, title = {Genetically determined telomere length in monoclonal gammopathy of undetermined significance, multiple myeloma risk and outcome.}, journal = {Blood cancer journal}, volume = {14}, number = {1}, pages = {200}, pmid = {39528488}, issn = {2044-5385}, }
@article {pmid39527587, year = {2024}, author = {Dankwa, S and Kosman, C and Dennis, M and Giorgi, EE and Vuong, K and Pahountis, I and Garza, A and Binuya, C and McCarthy, J and Mayer, BT and Ngo, JT and Enemuo, CA and Carnathan, DG and Stanfield-Oakley, S and Berendam, SJ and Weinbaum, C and Engelman, K and Magnani, DM and Chan, C and Ferrari, G and Silvestri, G and Amara, RR and Chahroudi, A and Permar, SR and Fouda, GG and Goswami, R}, title = {A novel HIV triple broadly neutralizing antibody (bNAb) combination-based passive immunization of infant rhesus macaques achieves durable protective plasma neutralization levels and mediates anti-viral effector functions.}, journal = {PloS one}, volume = {19}, number = {11}, pages = {e0312411}, pmid = {39527587}, issn = {1932-6203}, support = {P51 OD011132/OD/NIH HHS/United States ; U42 OD011023/OD/NIH HHS/United States ; }, mesh = {Animals ; *Macaca mulatta ; *Immunization, Passive/methods ; *HIV Antibodies/immunology/blood ; *HIV Infections/immunology/drug therapy/prevention &amp; control ; *Simian Immunodeficiency Virus/immunology ; *Antibodies, Neutralizing/immunology/blood ; Humans ; HIV-1/immunology ; Broadly Neutralizing Antibodies/immunology ; Simian Acquired Immunodeficiency Syndrome/prevention &amp; control/immunology ; }, abstract = {To eliminate vertical HIV transmission and achieve therapy-free viral suppression among children living with HIV, novel strategies beyond antiretroviral therapy (ART) are necessary. Our group previously identified a triple broadly neutralizing antibody (bNAb) combination comprising of 3BNC117, PGDM1400 and PGT151 that mediates robust in vitro neutralization and non-neutralizing effector functions against a cross-clade panel of simian human immunodeficiency viruses (SHIVs). In this study, we evaluated the safety, pharmacokinetics, and antiviral potency of this bNAb combination in infant rhesus macaques (RMs). We demonstrate that subcutaneous infusion of the triple bNAb regimen was well tolerated in pediatric monkeys and resulted in durable systemic and mucosal distribution. Plasma obtained from passively-immunized RMs demonstrated potent HIV-neutralizing and Fc-mediated antiviral effector functions. Finally, using the predicted serum neutralization 80% inhibitory dilution titer (PT80) biomarker threshold of >200, which was recently identified as a surrogate endpoint for evaluation of the preventative efficacy of bNAbs against mucosal viral acquisition in human clinical trials, we demonstrated that our regimen has PT80>200 against a large panel of plasma and breast milk-derived HIV strains and cross-clade SHIV variants. This data will guide the development of combination bNAbs for eliminating vertical HIV transmission and for achieving ART-free viral suppression among children living with HIV.}, }
@article {pmid39522103, year = {2024}, author = {Abbaspour, E and Mansoori, B and Karimzadhagh, S and Chalian, M and Pouramini, A and Sheida, F and Daskareh, M and Haseli, S}, title = {Machine learning and deep learning models for preoperative detection of lymph node metastasis in colorectal cancer: a systematic review and meta-analysis.}, journal = {Abdominal radiology (New York)}, volume = {}, number = {}, pages = {}, pmid = {39522103}, issn = {2366-0058}, abstract = {OBJECTIVE: To evaluate the diagnostic performance of Machine Learning (ML) and Deep Learning (DL) models for predicting preoperative Lymph Node Metastasis (LNM) in Colorectal Cancer (CRC) patients.<br><br>METHODS: A systematic review and meta-analysis were conducted following PRISMA-DTA and AMSTAR-2 guidelines. We searched PubMed, Web of Science, Embase, and Cochrane Library databases until February 16, 2024. Study quality and risk of bias were assessed using the QUADAS-2 tool. Data were analyzed using STATA v18, applying random-effects models to all analyses.<br><br>RESULTS: Twelve studies involving 8321 patients were included, with most published in 2021-2024 (9/12). The pooled AUC of ML models for predicting LNM in CRC patients was 0.87 (95% CI: 0.82-0.91, I[2]:86.17) with a sensitivity of 78% (95% CI: 69-87%) and a specificity of 77% (95% CI: 64%-90%). In addition, when assessing the AUC reported by radiologists, both junior and senior radiologists had similar performance, significantly lower than the ML models. (P&#x2009;<&#x2009;0.001). Subgroup analysis revealed higher AUCs in prospective studies (0.95, 95% CI: 0.87-1) compared to retrospective studies (0.85, 95% CI: 0.81-0.89) (P&#x2009;=&#x2009;0.03). Studies without external validation exhibited significantly higher AUCs than those with external validation (P&#x2009;<&#x2009;0.01). While there was no significant difference in AUC and sensitivity between the T1-T2 and T2-T4 stages, specificity was significantly higher in the T2-T4 stages than the low stages of T1 and T2 (95%, 95% CI: 92-98% vs. 61%, 95% CI: 44-78%; P&#x2009;<&#x2009;0.01).<br><br>CONCLUSION: ML models demonstrate strong potential for preoperative LNM staging and treatment planning in CRC, potentially reducing the need for additional surgeries and related health and financial burdens. Further prospective multicenter studies, with standardized reporting of algorithms, modality parameters, and LNM staging, are needed to validate these findings.}, }
@article {pmid39522029, year = {2024}, author = {Gregg, JR and Newcomb, L and Wu, R and Dennison, J and Davis, JW and Pettaway, C and Pisters, L and Ward, JF and Chapin, BF and Chéry, L and Urkmez, A and Fang, AM and Higgason, N and Troncoso, P and Daniel, CR and Logothetis, C and Thompson, TC and Hahn, AW and Liu, M and Zheng, Y and Lin, DW and Hanash, S and Irajizad, E and Fahrmann, J}, title = {Validation of a prognostic blood-based sphingolipid panel for men with localized prostate cancer followed on active surveillance.}, journal = {Biomarker research}, volume = {12}, number = {1}, pages = {134}, pmid = {39522029}, issn = {2050-7771}, support = {P50 CA140388/CA/NCI NIH HHS/United States ; P50 CA140388/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: We previously reported that increases in circulating sphingolipids are associated with elevated risk of biopsy Gleason grade group (GG) upgrading in men on Active Surveillance (AS) for prostate cancer. Here, we aimed to validate these findings and establish a blood-based sphingolipid biomarker panel for identifying men on AS who are at high-risk of biopsy GG upgrading.<br><br>METHODS: Men diagnosed with low- or intermediate-risk prostate cancer in one of two AS cohorts (CANARY PASS and MDACC) were followed for GG upgrading after diagnostic and confirmatory biopsy. The PASS cohort consisted of 544 patients whereas the MDACC Cohort consisted of 697 patients. The number of patients with GG upgrading during course of study follow-up in the PASS and MDACC cohorts were 98 (17.7%) and 133 (19.1%), respectively. Plasmas collected prior to confirmatory biopsy were used for mass spectrometry-based quantitation of 87 unique sphingolipid species. A neural network layer based on 21 sphingolipids was developed in the CANARY PASS cohort for predicting biopsy GG upgrading. Tertile-based thresholds for low-, intermediate-, and high-risk strata were subsequently developed for the sphingolipid panel as well as a model that combined the sphingolipid panel with PSA density and rate of core positivity on diagnostic biopsy. The resultant models and risk thresholds for GG upgrading were validated in the MDACC cohort. Performance was assessed using Cox proportional hazard models, C-index, AUC, and cumulative incidence curves.<br><br>RESULTS: The sphingolipid panel had a HR (per unit standard deviation increase) of 1.36 (95% CI: 1.07-1.70) and 1.35 (95% CI: 1.11-1.64) for predicting GG biopsy upgrading in the PASS and MDACC cohort, respectively. The model that combined the sphingolipid panel with PSA density and rate of core positivity achieved a HR of 1.63 (95% CI: 1.33-2.00) and 1.44 (1.25-1.66), respectively. Tertile-based thresholds, established in the PASS cohort, were applied to the independent MDACC cohort. Compared to the low-risk group, MDACC patients in the high-risk strata had a GG biopsy upgrade HR of 3.65 (95% CI: 2.21-6.02), capturing 50% of the patients that had biopsy upgrading during study follow-up.<br><br>CONCLUSIONS: The sphingolipid panel is independently associated with GG biopsy upgrading among men in two independent AS cohorts who have previously undergone diagnostic and confirmatory biopsy. The sphingolipid panel, together with clinical factors, provides a potential means for risk stratification to better guide clinical management of men on AS.}, }
@article {pmid39521703, year = {2024}, author = {Niraula, S and Gouli, S and Baran, AM and O'Regan, R and Tyburski, H and Zhang, H and Hardy, S and Mohile, N and Anders, CK and Dhakal, A}, title = {Effect of Breast Cancer Receptor Subtypes and CSF Cytology Status on Survival of Patients With Leptomeningeal Disease.}, journal = {Clinical breast cancer}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.clbc.2024.09.019}, pmid = {39521703}, issn = {1938-0666}, abstract = {BACKGROUND: It is unclear whether breast cancer (BC) subtypes or CSF cytology results are associated with overall survival (OS) among patients with BC leptomeningeal disease (LMD). This single-institution retrospective study compares OS among BC patients with LMD across various breast cancer subtypes and CSF cytology results.<br><br>METHODOLOGY: The study enrolled BC patients diagnosed with LMD between 2010 and 2023. Breast cancer subtypes were classified as A. ER+/HER2-, HER2+, or triple-negative BC (TNBC); B. HER2+, HER2-Low, HER2-Zero. CSF cytology subtypes included CSF+, CSF-, or CSF not tested (NT). OS was summarized via Kaplan-Meier analysis and compared using log-rank test. Cox models were used for multivariate analyses.<br><br>RESULTS: Out of 69 patients registered, median OS (95% CI) for ER+/HER2- (n = 33), HER2+ (n = 12) and TNBC (n = 24) subtypes were 8.0 (3.02, 24.8), 5.71 (1.61, not estimated) and 3.2 (1.11, 4.95) months (P = .17). In multivariate analysis, TNBC was associated with worse OS versus ER+/HER2- [Hazard Ratio (HR), 95% CI: 2.64, 1.23-5.80, P = .04]. HER2 subtypes (HER2-Zero, n = 21; HER2-Low, n = 32; HER2+, n = 12) showed no significant differences in OS. Median OS (95% CI) for CSF+ (n = 16), CSF- (n = 18), and CSF NT (n = 35) groups were 3.54 (1.61, 12.72), 13.41 (4.95, 61.93) and 3.28 (1.44, 6.92) months (P = .04). Multivariate analysis showed both CSF+ and CSF NT were associated with shorter OS compared to CSF- group [HR (95% CI) 4.50 (1.75, 12.11) for CSF+ vs. CSF-; 2.91 (1.45, 6.26) for CSF NT vs. CSF-; P = .002].<br><br>CONCLUSION: TNBC LMD group was associated with worse OS than ER+/HER2- BC LMD when adjusting for other prognostic factors. CSF- LMD patients had better OS than CSF+ or CSF NT LMD.}, }
@article {pmid39521614, year = {2024}, author = {Liao, JB and Dai, JY and Reichow, JL and Lim, JB and Hitchcock-Bernhardt, KM and Stanton, SE and Salazar, LG and Gooley, TA and Disis, ML}, title = {Magnitude of antigen-specific T-cell immunity the month after completing vaccination series predicts the development of long-term persistence of antitumor immune response.}, journal = {Journal for immunotherapy of cancer}, volume = {12}, number = {11}, pages = {}, pmid = {39521614}, issn = {2051-1426}, mesh = {Humans ; Female ; *Cancer Vaccines/immunology/therapeutic use ; *T-Lymphocytes/immunology ; Middle Aged ; Receptor, ErbB-2/immunology ; Male ; Aged ; Vaccination ; Adult ; Neoplasms/immunology ; }, abstract = {BACKGROUND: For best efficacy, vaccines must provide long-lasting immunity. To measure longevity, memory from B and T cells are surrogate endpoints for vaccine efficacy. When antibodies are insufficient for protection, the immune response must rely on T cells. The magnitude and differentiation of effective, durable immune responses depend on antigen-specific precursor frequencies. However, development of vaccines that induce durable T-cell responses for cancer treatment has remained elusive.<br><br>METHODS: To address long-lasting immunity, patients with HER2+ (human epidermal growth factor receptor 2) advanced stage cancer received HER2/neu targeted vaccines. Interferon-gamma (IFN-&#x3b3;) enzyme-linked immunosorbent spot measuring HER2/neu IFN-&#x3b3; T cells were analyzed from 86 patients from three time points: baseline, 1&#x2009;month after vaccine series, and long-term follow-up at 1 year, following one in vitro stimulation. The baseline and 1-month post-vaccine series responses were correlated with immunity at long-term follow-up by logistic regression. Immunity was modeled by non-linear functions using generalized additive models.<br><br>RESULTS: Antigen-specific T-cell responses at baseline were associated with a 0.33-log increase in response at long-term follow-up, 95%&#x2009;CI (0.11, 0.54), p=0.003. 63% of patients that had HER2/neu specific T cells at baseline continued to have responses at long-term follow-up. Increased HER2/neu specific T-cell response 1&#x2009;month after the vaccine series was associated with a 0.47-log increase in T-cell response at long-term follow-up, 95%&#x2009;CI (0.27, 0.67), p=2e-5. 74% of patients that had an increased IFN-&#x3b3; HER2 response 1&#x2009;month after vaccines retained immunity long-term. As the 1-month post-vaccination series precursor frequency of HER2+IFN-&#x3b3; T-cell responses increased, the probability of retaining these responses long-term increased (OR=1.49 for every one natural log increase of precursor frequency, p=0.0002), reaching an OR of 20 for a precursor frequency of 1:3,000 CONCLUSIONS: Patients not destined to achieve long-term immunity can be identified immediately after completing the vaccine series. Log-fold increases in antigen-specific precursor frequencies after vaccinations correlate with increased odds of retaining long-term HER2 immune responses. Further vaccine boosting or immune checkpoint inhibitors or other immune stimulator therapy should be explored in patients that do not develop antigen-specific T-cell responses to improve overall response rates.}, }
@article {pmid39521255, year = {2024}, author = {Fujiwara, N and Lopez, C and Marsh, TL and Raman, I and Marquez, CA and Paul, S and Mishra, SK and Kubota, N and Katz, C and Kanzaki, H and Gonzalez, M and Quirk, L and Deodhar, S and Selvakumar, P and Raj, P and Parikh, ND and Roberts, LR and Schwartz, ME and Nguyen, MH and Befeler, AS and Page-Lester, S and Srivastava, S and Feng, Z and Reddy, KR and Khaderi, S and Asrani, SK and Kanwal, F and El-Serag, HB and Marrero, JA and Singal, AG and Hoshida, Y}, title = {Phase 3 Validation of Prognostic Liver Secretome Signature With α-Fetoprotein Plus Age, Male Sex, Albumin-Bilirubin, and Platelets for Hepatocellular Carcinoma Risk Stratification in Cirrhosis.}, journal = {Gastroenterology}, volume = {}, number = {}, pages = {}, doi = {10.1053/j.gastro.2024.10.035}, pmid = {39521255}, issn = {1528-0012}, abstract = {BACKGROUND &amp; AIMS: Hepatocellular carcinoma (HCC) risk stratification is an urgent unmet need for cost-effective HCC screening and early detection in patients with cirrhosis to improve poor HCC prognosis.<br><br>METHODS: Molecular (prognostic liver secretome signature with &#x3b1;-fetoprotein) and clinical (aMAP [age, male sex, albumin-bilirubin, and platelets] score) variable-based scores were integrated into PAaM (prognostic liver secretome signature with &#x3b1;-fetoprotein plus age, male sex, albumin-bilirubin, and platelets), which was subsequently validated in 2 phase 3 biomarker validation studies: the statewide Texas HCC Consortium and nationwide HCC Early Detection Strategy prospective cohorts, following the prospective specimen collection, retrospective blinded evaluation design. The associations between baseline PAaM and incident HCC were assessed using Fine-Gray regression, with overall death and liver transplantation as competing events.<br><br>RESULTS: Of 2156 patients with cirrhosis in the Texas HCC Consortium, PAaM identified 404 (19%) high-risk, 903 (42%) intermediate-risk, and 849 (39%) low-risk patients with annual HCC incidence rates of 5.3%, 2.7%, and 0.6%, respectively. Compared with low-risk patients, high- and intermediate-risk groups had sub-distribution hazard ratios for incident HCC of 7.51 (95% CI, 4.42-12.8) and 4.20 (95% CI, 2.52-7.01), respectively. Of 1328 patients with cirrhosis in the HCC early detection strategy, PAaM identified 201 high-risk (15%), 540 intermediate-risk (41%), and 587 low-risk (44%) patients, with annual HCC incidence rates of 6.2%, 1.8%, and 0.8%, respectively. High- and intermediate-risk groups were associated with sub-distribution hazard ratios for incident HCC of 6.54 (95% CI, 3.85-11.1) and 1.77 (95% CI, 1.02-3.08), respectively. Subgroup analysis showed robust risk stratification across HCC etiologies, including metabolic dysfunction-associated steatotic liver disease and cured hepatitis C infection.<br><br>CONCLUSIONS: PAaM enables accurate HCC risk stratification in patients with cirrhosis from contemporary etiologies.}, }
@article {pmid39520444, year = {2024}, author = {Shetty, NS and Gaonkar, M and Pampana, A and Patel, N and Morrison, AC and Reiner, AP and Carson, AP and Yu, B and Psaty, BM and Kooperberg, C and Fatkin, D and Boerwinkle, E and Rotter, JI and Taylor, KD and Hou, L and Irvin, MR and Hall, ME and Maurer, M and Fornage, M and Armstrong, ND and Bart, N and Goyal, P and Rich, SS and Vasan, RS and Li, P and Arora, G and Arora, P}, title = {Cardiovascular Risk Factors and Genetic Risk in Transthyretin V142I Carriers.}, journal = {JACC. Heart failure}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jchf.2024.08.019}, pmid = {39520444}, issn = {2213-1787}, abstract = {BACKGROUND: Nearly 3% to 4% of Black individuals in the United States carry the transthyretin V142I variant, which increases their risk of heart failure. However, the role of cardiovascular (CV) risk factors (RFs) in influencing the risk of clinical outcomes among V142I variant carriers is unknown.<br><br>OBJECTIVES: This study aimed to assess the impact of CV RFs on the risk of heart failure in V142I carriers.<br><br>METHODS: This study included self-identified Black individuals without prevalent heart failure from 6 TOPMed (Trans-Omics for Precision Medicine) cohorts, the REGARDS (Reasons for Geographic And Racial Differences in Stroke) study, and the All of Us Research Program. The cohort was stratified based on the V142I genotype and the number of CV RFs (hypertension, diabetes, obesity, and hypercholesterolemia). Adjusted Cox models were used to assess the association of heart failure with the V142I genotype and CV RF profile, taking noncarriers with a favorable CV RF profile as reference.<br><br>RESULTS: The cross-sectional analysis, including 1,625 V142I carriers among 48,365 Black individuals, found that the prevalence of CV RFs did not vary by V142I carrier status. In the longitudinal analysis, there were 587 (3.2%) V142I carriers among 18,407 Black individuals (median age: 60 years [Q1-Q3: 52-68 years], 63.0% female). Among carriers, the heart failure risk was attenuated with a favorable (0 or 1 RF) CV RF profile (adjusted HR: 2.26; 95%&#xa0;CI: 1.58-3.23) compared with an unfavorable (3 or 4 RFs) CV RF profile (adjusted HR: 4.14; 95%&#xa0;CI: 2.79-6.14).<br><br>CONCLUSIONS: A favorable CV RF profile lowers but does not abrogate V142I variant-associated heart failure risk. This study highlights the importance of having a favorable CV RF profile among V142I carriers for risk reduction of heart failure.}, }
@article {pmid39516665, year = {2024}, author = {Xu, Y and Miller, CP and Xue, J and Zheng, Y and Warren, EH and Tykodi, SS and Akilesh, S}, title = {Single cell atlas of kidney cancer endothelial cells reveals distinct expression profiles and phenotypes.}, journal = {BJC reports}, volume = {2}, number = {1}, pages = {23}, pmid = {39516665}, issn = {2731-9377}, support = {KC180135//U.S. Department of Defense/ ; KC180135//U.S. Department of Defense/ ; KC180135//U.S. Department of Defense/ ; KC180135//U.S. Department of Defense/ ; KC180135//U.S. Department of Defense/ ; KC180135//U.S. Department of Defense/ ; KC180135//U.S. Department of Defense/ ; CA015704/CA/NCI NIH HHS/United States ; CA015704/CA/NCI NIH HHS/United States ; CA015704/CA/NCI NIH HHS/United States ; CA015704/CA/NCI NIH HHS/United States ; CA015704/CA/NCI NIH HHS/United States ; S10OD028685/NH/NIH HHS/United States ; }, abstract = {BACKGROUND: Tumor endothelial cells (TECs) represent the primary interface between the tumor microenvironment and circulating immune cells, however their phenotypes are incompletely understood in highly vascularized clear cell renal cell carcinoma (ccRCC).<br><br>METHODS: We purified tumor and matched normal endothelial cells (NECs) from ccRCC specimens and performed single-cell RNA-sequencing to create a reference-quality atlas available as a searchable web resource for gene expression patterns. We established paired primary TECs and NECs cultures for ex vivo functional testing.<br><br>RESULTS: TECs from multiple donors shared a common phenotype with increased expression of pathways related to extracellular matrix regulation, cell-cell communication, and insulin-like growth factor signaling. This phenotype was shared with hepatocellular carcinoma associated TECs, suggesting convergent TEC phenotypes between unrelated tumors. Cultured TECs stably maintained a core program of differentially regulated genes which promoted resistance to apoptosis after vascular endothelial growth factor removal and increased adhesiveness to subsets of immune cells including regulatory T-cells.<br><br>CONCLUSIONS: Our studies demonstrate that TECs have a distinct phenotype that is shared by TECs from different tumor types and stable in ex vivo culture. The distinct adhesive interaction of TECs with immune cells raises the possibility of their modulation to improve immune cell-based therapies for RCC.}, }
@article {pmid39516359, year = {2024}, author = {Stockem, CF and Einerhand, SMH and Rodríguez, IM and Salhi, Y and Pérez, E and Bakaloudi, DR and Talukder, R and Caramelo, B and Morales-Barrera, R and De Meulenaere, A and Rametta, A and Bottelli, A and Lefort, F and Giannatempo, P and Vulsteke, C and Carles, J and Duran, I and Grivas, P and de Liaño, AG and Robbrecht, DGJ and Valderrama, BP and van der Noort, V and van der Heijden, MS}, title = {Long-term survival following anti-PD-(L)1 monotherapy in advanced urothelial cancer and an assessment of potential prognostic clinical factors: a multicentre observational study.}, journal = {BJC reports}, volume = {2}, number = {1}, pages = {84}, pmid = {39516359}, issn = {2731-9377}, abstract = {BACKGROUND: Anti-PD-(L)1 agent are approved as first- and second-line treatment options in advanced urothelial cancer (UC), but information about long-term survival is scarce. There is a need for prognostic factors, as these may help in the decision-making concerning anti-PD-(L)1 in patients with UC. Here, we examined long-term survival following anti-PD-(L)1 in advanced UC and assessed clinical factors for their correlation with survival.<br><br>METHODS: We collected data from patients with advanced UC treated with anti-PD-(L)1 between 2013 and 2023. Overall- and progression-free survival (OS, PFS) were determined using the Kaplan-Meier method. Independent variables were analysed by uni- and multivariate Cox regression for their association with OS and PFS.<br><br>RESULTS: Survival analyses included 552 patients. Patient characteristics in our cohort were consistent with those of a typical advanced UC population. After median follow-up of 49 months, five-year OS and PFS rates were 16.0% and 6.9% respectively. The absence of visceral and/or bone metastases and elevated C-reactive protein level, gamma-glutamyltransferase level and neutrophil-to-lymphocyte ratio were identified as favourable prognostic factors for OS.<br><br>CONCLUSIONS: A selected subset of patients with advanced UC may experience long-term clinical benefit from anti-PD-(L)1 treatment. We identified prognostic factors that might be used for risk assessment and clinical trial stratification.}, }
@article {pmid39513720, year = {2024}, author = {Hansman, GS and Reese, T and Pancera, M and Rudd, PA and Masic, V and Haselhorst, T and von Itzstein, M}, title = {Structural analysis of a non-pathogenic hare calicivirus capsid bound to a histo-blood group antigen co-factor.}, journal = {Journal of virology}, volume = {}, number = {}, pages = {e0167524}, doi = {10.1128/jvi.01675-24}, pmid = {39513720}, issn = {1098-5514}, }
@article {pmid39513224, year = {2024}, author = {Bazhenova, L and Kim, DW and Cho, BC and Goel, S and Heist, R and Werner, TL and Eaton, KD and Wang, JS and Pant, S and Adkins, DR and Blakely, CM and Yan, X and Neuteboom, S and Christensen, JG and Chao, R and Bauer, T}, title = {Sitravatinib in patients with solid tumors selected by molecular alterations: results from a Phase Ib study.}, journal = {Future oncology (London, England)}, volume = {20}, number = {39}, pages = {3213-3227}, doi = {10.1080/14796694.2024.2418285}, pmid = {39513224}, issn = {1744-8301}, support = {N/A//Mirati Therapeutics/ ; }, mesh = {Humans ; Male ; Female ; Middle Aged ; *Neoplasms/genetics/drug therapy/mortality/pathology ; Aged ; Adult ; Aged, 80 and over ; Mutation ; Young Adult ; Treatment Outcome ; }, abstract = {Aim: We report clinical activity and safety of sitravatinib in patients with advanced cancer from basket cohorts with specific molecular alterations, in a Phase Ib study.Materials &amp; methods: Patients with advanced solid tumors harboring amplification, mutation, or rearrangement of MET, AXL, RET, NTRK, DDR2, KDR, PDGFRA, KIT or CBL received sitravatinib once daily. Primary end point was confirmed objective response rate (ORR).Results: In total, 113 patients were enrolled following a median of 3 (range 1-18) prior systemic regimens. Altered RET (n = 31), CBL (n = 31) and MET (n = 17) were most frequent cohorts. Overall, 68.9% had reduced tumor volume and most (61.5%) had a best objective response of stable disease. ORR was highest in patients with RET-rearranged non-small cell lung cancer (21.1%) but did not differ significantly from the null hypothesis (ORR ≤15%; p = 0.316). Median progression-free survival and overall survival (5.7 and 24.2 months, respectively) were also longest in the RET-rearranged non-small cell lung cancer cohort. Diarrhea (61.1%), fatigue (50.4%) and hypertension (46.9%) were the most frequent treatment-emergent adverse events. Most treatment-emergent adverse events were mild-to-moderate in severity. The study closed before the planned number of patients were enrolled in all cohorts.Conclusion: Sitravatinib had a manageable safety profile with modest signals of clinical activity in patients with molecularly selected solid tumors.Clinical trial registration: www.clinicaltrials.gov identifier is NCT02219711.}, }
@article {pmid39512128, year = {2024}, author = {Baxter-Lowe, LA and Wang, T and Kuxhausen, M and Spellman, SR and Maiers, M and Lee, S and Saultz, J and Arrieta-Bolaños, E and Gadalla, SM and Bolon, YT and Betts, BC}, title = {Novel Scoring System for Ranking Hematopoietic Stem Cell Transplantation.}, journal = {Clinical transplantation}, volume = {38}, number = {11}, pages = {e15478}, doi = {10.1111/ctr.15478}, pmid = {39512128}, issn = {1399-0012}, support = {//Pediatric Transplantation and Cellular Therapy Consortium/ ; //Seagen Inc./ ; U24 CA076518/CA/NCI NIH HHS/United States ; //BioLineRX/ ; //Iovance/ ; //Omeros Corporation/ ; //PPD Development, LP/ ; //Kyowa Kirin/ ; //OriGen BioMedical/ ; //Stemcell Technologies/ ; //MorphoSys/ ; //Med Learning Group/ ; //Blueprint Medicines/ ; //Karius/ ; //Vor Biopharma Inc./ ; /HL/NHLBI NIH HHS/United States ; //Blue Spark Technologies/ ; //Sanofi/ ; //Neovii Pharmaceuticals AG/ ; //Mesoblast/ ; //OptumHealth/ ; //Miller Pharmacal Group, Inc./ ; //ADC Therapeutics/ ; //BeiGene/ ; //the National Heart, Lung and Blood Institute/ ; //National Institute of Allergy and Infectious Diseases/ ; N00014-23-1-2057//Office of Naval Research/ ; //HistoGenetics/ ; //Miltenyi Biomedicine/ ; //Mallinckrodt Pharmaceuticals/ ; //Miltenyi Biotec, Inc./ ; //Janssen Research &amp; Development, LLC/ ; //U.S. Public Health Service/ ; //Pharmacyclics, LLC, An AbbVie Company/ ; //Kite, a Gilead Company/ ; //Janssen/Johnson &amp; Johnson/ ; //REGiMMUNE/ ; //AstraZeneca/ ; //Bristol Myers Squibb Co./ ; //Adienne SA/ ; //Kiadis Pharma/ ; //Actinium Pharmaceuticals, Inc./ ; //Novartis Pharmaceuticals Corporation/ ; //Medical College of Wisconsin/ ; //DKMS/ ; //Kashi Clinical Laboratories/ ; //STEMSOFT/ ; //Rigel Pharmaceuticals/ ; //Incyte Corporation/ ; //Alexion/ ; //Pfizer, Inc./ ; //Amgen, Inc./ ; N00014-24-1-2057//Office of Naval Research/ ; //Adaptive Biotechnologies Corporation/ ; //AlloVir, Inc./ ; //Stemline Technologies/ ; //Astellas Pharma US/ ; //Takeda Pharmaceuticals/ ; //AbbVie/ ; //Editas Medicine/ ; //Sarah Cannon/ ; //Gift of Life Marrow Registry/ ; //Sobi, Inc./ ; //CytoSen Therapeutics, Inc./ ; //bluebird bio, inc./ ; //Ossium Health, Inc./ ; //Registry Partners/ ; //MSA-EDITLife/ ; //Atara Biotherapeutics/ ; //Orca Biosystems, Inc./ ; //Millennium, the Takeda Oncology Co./ ; //Labcorp/ ; //CSL Behring/ ; //Medac GmbH/ ; //Gateway for Cancer Research/ ; //GlaxoSmithKline/ ; //Merck &amp; Co./ ; //Gamida-Cell, Ltd./ ; //CareDx Inc./ ; //Legend Biotech/ ; //Vertex Pharmaceuticals/ ; //Jazz Pharmaceuticals, Inc./ ; //Jasper Therapeutics/ ; 75R60222C00011/HRSA/HRSA HHS/United States ; //Xenikos BV/ ; //Talaris Therapeutics/ ; //Eurofins Viracor, DBA Eurofins Transplant Diagnostics/ ; //NMDP/ ; //Gift of Life Biologics/ ; //Elevance Health/ ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation ; Female ; Male ; Middle Aged ; *Graft vs Host Disease ; Adult ; Prognosis ; *HLA Antigens/immunology ; Follow-Up Studies ; *Histocompatibility Testing ; *Myelodysplastic Syndromes/therapy ; Young Adult ; Adolescent ; Survival Rate ; Aged ; Leukemia/therapy/mortality ; Child ; Unrelated Donors ; Retrospective Studies ; Child, Preschool ; }, abstract = {BACKGROUND: When human leukocyte antigen (HLA)-matched donors are not available for hematopoietic stem cell transplants (HSCT), there are no well-accepted guidelines for ranking 7/8 HLA-matched unrelated donors to achieve optimal transplant outcomes. A novel scoring system for ranking HLA mismatches for these donors was investigated.<br><br>METHODS: High-resolution HLA types were used to determine amino acid mismatches located in the HLA antigen-recognition domain. The location and physicochemical properties of mismatched amino acids were used to assign scores for peptide binding, T-cell receptor docking, and HLA structure/function. The scores were tested using a cohort of 2319 patients with leukemia or myelodysplastic syndrome who received their first unrelated donor transplant using conventional graft-versus-host disease (GVHD) prophylaxis between 2000 and 2014. Donors were 7/8 HLA-matched with a single HLA Class I mismatch. Primary outcomes were overall survival and acute GVHD.<br><br>RESULTS: The scores did not significantly (p&#xa0;<&#xa0;0.01) associate with transplant outcomes, although a Peptide Score = 0 (i.e., no differences in peptide binding; N&#xa0;=&#xa0;146, 6.3%) appears to have lower transplant-related mortality (TRM) compared to higher scores (p&#xa0;=&#xa0;0.019). HLA mismatches with Peptide Score&#xa0;=&#xa0;0 were predominately HLA-C*03:03/03:04 (62%), previously reported to be a permissive mismatch, and a group of 28 other HLA mismatches (38%) that showed similar associations with TRM.<br><br>CONCLUSIONS: This study suggests that HLA mismatches that do not alter peptide binding or orientation (Peptide Score&#xa0;=&#xa0;0) could expand the number of permissive HLA mismatches. Further investigation is needed to confirm this observation and to explore alternative scoring systems for ranking HLA mismatched donors.}, }
@article {pmid39510589, year = {2024}, author = {Demirci, RA and Gulati, R and Hawley, JE and Yezefski, T and Haffner, MC and Cheng, HH and Montgomery, RB and Schweizer, MT and Yu, EY and Nelson, PS and Chen, DL and Iravani, A}, title = {SPECT/CT in Early Response Assessment of Patients with Metastatic Castration-Resistant Prostate Cancer Receiving [177]Lu-PSMA-617.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {65}, number = {12}, pages = {1945-1951}, doi = {10.2967/jnumed.124.267665}, pmid = {39510589}, issn = {1535-5667}, support = {R37 CA286450/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms, Castration-Resistant/radiotherapy/diagnostic imaging/pathology ; Aged ; *Heterocyclic Compounds, 1-Ring/therapeutic use ; *Lutetium ; *Single Photon Emission Computed Tomography Computed Tomography ; Retrospective Studies ; *Dipeptides/therapeutic use ; Treatment Outcome ; *Neoplasm Metastasis ; Aged, 80 and over ; Prostate-Specific Antigen/blood ; Middle Aged ; }, abstract = {[177]Lu-PSMA-617 (LuPSMA) is a newly established treatment for patients with metastatic castration-resistant prostate cancer (mCRPC), but survival outcomes vary widely, and predictors of treatment responses are needed. This study investigated the role of total tumor volumes (TTVs) and new lesions (NLs) determined by LuPSMA SPECT/CT in early cycles to predict subsequent outcomes in a real-world practice setting. Methods: Between June and December 2022, consecutive patients with mCRPC who received at least 2 administrations of LuPSMA with SPECT/CT 24 h after treatment were retrospectively reviewed. We evaluated associations between TTVs and the appearance of NLs at cycles 2 and 3 with subsequent prostate-specific antigen (PSA) progression-free survival and overall survival (OS) using multivariate Cox regression. All analyses were adjusted for changes in PSA level relative to baseline. Results: Sixty-six mCRPC patients (median age, 74 y) received a median of 4 (interquartile range, 3-5) cycles of LuPSMA. Median follow-up starting at cycle 2 was 42 wk (interquartile range, 33-48 wk), with 24 of 66 patients deceased at the time of the analysis. Changes in TTV measured at the start of cycles 2 and 3 relative to baseline correlated significantly with corresponding changes in PSA level (r = 0.55 and 0.56), but absolute TTVs did not correlate significantly (r = 0.00 and 0.18). Patients with a higher absolute TTV at the start of cycle 2 had worse PSA progression-free survival and OS (hazard ratio [HR], 1.4 [95% CI, 1.1-1.8] and 2.1 [95% CI, 1.5-2.9]), with consistent results at the start of cycle 3 (HR, 2 [95% CI, 1.4-2.9] and 2 [95% CI, 1.2-3.2]). NLs were identified in 13 of 66 and 11 of 51 patients at the start of cycles 2 and 3. NLs at the start of cycle 2 were associated with worse OS (HR, 5.8 [95% CI, 1.9-17.5]), with consistent results at the start of cycle 3 (HR, 4.9 [95% CI, 1.3-18.6]). In multivariate analysis, a higher TTV and the appearance of NLs at the start of cycles 2 and 3 were independently associated with poorer OS. Conclusion: Higher TTVs and NLs on LuPSMA SPECT/CT at the start of cycles 2 and 3 were independently associated with higher risk of death. These measures provided prognostic information independent of changes in PSA. Development of prognostic and predictive models including TTV, NLs, and PSA changes is warranted.}, }
@article {pmid39509091, year = {2024}, author = {Unger, JM and Till, C and Tangen, CM and Hershman, DL and Goodman, PJ and LeBlanc, M and Barlow, WE and Vaidya, R and Minasian, LM and Parnes, HL and Thompson, IM}, title = {Long-Term Adverse Effects and Complications After Prostate Cancer Treatment.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, pmid = {39509091}, issn = {2374-2445}, abstract = {IMPORTANCE: Due to the often indolent nature of prostate cancer (PCA), treatment decisions must weigh the risks and benefits of cancer control with those of treatment-associated morbidities.<br><br>OBJECTIVE: To characterize long-term treatment-related adverse effects and complications in patients treated for PCA compared to a general population of older males.<br><br>This cohort study used a novel approach linking data from 2 large PCA prevention clinical trials (the Prostate Cancer Prevention Trial and the Selenium and Vitamin-E Cancer Prevention Trial) with Medicare claims records. This analysis included patients with PCA who had been treated with prostatectomy or radiotherapy compared with an untreated control group. Multivariable Cox regression was used, with a time-varying covariate for the occurrence of PCA treatment, adjusted for age, race, and year of time-at-risk initiation, and stratified by study and intervention arm. Data analyses were performed from September 21, 2022, to March 18, 2024.<br><br>EXPOSURE: Prostatectomy and radiotherapy occurring after a PCA diagnosis, identified from trial data or Medicare claims records.<br><br>MAIN OUTCOMES AND MEASURES: Ten potential PCA treatment-related complications identified from Medicare claims data.<br><br>RESULTS: The study sample comprised 29&#x202f;196 participants (mean [SD] age at time-at-risk initiation, 68.7 [4.8] years). Of these, 3946 participants had PCA, among whom 655 were treated with prostatectomy and 1056 with radiotherapy. The 12-year hazard risk of urinary or sexual complications was 7.23 times greater for those with prostatectomy (95% CI, 5.96-8.78; P <&#x2009;.001) and 2.76 times greater for radiotherapy (95% CI, 2.26-3.37; P <&#x2009;.001) compared to untreated participants. Moreover, among participants treated with radiotherapy, there was a nearly 3-fold greater hazard risk of bladder cancer than in the untreated (hazard ratio [HR], 2.78; 95% CI, 1.92-4.02; P <&#x2009;.001), as well as an approximately 100-fold increased hazard risk of radiation-specific outcomes including radiation cystitis (HR, 131.47; 95% CI, 52.48-329.35; P <&#x2009;.001) and radiation proctitis (HR, 87.91; 95% CI, 48.12-160.61; P <&#x2009;.001). The incidence per 1000 person-years of any 1 of the 10 treatment-related complications was 124.26 for prostatectomy, 62.15 for radiotherapy, and 23.61 for untreated participants.<br><br>CONCLUSIONS AND RELEVANCE: This cohort study found that, even after accounting for age-related symptoms and disease, PCA treatment was associated with higher rates of complications in the 12 years after treatment. Given the uncertain benefit of PCA treatment for most patients, these findings highlight the importance of patient counseling before PCA screening and treatment and provide a rationale for pursuing opportunities for cancer prevention.}, }
@article {pmid39508344, year = {2024}, author = {Chappidi, MR and Lin, DW and de la Calle, CM}, title = {Editorial Comment.}, journal = {The Journal of urology}, volume = {}, number = {}, pages = {101097JU0000000000004307}, doi = {10.1097/JU.0000000000004307}, pmid = {39508344}, issn = {1527-3792}, }
@article {pmid39507884, year = {2024}, author = {Childs-Kean, LM and Beieler, AM and Cortés-Penfield, N and Keller, SC and Rivera, CG and Ryan, KL and Yoke, LH and Mahoney, MV}, title = {A Bundle of the "Top 10" Outpatient Parenteral Antimicrobial Therapy Publications in 2023.}, journal = {Open forum infectious diseases}, volume = {11}, number = {11}, pages = {ofae635}, pmid = {39507884}, issn = {2328-8957}, abstract = {Outpatient parenteral antimicrobial therapy (OPAT) has become more common in infectious diseases practice settings. Similarly, OPAT-related publications have also increased. The objective of this article was to summarize clinically important OPAT-related publications from 2023. Eighty-one articles were found on initial search, with 52 meeting inclusion criteria. A survey containing the 19 articles that had at least 1 citation was sent to an email listserv of multidisciplinary clinicians with OPAT experience. This article summarizes the "top 10" 2023 OPAT articles from the survey results.}, }
@article {pmid39505858, year = {2024}, author = {Srinivasan, S and Kryza, T and Bock, N and Tse, BWC and Sokolowski, KA and Janaththani, P and Fernando, A and Moya, L and Stephens, C and Dong, Y and Röhl, J and Alinezhad, S and Vela, I and Perry-Keene, JL and Buzacott, K and Nica, R and ,  and Gago-Dominguez, M and ,  and Schleutker, J and Maier, C and Muir, K and Tangen, CM and Gronberg, H and Pashayan, N and Albanes, D and Wolk, A and Stanford, JL and Berndt, SI and Mucci, LA and Koutros, S and Cussenot, O and Sorensen, KD and Grindedal, EM and Travis, RC and Haiman, CA and MacInnis, RJ and Vega, A and Wiklund, F and Neal, DE and Kogevinas, M and Penney, KL and Nordestgaard, BG and Brenner, H and John, EM and Gamulin, M and Claessens, F and Melander, O and Dahlin, A and Stattin, P and Hallmans, G and Häggström, C and Johansson, R and Thysell, E and Rönn, AC and Li, W and Brown, N and Dimeski, G and Shepherd, B and Dadaev, T and Brook, MN and Spurdle, AB and Stenman, UH and Koistinen, H and Kote-Jarai, Z and Klein, RJ and Lilja, H and Ecker, RC and Eeles, R and ,  and ,  and Clements, J and Batra, J}, title = {A PSA SNP associates with cellular function and clinical outcome in men with prostate cancer.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {9587}, pmid = {39505858}, issn = {2041-1723}, support = {AQIRF175-2019RD2//State of Queensland | Advance Queensland/ ; R01 CA244948/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; U01 CA199338/CA/NCI NIH HHS/United States ; R01 CA175491/CA/NCI NIH HHS/United States ; W81XWH-19-1-0343//U.S. Department of Defense (United States Department of Defense)/ ; }, mesh = {Male ; Humans ; *Prostatic Neoplasms/genetics/pathology/metabolism/mortality ; *Polymorphism, Single Nucleotide ; *Prostate-Specific Antigen/blood/metabolism ; *Kallikreins/genetics/metabolism ; Genetic Predisposition to Disease ; Aged ; Animals ; Chromosomes, Human, Pair 19/genetics ; Middle Aged ; Mice ; Alleles ; Cell Line, Tumor ; }, abstract = {Genetic variation at the 19q13.3 KLK locus is linked with prostate cancer susceptibility in men. The non-synonymous KLK3 single nucleotide polymorphism (SNP), rs17632542 (c.536 T > C; Ile163Thr-substitution in PSA) is associated with reduced prostate cancer risk, however, the functional relevance is unknown. Here, we identify that the SNP variant-induced change in PSA biochemical activity mediates prostate cancer pathogenesis. The 'Thr' PSA variant leads to small subcutaneous tumours, supporting reduced prostate cancer risk. However, 'Thr' PSA also displays higher metastatic potential with pronounced osteolytic activity in an experimental metastasis in-vivo model. Biochemical characterisation of this PSA variant demonstrates markedly reduced proteolytic activity that correlates with differences in in-vivo tumour burden. The SNP is associated with increased risk for aggressive disease and prostate cancer-specific mortality in three independent cohorts, highlighting its critical function in mediating metastasis. Carriers of this SNP allele have reduced serum total PSA and a higher free/total PSA ratio that could contribute to late biopsy decisions and delay in diagnosis. Our results provide a molecular explanation for the prominent 19q13.3 KLK locus, rs17632542 SNP, association with a spectrum of prostate cancer clinical outcomes.}, }
@article {pmid39505278, year = {2024}, author = {Sutherland, NM and Zhou, B and Zhang, L and Ong, MS and Hong, JS and Pak, A and Liu, KJ and Frigault, MJ and Maus, MV and Hill, JA and Reynolds, K and Walter, JE and Camargo, CA and Barmettler, S}, title = {Association of CD19[+]-targeted chimeric antigen receptor (CAR) T-cell therapy with hypogammaglobulinemia, infection, and mortality.}, journal = {The Journal of allergy and clinical immunology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaci.2024.10.021}, pmid = {39505278}, issn = {1097-6825}, abstract = {BACKGROUND: CD19-targeted chimeric antigen receptor T-cell therapy (CAR-T therapy) has revolutionized the treatment of hematologic malignancies. As these cells target CD19[+] receptors on B cells, there is the potential for B-cell aplasia and hypogammaglobulinemia. Data on the degree and clinical significance of hypogammaglobulinemia are sparse.<br><br>OBJECTIVES: We sought to evaluate hypogammaglobulinemia after CD19-targeted CAR-T therapy and risk factors for hypogammaglobulinemia, infections, and mortality.<br><br>METHODS: We performed a retrospective evaluation of 579 patients receiving CD19-directed CAR-T therapy and evaluated demographics, hypogammaglobulinemia (IgG &#x2264;600 mg/dL), infections prior to and after CAR-T therapy, and risk factors for hypogammaglobulinemia, infection, hospitalizations, and mortality.<br><br>RESULTS: Patients had a mean age of 64 years and 64% were male. Prior to CAR-T therapy, 60% of patients had hypogammaglobulinemia, which increased to 91% post-CAR-T therapy. Mean IgG levels decreased from pre- to post-CAR-T therapy levels (587 to 362 mg/dL; P&#xa0;< .0001). Thirty-seven percent of patients developed a serious infection post-CAR-T therapy. Hypogammaglobulinemia prior to CAR-T therapy was associated with worsening hypogammaglobulinemia after CAR-T therapy. Hypogammaglobulinemia post CAR-T therapy was associated with an increased risk of serious infection following CAR-T therapy (incidence rate ratio: 2.7; 95% CI: 1.5-5.2; P&#xa0;=&#xa0;.002). Risk factors for mortality included mild hypogammaglobulinemia (400 mg/dL&#xa0;< IgG&#xa0;&#x2264; 600 mg/dL), infections &#x2264;100 days post-CAR-T therapy, and hospitalizations for infections. Immunoglobulin replacement was associated with a decreased risk of mortality.<br><br>CONCLUSIONS: We identified &#x223c;90% of patients with hypogammaglobulinemia after CAR-T therapy. Hypogammaglobulinemia before CAR-T therapy was strongly predictive of worsening hypogammaglobulinemia after CAR-T therapy, which was associated with an increased risk of serious infection and mortality post CAR-T therapy. Increased immunological monitoring is needed to identify high-risk patients who may benefit from interventions to decrease morbidity and mortality.}, }
@article {pmid39505259, year = {2024}, author = {Karim, NA and Miao, J and Reckamp, KL and Gay, CM and Byers, LA and Zhao, YQ and Redman, MW and Carrizosa, DR and Wang, WL and Petty, WJ and Mehta, K and Faller, BA and Agamah, ES and Kasbari, SS and Malisetti, RK and Kumar, A and Schallenkamp, J and Alluri, KC and Gray, JE and Kelly, K}, title = {Phase II randomized study of maintenance atezolizumab (A) versus atezolizumab + talazoparib (AT) in patients with SLFN11 positive extensive stage small cell lung cancer. S1929.}, journal = {Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtho.2024.10.021}, pmid = {39505259}, issn = {1556-1380}, abstract = {PURPOSE: To evaluate whether the addition of a poly (ADP-ribose) polymerase inhibitor (PARPi) talazoparib to maintenance immune checkpoint inhibitor (ICI) atezolizumab following frontline chemoimmunotherapy improved outcomes in patients with Schlafen 11 (SLFN11)-positive extensive stage small cell lung cancer (ES-SCLC).<br><br>METHODS: Patients with newly diagnosed SLFN11 expressing (H-score &#x2265; 1, evaluated centrally) ES-SCLC were randomized to maintenance atezolizumab (A) versus atezolizumab plus talazoparib (AT) following frontline chemotherapy plus atezolizumab. The primary objective was to compare progression-free survival (PFS) using a 1-sided 10% level stratified log-rank test. Secondary endpoints included objective response rate (ORR), overall survival (OS), and toxicity. Target sample size was 84 eligible patients.<br><br>RESULTS: From June 15, 2020 to December 15, 2022, 106 eligible patients were randomized (54 to AT and 52 to A). PFS was improved with AT versus A (hazard ratio [HR], 0.66; 80% confidence interval [CI]: 0.50-0.86; 1-sided P = 0.019) with a median PFS of 2.9 and 2.4 months; OS was not different between groups (HR, 0.98; 80% CI: 0.71-1.36; 1-sided P = 0.47). Grade &#x2265; 3 non-hematologic treatment-related adverse events (TRAEs) occurred in 17% of patients with AT and 14% of patients with A. Grade &#x2265; 3 hematological TRAEs were more common in AT (50%) than in A (4%) (P < 0.001).<br><br>CONCLUSION: Maintenance AT improved PFS in patients with SLFN11-positive ES-SCLC that did not progress following initial chemo-immunotherapy. Hematologic toxicity, primarily grade 3 anemia, was increased with AT, as expected. Prospective biomarker-selection was demonstrated, paving the way for future evaluation of novel therapies in molecularly defined SCLC populations.}, }
@article {pmid39503494, year = {2024}, author = {Greninger, AL and Larcena, A and Patel, A and Webster, B and Ulen, C and Green, DF and King, D and Patel, DR and McElvania, E and Harnett, G and Jandali, I and Gibson, J and Killion, J and Atwi, J and Bergmann, K and Slade, L and Allen Staat, M and Faron, M and Washington, M and Patel, R and Annamalai, R and Ackerman, R and Stewart, WP and Amador, YM and Rao, D and Liu, X and Raman, A}, title = {Prospective, multi-site evaluation of the Cepheid Xpert Xpress CoV-2 plus test on nasal and nasopharyngeal swabs.}, journal = {Journal of clinical microbiology}, volume = {}, number = {}, pages = {e0121924}, doi = {10.1128/jcm.01219-24}, pmid = {39503494}, issn = {1098-660X}, abstract = {UNLABELLED: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues its largely aseasonal spread with millions of cases per year. Highly sensitive, point-of-care testing is critical for rapid detection of coronavirus disease 2019 (COVID-19) cases and initiation of antiviral therapy to avert adverse health outcomes and reduce onward transmission of the virus. While hundreds of COVID-19 diagnostics received emergency use authorization from the FDA during the pandemic, significantly fewer have navigated the course to FDA clearance or approval. Here, we determined the clinical performance of the Cepheid Xpert Xpress CoV-2 plus for detection of SARS-CoV-2 in 3,750 anterior nasal swab (NS) specimens and nasopharyngeal swab (NPS) from 32 sites in comparison to the FDA-authorized BioFire Respiratory Panel 2.1. Three-quarters of specimens collected were tested on the Xpert Xpress CoV-2 plus in the point-of-care setting. Overall positive percent agreement (PPA) was 98.1% (95% CI: 96.7%-98.9%) and negative percent agreement (NPA) was 98.3% (97.7%-98.7%). Performance of the Xpert Xpress CoV-2 plus was slightly improved in NS compared to NPS specimens, with PPA of 99.3% versus 97.0% (Fisher's exact test, P = 0.06) and NPA of 98.3% versus 98.2% (P = 0.89), respectively. Assay PPA was similar between untrained and trained users (98.7% vs 97.3%, P = 0.75), while NPA was slightly improved for untrained users (99.0% vs 97.6%, P = 0.0003). This study showed that Cepheid Xpert Xpress COV-2 plus is highly sensitive and specific/has high PPA and NPA for detection of SARS-CoV-2 from both NS and NPS specimens.<br><br>IMPORTANCE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to cause millions of infections and tens of thousands of deaths per year in the United States. While the FDA authorized hundreds of SARS-CoV-2 tests during the public health emergency, significantly fewer have made the transition to being cleared or approved. There continues to be a need for FDA-authorized point-of-care SARS-CoV-2 testing that can be performed by untrained users. We conducted a large prospective study of the Cepheid Xpert Xpress CoV-2 plus test for detection of SARS-CoV-2 in both nasal and nasopharyngeal swabs by trained and untrained users. The assay demonstrated excellent clinical performance characteristics and, as a result of this study, was cleared by the FDA.}, }
@article {pmid39499893, year = {2024}, author = {Iyer, G and Tangen, CM and Sarfaty, M and Regazzi, AM and Lee, IL and Fong, M and Choi, W and Dinney, CPN and Flaig, TW and Thompson, IM and Lerner, SP and McConkey, DJ and Rosenberg, JE}, title = {DNA Damage Response Alterations Predict for Neoadjuvant Chemotherapy Sensitivity in Muscle-Invasive Bladder Cancer: A Correlative Analysis of the SWOG S1314 Trial.}, journal = {JCO precision oncology}, volume = {8}, number = {}, pages = {e2400287}, doi = {10.1200/PO.24.00287}, pmid = {39499893}, issn = {2473-4284}, mesh = {Humans ; *Urinary Bladder Neoplasms/drug therapy/genetics/pathology ; Male ; Female ; *Neoadjuvant Therapy ; Middle Aged ; Aged ; *DNA Damage ; Xeroderma Pigmentosum Group D Protein/genetics ; Cisplatin/therapeutic use ; Neoplasm Invasiveness ; Adult ; }, abstract = {PURPOSE: Alterations in DNA damage response (DDR) genes, including ERCC2, have been correlated with response to neoadjuvant cisplatin-based chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC). The SWOG 1314 (S1314) trial enrolled patients with MIBC who received one of two NAC regimens followed by radical cystectomy. We examined the prevalence of DDR alterations in NAC responders versus nonresponders and correlated DDR alteration status with response.<br><br>METHODS: Pretreatment tumor specimens from 179 evaluable patients underwent next-generation sequencing (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets assay). Associations were determined between any or only deleterious alterations within nine predefined DDR genes, or any alterations in ERCC2, and progression-free survival (PFS) and overall survival using Cox regression, and, in a subset of evaluable patients, pathologic response (complete response, pT0, or downstaging to <pT2) using logistic regression, adjusting for clinical stage and performance status.<br><br>RESULTS: Deleterious DDR alterations were detected in 41 (23%) of 179 patients. Of the 151 patients evaluable for pathologic response, patients with deleterious DDR alterations (n = 39) demonstrated a higher pathologic response rate than those without (odds ratio [OR], 3.24 [95% CI, 1.51 to 6.94]; P = .003). In 24 ERCC2-mutant patients, the OR for pT0 was 3.33 (95% CI, 1.35 to 8.22; P = .009) and for <pT2 was 2.33 (95% CI, 0.92 to 5.89; P = .073). The association between deleterious DDR alterations and PFS provided an estimate of hazard ratio, 0.54 (95% CI, 0.29 to 1.01; P = .053).<br><br>CONCLUSION: Deleterious DDR alterations were associated with pathologic response following NAC in S1314. Functional validation of ERCC2 and other DDR alterations is underway to help refine such alterations as biomarkers of NAC in patients with bladder cancer.}, }
@article {pmid39498208, year = {2024}, author = {Hyde, ET and Nguyen, S and LaMonte, MJ and Di, C and Bellettiere, J and Tinker, LF and Foraker, RE and Tindle, HA and Stefanick, ML and LaCroix, AZ}, title = {Influence of physical activity measurement on the association between Life's Essential 8 and incident cardiovascular disease in older women.}, journal = {Preventive medicine reports}, volume = {47}, number = {}, pages = {102904}, pmid = {39498208}, issn = {2211-3355}, abstract = {OBJECTIVE: The American Heart Association's Life's Essential 8 (LE8) metric includes self-reported physical activity as one of the metrics for assessing cardiovascular health. Self-reported physical activity is prone to misclassification, whereas accelerometer measures are less biased. We examined associations of LE8 and incident cardiovascular disease (CVD) using self-reported and accelerometer-measured physical activity.<br><br>METHODS: Participants in the Women's Health Initiative (WHI) Objective Physical Activity and Cardiovascular Health Study (n&#xa0;=&#xa0;4,243; mean age&#xa0;=&#xa0;79&#xa0;&#xb1;&#xa0;7 years) with no CVD history completed the WHI physical activity questionnaire and the Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire prior to wearing a hip-worn accelerometer for up to seven days in 2012-2014. LE8 components (physical activity, diet, sleep, body mass index, smoking, blood pressure, non-HDL cholesterol, and glucose) were scored according to guidelines. Scores were created using five physical activity measures: WHI questionnaire (LE8WHI), CHAMPS (LE8CHAMPS), accelerometer-measured physical activity (LE8A), and sample quantiles of accelerometer-measured physical activity (LE8AQ) and daily steps (LE8STEPS). Hazard ratios (HR) for physician-adjudicated CVD were estimated using Cox regression.<br><br>RESULTS: 707 incident CVD events occurred over an average 7.5&#xa0;years. Multivariable HRs (95&#xa0;% CI) comparing women in the highest vs. lowest quartiles of LE8 scores were: LE8WHI&#xa0;=&#xa0;0.53 (0.43-0.67), LE8CHAMPS&#xa0;=&#xa0;0.47 (0.38-0.60), LE8A&#xa0;=&#xa0;0.44 (0.36-0.56), LE8AQ&#xa0;=&#xa0;0.44 (0.35-0.55), and LE8STEPS&#xa0;=&#xa0;0.45 (0.35-0.57).<br><br>CONCLUSIONS: The LE8-incident CVD association varies by physical activity measurement, however all methods showed reduced risk. Device-measures of physical activity may be more accurate in the LE8, but when impractical to implement, also support use of self-reported measures.}, }
@article {pmid39495136, year = {2024}, author = {Singal, AG and Parikh, ND and Kanwal, F and Marrero, JA and Deodhar, S and Page-Lester, S and Lopez, C and Feng, Z and Tayob, N}, title = {National Liver Cancer Screening Trial (TRACER) study protocol.}, journal = {Hepatology communications}, volume = {8}, number = {11}, pages = {}, pmid = {39495136}, issn = {2471-254X}, support = {U01 CA271887/CA/NCI NIH HHS/United States ; U24 CA086368/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Liver Neoplasms/diagnosis/blood/diagnostic imaging ; *Early Detection of Cancer/methods ; *alpha-Fetoproteins/analysis ; *Carcinoma, Hepatocellular/diagnosis/blood/diagnostic imaging ; Male ; Female ; *Biomarkers, Tumor/blood ; Prothrombin/analysis ; Ultrasonography ; Hepatitis B, Chronic/diagnosis/blood ; Middle Aged ; Protein Precursors/blood ; Adult ; Liver Cirrhosis/blood/diagnosis/diagnostic imaging ; Aged ; Pragmatic Clinical Trials as Topic ; Biomarkers ; }, abstract = {BACKGROUND: Professional guidelines recommend HCC screening in at-risk patients using semi-annual ultrasound with or without alpha-fetoprotein (AFP); however, this strategy has limited effectiveness due to low adherence and sensitivity. Increasing data support the potential role of blood-based biomarker panels, which could improve both aspects. The biomarker panel GALAD, comprised of sex, age, and 3 blood biomarkers (AFP, AFP-L3, and des-carboxy prothrombin des-carboxy prothrombin), has shown high sensitivity and specificity in biomarker phase II (case-control) and phase III (retrospective cohort) validation studies. However, prospective validation in a large phase IV biomarker clinical utility trial is necessary before its adoption in practice.<br><br>METHODS: The National Liver Cancer Screening Trial is an adaptive pragmatic randomized phase IV trial, which began enrollment in January 2024, comparing ultrasound-based versus biomarker-based screening in 5500 patients with chronic hepatitis B infection or cirrhosis from any etiology. Eligible patients are randomly assigned in a 1:1 ratio to semi-annual screening with ultrasound &#xb1; alpha-fetoprotein (arm A) or semi-annual screening with GALAD (arm B). Randomization is stratified by enrollment site, liver disease severity (per Child-Pugh class), liver disease etiology (viral, nonviral, and noncirrhotic HBV), and sex. Patients are being recruited from 15 sites (a mix of tertiary care academic referral centers, safety-net health systems, and large community health systems) over a 3-year period, and the primary endpoint, reduction in late-stage HCC, will be assessed at the end of year 5.5.<br><br>DISCUSSION: The results of this trial will inform the best strategy for HCC screening and early-stage detection in patients with chronic liver diseases. If GALAD shows superiority, HCC screening would primarily shift from an ultrasound-based strategy to the adoption of the biomarker panel.<br><br>TRIAL REGISTRATION: NCT06084234.<br><br>TRIAL STATUS: The TRACER Study is actively enrolling.}, }
@article {pmid39493537, year = {2024}, author = {Colquhoun, R and O'Toole, &#xc1; and Hill, V and McCrone, JT and Yu, X and Nicholls, SM and Poplawski, R and Whalley, T and Groves, N and Ellaby, N and Loman, N and Connor, T and Rambaut, A}, title = {A phylogenetics and variant calling pipeline to support SARS-CoV-2 genomic epidemiology in the UK.}, journal = {Virus evolution}, volume = {10}, number = {1}, pages = {veae083}, pmid = {39493537}, issn = {2057-1577}, support = {MR/L015080/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {In response to the escalating SARS-CoV-2 pandemic, in March 2020 the COVID-19 Genomics UK (COG-UK) consortium was established to enable national-scale genomic surveillance in the UK. By the end of 2020, 49% of all SARS-CoV-2 genome sequences globally had been generated as part of the COG-UK programme, and to date, this system has generated >3 million SARS-CoV-2 genomes. Rapidly and reliably analysing this unprecedented number of genomes was an enormous challenge. To fulfil this need and to inform public health decision-making, we developed a centralized pipeline that performs quality control, alignment, and variant calling and provides the global phylogenetic context of sequences. We present this pipeline and describe how we tailored it as the pandemic progressed to scale with the increasing amounts of data and to provide the most relevant analyses on a daily basis.}, }
@article {pmid39492698, year = {2024}, author = {Heldman, MR and Boeckh, MJ and Limaye, AP}, title = {Current and future strategies for the prevention and treatment of cytomegalovirus infections in transplantation.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciae535}, pmid = {39492698}, issn = {1537-6591}, abstract = {Successful prevention and treatment of cytomegalovirus (CMV) infection remains a central focus of clinical care in solid organ and allogeneic hematopoietic cell transplantation. Over the past 5 years, pivotal clinical trials have created new paradigms in CMV prevention, including diverging approaches in HCT and SOT. We review recent advances in CMV risk assessment and progress in antiviral and immune-based strategies for CMV prevention and treatment. We highlight approaches to optimize CMV-specific immunity through vaccination, monoclonal antibodies, and virus-specific T-cells. Observational studies and interventional trials of commercially-available CMV cell-mediated immunity assays for refining preventive and treatment strategies are summarized. Finally, we discuss the importance of enhancing CMV-specific immunity to mitigate the negative impacts of CMV in different transplant settings. CMV infections in recipients of chimeric antigen receptor-T (CAR-T) cell therapies and other immunocompromised populations are growing areas of importance that are beyond the scope of this review.}, }
@article {pmid39490766, year = {2024}, author = {Bricker, JB and Sullivan, BM and Mull, KE and Lavista-Ferres, J and Santiago-Torres, M}, title = {Efficacy of a conversational chatbot for cigarette smoking cessation: Protocol of the QuitBot full-scale randomized controlled trial.}, journal = {Contemporary clinical trials}, volume = {147}, number = {}, pages = {107727}, pmid = {39490766}, issn = {1559-2030}, support = {R01 CA247156/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Smoking Cessation/methods/psychology ; *Motivation ; Female ; Male ; *Text Messaging ; Communication ; Adult ; Middle Aged ; Cigarette Smoking/therapy/psychology ; Counseling/methods ; }, abstract = {Globally, cigarette smoking results in over 8 million premature annual deaths. Addressing this issue requires high-impact, cost-effective population-level interventions for smoking cessation. Conversational chatbots offer a potential solution given the recent advancements in machine learning and large language models. Chatbots can deliver supportive, empathetic behaviors, personalized responses, and timely advice tailored to users' needs that is engaging through therapeutic conversations aimed at creating lasting social-emotional connections. Despite their promise, little is known about the efficacy and underlying mechanisms of chatbots for cigarette smoking cessation. We developed QuitBot, a quit smoking program of two to three-minute conversations covering topics ranging from motivations to quit, setting a quit date, choosing cessation medications, coping with triggers, maintaining abstinence, and recovering from a relapse. QuitBot employs conversational interactions, powered by an expert-curated large language model, allowing users to ask questions and receive personalized guidance on quitting smoking. Here, we report the design and execution of a randomized clinical trial comparing QuitBot (n = 760) against Smokefree TXT (SFT) text messaging program (n = 760), with a 12-month follow-up period. Both interventions include 42-days of content on motivations to quit, skills to cope with triggers, and relapse prevention. The key distinction between QuitBot and SFT is that QuitBot has communication and engagement features. This study aims to determine: whether QuitBot yields higher quit rates than SFT; and whether therapeutic alliance processes and engagement are mechanisms underlying cessation outcomes. Additionally, we will explore whether baseline factors including trust, social support, and demographics, moderate the efficacy of QuitBot. Trial Registration numberClinicalTrials.govNCT04308759.}, }
@article {pmid39490125, year = {2024}, author = {Walia, R and Fertrin, KY and Sabath, DE}, title = {A Winding Road to Health Care Equity in Sickle Cell Disease.}, journal = {Clinics in laboratory medicine}, volume = {44}, number = {4}, pages = {693-704}, doi = {10.1016/j.cll.2024.07.005}, pmid = {39490125}, issn = {1557-9832}, mesh = {*Anemia, Sickle Cell/therapy ; Humans ; Health Equity ; Health Services Accessibility ; Healthcare Disparities ; }, abstract = {Sickle cell disease (SCD) is a genetic disorder where red blood cells sickle, causing anemia and pain. Historically linked to marginalized groups, SCD saw little progress in treatment strategies for decades. Addressing these requires holistic strategies including dedicated centers, education, patient inclusion, and tackling implicit bias. Efforts must ensure treatments are accessible and stigma-free. Progress depends on collaboration and advocacy, aiming for an equitable, patient-focused health care system responsive to the unique needs of those with SCD. This review illustrates the actionable steps that the medical community can take to improve care for patients with SCD.}, }
@article {pmid39490124, year = {2024}, author = {Walia, R and Fertrin, KY and Sabath, DE}, title = {History, Advances, and Challenges of Sickle Cell Disease Treatment.}, journal = {Clinics in laboratory medicine}, volume = {44}, number = {4}, pages = {679-691}, doi = {10.1016/j.cll.2024.07.004}, pmid = {39490124}, issn = {1557-9832}, mesh = {*Anemia, Sickle Cell/therapy ; Humans ; *Genetic Therapy ; Antisickling Agents/therapeutic use ; History, 20th Century ; History, 21st Century ; }, abstract = {Sickle cell disease (SCD) is marked by red blood cells that deform into a sickle shape, causing severe health complications. Historic neglect and slow therapeutic progress have left many, especially African descendants, vulnerable. Recent treatment strides include novel drugs and gene therapy, promising improved management. Nonetheless, challenges persist with treatment adoption because of cost, adverse effects, and accessibility. Advancements hold hope for enhanced life quality and longevity for SCD patients.}, }
@article {pmid39489920, year = {2024}, author = {Li, C and Georgakopoulou, A and Paschoudi, K and Anderson, AK and Huang, L and Gil, S and Giannaki, M and Vlachaki, E and Newby, GA and Liu, DR and Yannaki, E and Kiem, HP and Lieber, A}, title = {Introducing a hemoglobin G-Makassar variant in HSCs by in vivo base editing treats sickle cell disease in mice.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {32}, number = {12}, pages = {4353-4371}, doi = {10.1016/j.ymthe.2024.10.018}, pmid = {39489920}, issn = {1525-0024}, support = {R01 AI174304/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; *Anemia, Sickle Cell/therapy/genetics ; *Gene Editing/methods ; Mice ; *Genetic Vectors/genetics/administration &amp; dosage ; *Disease Models, Animal ; *Hematopoietic Stem Cells/metabolism ; Humans ; *Genetic Therapy/methods ; Hematopoietic Stem Cell Transplantation/methods ; Mutation ; Adenoviridae/genetics ; Hemoglobin, Sickle/genetics ; Transduction, Genetic ; CRISPR-Cas Systems ; }, abstract = {Precise repair of the pathogenic mutation in hematopoietic stem cells (HSCs) represents an ideal cure for patients with sickle cell disease (SCD). Here, we demonstrate correction of the SCD phenotype by converting the sickle mutation codon (GTG) into a benign G-Makassar variant (GCG) using in vivo base editing in HSCs. We show successful production of helper-dependent adenoviral vectors expressing an all-in-one base editor mapping to the sickle mutation site. In HSC-enriched cells from SCD patients, transduction with the base editing vector in vitro resulted in 35% GTG > GCG conversion and phenotypic improvements in the derived red blood cells. After ex vivo transduction of HSCs from an SCD mouse model and subsequent transplantation, we achieved an average of 88% editing at the target site in transplanted mice. Importantly, in vivo HSC base editing followed by selection generated 24.5% Makassar variant in long-term repopulating HSCs of SCD mice. The treated animals demonstrated correction of disease hallmarks without any noticeable side effects. Off-target analyses at top-scored genomic sites revealed no off-target editing. This in vivo approach requires a single non-integrating vector, only intravenous/subcutaneous injections, and minimal in vivo selection. This technically simple approach holds potential for scalable applications in resource-limiting regions where SCD is prevalent.}, }
@article {pmid39487536, year = {2024}, author = {Patty, BJ and Jordan, C and Lardo, SM and Troy, K and Hainer, SJ}, title = {H3.3K122A results in a neomorphic phenotype in mouse embryonic stem cells.}, journal = {Epigenetics &amp; chromatin}, volume = {17}, number = {1}, pages = {32}, pmid = {39487536}, issn = {1756-8935}, support = {R35 GM133732/GM/NIGMS NIH HHS/United States ; S10 OD028483/OD/NIH HHS/United States ; R35GM133732/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Histones/metabolism ; Mice ; *Mouse Embryonic Stem Cells/metabolism/cytology ; *Phenotype ; Cell Differentiation ; Protein Processing, Post-Translational ; Acetylation ; }, abstract = {Canonical histone H3 and histone variant H3.3 are posttranslationally modified with the genomic distribution of these marks denoting different features and these modifications may influence transcription. While the majority of posttranslational modifications occur on histone tails, there are defined modifications within the globular domain, such as acetylation of H3K122/H3.3K122. To understand the function of the amino acid H3.3K122 in transcriptional regulation, we attempted to generate H3.3K122A mouse embryonic stem (mES) cells but were unsuccessful. Through multi-omic profiling of mutant cell lines harboring two or three of four H3.3 targeted alleles, we have uncovered that H3.3K122A is neomorphic and results in lethality. This is surprising as prior studies demonstrate H3.3-null mES cells are viable and pluripotent but exhibit a reduced differentiation capacity. Together, these studies have uncovered a novel dependence of a globular domain residue within H3.3 for viability and broadened our understanding of how histone variants contribute to transcription regulation and pluripotency in mES cells.}, }
@article {pmid39484623, year = {2024}, author = {Jagota, M and Hsu, C and Mazumder, T and Sung, K and DeWitt, WS and Listgarten, J and Matsen, FA and Ye, CJ and Song, YS}, title = {Learning antibody sequence constraints from allelic inclusion.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39484623}, issn = {2692-8205}, support = {R35 GM134922/GM/NIGMS NIH HHS/United States ; }, abstract = {Antibodies and B-cell receptors (BCRs) are produced by B cells, and are built of a heavy chain and a light chain. Although each B cell could express two different heavy chains and four different light chains, usually only a unique pair of heavy chain and light chain is expressed-a phenomenon known as allelic exclusion. However, a small fraction of naive-B cells violate allelic exclusion by expressing two productive light chains, one of which has impaired function; this has been called allelic inclusion. We demonstrate that these B cells can be used to learn constraints on antibody sequence. Using large-scale single-cell sequencing data from humans, we find examples of light chain allelic inclusion in thousands of naive-B cells, which is an order of magnitude larger than existing datasets. We train machine learning models to identify the abnormal sequences in these cells. The resulting models correlate with antibody properties that they were not trained on, including polyreactivity, surface expression, and mutation usage in affinity maturation. These correlations are larger than what is achieved by existing antibody modeling approaches, indicating that allelic inclusion data contains useful new information. We also investigate the impact of similar selection forces on the heavy chain in mouse, and observe that pairing with the surrogate light chain significantly restricts heavy chain diversity.}, }
@article {pmid39484476, year = {2024}, author = {Arora, S and Nuechterlein, N and Jensen, M and Glatzer, G and Sievers, P and Varadharajan, S and Korshunov, A and Sahm, F and Mack, SC and Taylor, MD and Holland, EC}, title = {Transcriptomic landscape identifies two unrecognized ependymoma subtypes and novel pathways in medulloblastoma.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39484476}, issn = {2692-8205}, support = {R35 CA253119/CA/NCI NIH HHS/United States ; }, abstract = {Medulloblastoma and ependymoma are prevalent pediatric central nervous system tumors with significant molecular and clinical heterogeneity. We collected bulk RNA sequencing data from 888 medulloblastoma and 370 ependymoma tumors to establish a comprehensive reference landscape. Following rigorous batch effect correction, normalization, and dimensionality reduction, we constructed a unified landscape to explore gene expression, signaling pathways, gene fusions, and copy number variations. Our analysis revealed distinct clustering patterns, including two primary ependymoma compartments, EPN-E1 and EPN-E2, each with specific gene fusions and molecular signatures. In medulloblastoma, we achieved precise stratification of Group 3/4 tumors by subtype and in SHH tumors by patient age. Our landscape serves as a vital resource for identifying biomarkers, refining diagnoses, and enables the mapping of new patients' bulk RNA-seq data onto the reference framework to facilitate accurate disease subtype identification. The landscape is accessible via Oncoscape, an interactive platform, empowering global exploration and application.}, }
@article {pmid39484446, year = {2024}, author = {,  and Dekker, J and Oksuz, BA and Zhang, Y and Wang, Y and Minsk, MK and Kuang, S and Yang, L and Gibcus, JH and Krietenstein, N and Rando, OJ and Xu, J and Janssens, DH and Henikoff, S and Kukalev, A and Willemin, A and Winick-Ng, W and Kempfer, R and Pombo, A and Yu, M and Kumar, P and Zhang, L and Belmont, AS and Sasaki, T and van Schaik, T and Brueckner, L and Peric-Hupkes, D and van Steensel, B and Wang, P and Chai, H and Kim, M and Ruan, Y and Zhang, R and Quinodoz, SA and Bhat, P and Guttman, M and Zhao, W and Chien, S and Liu, Y and Venev, SV and Plewczynski, D and Azcarate, II and Szabó, D and Thieme, CJ and Szczepińska, T and Chiliński, M and Sengupta, K and Conte, M and Esposito, A and Abraham, A and Zhang, R and Wang, Y and Wen, X and Wu, Q and Yang, Y and Liu, J and Boninsegna, L and Yildirim, A and Zhan, Y and Chiariello, AM and Bianco, S and Lee, L and Hu, M and Li, Y and Barnett, RJ and Cook, AL and Emerson, DJ and Marchal, C and Zhao, P and Park, P and Alver, BH and Schroeder, A and Navelkar, R and Bakker, C and Ronchetti, W and Ehmsen, S and Veit, A and Gehlenborg, N and Wang, T and Li, D and Wang, X and Nicodemi, M and Ren, B and Zhong, S and Phillips-Cremins, JE and Gilbert, DM and Pollard, KS and Alber, F and Ma, J and Noble, WS and Yue, F}, title = {An integrated view of the structure and function of the human 4D nucleome.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39484446}, issn = {2692-8205}, support = {U54 DK107981/DK/NIDDK NIH HHS/United States ; U54 DK107977/DK/NIDDK NIH HHS/United States ; U54 DK107967/DK/NIDDK NIH HHS/United States ; U01 DA052715/DA/NIDA NIH HHS/United States ; U01 CA200060/CA/NCI NIH HHS/United States ; U54 DK107979/DK/NIDDK NIH HHS/United States ; U01 DK127405/DK/NIDDK NIH HHS/United States ; U01 HL129998/HL/NHLBI NIH HHS/United States ; U01 CA200147/CA/NCI NIH HHS/United States ; UM1 HG011593/HG/NHGRI NIH HHS/United States ; U01 HL130007/HL/NHLBI NIH HHS/United States ; UM1 HG011536/HG/NHGRI NIH HHS/United States ; U54 DK107980/DK/NIDDK NIH HHS/United States ; U01 DA052769/DA/NIDA NIH HHS/United States ; U01 DA040612/DA/NIDA NIH HHS/United States ; U01 DK127420/DK/NIDDK NIH HHS/United States ; U54 DK107965/DK/NIDDK NIH HHS/United States ; UM1 HG011585/HG/NHGRI NIH HHS/United States ; U01 CA200059/CA/NCI NIH HHS/United States ; U01 HL157989/HL/NHLBI NIH HHS/United States ; }, abstract = {The dynamic three-dimensional (3D) organization of the human genome (the "4D Nucleome") is closely linked to genome function. Here, we integrate a wide variety of genomic data generated by the 4D Nucleome Project to provide a detailed view of human 3D genome organization in widely used embryonic stem cells (H1-hESCs) and immortalized fibroblasts (HFFc6). We provide extensive benchmarking of 3D genome mapping assays and integrate these diverse datasets to annotate spatial genomic features across scales. The data reveal a rich complexity of chromatin domains and their sub-nuclear positions, and over one hundred thousand structural loops and promoter-enhancer interactions. We developed 3D models of population-based and individual cell-to-cell variation in genome structure, establishing connections between chromosome folding, nuclear organization, chromatin looping, gene transcription, and DNA replication. We demonstrate the use of computational methods to predict genome folding from DNA sequence, uncovering potential effects of genetic variants on genome structure and function. Together, this comprehensive analysis contributes insights into human genome organization and enhances our understanding of connections between the regulation of genome function and 3D genome organization in general.}, }
@article {pmid39484284, year = {2024}, author = {Violari, A and Otwombe, K and Hahn, W and Chen, S and Josipovic, D and Baba, V and Angelidou, A and Smolen, KK and Levy, O and Mkhize, NN and Woodward, AS and Martin, TM and Haynes, B and Williams, WB and Sagawa, ZK and Kublin, J and Polakowski, L and Isaacs, MB and Yen, C and Tomaras, G and Corey, L and Janes, H and Gray, G}, title = {Safety and implementation of a phase 1 randomized GLA-SE-adjuvanted CH505TF gp120 HIV vaccine trial in newborns.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39484284}, support = {K08 AI168487/AI/NIAID NIH HHS/United States ; U19 AI168643/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; HHSN272201800047C/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: The neonatal immune system is uniquely poised to generate broadly neutralizing antibodies (bnAbs) and thus infants are ideal for evaluating HIV vaccine candidates. We present the design and safety of a novel glucopyranosyl lipid A (GLA)-stable emulsion (SE) adjuvant admixed with a first-in-infant CH505 transmitter-founder (CH505TF) gp120 immunogen designed to induce precursors for bnAbs against HIV.<br><br>METHODS: HVTN 135 is a phase I randomized, placebo-controlled trial of CH505TF+GLA-SE or placebo. Healthy infants in South Africa aged &#x2264;5 days, born to mothers living with HIV but HIV nucleic acid negative at birth were randomized to five doses of CH505TF + GLA-SE or placebo at birth and 8, 16, 32, and 54 weeks.<br><br>RESULTS: 38 infants (median age = 4 days; interquartile range 4, 4.75 days) were enrolled November 2020 to January 2022. Among 28 (10) infants assigned to receive CH505TF + GLA-SE (placebo), most (32/38) completed the 5-dose immunization series and follow-up (35/38). Solicited local and systemic reactions were more frequent in vaccine (8, 28.6% local; 16, 57.1% systemic) vs. placebo recipients (1, 10% local, p = 0.25; 4, 40.0% systemic, p = 0.38). All events were Grade 1 except two Grade 2 events (pain, lethargy). Serious vaccine-related adverse events were not recorded.<br><br>CONCLUSIONS: This study illustrates the feasibility of conducting trials of novel adjuvanted HIV vaccines in HIV-exposed infants receiving standard infant vaccinations. The safety profile of the CH505TF + GLA-SE vaccine was reassuring.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT04607408.<br><br>FUNDING: National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH).}, }
@article {pmid39486411, year = {2024}, author = {Davar, D and Morrison, RM and Dzutsev, AK and Karunamurthy, A and Chauvin, JM and Amatore, F and Deutsch, JS and Das Neves, RX and Rodrigues, RR and McCulloch, JA and Wang, H and Hartman, DJ and Badger, JH and Fernandes, MR and Bai, Y and Sun, J and Cole, AM and Aggarwal, P and Fang, JR and Deitrick, C and Bao, R and Duvvuri, U and Sridharan, SS and Kim, SW and A Choudry, H and Holtzman, MP and Pingpank, JF and O'Toole, JP and DeBlasio, R and Jin, Y and Ding, Q and Gao, W and Groetsch, C and Pagliano, O and Rose, A and Urban, C and Singh, J and Divarkar, P and Mauro, D and Bobilev, D and Wooldridge, J and Krieg, AM and Fury, MG and Whiteaker, JR and Zhao, L and Paulovich, AG and Najjar, YG and Luke, JJ and Kirkwood, JM and Taube, JM and Park, HJ and Trinchieri, G and Zarour, HM}, title = {Neoadjuvant vidutolimod and nivolumab in high-risk resectable melanoma: A prospective phase II trial.}, journal = {Cancer cell}, volume = {42}, number = {11}, pages = {1898-1918.e12}, pmid = {39486411}, issn = {1878-3686}, support = {P50 CA254865/CA/NCI NIH HHS/United States ; R01 CA257265/CA/NCI NIH HHS/United States ; R01 CA222203/CA/NCI NIH HHS/United States ; U01 CA268806/CA/NCI NIH HHS/United States ; U01 CA271407/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Melanoma/drug therapy/immunology/genetics ; *Nivolumab/administration &amp; dosage/therapeutic use ; Male ; Female ; Middle Aged ; *Neoadjuvant Therapy/methods ; Prospective Studies ; Aged ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use/pharmacology ; Adult ; Lymphocytes, Tumor-Infiltrating/immunology/drug effects ; Tumor Microenvironment/immunology/drug effects ; Gastrointestinal Microbiome/drug effects ; Immune Checkpoint Inhibitors/therapeutic use/pharmacology/administration &amp; dosage ; }, abstract = {Intratumoral TLR9 agonists and anti-PD-1 produce clinical responses and broad immune activation. We conducted a single-arm study of neoadjuvant TLR9 agonist vidutolimod combined with anti-PD-1 nivolumab in high-risk resectable melanoma. In 31 evaluable patients, 55% major pathologic response (MPR) was observed, meeting primary endpoint. MPR was associated with necrosis, and melanophagocytosis with increased CD8[+] tumor-infiltrating lymphocytes and plasmacytoid dendritic cells (pDCs) in the tumor microenvironment, and increased frequencies of Ki67[+]CD8[+] T cells peripherally. MPRs had an enriched pre-treatment gene signature of myeloid cells, and response to therapy was associated with gene signatures of immune cells, pDCs, phagocytosis, and macrophage activation. MPRs gut microbiota were enriched for Gram-negative bacteria belonging to the Bacteroidaceae and Enterobacteriaceae families and the small subgroup of Gram-negative Firmicutes. Our findings support that combined vidutolimod and nivolumab stimulates a broad anti-tumor immune response and is associated with distinct baseline myeloid gene signature and gut microbiota. ClinicalTrials.gov identifier: NCT03618641.}, }
@article {pmid39486408, year = {2024}, author = {Borda, V and Loesch, DP and Guo, B and Laboulaye, R and Veliz-Otani, D and French, JN and Leal, TP and Gogarten, SM and Ikpe, S and Gouveia, MH and Mendes, M and Abecasis, GR and Alvim, I and Arboleda-Bustos, CE and Arboleda, G and Arboleda, H and Barreto, ML and Barwick, L and Bezzera, MA and Blangero, J and Borges, V and Caceres, O and Cai, J and Chana-Cuevas, P and Chen, Z and Custer, B and Dean, M and Dinardo, C and Domingos, I and Duggirala, R and Dieguez, E and Fernandez, W and Ferraz, HB and Gilliland, F and Guio, H and Horta, B and Curran, JE and Johnsen, JM and Kaplan, RC and Kelly, S and Kenny, EE and Konkle, BA and Kooperberg, C and Lescano, A and Lima-Costa, MF and Loos, RJF and Manichaikul, A and Meyers, DA and Naslavsky, MS and Nickerson, DA and North, KE and Padilla, C and Preuss, M and Raggio, V and Reiner, AP and Rich, SS and Rieder, CR and Rienstra, M and Rotter, JI and Rundek, T and Sacco, RL and Sanchez, C and Sankaran, VG and Santos-Lobato, BL and Schumacher-Schuh, AF and Scliar, MO and Silverman, EK and Sofer, T and Lasky-Su, J and Tumas, V and Weiss, ST and ,  and ,  and ,  and Mata, IF and Hernandez, RD and Tarazona-Santos, E and O'Connor, TD}, title = {Genetics of Latin American Diversity Project: Insights into population genetics and association studies in admixed groups in the Americas.}, journal = {Cell genomics}, volume = {4}, number = {11}, pages = {100692}, pmid = {39486408}, issn = {2666-979X}, mesh = {Humans ; Latin America ; *Genetics, Population ; Genome-Wide Association Study ; Haplotypes ; Algorithms ; Genetic Variation/genetics ; Software ; }, abstract = {Latin Americans are underrepresented in genetic studies, increasing disparities in personalized genomic medicine. Despite available genetic data from thousands of Latin Americans, accessing and navigating the bureaucratic hurdles for consent or access remains challenging. To address this, we introduce the Genetics of Latin American Diversity (GLAD) Project, compiling genome-wide information from 53,738 Latin Americans across 39 studies representing 46 geographical regions. Through GLAD, we identified heterogeneous ancestry composition and recent gene flow across the Americas. Additionally, we developed GLAD-match, a simulated annealing-based algorithm, to match the genetic background of external samples to our database, sharing summary statistics (i.e., allele and haplotype frequencies) without transferring individual-level genotypes. Finally, we demonstrate the potential of GLAD as a critical resource for evaluating statistical genetic software in the presence of admixture. By providing this resource, we promote genomic research in Latin Americans and contribute to the promises of personalized medicine to more people.}, }
@article {pmid39486012, year = {2024}, author = {Dubois, MM and Jao, J and Sun, S and Legbedze, J and Schenkel, S and Mmasa, N and Kgole, SW and Masasa, G and Happel, AU and Iwase, SC and Haghighat, R and Moyo, S and Sharma, TS and Edlefsen, PT and Shao, D and Jaspan, H and Powis, KM}, title = {Infectious Morbidity and All-cause Mortality of Infants HIV-exposed Uninfected Compared to Infants HIV-unexposed Uninfected in Botswana.}, journal = {The Pediatric infectious disease journal}, volume = {}, number = {}, pages = {}, doi = {10.1097/INF.0000000000004603}, pmid = {39486012}, issn = {1532-0987}, abstract = {Some studies have reported increased infectious morbidity and all-cause mortality risk among infants HIV-exposed uninfected compared with infants HIV-unexposed uninfected. In a retrospective analysis of infants enrolled in the Botswana-based Tshilo Dikotla study, we found no difference in the prevalence of infectious hospitalizations or deaths from any cause in the first year of life by perinatal HIV exposure.}, }
@article {pmid39485483, year = {2024}, author = {Roberti, S and van Leeuwen, FE and Diallo, I and de Vathaire, F and Schaapveld, M and Leisenring, WM and Howell, RM and Armstrong, GT and Moskowitz, CS and Smith, SA and Aleman, BMP and Krul, IM and Russell, NS and Pfeiffer, RM and Hauptmann, M}, title = {Prediction of breast cancer risk for adolescents and young adults with Hodgkin lymphoma.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djae274}, pmid = {39485483}, issn = {1460-2105}, support = {P30 CA021765/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: While female survivors of Hodgkin lymphoma (HL) have an increased risk of breast cancer (BC), no BC risk prediction model is available. We developed such models incorporating mean radiation dose to the breast or breast quadrant-specific radiation doses.<br><br>METHODS: Relative risks and age-specific incidence for BC and competing events (mortality or other subsequent cancer) were estimated from 1194 Dutch five-year HL survivors, treated at ages 11-40 during 1965-2000. Predictors were doses to ten breast segments or mean breast radiation dose, BC family history, year of and age at HL diagnosis, ages at menopause and first live birth. Models were independently validated using U.S. Childhood Cancer Survivor Study cohort participants.<br><br>RESULTS: Predicted absolute BC risks 25 years after HL diagnosis ranged from 1.0% for survivors diagnosed at ages 20-24, with <10&#x2009;Gy mean breast radiation dose and menopausal 5 years after HL diagnosis, to 22.0% for survivors 25-29 years at diagnosis, &#x2265;25&#x2009;Gy mean breast dose, and no menopause within 5 years. In external validation, the observed/expected BC case ratio was 1.19 (95% confidence interval 0.97 to 1.47) for the breast segment-specific doses model, and 1.29 (1.05 to 1.60) for the mean breast dose model. The areas under the receiver operating characteristic curve were 0.68 (0.63 to 0.74) and 0.68 (0.62 to 0.73), respectively.<br><br>CONCLUSION: Breast segment-specific or mean breast radiation dose with personal and clinical characteristics predicted absolute BC risk in HL survivors with moderate discrimination but good calibration, rendering the models useful for clinical decision-making.}, }
@article {pmid39485274, year = {2025}, author = {Larson, JD and Heitkamp, NA and Murray, LE and Popchock, AR and Biggins, S and Asbury, CL}, title = {Kinetochores grip microtubules with directionally asymmetric strength.}, journal = {The Journal of cell biology}, volume = {224}, number = {1}, pages = {}, pmid = {39485274}, issn = {1540-8140}, support = {F32 GM136010/GM/NIGMS NIH HHS/United States ; T32HL007312/NH/NIH HHS/United States ; T32 HL007312/HL/NHLBI NIH HHS/United States ; R01 GM079373/GM/NIGMS NIH HHS/United States ; //University of Washington/ ; /HHMI/Howard Hughes Medical Institute/United States ; R01 GM064386/GM/NIGMS NIH HHS/United States ; //Washington Research Foundation/ ; R35 GM134842/GM/NIGMS NIH HHS/United States ; }, mesh = {*Kinetochores/metabolism ; *Microtubules/metabolism ; Humans ; *Mitosis ; Saccharomyces cerevisiae/metabolism/genetics ; Saccharomyces cerevisiae Proteins/metabolism/genetics ; Microtubule-Associated Proteins/metabolism/genetics ; Chromosome Segregation ; HeLa Cells ; }, abstract = {For accurate mitosis, all chromosomes must achieve "biorientation," with replicated sister chromatids coupled via kinetochores to the plus ends of opposing microtubules. However, kinetochores first bind the sides of microtubules and subsequently find plus ends through a trial-and-error process; accurate biorientation depends on the selective release of erroneous attachments. Proposed mechanisms for error-correction have focused mainly on plus-end attachments. Whether erroneous side attachments are distinguished from correct side attachments is unknown. Here, we show that side-attached kinetochores are very sensitive to microtubule polarity, gripping sixfold more strongly when pulled toward plus versus minus ends. This directionally asymmetric grip is conserved in human and yeast subcomplexes, and it correlates with changes in the axial arrangement of subcomplexes within the kinetochore, suggesting that internal architecture dictates attachment strength. We propose that the kinetochore's directional grip promotes accuracy during early mitosis by stabilizing correct attachments even before both sisters have found plus ends.}, }
@article {pmid39485107, year = {2024}, author = {Loroña, NC and Othus, M and Malone, KE and Linden, HM and Tang, MC and Li, CI}, title = {Metabolic syndrome and risks of breast cancer outcomes for luminal, triple-negative, and HER2-overexpressing subtypes.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-24-1167}, pmid = {39485107}, issn = {1538-7755}, support = {T32 CA009168/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: We evaluated the association between metabolic syndrome (obesity plus two metabolic risk factors) and breast cancer outcomes according to molecular subtype.<br><br>METHODS: This population-based prospective cohort consisted of 3,267 women aged 20-69 diagnosed with a first primary invasive breast cancer from 2004-2015 in the Seattle-Puget Sound region. Breast cancer was categorized into three subtypes based on estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression: luminal (ER+), triple-negative (ER-/PR-/HER2-), and HER2-overexpressing (H2E) (ER-/HER2+). We used time-varying Cox models to assess the association between prevalent and incident metabolic syndrome and risks of recurrence, breast cancer-specific mortality, and all-cause mortality.<br><br>RESULTS: Metabolic syndrome was associated with a greater risk of recurrence (HR:3.24; 95% CI:1.13-9.33) and breast cancer-specific mortality (HR:5.34; 95% CI:2.32-12.31) only for the H2E subtype, and greater risks of all-cause mortality for luminal (HR:1.92; 95% CI:1.37-2.68), H2E (HR:5.09; 95% CI:2.51-10.32), and all cases combined (HR:1.90; 95% CI:1.42,2.53). We also observed heterogeneity in recurrence and mortality outcomes across specific components of metabolic syndrome and molecular subtypes.<br><br>CONCLUSIONS: Metabolic syndrome is associated with all-cause mortality among women with breast cancer and with breast cancer-specific mortality among women with the H2E subtype.<br><br>IMPACT: These results highlight the importance of managing comorbidities to decrease the risk for adverse outcomes among breast cancer survivors.}, }
@article {pmid39479331, year = {2024}, author = {Armenian, SH and Hudson, MM and Lindenfeld, L and Chen, S and Chow, EJ and Colan, S and Echevarria, M and Wong, FL and Chen, MH and Bhatia, S}, title = {Carvedilol to Improve Cardiac Remodeling in Anthracycline-Exposed Childhood Cancer Survivors: Subgroup Analysis of COG ALTE1621.}, journal = {JACC. CardioOncology}, volume = {6}, number = {5}, pages = {791-793}, pmid = {39479331}, issn = {2666-0873}, support = {R01 CA196854/CA/NCI NIH HHS/United States ; UG1 CA189955/CA/NCI NIH HHS/United States ; U10 CA098543/CA/NCI NIH HHS/United States ; K12 CA001727/CA/NCI NIH HHS/United States ; U10 CA180886/CA/NCI NIH HHS/United States ; }, }
@article {pmid39478506, year = {2024}, author = {Lynch, MM and Al-Marayaty, R and Obeidin, F and Alexiev, BA and Chen, EY and Viveiros, P and Schroeder, BA and Hudkins, K and Fan, TM and Redman, MW and Baker, KK and Jour, G and Cranmer, LD and Pollack, SM}, title = {B7-H3 is widely expressed in soft tissue sarcomas.}, journal = {BMC cancer}, volume = {24}, number = {1}, pages = {1336}, pmid = {39478506}, issn = {1471-2407}, support = {R01CA244872/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *B7 Antigens/metabolism ; *Sarcoma/metabolism/pathology ; Female ; Male ; Middle Aged ; Retrospective Studies ; Adult ; Aged ; Biomarkers, Tumor/metabolism ; Immunohistochemistry ; Aged, 80 and over ; Young Adult ; Adolescent ; }, abstract = {PURPOSE: Targeted therapy development in soft tissue sarcoma (STS) has been burdened by the heterogeneity of this group of rare tumors. B7 homolog 3 protein (B7-H3) is a molecule in the same family as programmed death-ligand 1 (PD-L1). It has limited expression in noncancerous tissues and is overexpressed in many cancers, making it an attractive target for cancer therapy, and clinical trials targeting B7-H3 are actively underway. While available data demonstrate high expression levels of B7-H3 in individual sarcoma subtypes, its expression patterns across STS subtypes are not well described. The purpose of this study was to characterize the expression patterns of B7-H3 in STS.<br><br>PATIENTS AND METHODS: This retrospective analysis evaluated STS tumor specimens from patients with a variety of different subtypes. Specimens were evaluated by immunohistochemistry (IHC) for expression and staining pattern of B7-H3 both in tumors and in associated vasculature.<br><br>RESULTS: Specimens from 153 sarcoma patients included 15 different STS subtypes. B7-H3 was broadly expressed in 97% of samples (95% CI 0.93-0.99) and 69.2% demonstrated high levels of B7-H3 expression (95% CI 0.61-0.76). No significant association between B7-H3 positivity or expression level and prior treatment(s), tumor size, tumor grade, or patient age. B7-H3 positivity in vessels was found in 94.7% (145/153) of samples. In tumors that had been previously assessed for PD-L1 and PD-1, there was no correlation between B7-H3 positivity or expression and the positivity or expression level of PD-L1 or PD-1.<br><br>CONCLUSION: These data show high levels of B7-H3 positivity across soft tissue sarcoma subtypes, suggesting its feasibility as a therapeutic target for future sarcoma treatments. Future clinical trials are needed to evaluate whether targeting B7-H3 can provide clinical benefit to help patients with sarcoma.}, }
@article {pmid39478321, year = {2024}, author = {Dombrowski, JC and Donnell, D and Grabow, C and Cohen, SE and Cannon, CA and Brown, CE and Buchbinder, SP and Celum, C and Luetkemeyer, AF}, title = {Evidence-Informed Provision of Doxycycline Post-Exposure Prophylaxis for Prevention of Bacterial Sexually Transmitted Infections.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciae527}, pmid = {39478321}, issn = {1537-6591}, abstract = {Doxycycline post-exposure prophylaxis (doxy-PEP) reduces the risk of bacterial sexually transmitted infections (STIs) among men who have sex with men and transgender women. In the United States, doxy-PEP is in an early stage of integration into clinical practice, and national guidelines for its use were recently released. The goal of this manuscript is to provide practical guidance for clinicians who are considering or currently prescribing doxy-PEP. We address five clinical questions using post hoc analyses of data from the DoxyPEP randomized controlled trial and discuss the potential implications and limitations of each question with the goal of informing clinical practice and implementation of doxy-PEP programs. The questions address patient eligibility criteria for doxy-PEP, the expected benefit and associated doxy-PEP doses for the average patient, the initial number of doses prescribed, and laboratory monitoring of persons taking doxy-PEP.}, }
@article {pmid39477498, year = {2024}, author = {Huang, RR and Zuo, C and Mona, CE and Holzgreve, A and Morrissey, C and Nelson, PS and Brady, L and True, L and Sisk, A and Czernin, J and Calais, J and Ye, H}, title = {FAP and PSMA Expression by Immunohistochemistry and PET Imaging in Castration-Resistant Prostate Cancer: A Translational Pilot Study.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {65}, number = {12}, pages = {1952-1958}, pmid = {39477498}, issn = {1535-5667}, mesh = {Humans ; Male ; *Prostatic Neoplasms, Castration-Resistant/diagnostic imaging/metabolism/pathology ; Pilot Projects ; *Serine Endopeptidases/metabolism ; *Antigens, Surface/metabolism ; *Glutamate Carboxypeptidase II/metabolism ; *Immunohistochemistry ; Aged ; *Endopeptidases ; Positron-Emission Tomography ; Middle Aged ; Membrane Proteins/metabolism ; Gelatinases/metabolism ; Gene Expression Regulation, Neoplastic ; Translational Research, Biomedical ; Aged, 80 and over ; }, abstract = {Prostate-specific membrane antigen (PSMA) is a theranostic target for metastatic prostate cancer (PCa). However, castration-resistant PCa (CRPC) may lose PSMA expression after systemic therapy. Fibroblast activation protein (FAP), expressed by carcinoma-associated fibroblasts in various cancer types, including PCa, has the potential to be an alternative target. In this study, we evaluated FAP expression in CRPC to assess its potential, using PSMA as a comparison. Methods: FAP expression was assessed using immunohistochemistry in 116 CRPC tumors: 78 adenocarcinomas, 11 small cell carcinomas, and 27 anaplastic carcinomas. Correlation analysis between manual scoring and automated scoring was performed on 54 whole-slide sections of metastatic CRPC. Paired FAP and PSMA stains were assessed in tissue microarray cores of CRPC (n = 62), consisting of locally advanced CRPC (n = 9) and metastatic CRPC (n = 53). FAP and PSMA positivity was defined by an immunohistochemistry score of at least 10. To explore the correlation of PSMA and FAP inhibitor (FAPi) PET imaging and immunohistochemistry, a preliminary analysis of 4 patients included in a [[68]Ga]-FAPi-46 imaging trial (NCT04457232) was conducted. Results: Manual and automated scoring of FAP yielded results with strong correlations. Overall, FAP expression in CRPC was notably lower than PSMA expression (median immunoscores, 14 vs. 72; P < 0.001). Different histologic subtypes of CRPC demonstrated distinct levels of PSMA expression, whereas their FAP expression levels were comparable. Among the 19 PSMA-negative tumors, 11 (58%) exhibited FAP positivity. FAP expression levels in lymph node metastases were significantly lower than those in nonnodal metastases (P = 0.021). Liver metastases showed significant enrichment of tumors with strong FAP expression compared with nonliver lesions (P = 0.016). In the 4 clinical trial patients, the biopsied metastatic lesions showed lower uptake on FAPi PET than on PSMA PET (median SUVmax, 9.6 vs. 14.5), consistent with FAP expression that was lower than PSMA expression in the corresponding tumor biopsy samples (median immunoscores, 30 vs. 160). Conclusion: Because of the low FAP expression levels in CRPC, the utility of FAPi PET imaging may be limited. Although FAPi PET imaging may be further tested in PSMA-negative CRPC, such as small cell carcinoma, other molecular imaging modalities should be evaluated as alternative choices.}, }
@article {pmid39475359, year = {2024}, author = {Fléchon, A and Morales-Barrera, R and Powles, T and Alva, A and Özgüroğlu, M and Csöszi, T and Loriot, Y and Rodriguez-Vida, A and Géczi, L and Cheng, SY and Fradet, Y and Oudard, S and Vulsteke, C and Gunduz, S and Mamtani, R and Yu, EY and Montesa Pino, A and Anido, U and Sendur, MAN and Gravis, G and Révész, J and Kostorov, V and Huillard, O and Ma, J and Rajasagi, M and Vajdi, A and Lunceford, J and Cristescu, R and Imai, K and Homet Moreno, B and Matsubara, N}, title = {Association of Tumor Mutational Burden and PD-L1 with the Efficacy of Pembrolizumab with or without Chemotherapy versus Chemotherapy in Advanced Urothelial Carcinoma.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {30}, number = {23}, pages = {5353-5364}, pmid = {39475359}, issn = {1557-3265}, mesh = {Humans ; *Antibodies, Monoclonal, Humanized/administration &amp; dosage/therapeutic use ; *B7-H1 Antigen/genetics ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; *Mutation ; Female ; Male ; Aged ; Middle Aged ; Exome Sequencing ; Biomarkers, Tumor/genetics ; Carcinoma, Transitional Cell/drug therapy/genetics/pathology/mortality ; Urologic Neoplasms/drug therapy/genetics/pathology/mortality ; Urinary Bladder Neoplasms/drug therapy/genetics/pathology/mortality ; Antineoplastic Agents, Immunological/therapeutic use ; Aged, 80 and over ; }, abstract = {PURPOSE: The three-arm, phase III KEYNOTE-361 study did not meet its dual primary endpoints of progression-free survival (PFS) or overall survival (OS) with first-line pembrolizumab plus chemotherapy versus chemotherapy in advanced urothelial carcinoma. This prespecified exploratory analysis assessed the association of tumor mutational burden (TMB) and PD-L1 combined positive score (CPS) with clinical outcomes.<br><br>PATIENTS AND METHODS: TMB and PD-L1 CPS were determined via whole-exome sequencing and PD-L1 IHC 22C3 pharmDx, respectively. The association was evaluated in each treatment arm using logistic regression [objective response rate (ORR)] and Cox proportional hazards regression models (PFS and OS); one-sided (pembrolizumab monotherapy; pembrolizumab plus chemotherapy) and two-sided (chemotherapy) nominal P values were calculated. Significance was prespecified at &#x3b1; = 0.05 without multiplicity adjustment. Efficacy was evaluated by prespecified cutoffs of 175 mutations/exome (TMB) and CPS 10 (PD-L1).<br><br>RESULTS: Of the 993 treated patients, 820 (82.6%) and 993 (100%) had evaluable TMB and CPS data, respectively. Continuous TMB was positively associated with ORR, PFS, and OS for pembrolizumab monotherapy (one-sided P < 0.001, P < 0.001, and P = 0.007, respectively); PFS and OS for pembrolizumab plus chemotherapy (one-sided P = 0.007 and P = 0.010, respectively); and OS for chemotherapy alone (two-sided P = 0.040). Continuous PD-L1 CPS showed evidence of anticipated association with ORR and PFS for pembrolizumab monotherapy. The subgroup with TMB &#x2265;175 mutations/exome and PD-L1 CPS &#x2265;10 had the highest PFS and OS improvements with pembrolizumab alone or with chemotherapy versus chemotherapy alone.<br><br>CONCLUSIONS: These data suggest that TMB may be predictive of the response to pembrolizumab alone or with chemotherapy in advanced urothelial carcinoma.}, }
@article {pmid39475323, year = {2024}, author = {Kessler, RC and Bossarte, RM and Hwang, I and Luedtke, A and Naifeh, JA and Nock, MK and Petukhova, M and Sadikova, E and Sampson, NA and Sverdrup, E and Zubizarreta, JR and Wager, S and Wagner, J and Stein, MB and Ursano, RJ}, title = {A prediction model for differential resilience to the effects of combat-related stressors in US army soldiers.}, journal = {International journal of methods in psychiatric research}, volume = {33}, number = {4}, pages = {e70006}, pmid = {39475323}, issn = {1557-0657}, support = {U01MH087981/MH/NIMH NIH HHS/United States ; HU0001-15-2-0004//U.S. Department of Defense/ ; U01MH087981//U.S. Army/ ; }, mesh = {Humans ; *Military Personnel/psychology ; *Resilience, Psychological ; Adult ; Male ; Female ; *Stress Disorders, Post-Traumatic/diagnosis ; United States ; Young Adult ; *Combat Disorders/diagnosis ; Follow-Up Studies ; Afghan Campaign 2001- ; Retrospective Studies ; Adolescent ; Stress, Psychological ; }, abstract = {OBJECTIVES: To develop a composite score for differential resilience to effects of combat-related stressors (CRS) on persistent DSM-IV post-traumatic stress disorder (PTSD) among US Army combat arms soldiers using survey data collected before deployment.<br><br>METHODS: A sample of n&#xa0;=&#xa0;2542 US Army combat arms soldiers completed a survey shortly before deployment to Afghanistan and then again two to three and 8-9&#xa0;months after redeployment. Retrospective self-reports were obtained about CRS. Precision treatment methods were used to determine whether differential resilience to persistent PTSD in the follow-up surveys could be developed from pre-deployment survey data in a 60% training sample and validated in a 40% test sample.<br><br>RESULTS: 40.8% of respondents experienced high CRS and 5.4% developed persistent PTSD. Significant test sample heterogeneity was found in resilience (t&#xa0;=&#xa0;2.1, p&#xa0;=&#xa0;0.032), with average treatment effect (ATE) of high CRS in the 20% least resilient soldiers of 17.1% (SE&#xa0;=&#xa0;5.5%) compared to ATE&#xa0;=&#xa0;3.8% (SE&#xa0;=&#xa0;1.2%) in the remaining 80%. The most important predictors involved recent and lifetime pre-deployment distress disorders.<br><br>CONCLUSIONS: A reliable pre-deployment resilience score can be constructed to predict variation in the effects of high CRS on persistent PTSD among combat arms soldiers. Such a score could be used to target preventive interventions to reduce PTSD or other resilience-related outcomes.}, }
@article {pmid39474526, year = {2024}, author = {McCamy, W and Yousefiasl, M and Tretiakova, M and Jagtiani, M and Hall, E}, title = {Metastatic SMARCB1-Deficient Renal Medullary Carcinoma without Hemoglobinopathy with Durable and Dramatic Response to Pembrolizumab plus Lenvatinib: Case Report.}, journal = {Case reports in oncology}, volume = {17}, number = {1}, pages = {1025-1033}, pmid = {39474526}, issn = {1662-6575}, abstract = {INTRODUCTION: Renal medullary carcinoma (RMC) is a rare form of renal cell carcinoma (RCC) that is typically associated with a loss of function in SMARCB1 and diagnosis of sickle cell or other hemoglobinopathy. In rare cases, this disease can be seen in patients without hemoglobinopathy and is classified as "SMARCB1-deficient RMC without hemoglobinopathy" or referred to as "RCC unclassified with medullary phenotype" in some of the literature. Platinum-based cytotoxic chemotherapy is currently the recommended first-line treatment for this rare disease.<br><br>CASE PRESENTATION: Here we report a 53-year-old male who was diagnosed with metastatic SMARCB1-deficient RMC without hemoglobinopathy after presenting with left flank and abdominal pain. After initiating first-line pembrolizumab and lenvatinib systemic therapy, imaging showed regression at 6 weeks. To date, this patient continues to show a near complete response to this treatment regimen.<br><br>CONCLUSION: To our knowledge, this is the first documented case of SMARCB1-deficient RMC without hemoglobinopathy to receive this treatment regimen and show such a response.}, }
@article {pmid39473183, year = {2024}, author = {Rao, H and Weiss, MC and Moon, JY and Perreira, KM and Daviglus, ML and Kaplan, R and North, KE and Argos, M and Fernández-Rhodes, L and Sofer, T}, title = {Advancements in genetic research by the Hispanic Community Health Study/Study of Latinos: A 10-year retrospective review.}, journal = {HGG advances}, volume = {6}, number = {1}, pages = {100376}, doi = {10.1016/j.xhgg.2024.100376}, pmid = {39473183}, issn = {2666-2477}, support = {R01 HL163262/HL/NHLBI NIH HHS/United States ; }, abstract = {The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) is a multicenter, longitudinal cohort study designed to evaluate environmental, lifestyle, and genetic risk factors as they relate to cardiometabolic and other chronic diseases among Hispanic/Latino populations in the United States. Since the study's inception in 2008, as a result of the study's robust genetic measures, HCHS/SOL has facilitated major contributions to the field of genetic research. This 10-year retrospective review highlights the major findings for genotype-phenotype relationships and advancements in statistical methods owing to the HCHS/SOL. Furthermore, we discuss the ethical and societal challenges of genetic research, especially among Hispanic/Latino adults in the United States. Continued genetic research, ancillary study expansion, and consortia collaboration through HCHS/SOL will further drive knowledge and advancements in human genetics research.}, }
@article {pmid39472576, year = {2024}, author = {Janssens, DH and Duran, M and Otto, DJ and Wu, W and Xu, Y and Kirkey, D and Mullighan, CG and Yi, JS and Meshinchi, S and Sarthy, JF and Ahmad, K and Henikoff, S}, title = {MLL oncoprotein levels influence leukemia lineage identities.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {9341}, pmid = {39472576}, issn = {2041-1723}, support = {Henikoff//Howard Hughes Medical Institute (HHMI)/ ; R01 HG010492/HG/NHGRI NIH HHS/United States ; Derek Janssens//Hartwell Foundation (The Hartwell Foundation)/ ; NCI R35 CA297695//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; Mullighan//American Lebanese Syrian Associated Charities (ALSAC)/ ; }, mesh = {*Myeloid-Lymphoid Leukemia Protein/metabolism/genetics ; Humans ; *Leukemia, Myeloid, Acute/genetics/metabolism ; *Oncogene Proteins, Fusion/metabolism/genetics ; *Cell Lineage/genetics ; *Histone-Lysine N-Methyltransferase/metabolism/genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics/metabolism/pathology ; Gene Expression Regulation, Leukemic ; Proto-Oncogene Proteins/metabolism/genetics ; Mutation ; Translocation, Genetic ; Hematopoietic Stem Cells/metabolism ; Chromatin/metabolism ; }, abstract = {Chromosomal translocations involving the mixed-lineage leukemia (MLL) locus generate potent oncogenic fusion proteins (oncoproteins) that disrupt regulation of developmental gene expression. By profiling the oncoprotein-target sites of 36 broadly representative MLL-rearranged leukemia samples, including three samples that underwent a lymphoid-to-myeloid lineage-switching event in response to therapy, we find the genomic enrichment of the oncoprotein is highly variable between samples and subject to dynamic regulation. At high levels of expression, the oncoproteins preferentially activate either an acute lymphoblastic leukemia (ALL) program, enriched for pro-B-cell genes, or an acute myeloid leukemia (AML) program, enriched for hematopoietic-stem-cell genes. The fusion-partner-specific-binding patterns over these gene sets are highly correlated with the prevalence of each mutation in ALL versus AML. In lineage-switching samples the oncoprotein levels are reduced and the oncoproteins preferentially activate granulocyte-monocyte progenitor (GMP) genes. In a sample that lineage switched during treatment with the menin inhibitor revumenib, the oncoprotein and menin are reduced to undetectable levels, but ENL, a transcriptional cofactor of the oncoprotein, persists on numerous oncoprotein-target loci, including genes in the GMP-like lineage-switching program. We propose MLL oncoproteins promote lineage-switching events through dynamic chromatin binding at lineage-specific target genes, and may support resistance to menin inhibitors through similar changes in chromatin occupancy.}, }
@article {pmid39472320, year = {2024}, author = {Zhang, R and Bozic, I}, title = {Accumulation of Oncogenic Mutations During Progression from Healthy Tissue to Cancer.}, journal = {Bulletin of mathematical biology}, volume = {86}, number = {12}, pages = {142}, pmid = {39472320}, issn = {1522-9602}, support = {DMS-2045166//National Science Foundation/ ; }, mesh = {Humans ; *Colorectal Neoplasms/genetics/pathology ; *Disease Progression ; *Mutation ; *Mathematical Concepts ; *Oncogenes/genetics ; *Models, Genetic ; *Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics/pathology ; Neoplasms/genetics/pathology ; Carcinogenesis/genetics ; Mutation Accumulation ; Precancerous Conditions/genetics/pathology ; Computer Simulation ; }, abstract = {Cancers are typically fueled by sequential accumulation of driver mutations in a previously healthy cell. Some of these mutations, such as inactivation of the first copy of a tumor suppressor gene, can be neutral, and some, like those resulting in activation of oncogenes, may provide cells with a selective growth advantage. We study a multi-type branching process that starts with healthy tissue in homeostasis and models accumulation of neutral and advantageous mutations on the way to cancer. We provide results regarding the sizes of premalignant populations and the waiting times to the first cell with a particular combination of mutations, including the waiting time to malignancy. Finally, we apply our results to two specific biological settings: initiation of colorectal cancer and age incidence of chronic myeloid leukemia. Our model allows for any order of neutral and advantageous mutations and can be applied to other evolutionary settings.}, }
@article {pmid39472202, year = {2024}, author = {Oh, WK and Agarwal, N and Bryce, A and Barata, P and Bugler, C and Carlsson, SV and Cornell, B and Dahut, W and George, D and Loeb, S and Montgomery, B and Morris, D and Mucci, LA and Omlin, A and Palapattu, G and Riaz, IB and Ryan, C and Schoen, MW and Washington, SL and Gillessen, S}, title = {What's in a Name? Why Words Matter in Advanced Prostate Cancer.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2024.10.017}, pmid = {39472202}, issn = {1873-7560}, abstract = {Much of the disease nomenclature used for patients with advanced prostate cancer has negative connotations and can be confusing or intimidating. Experts in the field convened to recommend a clearer and more accurate approach to defining the nomenclature.}, }
@article {pmid39470729, year = {2024}, author = {Nelson, BH and Hamilton, PT and Phung, MT and Milne, K and Harris, B and Thornton, S and Stevens, DL and Kalaria, S and Singh, K and Laumont, CM and Moss, E and Alimujiang, A and Meagher, NS and Bolithon, A and Fereday, S and Kennedy, CJ and Hendley, J and Ariyaratne, D and Alsop, K and Traficante, N and Goode, EL and Karnezis, AN and Shen, H and Richardson, J and McKinnon Deurloo, C and Chase, A and Grout, B and Doherty, JA and Harris, HR and Cushing-Haugen, KL and Anglesio, MS and Heinze, K and Huntsman, D and Talhouk, A and Hanley, GE and Alsop, J and Jimenez-Linan, M and Pharoah, PD and Boros, J and Brand, AH and Harnett, PR and Sharma, R and Hecht, JL and Sasamoto, N and Terry, KL and Karlan, BY and Lester, J and Carney, ME and Goodman, MT and Hernandez, BY and Wilkens, LR and Behrens, S and Turzanski Fortner, R and Fasching, PA and Bisinotto, C and Candido Dos Reis, FJ and Ghatage, P and Köbel, M and Elishaev, E and Modugno, F and Cook, LS and Le, ND and Gentry-Maharaj, A and Menon, U and García, MJ and Rodriguez-Antona, C and Farrington, KM and Kelemen, LE and Kommoss, S and Staebler, A and Garsed, DW and Brenton, JD and Piskorz, AM and Bowtell, DD and DeFazio, A and Ramus, SJ and Pike, MC and Pearce, CL}, title = {Immunological and molecular features of the tumor microenvironment of long-term survivors of ovarian cancer.}, journal = {The Journal of clinical investigation}, volume = {}, number = {}, pages = {}, doi = {10.1172/JCI179501}, pmid = {39470729}, issn = {1558-8238}, abstract = {BACKGROUND: Despite an overall poor prognosis, about 15% of patients with advanced-stage tubo-ovarian high-grade serous carcinoma (HGSC) survive ten or more years after standard treatment.<br><br>METHODS: We evaluated the tumor microenvironment of this exceptional, understudied group using a large international cohort enriched for long-term survivors (LTS; 10+ years; n = 374) compared to medium-term (MTS; 5-7.99 years; n = 433) and short-term survivors (STS; 2-4.99 years; n = 416). Primary tumor samples were immunostained and scored for intra-epithelial and intra-stromal densities of 10 immune-cell subsets (including T cells, B cells, plasma cells, myeloid cells, PD-1+ cells, and PD-L1+ cells) and epithelial content.<br><br>RESULTS: Positive associations with LTS compared to STS were seen for 9/10 immune-cell subsets. In particular, the combination of intra-epithelial CD8+ T cells and intra-stromal B cells showed near five-fold increased odds of LTS compared to STS. All of these associations were stronger in tumors with high epithelial content and/or the C4/Differentiated molecular subtype, despite immune-cell densities generally being higher in tumors with low epithelial content and/or the C2/Immunoreactive molecular subtype.<br><br>CONCLUSIONS: The tumor microenvironment of HGSC long-term survivors is distinguished by the intersection of T and B cell co-infiltration, high epithelial content and C4/Differentiated molecular subtype, features which may inspire new approaches to immunotherapy.<br><br>FUNDING: Ovarian Cancer Research Program (OCRP) of the Congressionally Directed Medical Research Program (CDMRP), U.S. Department of Defense (DOD); American Cancer Society; BC Cancer Foundation; Canada's Networks of Centres of Excellence; Canadian Cancer Society; Canadian Institutes of Health Research; Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania, Cancer Foundation of Western Australia; Cancer Institute NSW; Cancer Research UK; Deutsche Forschungsgesellschaft; ELAN Funds of the University of Erlangen-Nuremberg; Fred C. and Katherine B. Andersen Foundation; Genome BC; German Cancer Research Center; German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research; Instituto de Salud Carlos III; Mayo Foundation; Minnesota Ovarian Cancer Alliance; Ministerio de Econom&#xed;a y Competitividad; MRC; National Center for Advancing Translational Sciences; National Health and Medical Research Council of Australia (NHMRC); Ovarian Cancer Australia; Peter MacCallum Foundation; Sydney West Translational Cancer Research Centre; Terry Fox Research Institute; The Eve Appeal (The Oak Foundation); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; University of Pittsburgh School of Medicine; U.S. National Cancer Institute of the National Institutes of Health; VGH &amp; UBC Hospital Foundation; Victorian Cancer Agency.}, }
@article {pmid39470275, year = {2024}, author = {Piliper, EA and Reed, JC and Greninger, AL}, title = {Clinical validation of an RSV neutralization assay and analysis of cross-sectional sera associated with 2021-2023 RSV outbreaks to investigate the immunity debt hypothesis.}, journal = {Microbiology spectrum}, volume = {12}, number = {12}, pages = {e0211524}, pmid = {39470275}, issn = {2165-0497}, abstract = {UNLABELLED: Respiratory syncytial virus (RSV) is a leading cause of acute respiratory infections and hospitalization in infants and the elderly. Newly approved vaccines and the prophylactic antibody nirsevimab have heightened interest in RSV immunologic surveillance, necessitating the development of high-throughput assays assessing anti-RSV neutralizing activity. Quantitative viral neutralization remains the best correlate of protection for RSV infection and the gold standard for RSV immunological testing. Here, we developed a high-throughput RSV strain A2 focus-reduction neutralization test validated to Clinical Laboratory Improvement Amendments (CLIA)/ Good Clinical Laboratory Practices (GCLP) standards using both clinical specimens and commercially available reference sera. The assay is highly accurate, generating reference serum neutralizing titers within twofold of established assays, with an analytical measurement range between 8 and 1,798 international units per mL (IU/mL). Neutralizing activity measured by the assay strongly correlated with antibody titer determined via indirect enzyme-linked immunosorbent assay (ELISA) (ρ = 1.0, P = 0.0014). Individuals recently having tested positive via quantitative reverse transcription polymerase chain reaction (RT-qPCR) for RSV had a 9.1-fold higher geometric mean neutralizing titer relative to RSV PCR negatives (P-value = 0.09). The validated assay was then used to investigate the immunity debt hypothesis for resurgent RSV outbreaks in the 2022-2023 season, using adult clinical remnant sera sent for herpes simplex virus (HSV)-1/2 antibody testing. There was no difference in geometric mean anti-RSV neutralizing titers between sera sampled before and after the 2022-2023 RSV outbreak (P = 0.68). These data are consistent with limited changes in RSV-neutralizing antibody levels in adults across the 2022-23 RSV outbreak.<br><br>IMPORTANCE: Population surveillance studies of serum-neutralizing activity against RSV are crucial for evaluating RSV vaccine efficacy and vulnerabilities to new strains. Here, we designed and validated a high-throughput assay for assessing anti-RSV neutralizing activity, standardized its measurements for comparison with other methodologies, and demonstrated its applicability to real-world samples. Our assay is precise, linear, and yields measurements consistent with other standardized assays, offering a methodology useful for large-scale studies of RSV immunity. We also find no significant difference in neutralizing titers among adults between those taken before and after large RSV outbreaks associated with the latter stages of the coronavirus disease of 2019 (COVID-19) public health emergency, underlining the need for a greater understanding of the dynamics of serological responses to RSV infection.}, }
@article {pmid39468273, year = {2024}, author = {Kim, D and Cooper, JA and Helfman, DM}, title = {Loss of myosin light chain kinase induces the cellular senescence associated secretory phenotype to promote breast epithelial cell migration.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {25786}, pmid = {39468273}, issn = {2045-2322}, support = {NFR 2018R1A2A2A05021262//National Research Foundation of Korea/ ; NFR 2018R1A2A2A05021262//National Research Foundation of Korea/ ; }, mesh = {Female ; Humans ; Breast/metabolism/pathology ; Breast Neoplasms/pathology/metabolism/genetics ; *Cell Movement ; Cellular Senescence ; *Cyclin-Dependent Kinase Inhibitor p21/metabolism/genetics ; *Epithelial Cells/metabolism ; Intercellular Adhesion Molecule-1/metabolism/genetics ; *Myosin-Light-Chain Kinase/metabolism/genetics ; Proto-Oncogene Proteins c-akt/metabolism ; Senescence-Associated Secretory Phenotype ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism ; Tumor Suppressor Protein p53/metabolism/genetics ; }, abstract = {Overexpression or activation of oncogenes or loss of tumor-suppressor genes can induce cellular senescence as a defense mechanism against tumor development, thereby maintaining cellular homeostasis. However, cancer cells can circumvent this senescent state and continue to spread. Myosin light chain kinase (MLCK) is downregulated in many breast cancers. Here we report that downregulation of MLCK in normal breast epithelial cells induces a senescence-associated secretory phenotype and stimulates migration. The reduction of MLCK results in increased p21[Cip1] expression, dependent on p53 and the AKT-mammalian target of rapamycin pathway. Subsequently, p21[Cip1] promotes the secretion of soluble ICAM-1, IL-1α, IL-6 and IL-8, thereby enhancing collective cell migration in a non-cell-autonomous manner. These findings provide new mechanistic insights into the role of MLCK in cellular senescence and cancer progression.}, }
@article {pmid39468212, year = {2024}, author = {Tsue, AF and Kania, EE and Lei, DQ and Fields, R and McGann, CD and Marciniak, DM and Hershberg, EA and Deng, X and Kihiu, M and Ong, SE and Disteche, CM and Kugel, S and Beliveau, BJ and Schweppe, DK and Shechner, DM}, title = {Multiomic characterization of RNA microenvironments by oligonucleotide-mediated proximity-interactome mapping.}, journal = {Nature methods}, volume = {21}, number = {11}, pages = {2058-2071}, pmid = {39468212}, issn = {1548-7105}, support = {902616//American Heart Association (American Heart Association, Inc.)/ ; R37CA241472//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; GM131745//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; 1R01GM138799-01//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; S10OD021502//U.S. Department of Health &amp; Human Services | NIH | NIH Office of the Director (OD)/ ; T32HG000035//U.S. Department of Health &amp; Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; T32GM007750//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; UM1HG011586//U.S. Department of Health &amp; Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; R35 GM131745/GM/NIGMS NIH HHS/United States ; 1R35GM137916//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; 1R35GM150919-01//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; 1R01HL160825-01//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01 GM138799/GM/NIGMS NIH HHS/United States ; DEB2016186//National Science Foundation (NSF)/ ; R01GM129090//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R35 GM150919/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Mice ; *In Situ Hybridization, Fluorescence/methods ; Biotinylation ; Oligonucleotides/genetics/chemistry ; Humans ; RNA, Long Noncoding/genetics ; RNA/genetics/metabolism ; }, abstract = {RNA molecules form complex networks of molecular interactions that are central to their function and to cellular architecture. But these interaction networks are difficult to probe in situ. Here, we introduce Oligonucleotide-mediated proximity-interactome MAPping (O-MAP), a method for elucidating the biomolecules near an RNA of interest, within its native context. O-MAP uses RNA-fluorescence in situ hybridization-like oligonucleotide probes to deliver proximity-biotinylating enzymes to a target RNA in situ, enabling nearby molecules to be enriched by streptavidin pulldown. This induces exceptionally precise biotinylation that can be easily optimized and ported to new targets or sample types. Using the noncoding RNAs 47S, 7SK and Xist as models, we develop O-MAP workflows for discovering RNA-proximal proteins, transcripts and genomic loci, yielding a multiomic characterization of these RNAs' subcellular compartments and new regulatory interactions. O-MAP requires no genetic manipulation, uses exclusively off-the-shelf parts and requires orders of magnitude fewer cells than established methods, making it accessible to most laboratories.}, }
@article {pmid39466880, year = {2024}, author = {Ruiz, F and Foreman, WB and Lilly, M and Baharani, VA and Depierreux, DM and Chohan, V and Taylor, AL and Guenthoer, J and Ralph, D and Matsen Iv, FA and Chu, HY and Bieniasz, PD and Côté, M and Starr, TN and Overbaugh, J}, title = {Delineating the functional activity of antibodies with cross-reactivity to SARS-CoV-2, SARS-CoV-1 and related sarbecoviruses.}, journal = {PLoS pathogens}, volume = {20}, number = {10}, pages = {e1012650}, pmid = {39466880}, issn = {1553-7374}, support = {R01 AI146028/AI/NIAID NIH HHS/United States ; P01 AI165075/AI/NIAID NIH HHS/United States ; P01 AI167966/AI/NIAID NIH HHS/United States ; DP2 AI177890/AI/NIAID NIH HHS/United States ; S10 OD021644/OD/NIH HHS/United States ; P30 CA042014/CA/NCI NIH HHS/United States ; }, mesh = {*SARS-CoV-2/immunology ; *Cross Reactions/immunology ; *Antibodies, Viral/immunology ; Humans ; Animals ; *Spike Glycoprotein, Coronavirus/immunology ; *Antibodies, Neutralizing/immunology ; *COVID-19/immunology/virology ; Epitopes/immunology ; Mice ; Severe acute respiratory syndrome-related coronavirus/immunology ; Betacoronavirus/immunology ; }, abstract = {The recurring spillover of pathogenic coronaviruses and demonstrated capacity of sarbecoviruses, such SARS-CoV-2, to rapidly evolve in humans underscores the need to better understand immune responses to this virus family. For this purpose, we characterized the functional breadth and potency of antibodies targeting the receptor binding domain (RBD) of the spike glycoprotein that exhibited cross-reactivity against SARS-CoV-2 variants, SARS-CoV-1 and sarbecoviruses from diverse clades and animal origins with spillover potential. One neutralizing antibody, C68.61, showed remarkable neutralization breadth against both SARS-CoV-2 variants and viruses from different sarbecovirus clades. C68.61, which targets a conserved RBD class 5 epitope, did not select for escape variants of SARS-CoV-2 or SARS-CoV-1 in culture nor have predicted escape variants among circulating SARS-CoV-2 strains, suggesting this epitope is functionally constrained. We identified 11 additional SARS-CoV-2/SARS-CoV-1 cross-reactive antibodies that target the more sequence conserved class 4 and class 5 epitopes within RBD that show activity against a subset of diverse sarbecoviruses with one antibody binding every single sarbecovirus RBD tested. A subset of these antibodies exhibited Fc-mediated effector functions as potent as antibodies that impact infection outcome in animal models. Thus, our study identified antibodies targeting conserved regions across SARS-CoV-2 variants and sarbecoviruses that may serve as therapeutics for pandemic preparedness as well as blueprints for the design of immunogens capable of eliciting cross-neutralizing responses.}, }
@article {pmid39466048, year = {2024}, author = {Fogel, JM and Persaud, D and Piwowar-Manning, E and Richardson, P and Szewczyk, J and Marzinke, MA and Wang, Z and Guo, X and McCauley, M and Farrior, J and Tran, HV and Ungsedhapand, C and Mathew, CA and Mpendo, J and Rinehart, AR and Rooney, JF and Cohen, MS and Hanscom, B and Grinsztejn, B and Hosseinipour, MC and Delany-Moretlwe, S and Landovitz, RJ and Eshleman, SH and , }, title = {HIV DNA Levels in Persons Who Acquired HIV in the Setting of Long-Acting Cabotegravir for HIV Prevention: Analysis of Cases from HPTN 083 and 084.}, journal = {AIDS research and human retroviruses}, volume = {}, number = {}, pages = {}, doi = {10.1089/aid.2024.0049}, pmid = {39466048}, issn = {1931-8405}, abstract = {We evaluated HIV DNA levels in individuals who received long-acting cabotegravir (CAB-LA) or tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) pre-exposure prophylaxis in the HPTN 083 and 084 trials and had HIV DNA testing performed to help determine HIV status. HIV DNA testing was performed using peripheral blood mononuclear cell (PBMC) samples collected after a reactive HIV test was obtained at a study site. DNA was quantified using droplet digital PCR (lower limit of detection [LLOD]: 4.09 copies/million PBMCs). Final HIV status and the timing of the first HIV-positive visit were determined by an independent adjudication committee based on HIV test results from real-time site testing and retrospective testing at a centralized laboratory. HIV DNA testing was performed for 133 participants [21 HIV-positive (7 CAB-LA arm, 14 TDF/FTC arm) and 112 HIV-negative; 1-6 tests/person]. For persons with HIV, the time between the first HIV-positive visit and collection of the first sample for DNA testing was a median of 81 days for those receiving CAB-LA (range 41-246) and 11 days for those receiving TDF/FTC (range 3-127). Four (57.1%) of the seven CAB-LA cases with infection had a low initial DNA result [three detected <LLOD; one near the LLOD (4.2 copies/10[6] PBMCs); in 2/4 cases, the DNA level was still <10 copies/10[6] PBMCs ≥40 weeks after the first HIV-positive visit. In contrast, only 3/14 (21.4%) of the TDF/FTC cases had a low or negative initial DNA test result (one not detected; two <10 copies/10[6] PBMCs). In this study, the time between the first HIV-positive visit and the first DNA test was longer in the CAB-LA cases than the TDF/FTC cases. Despite this difference, low or undetectable DNA levels were more frequently observed in the CAB-LA cases. This suggests that CAB-LA exposure may limit seeding of the HIV reservoir in early infection.}, }
@article {pmid39466024, year = {2024}, author = {Jaeger-Ruckstuhl, CA and Specht, JM and Voutsinas, JM and MacMillan, HR and Wu, QV and Muhunthan, V and Berger, C and Pullarkat, S and Wright, JH and Yeung, CCS and Hyun, TS and Seaton, B and Aicher, LD and Song, X and Pierce, RH and Lo, Y and Cole, GO and Lee, SM and Newell, EW and Maloney, DG and Riddell, SR}, title = {Phase 1 Study of ROR1 Specific CAR T Cells in Advanced Hematopoietic and Epithelial Malignancies.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-24-2172}, pmid = {39466024}, issn = {1557-3265}, support = {R01 CA114536/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is expressed in hematopoietic and epithelial cancers but has limited expression on normal adult tissues. This phase 1 study evaluated the safety of targeting ROR1 with autologous T-lymphocytes engineered to express a ROR1 chimeric antigen receptor (CAR). Secondary objectives evaluated persistence, trafficking, and antitumor activity of CAR T cells.<br><br>PATIENTS &amp; METHODS: Twenty-one patients with ROR1+ tumors received CAR T cells at one of four dose levels (DL): 3.3x105/1x106/3.3x106/1x107 cells/kg, administered after lymphodepletion with Cyclophosphamide/Fludarabine (Cy/Flu) or Oxaliplatin/Cyclophosphamide (Ox/Cy). Cohort A included patients with chronic lymphocytic leukemia (CLL, n=3); cohort B included patients with triple-negative breast cancer (TNBC, n=10) or non-small-cell lung cancer (NSCLC, n=8). A second infusion was administered to one patient in cohort A with residual CLL in the marrow and three patients in cohort B with stable disease after first infusion.<br><br>RESULTS: Treatment was well tolerated apart from one dose limiting toxicity at DL4 in a patient with advanced NSCLC. Two of the three (67%) CLL patients showed robust CAR T expansion and a rapid antitumor response. In patients with NSCLC and TNBC, CAR T cells expanded to variable levels, infiltrated tumor poorly, and one of eighteen patients (5.5%) achieved partial response by RECIST 1.1.<br><br>CONCLUSION: ROR1 CAR T cells were well tolerated in most patients. Antitumor activity was observed in CLL but was limited in TNBC and NSCLC. Immunogenicity of the CAR and lack of sustained tumor infiltration were identified as limitations.}, }
@article {pmid39465550, year = {2024}, author = {O'Donnell, PH and Loriot, Y and Csoszi, T and Matsubara, N and Shin, SJ and Park, SH and Atduev, V and Gumus, M and Karaca, SB and Grivas, P and de Wit, R and Castellano, DE and Powles, T and Vuky, J and Zhao, Y and O'Hara, K and Okpara, CE and Franco, S and Homet Moreno, B and Żołnierek, J and Siefker-Radtke, AO}, title = {Efficacy and safety of pembrolizumab in patients with advanced urothelial carcinoma deemed potentially ineligible for platinum-containing chemotherapy: Post hoc analysis of KEYNOTE-052 and LEAP-011.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.35601}, pmid = {39465550}, issn = {1097-0142}, support = {//Merck Sharp &amp; Dohme LLC, a subsidiary of Merck &amp; Co, Inc. (Rahway, New Jersey, USA)/ ; }, abstract = {BACKGROUND: First-line pembrolizumab monotherapy is a standard of care for platinum-ineligible patients with advanced urothelial carcinoma (UC). No global standardized definition of platinum ineligibility exists. This study aimed to evaluate the efficacy and safety of pembrolizumab monotherapy in patients with UC who met various criteria for platinum ineligibility.<br><br>METHODS: Patients from KEYNOTE-052 and LEAP-011 deemed potentially platinum ineligible were pooled for this post hoc exploratory analysis as follows: group 1: Eastern Cooperative Oncology Group performance status (ECOG PS) 2; group 2: ECOG PS 2 and age &#x2265;80 years, renal dysfunction, or visceral disease; and group 3: any two other factors regardless of ECOG PS. Patients received pembrolizumab 200 mg intravenously every 3 weeks. End points included objective response rate (ORR), progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1, by blinded independent central review, overall survival (OS), and safety.<br><br>RESULTS: A total of 612 patients treated with pembrolizumab from KEYNOTE-052 (n&#xa0;=&#xa0;370) and LEAP-011 (n&#xa0;=&#xa0;242) were included; the median (range) follow-up was 56.3 months (51.2-65.3 months) and 12.8 months (0.2-25.1 months), respectively. For group 1, ORR was 26.2%, median PFS was 2.7 months, and median OS was 10.1 months. For group 2, ORR ranged from 23.5% to 33.3%, median PFS ranged from 2.1 to 4.4 months, and median OS ranged from 9.1 to 10.1 months. For group 3, ORR ranged from 25.7% to 27.9%, median PFS ranged from 2.1 to 2.8 months, and median OS ranged from 9.0 to 10.6 months. Treatment-related adverse event rates were consistent across groups.<br><br>CONCLUSIONS: Frontline pembrolizumab has consistent antitumor activity and safety in patients with advanced UC categorized as potentially ineligible for platinum-based chemotherapy, regardless of the variable definitions of platinum ineligibility used.}, }
@article {pmid39464162, year = {2024}, author = {Russell, ML and Trofimov, A and Bradley, P and Matsen, FA}, title = {Statistical analysis of repertoire data demonstrates the influence of microhomology in V(D)J recombination.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39464162}, issn = {2692-8205}, support = {S10 OD028685/OD/NIH HHS/United States ; R01 AI146028/AI/NIAID NIH HHS/United States ; R35 GM142795/GM/NIGMS NIH HHS/United States ; R01 AI136514/AI/NIAID NIH HHS/United States ; R35 GM141457/GM/NIGMS NIH HHS/United States ; }, abstract = {V(D)J recombination generates the diverse B and T cell receptors essential for recognizing a wide array of antigens. This diversity arises from the combinatorial assembly of V(D)J genes and the junctional deletion and insertion of nucleotides. While previous in vitro studies have shown that microhomology--short stretches of sequence homology between gene ends--can bias the recombination process, the extent of microhomology's impact in vivo, particularly in humans, remains unknown. In this paper, we assess how germline-encoded microhomology influences trimming and ligation during V(D)J recombination using statistical inference on previously-published high-throughput TCRα repertoire sequencing data. We find that microhomology increases both trimming and ligation probabilities, making it an important predictor of recombination outcomes. These effects are consistent across different receptor loci and sequence types. Further, we demonstrate that accounting for microhomology effects significantly alters sequence annotation probabilities and rankings, highlighting its practical importance for accurately inferring the V(D)J recombination events that generated an observed sequence. Together, these results enhance our understanding of how microhomologous nucleotides shape the human V(D)J recombination process.}, }
@article {pmid39464160, year = {2024}, author = {Hsieh, YP and O'Keefe, IP and Sun, W and Wang, Z and Yang, H and Vu, LM and Ernst, RK and Dandekar, AA and Malik, HS}, title = {A novel PhoPQ-potentiated mechanism of colistin resistance impairs membrane integrity in Pseudomonas aeruginosa.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39464160}, issn = {2692-8205}, support = {R01 AI104895/AI/NIAID NIH HHS/United States ; R35 GM152107/GM/NIGMS NIH HHS/United States ; }, abstract = {Polymicrobial communities are often recalcitrant to antibiotic treatment because interactions between different microbes can dramatically alter their responses and susceptibility to antimicrobials. However, the mechanisms of evolving antimicrobial resistance in such polymicrobial environments are poorly understood. We previously reported that Mg[2+] depletion caused by the fungus Candida albicans can enable Pseudomonas aeruginosa to acquire significant resistance to colistin, a last-resort antibiotic targeting bacterial membrane. Here, we dissect the genetic and biochemical basis of this increased colistin resistance. We show that P. aeruginosa cells can acquire colistin resistance using three distinct evolutionary trajectories involving mutations in genes involved in lipid A biosynthesis, lipid A modifications that are dependent on low Mg[2+], and a putative Mg[2+] transporter, PA4824. These mutations confer colistin resistance by altering acyl chains, hydroxylation, and aminoarabinose modification of lipid A moieties on the bacterial outer membrane. In all cases, enhanced colistin resistance initially depends on the low Mg[2+]-responsive PhoPQ pathway, which potentiates the evolution of resistance mutations and lipid A modifications that do not occur without Mg[2+] depletion. However, the PhoPQ pathway is not required to maintain high colistin resistance in all cases. In most cases, the genetic and biochemical changes associated with these novel forms of colistin resistance also impair bacterial membrane integrity, leading to fitness costs. Our findings provide molecular insights into how nutritional competition drives a novel antibiotic resistance mechanism and its ensuing fitness tradeoffs.}, }
@article {pmid39464114, year = {2024}, author = {Bridge, J and Johnson, MJ and Kim, J and Wenthe, S and Krueger, J and Wick, B and Kluesner, M and Crane, AT and Bell, J and Skeate, JG and Moriarity, BS and Webber, BR}, title = {Efficient multiplex non-viral engineering and expansion of polyclonal γδ CAR-T cells for immunotherapy.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39464114}, issn = {2692-8205}, support = {R01 AI161017/AI/NIAID NIH HHS/United States ; P30 CA077598/CA/NCI NIH HHS/United States ; U24 OD026641/OD/NIH HHS/United States ; R21 CA237789/CA/NCI NIH HHS/United States ; U54 CA232561/CA/NCI NIH HHS/United States ; R21 AI163731/AI/NIAID NIH HHS/United States ; P01 CA254849/CA/NCI NIH HHS/United States ; R01 AI146009/AI/NIAID NIH HHS/United States ; U54 CA268069/CA/NCI NIH HHS/United States ; P50 CA136393/CA/NCI NIH HHS/United States ; }, abstract = {Gamma delta (γδ) T cells are defined by their unique ability to recognize a limited repertoire of non-peptide, non-MHC-associated antigens on transformed and pathogen-infected cells. In addition to their lack of alloreactivity, γδ T cells exhibit properties distinct from other lymphocyte subsets, prompting significant interest in their development as an off-the-shelf cellular immunotherapeutic. However, their low abundance in circulation, heterogeneity, limited methods for ex vivo expansion, and under-developed methodologies for genetic modification have hindered basic study and clinical application of γδ T cells. Here, we implement a feeder-free, scalable approach for ex vivo manufacture of polyclonal, non-virally modified, gene edited chimeric antigen receptor (CAR)-γδ T cells in support of therapeutic application. Engineered CAR-γδ T cells demonstrate high function in vitro and and in vivo. Longitudinal in vivo pharmacokinetic profiling of adoptively transferred polyclonal CAR-γδ T cells uncover subset-specific responses to IL-15 cytokine armoring and multiplex base editing. Our results present a robust platform for genetic modification of polyclonal CAR-γδ T cells and present unique opportunities to further define synergy and the contribution of discrete, engineered CAR-γδ T cell subsets to therapeutic efficacy in vivo.}, }
@article {pmid39462857, year = {2024}, author = {Panch, SR and Vassallo, RR and Adams, S and Borge, DP and Gammon, R and Gandhi, MJ and Philogene, M and Sullivan, HC and Wu, Y and Kopko, P}, title = {Management of human leukocyte antigen-mediated platelet transfusion refractoriness: Brief synopsis and recent literature review.}, journal = {Transfusion}, volume = {}, number = {}, pages = {}, doi = {10.1111/trf.18036}, pmid = {39462857}, issn = {1537-2995}, }
@article {pmid39456570, year = {2024}, author = {Lim, SYT and Huo, J and Laszlo, GS and Cole, FM and Kehret, AR and Li, J and Lunn-Halbert, MC and Persicke, JL and Rupert, PB and Strong, RK and Walter, RB}, title = {Optimizing Siglec-8-Directed Immunotherapy for Eosinophilic and Mast Cell Disorders.}, journal = {Cancers}, volume = {16}, number = {20}, pages = {}, pmid = {39456570}, issn = {2072-6694}, support = {R21-AI150566//National Institute of Health (NIH)/National Institute of Allergy and Infectious Diseases/ ; }, abstract = {Background/Objective: Current treatments for eosinophilic and mast cell disorders are often ineffective. One promising target to improve outcomes is sialic acid-binding immunoglobulin-like lectin-8 (Siglec-8). As limitations, there are few Siglec-8 monoclonal antibodies (mAbs) available to date, and Siglec-8-directed treatments have so far primarily focused on unconjugated mAbs, which may be inadequate, especially against mast cells. Methods: Here, we used transgenic mice to raise a diverse panel of fully human mAbs that either recognize the V-set domain, membrane-distal C2-set domain, or membrane-proximal C2-set domain of full-length Siglec-8 as a basis for novel therapeutics. Results: All mAbs were efficiently internalized into Siglec-8-expressing cells, suggesting their potential to deliver cytotoxic payloads. Tool T cell-engaging bispecific antibodies (BiAbs) and chimeric antigen receptor (CAR)-modified natural killer (NK) cells using single-chain variable fragments from Siglec-8 mAbs showed highly potent cytolytic activity against Siglec-8-positive cells even in cases of very low target antigen abundance, whereas they elicited no cytolytic activity against Siglec-8-negative target cells. Siglec-8[V-set]-directed T cell-engaging BiAbs and Siglec-8[V-set]-directed CAR-modified NK cells induced substantially greater cytotoxicity against cells expressing an artificial smaller Siglec-8 variant containing only the V-set domain than cells expressing full-length Siglec-8, consistent with the notion that targeting membrane-proximal epitopes enhances effector functions of Siglec-8 antibody-based therapeutics. Indeed, unconjugated Siglec-8[C2-set] mAbs, Siglec-8[C2-set]-directed T cell-engaging BiAbs, and Siglec-8[C2-set]-directed CAR-modified NK cells showed high antigen-specific cytolytic activity against Siglec-8-positive human cell lines and primary patient eosinophils. Conclusions: Together, these data demonstrate Siglec-8-directed immunotherapies can be highly potent, supporting their further development for eosinophilic and mast cell disorders.}, }
@article {pmid39454280, year = {2024}, author = {Pidala, JA and Kim, J and Kalos, D and Cutler, CS and DeFilipp, Z and Flowers, ME and Hamilton, BK and Chin, KK and Rotta, M and El Jurdi, N and Hamadani, M and Ahmed, G and Kitko, CL and Ponce, DM and Sung, AD and Tang, H and Farhadfar, N and Nemecek, ER and Pusic, I and Qayed, M and Rangarajan, HG and Hogan, WJ and Etra, AM and Jaglowski, SM}, title = {Ibrutinib for therapy of steroid-refractory chronic graft vs. host disease: A multicenter real-world analysis.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024014374}, pmid = {39454280}, issn = {2473-9537}, abstract = {To examine activity of ibrutinib in steroid-refractory chronic GVHD (SR-cGVHD) after FDA approval, we conducted a multicenter retrospective study. Data were standardly collected (N=270 from 19 centers). Involved organs included skin (75%), eye (61%), mouth (54%), joint/fascia (47%), GI (26%), lung (27%), liver (19%), genital (7%), other (4.4%). NIH severity was mild in 5.7%, moderate 42%, severe 53%. 39% had overlap subtype. KPS was ≥ 80% in 72%. Median prednisone (mg/kg) was 0.21 (0-2.27). Ibrutinib was started at median of 18.2 months after cGVHD onset and in earlier lines of therapy (2nd line: 26%, 3rd: 30%, 4th: 21%, 5th: 9.6%, 6th: 10%, 7th or higher: 1.2%)). Among evaluable subjects, the 6 month NIH overall response rate (CR/PR) was 45% (PR 42%, CR 3%). Median duration of response was 15 months (range 1-46). Liver involvement had association with 6 month ORR (multivariate (MVA) OR 5.49 (95% CI 2.3-14.2, p <0.001). Best overall response was 56%, with most (86%) achieving by 1-3 months. With median follow up for survivors of 30.5 months, FFS was 59% (53-65%) at 6 months and 41% (36-48%) at 12 months. On MVA, increased age (HR 1.01, 95% CI 1.0-1.02, p=0.033), higher baseline prednisone (HR 1.92, 1.09-3.38, p=0.032), and lung involvement (HR 1.58, 1.1-2.28, p=0.016) had worse FFS. Ibrutinib discontinuation was most commonly due to progressive cGVHD (44%) or toxicity (42%). These data support that ibrutinib has activity in SR-cGVHD, provide new insight into factors associated with response and FFS, and demonstrate the toxicity profile associated with discontinuation.}, }
@article {pmid39454232, year = {2024}, author = {, }, title = {Global, regional, and national burden of injuries, and burden attributable to injuries risk factors, 1990 to 2019: results from the Global Burden of Disease study 2019.}, journal = {Public health}, volume = {237}, number = {}, pages = {212-231}, doi = {10.1016/j.puhe.2024.06.011}, pmid = {39454232}, issn = {1476-5616}, mesh = {Humans ; *Global Burden of Disease/trends ; *Wounds and Injuries/epidemiology/mortality ; Risk Factors ; Male ; Female ; *Global Health/statistics &amp; numerical data ; Adult ; Middle Aged ; *Disability-Adjusted Life Years ; Adolescent ; Young Adult ; Aged ; Child, Preschool ; Infant ; Child ; Cause of Death ; Incidence ; Cost of Illness ; }, abstract = {OBJECTIVES: In this study, the trends and current situation of the injury burden as well as attributable burden to injury risk factors at global, regional, and national levels based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 are presented.<br><br>STUDY DESIGN: To assess the attributable burden of injury risk factors, the data of interest on data sources were retrieved from the Global Health Data Exchange (GHDx) and analyzed.<br><br>METHODS: Cause-specific death from injuries was estimated using the Cause of Death Ensemble model in the GBD 2019. The burden attributable to each injury risk factor was incorporated in the population attributable fraction to estimate the total attributable deaths and disability-adjusted life years. The Socio-demographic Index (SDI) was used to evaluate countries' developmental status.<br><br>RESULTS: Globally, there were 713.9 million (95% uncertainty interval [UI]: 663.8 to 766.9) injuries incidence and 4.3 million (UI: 3.9 to 4.6) deaths caused by injuries in 2019. There was an inverse relationship between age-standardized disability-adjusted life year rate and SDI quintiles in 2019. Overall, low bone mineral density was the leading risk factor of injury deaths in 2019, with a contribution of 10.5% (UI: 9.0 to 11.6) of total injuries and age-standardized deaths, followed by occupational risks (7.0% [UI: 6.3-7.9]) and alcohol use (6.8% [UI: 5.2 to 8.5]).<br><br>CONCLUSION: Various risks were responsible for the imposed burden of injuries. This study highlighted the small but persistent share of injuries in the global burden of diseases and injuries to provide beneficial data to produce proper policies to reach an effective global injury prevention plan.}, }
@article {pmid39454203, year = {2024}, author = {Farhadfar, N and Lee, SJ}, title = {Reply to Letter to Editor by Fingrut, et al.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024014712}, pmid = {39454203}, issn = {2473-9537}, }
@article {pmid39454125, year = {2024}, author = {Mosher, CE and Lee, S and Addington, EL and Park, S and Lewson, AB and Snyder, S and Hirsh, AT and Bricker, JB and Miller, KD and Ballinger, TJ and Schneider, BP and Storniolo, AM and Newton, EV and Champion, VL and Johns, SA}, title = {Randomized Controlled Trial of Acceptance and Commitment Therapy for Fatigue Interference With Functioning in Metastatic Breast Cancer.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2400965}, doi = {10.1200/JCO.24.00965}, pmid = {39454125}, issn = {1527-7755}, abstract = {PURPOSE: Fatigue is a highly prevalent and disabling symptom for patients with metastatic breast cancer (MBC). Evidence-based interventions for managing fatigue in advanced cancer populations are lacking. This phase II randomized controlled trial tested the effect of acceptance and commitment therapy (ACT) on fatigue interference with functioning in patients with MBC.<br><br>METHODS: Eligible patients were women with stage IV breast cancer who had moderate to severe fatigue interference. Patients completed a baseline assessment that included self-report measures of fatigue interference with activities, mood, and cognition (primary outcome) and sleep interference with functioning, engagement in daily activities, and quality of life (QOL; secondary outcomes). Then patients were randomly assigned to six weekly telephone-delivered sessions of either ACT (n = 116) or education/support (n = 120). Follow-up assessments occurred at 2 weeks, 3 months, and 6 months postintervention (means, 9.69, 20.51, and 33.59 weeks postbaseline, respectively).<br><br>RESULTS: Linear mixed model analyses showed that compared with patients in the education/support condition, patients in the ACT condition reported significantly less fatigue interference (P = .018). These results were significant at 2 weeks and 6 months postintervention. ACT's effect on sleep interference was not statistically significant after the Sidak adjustment for multiple comparisons (P = .037). ACT patients showed a steady decline in sleep interference, a trend that was not found for education/support patients. Engagement in daily activities and QOL did not significantly differ between study groups, except for functional QOL (P = .006). Compared with education/support patients, ACT patients showed significantly better functional QOL at 2 weeks and 6 months postintervention.<br><br>CONCLUSION: Results suggest that a brief, telephone-delivered ACT intervention can reduce fatigue interference with functioning in patients with MBC.}, }
@article {pmid39453463, year = {2024}, author = {Collienne, L and Barker, M and Suchard, MA and Matsen Iv, FA}, title = {Phylogenetic tree instability after taxon addition: empirical frequency, predictability, and consequences for online inference.}, journal = {Systematic biology}, volume = {}, number = {}, pages = {}, doi = {10.1093/sysbio/syae059}, pmid = {39453463}, issn = {1076-836X}, abstract = {Online phylogenetic inference methods add sequentially arriving sequences to an inferred phylogeny without the need to recompute the entire tree from scratch. Some online method implementations exist already, but there remains concern that additional sequences may change the topological relationship among the original set of taxa. We call such a change in tree topology a lack of stability for the inferred tree. In this paper, we analyze the stability of single taxon addition in a Maximum Likelihood framework across 1, 000 empirical datasets. We find that instability occurs in almost 90% of our examples, although observed topological differences do not always reach significance under the AU-test. Changes in tree topology after addition of a taxon rarely occur close to its attachment location, and are more frequently observed in more distant tree locations carrying low bootstrap support. To investigate whether instability is predictable, we hypothesize sources of instability and design summary statistics addressing these hypotheses. Using these summary statistics as input features for machine learning under random forests, we are able to predict instability and can identify the most influential features. In summary, it does not appear that a strict insertion-only online inference method will deliver globally optimal trees, although relaxing insertion strictness by allowing for a small number of final tree rearrangements or accepting slightly suboptimal solutions appears feasible.}, }
@article {pmid39453271, year = {2024}, author = {Shaik, F and Uldrick, TS and Mazinu, M and Gwebushe, N and Mosam, A}, title = {Early Changes in Health-Related Quality of Life as a Biomarker of Survival in African Patients with HIV-Associated Kaposi Sarcoma.}, journal = {Tropical medicine and infectious disease}, volume = {9}, number = {10}, pages = {}, pmid = {39453271}, issn = {2414-6366}, support = {SELF-INITIATED RESEARCH (SIR) GRANT//South African Medical Research Council/ ; }, abstract = {Sub-Saharan Africa bears the largest public health burden of Kaposi sarcoma (KS), a leading cause of cancer mortality. Quality of life (QOL) assessments in cancer patients can provide information on prognosis beyond traditional biomarkers or biological measures. The prognostic value of QOL measures in patients with HIV-KS was evaluated. Prognostic associations of baseline QOL scores (by quartiles or thresholds for clinical importance) and changes in QOL scores (using minimum important difference) over the first 3 months of therapy were evaluated in 112 participants with HIV-KS randomised to receive ART, with or without chemotherapy. Cox's regression analysis assessed the prognostic contribution of QOL scores from the EORTC QLQ-C30 questionnaire. Survival curves were generated using the Kaplan-Meier method. Baseline QOL scores did not predict overall survival. The change in the 3-month QOL scores for the global health scale, fatigue, and pain domains was prognostic; the hazard ratios were 3.88 (95% CI 1.32-11.38, p = 0.01), 3.72 (95% CI 1.61-8.62, p = 0.00) and 5.96 (95% CI 2.46-14.43, p = 0.00), respectively. QOL assessments can provide useful prognostic information in patients with HIV-KS. Patients lacking meaningful improvement early into treatment represent a population at high risk of death.}, }
@article {pmid39450393, year = {2024}, author = {Sanchez, E and Krantz, EM and Escobar, ZK and Tverdek, F and Rosen, EA and Oshima, MU and Carpenter, PA and Pergam, SA and Liu, C}, title = {Epidemiology and Outcomes of Recurrent C Difficile Infection Among Hematopoietic Cell Transplant Recipients: A Single-center, Retrospective 10-year Study.}, journal = {Open forum infectious diseases}, volume = {11}, number = {10}, pages = {ofae570}, pmid = {39450393}, issn = {2328-8957}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; T32 AI118690/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: There are limited data on the contemporary epidemiology of recurrent Clostridioides difficile infection (CDI) among hematopoietic cell transplant (HCT) recipients. We aimed to determine the incidence, risk factors, and outcomes for recurrent CDI among HCT recipients.<br><br>METHODS: We conducted a retrospective study of adult HCT recipients between 2012 and 2021 diagnosed with index CDI between HCT day -7 and +100. Recurrent CDI was defined as new symptoms and a positive test within 12 weeks after treatment for index CDI. Cox proportional hazards models were used to investigate associations between prespecified variables (age, neutropenia, exposure to antibiotics with antianaerobic coverage, cytomegalovirus viremia/disease, and metronidazole monotherapy) and recurrent infection, presented as hazard ratios with 95% confidence intervals (CI).<br><br>RESULTS: Of 3479 HCT recipients, 416 (12%) had index CDI and were treated with oral vancomycin (31%), metronidazole (41%), oral vancomycin and metronidazole (29%). Of 381 patients eligible for recurrent CDI analysis, 35 had recurrent infection; cumulative incidence was 10% (95% CI, 7-13) at 12 weeks. In the 14 days after recurrence, 2/25 (8%) patients required hospital admission; none died within 30 days. Metronidazole monotherapy for treatment of index CDI was associated with an increased rate of recurrence (adjusted hazard ratio, 2.0; 95% CI, 1.0-4.0; P = .048).<br><br>CONCLUSIONS: Recurrent CDI occurred in 10% of HCT recipients in the early posttransplant period and was associated with use of metronidazole. Further study is needed to characterize risk factors for recurrent CDI among HCT recipients to guide use of agents aimed at preventing recurrence.}, }
@article {pmid39449055, year = {2024}, author = {Behera, S and Belyeu, JR and Chen, X and Paulin, LF and Nguyen, NQH and Newman, E and Mahmoud, M and Menon, VK and Qi, Q and Joshi, P and Marcovina, S and Rossi, M and Roller, E and Han, J and Onuchic, V and Avery, CL and Ballantyne, CM and Rodriguez, CJ and Kaplan, RC and Muzny, DM and Metcalf, GA and Gibbs, RA and Yu, B and Boerwinkle, E and Eberle, MA and Sedlazeck, FJ}, title = {Identification of allele-specific KIV-2 repeats and impact on Lp(a) measurements for cardiovascular disease risk.}, journal = {BMC medical genomics}, volume = {17}, number = {1}, pages = {255}, pmid = {39449055}, issn = {1755-8794}, mesh = {Humans ; *Cardiovascular Diseases/genetics ; *Alleles ; *Lipoprotein(a)/genetics/blood ; DNA Copy Number Variations ; Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; }, abstract = {The abundance of Lp(a) protein holds significant implications for the risk of cardiovascular disease (CVD), which is directly impacted by the copy number (CN) of KIV-2, a 5.5 kbp sub-region. KIV-2 is highly polymorphic in the population and accurate analysis is challenging. In this study, we present the DRAGEN KIV-2 CN caller, which utilizes short reads. Data across 166 WGS show that the caller has high accuracy, compared to optical mapping and can further phase approximately 50% of the samples. We compared KIV-2 CN numbers to 24 previously postulated KIV-2 relevant SNVs, revealing that many are ineffective predictors of KIV-2 copy number. Population studies, including USA-based cohorts, showed distinct KIV-2 CN, distributions for European-, African-, and Hispanic-American populations and further underscored the limitations of SNV predictors. We demonstrate that the CN estimates correlate significantly with the available Lp(a) protein levels and that phasing is highly important.}, }
@article {pmid39448999, year = {2024}, author = {Thuo, N and Bardon, AR and Mogere, P and Kiptinness, C and Casmir, E and Wairimu, N and Owidi, E and Okello, P and Mugo, NR and Baeten, JM and Ngure, K and Ortblad, KF}, title = {Acceptability of six-monthly PrEP dispensing supported with interim HIV self-testing to simplify PrEP delivery in Kenya: findings from qualitative research.}, journal = {BMC health services research}, volume = {24}, number = {1}, pages = {1281}, pmid = {39448999}, issn = {1472-6963}, support = {R00 MH121166/MH/NIMH NIH HHS/United States ; R01 MH113572/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; Kenya ; *Pre-Exposure Prophylaxis/methods ; Female ; Male ; *HIV Infections/prevention &amp; control ; Adult ; *Qualitative Research ; *Self-Testing ; *Patient Acceptance of Health Care/statistics &amp; numerical data ; Anti-HIV Agents/therapeutic use/administration &amp; dosage ; Young Adult ; HIV Testing/methods ; Interviews as Topic ; }, abstract = {BACKGROUND: In Africa, dispensing oral HIV pre-exposure prophylaxis (PrEP) within already strained public health facilities has led to prolonged waiting periods and suboptimal experiences for clients. We sought to explore the acceptability of dispensing PrEP semiannually with interim HIV self-testing (HIVST) versus quarterly PrEP dispensing with clinic-based HIV testing to optimize clinic-delivered PrEP services.<br><br>METHODS: We conducted a qualitative study within a non-inferiority individual-level randomized controlled trial testing the effect of six-monthly PrEP dispensing with HIVST compared to the standard-of-care three-monthly PrEP dispensing on PrEP clinical outcomes in Kenya (ClinicalTrials.gov: NCT03593629). Eligible participants were &#x2265;&#x2009;18 years, refilling PrEP for the first time, and either in an HIV serodifferent relationship (men and women) or singly enrolled (women only). A subset of participants in the intervention group completed serial in-depth interviews (IDIs) at enrollment, six months, and 12 months. We utilized stratified purposive sampling to ensure representation across participant groups. We analyzed our qualitative data thematically using a combination of inductive and deductive approaches, the latter guided by the Theoretical Framework of Acceptability (TFA).<br><br>RESULTS: Between May 2018 and June 2021, we conducted 120 serial IDIs with 55 participants; 64% (35/55) were in a serodifferent relationship, 64% (35/55) were women, and the median age was 32 years (IQR 27-40). Overall, participants found this novel PrEP delivery model highly acceptable; it was well-liked, private (TFA construct: affective attitude), and less burdensome (TFA construct: burden) compared to standard PrEP delivery. Additionally, participants were confident in their ability to participate in the intervention (TFA construct: self-efficacy). Some participants, however, highlighted model disadvantages, including fewer opportunities for in-person counseling and potentially less accurate HIV testing (TFA construct: opportunity costs). Ultimately, most participants reported that the intervention allowed them to achieve their HIV prevention goals (TFA construct: perceived effectiveness) and that their confidence in at-home HIVST and PrEP continuation increased following each semiannual clinic visit.<br><br>CONCLUSIONS: Semiannual PrEP clinic visits supported with six-monthly drug dispensing and interim HIVST was acceptable among PrEP users who experienced the intervention in Kenya. More comprehensive pre-intervention counseling and training on HIVST may help alleviate the client concerns presented, which were often resolved over time with intervention experience.}, }
@article {pmid39447443, year = {2024}, author = {Ronsley, R and Cole, B and Ketterl, T and Wright, J and Ermoian, R and Hoffman, LM and Margol, AS and Leary, SES}, title = {Pediatric Central Nervous System Embryonal Tumors: Presentation, Diagnosis, Therapeutic Strategies, and Survivorship-A Review.}, journal = {Pediatric neurology}, volume = {161}, number = {}, pages = {237-246}, doi = {10.1016/j.pediatrneurol.2024.09.031}, pmid = {39447443}, issn = {1873-5150}, mesh = {Humans ; *Neoplasms, Germ Cell and Embryonal/therapy/diagnosis ; *Central Nervous System Neoplasms/therapy/diagnosis ; Child ; Survivorship ; Cancer Survivors ; }, abstract = {Central nervous system (CNS) embryonal tumors represent a diverse group of neoplasms and have a peak incidence in early childhood. These tumors can be located anywhere within the CNS, and presenting symptoms typically represent tumor location. These tumors display distinctive findings on neuroimaging and are staged using magnetic resonance imaging of the brain and spine as well as evaluation of cerebrospinal fluid. Diagnosis is made based on an integrated analysis of histologic and molecular features via tissue sampling. Risk stratification is based on integration of clinical staging and extent of resection with histologic and molecular risk factors. The therapeutic approach for these tumors is multimodal and includes surgery, chemotherapy, and radiation, tailored to the individual patient factors (including age) and specific tumor type. Comprehensive supportive care including management of nausea, nutrition support, pain, fertility preservation, and mitigation of therapy-related morbidity (including hearing protection) is imperative through treatment of CNS embryonal tumors. Despite advances in therapy and supportive care, the long-term consequences of current treatment strategies are substantial. Integration of less toxic, molecularly targeted therapies and a comprehensive, multidisciplinary approach to survivorship care are essential to improving survival and the overall quality of life for survivors.}, }
@article {pmid39447094, year = {2024}, author = {Sehn, LH and Bartlett, NL and Matasar, MJ and Schuster, SJ and Assouline, SE and Giri, P and Kuruvilla, J and Shadman, M and Cheah, CY and Dietrich, S and Fay, K and Ku, M and Nastoupil, LJ and Wei, MC and Yin, S and To, I and Kaufman, D and Kwan, A and Penuel, E and Bolen, CR and Budde, LE}, title = {Long-term 3-year follow-up of mosunetuzumab in relapsed or refractory follicular lymphoma after ≥2 prior therapies.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024025454}, pmid = {39447094}, issn = {1528-0020}, abstract = {Mosunetuzumab, a CD20xCD3 T-cell engaging bispecific antibody, redirects T cells to eliminate malignant B cells. We present updated efficacy and safety data of a pivotal phase 1/2 study after a median follow-up of 37.4 months in 90 patients with relapsed/refractory (R/R) follicular lymphoma (FL) and ≥2 prior lines of therapy treated with fixed-duration mosunetuzumab. Investigator-assessed complete response (CR) rate and objective response rate (ORR) were 60.0% (95% confidence interval [CI], 49.1-70.2) and 77.8% (95% CI, 67.8-85.9), respectively. Among 70 responders, median duration of response was 35.9 months (95% CI, 20.7-not estimable [NE]). Among 54 patients who achieved CR, 49 remained in CR at the end of treatment; median duration of complete response was not reached (NR) (95% CI, 33.0-NE); Kaplan-Meier-estimated 30-month remission rate was 72.4% (95% CI, 59.2-85.6). Estimated 36-month overall survival (OS) rate was 82.4% (95% CI, 73.8-91.0); median OS was NR (95% CI, NE-NE). Median progression-free survival was 24.0 months (95% CI, 12.0-NE). Median time to CD19+ B-cell recovery was 18.4 months (95% CI, 12.8-25.0) following 8 cycles of mosunetuzumab treatment. No new cytokine release syndrome events or fatal, serious, or Grade ≥3 adverse events were reported. With extended follow-up, mosunetuzumab demonstrated high response rates, durable remissions and manageable safety with no long-term concerns. This supports outpatient mosunetuzumab administration as an off-the-shelf, fixed-duration, safe and effective treatment for patients with R/R FL, including those with high-risk disease. Trial registration: www.clinicaltrials.gov (NCT02500407).}, }
@article {pmid39447043, year = {2024}, author = {McDougall, JA and Adler Jaffe, S and Jacobson, K and Shaver, TL and Wilson, JLF and Baca, K and Boyce, T and Tawfik, B and Page-Reeves, J}, title = {Randomized pilot trial of an unconditional cash transfer intervention to address food insecurity in oncology.}, journal = {JNCI cancer spectrum}, volume = {8}, number = {6}, pages = {}, pmid = {39447043}, issn = {2515-5091}, support = {UG1 CA189824/CA/NCI NIH HHS/United States ; 2UG1CA189824//Wake Forest NCI Community Oncology Research Program/ ; }, mesh = {Humans ; Female ; Pilot Projects ; *Food Insecurity ; *Cancer Survivors ; *Quality of Life ; Middle Aged ; *Breast Neoplasms ; *Genital Neoplasms, Female/therapy ; Diet/economics ; Aged ; Adult ; Social Determinants of Health ; Food Supply/economics/statistics &amp; numerical data ; }, abstract = {Screening for food insecurity and other social determinants of health is being integrated into oncology practice. We performed a pilot randomized trial to investigate whether an unconditional cash transfer (UCT) could be used to address food insecurity among female breast and gynecological cancer survivors. Food-insecure cancer survivors completed a baseline survey and were randomly assigned to receive $100/month for 3 months (UCT) or usual care (UC). Participants (n = 14) completed a follow-up survey after 3 months, and we compared changes in health-related quality of life, indicators of food insecurity, diet quality, and whether a participant had to forgo, delay, or make changes to medical care because of cost. The UCT was associated with higher physical health scores, fewer indicators of food insecurity, better diet quality, and a lower likelihood of forgoing medical care than those who received UC. Our results suggest that UCTs can improve outcomes for food-insecure cancer survivors.}, }
@article {pmid39446892, year = {2024}, author = {Schaefer, R and Donaldson, L and Leus, M and Osakwe, CE and Chimukangara, B and Dalal, S and Duerr, A and Gao, F and Glidden, DV and Grinsztejn, B and Justman, J and Kumwenda, G and Laeyendecker, O and Lee, HY and Maldarelli, F and Mayer, KH and Murray, J and Parekh, BS and Rice, B and Robertson, MN and Saito, S and Vannappagari, V and Warren, M and Zeballos, D and Zinserling, J and Miller, V}, title = {Promising results of HIV prevention trials highlight the benefits of collaboration in global health: The perspective of the Forum HIV Recency Assay Working Group.}, journal = {PLOS global public health}, volume = {4}, number = {10}, pages = {e0003878}, pmid = {39446892}, issn = {2767-3375}, support = {001/WHO_/World Health Organization/International ; }, }
@article {pmid39446266, year = {2024}, author = {Gichane, MW and Velloza, J and Hosek, S and Beauchamp, G and Anderson, P and Delany-Moretlwe, S and Celum, C and , }, title = {Hoping to Adhere? Examining the Relationship Between Hope and Pre-exposure Prophylaxis Willingness, Adherence, and Persistence Among Young Women in South Africa and Zimbabwe (HPTN 082).}, journal = {AIDS and behavior}, volume = {}, number = {}, pages = {}, pmid = {39446266}, issn = {1573-3254}, support = {UM1AI068619//National Institute of Allergy and Infectious Diseases/ ; UM1AI068617//National Institute of Allergy and Infectious Diseases/ ; UM1AI068613//National Institute of Allergy and Infectious Diseases/ ; K01MH134775/MH/NIMH NIH HHS/United States ; }, abstract = {Hope is a powerful psychological construct which is linked to positive health. Greater hope is associated with improved antiretroviral therapy adherence; however, less is known about the impact of hope on oral pre-exposure prophylaxis (PrEP) outcomes. HIV Prevention Trials Network 082, was an open-label PrEP study among young women (ages 16-25) in South Africa and Zimbabwe. Hope was measured at baseline and follow-up using a subset of the Hope for the Future Scale (score range 6-24) and PrEP willingness was measured using a subscale of the HIV Prevention Readiness Measure (score range 6-30). Intracellular tenofovir-diphosphate (TFV-DP) concentrations were obtained from dried blood spot samples at weeks 13, 26, and 52; high PrEP adherence was defined as TFV-DP concentrations ≥ 700 fmol/punch. Persistence was defined as TFV-DP > 16 fmol/punch at weeks 26 and 52. Linear regression and generalized estimating equations were used to assess the relationship between hope and PrEP willingness, adherence, and persistence. The median age of participants (n = 432) was 21 years (interquartile range [IQR]: 19-22). The mean hope score at baseline was 21.0 (SD = 3.4). Although hope was positively associated with PrEP willingness (β = 0.22, 95% CI 0.15, 0.37), it was not associated with high PrEP adherence (aRR = 1.00, 95% CI 0.96, 1.05), or persistence at follow-up (aRR = 1.02, 95% CI 0.99, 1.05). While cultivating hope may be an important strategy in building willingness to take oral PrEP, it may not be enough to sustain PrEP adherence or persistence.}, }
@article {pmid39445720, year = {2024}, author = {Compton, ZT and Mellon, W and Harris, VK and Rupp, S and Mallo, D and Kapsetaki, SE and Wilmot, M and Kennington, R and Noble, K and Baciu, C and Ramirez, LN and Peraza, A and Martins, B and Sudhakar, S and Aksoy, S and Furukawa, G and Vincze, O and Giraudeau, M and Duke, EG and Spiro, S and Flach, E and Davidson, H and Li, CI and Zehnder, A and Graham, TA and Troan, BV and Harrison, TM and Tollis, M and Schiffman, JD and Aktipis, CA and Abegglen, LM and Maley, CC and Boddy, AM}, title = {Cancer Prevalence across Vertebrates.}, journal = {Cancer discovery}, volume = {}, number = {}, pages = {OF1-OF18}, doi = {10.1158/2159-8290.CD-24-0573}, pmid = {39445720}, issn = {2159-8290}, support = {P01 CA091955/CA/NCI NIH HHS/United States ; OTKA K143421//Agence Nationale de la Recherche (ANR)/ ; U54 CA217376/CA/NCI NIH HHS/United States ; ADHS18-198847//Arizona Biomedical Research Commission (ABRC)/ ; U2C CA233254/CA/NCI NIH HHS/United States ; //Hyundai Hope On Wheels (Hope On Wheels)/ ; BC132057//Congressionally Directed Medical Research Programs (CDMRP)/ ; R01 CA140657/CA/NCI NIH HHS/United States ; R21 CA257980/CA/NCI NIH HHS/United States ; T32 CA272303/CA/NCI NIH HHS/United States ; COVER ANR-23-CE02-0019//Agence Nationale de la Recherche (ANR)/ ; }, abstract = {Cancer is pervasive across multicellular species, but what explains the differences in cancer prevalence across species? Using 16,049 necropsy records for 292 species spanning three clades of tetrapods (amphibians, sauropsids, and mammals), we found that neoplasia and malignancy prevalence increases with adult mass (contrary to Peto's paradox) and somatic mutation rate but decreases with gestation time. The relationship between adult mass and malignancy prevalence was only apparent when we controlled for gestation time. Evolution of cancer susceptibility appears to have undergone sudden shifts followed by stabilizing selection. Outliers for neoplasia prevalence include the common porpoise (<1.3%), the Rodrigues fruit bat (<1.6%), the black-footed penguin (<0.4%), ferrets (63%), and opossums (35%). Discovering why some species have particularly high or low levels of cancer may lead to a better understanding of cancer syndromes and novel strategies for the management and prevention of cancer. Significance: Evolution has discovered mechanisms for suppressing cancer in a wide variety of species. By analyzing veterinary necropsy records, we can identify species with exceptionally high or low cancer prevalence. Discovering the mechanisms of cancer susceptibility and resistance may help improve cancer prevention and explain cancer syndromes.}, }
@article {pmid39442617, year = {2024}, author = {Hortobagyi, GN and Lacko, A and Sohn, J and Cruz, F and Ruiz Borrego, M and Manikhas, A and Hee Park, Y and Stroyakovskiy, D and Yardley, DA and Huang, CS and Fasching, PA and Crown, J and Bardia, A and Chia, S and Im, SA and Martin, M and Loi, S and Xu, B and Hurvitz, S and Barrios, C and Untch, M and Moroose, R and Visco, F and Parnizari, F and Zarate, JP and Li, Z and Waters, S and Chakravartty, A and Slamon, D}, title = {A phase III trial of adjuvant ribociclib plus endocrine therapy versus endocrine therapy alone in patients with HR-positive/HER2-negative early breast cancer: final invasive disease-free survival results from the NATALEE trial.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.annonc.2024.10.015}, pmid = {39442617}, issn = {1569-8041}, abstract = {BACKGROUND: NATALEE assessed efficacy and tolerability of 3 years of adjuvant ribociclib plus a nonsteroidal aromatase inhibitor (NSAI) compared with an NSAI alone in a broad population of patients with hormone receptor (HR)-positive/human epidermal growth factor 2 (HER2)-negative early breast cancer, including a select group without nodal involvement. This is the final preplanned analysis of invasive disease-free survival (iDFS).<br><br>PATIENTS AND METHODS: Premenopausal/postmenopausal women and men were randomized 1 : 1 to ribociclib (n&#xa0;= 2549; 400 mg/day, 3 weeks on/1 week off for 36 months) plus NSAI (letrozole 2.5 mg/day or anastrozole 1 mg/day for 60 months) or NSAI alone (n&#xa0;= 2552). Men and premenopausal women also received goserelin (3.6 mg once every 28 days). Patients had anatomical stage IIA (N0 with additional risk factors or N1), IIB, or III disease. The primary endpoint was iDFS. Secondary efficacy endpoints were recurrence-free survival (RFS), distant DFS, and overall survival. This final iDFS analysis was planned after &#x223c;500 events.<br><br>RESULTS: At data cut-off (21 July 2023), ribociclib was stopped for 1996 patients (78.3%); 1091 (42.8%) completed 3 years of ribociclib, and ribociclib treatment was ongoing for 528 (20.7%). Median follow-up for iDFS was 33.3 months. Overall, 226 and 283 iDFS events occurred with ribociclib plus NSAI versus NSAI alone, respectively. Ribociclib plus NSAI demonstrated significant iDFS benefit over NSAI alone [hazard ratio 0.749, 95% confidence interval (CI) 0.628-0.892; P&#xa0;= 0.0012]. The 3-year iDFS rates were 90.7% (95% CI 89.3% to 91.8%) versus 87.6% (95% CI 86.1% to 88.9%). A consistent benefit was observed across prespecified subgroups, including stage (II/III) and nodal status (positive/negative). Distant DFS and RFS favored ribociclib plus NSAI. Overall survival data were immature. No new safety signals were observed.<br><br>CONCLUSIONS: With longer follow-up and most patients off ribociclib, NATALEE continues to demonstrate iDFS benefit with ribociclib plus NSAI over NSAI alone in the overall population and across key subgroups. Observed adverse events remained stable.}, }
@article {pmid39442371, year = {2024}, author = {Yonemori, K and Boni, V and Min, KG and Meniawy, TM and Lombard, J and Kaufman, PA and Richardson, DL and Bender, L and Okera, M and Matsumoto, K and Giridhar, KV and García-Sáenz, JA and Prenen, H and de Speville Uribe, BD and Dizon, DS and Garcia-Corbacho, J and Van Nieuwenhuysen, E and Li, Y and Estrem, ST and Nguyen, B and Bacchion, F and Ismail-Khan, R and Jhaveri, K and Banda, K}, title = {Imlunestrant, an oral selective estrogen receptor degrader, as monotherapy and combined with abemaciclib, in recurrent/advanced ER-positive endometrioid endometrial cancer: Results from the phase 1a/1b EMBER study.}, journal = {Gynecologic oncology}, volume = {191}, number = {}, pages = {172-181}, doi = {10.1016/j.ygyno.2024.10.006}, pmid = {39442371}, issn = {1095-6859}, abstract = {OBJECTIVE: Imlunestrant is a next-generation oral selective estrogen receptor degrader designed to deliver continuous estrogen receptor (ER) target inhibition. EMBER is a phase 1a/b trial of imlunestrant, as monotherapy and combined with targeted therapy, in patients with ER+ advanced breast cancer or endometrioid endometrial cancer (EEC). This report focuses on patients with ER+ EEC.<br><br>METHODS: EMBER used an i3&#xa0;+&#xa0;3 dose-escalation design to determine the recommended phase 2 dose (RP2D) followed by dose-expansion cohorts (1:1 randomization): imlunestrant monotherapy and imlunestrant plus abemaciclib (150&#xa0;mg twice daily). Eligible patients had measurable disease and progression or recurrence after platinum-containing chemotherapy. Prior fulvestrant or aromatase inhibitor was not allowed. Secondary endpoints included safety, pharmacokinetics and antitumor activity.<br><br>RESULTS: In total, 72 patients with a median of 2 prior anticancer therapies were treated. Among the 39 patients who received imlunestrant (400&#xa0;mg [RP2D], n&#xa0;=&#xa0;33; 800&#xa0;mg, n&#xa0;=&#xa0;6), the most common treatment-emergent adverse events (TEAEs) were grade 1-2 nausea (35.9&#xa0;%), diarrhea (25.6&#xa0;%), urinary tract infection (25.6&#xa0;%), and abdominal pain (20.5&#xa0;%). Overall response rate (ORR) was 10.3&#xa0;%, clinical benefit rate (CBR) was 33.3&#xa0;%, and median progression-free survival (mPFS) was 3.8&#xa0;months (95&#xa0;% CI, 1.8-6.7). Among the 33 patients who received imlunestrant (400&#xa0;mg [RP2D], n&#xa0;=&#xa0;29; 800&#xa0;mg, n&#xa0;=&#xa0;4) plus abemaciclib, the most common TEAEs were diarrhea (87.9&#xa0;%), nausea (66.7&#xa0;%), fatigue (48.5&#xa0;%), and anemia (45.5&#xa0;%). ORR was 18.2&#xa0;%, CBR was 42.4&#xa0;%, and mPFS was 6.8&#xa0;months (95&#xa0;% CI, 2.1-12).<br><br>CONCLUSION: Imlunestrant, as monotherapy and combined with abemaciclib, has a manageable safety profile with preliminary evidence of antitumor activity in patients with ER+ EEC.}, }
@article {pmid39441907, year = {2024}, author = {Oshima, MU and Higgins, J and Jenkins, I and Randolph, T and Smith, T and Valentine, C and Salk, J and Yeung, C and Beppu, L and Campbell, J and Carpenter, PA and Lee, SJ and Flowers, ME and Radich, JP and Storb, R}, title = {Characterization of clonal dynamics using duplex sequencing in donor-recipient pairs decades after hematopoietic cell transplantation.}, journal = {Science translational medicine}, volume = {16}, number = {770}, pages = {eado5108}, doi = {10.1126/scitranslmed.ado5108}, pmid = {39441907}, issn = {1946-6242}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation ; *Tissue Donors ; Adult ; Middle Aged ; Male ; Mutation/genetics ; Female ; Young Adult ; Child ; Clonal Hematopoiesis/genetics ; Transplant Recipients ; Adolescent ; }, abstract = {After allogeneic hematopoietic cell transplantation (HCT), a very small number of donor stem cells reconstitute the recipient hematopoietic system, whereas the donor is left with a near-normal pool of stem cells. We hypothesized that the increased replicative stress on transplanted donor cells in the recipient could lead to the disproportionate proliferation of clonal hematopoiesis (CH) variants. We obtained blood samples from 16 related donor-recipient pairs at a median of 33.8 years (range: 6.6 to 45.7) after HCT, including the longest surviving HCT recipients in the world. For 11 of 16 pairs, a donor sample from the time of HCT was available for comparison. We performed ultrasensitive duplex sequencing of genes recurrently mutated in myeloid malignancies and CH, as well as a set of functionally neutral genomic regions representative of human genomic content at large. CH variants were observed in all donors, even those as young as 12 years old. Where donor pre-HCT sample was available, the average mutation rate in donors compared to recipients post-HCT was similar (2.0% versus 2.6% per year, respectively) within genes recurrently mutated in myeloid malignancies. Twenty-two (5.6%) of the 393 variants shared between paired donors and recipients post-HCT showed ≥10-fold higher variant allele frequency (VAF) in the recipient. A longer time since HCT was positively associated with the expansion of shared variant VAFs in the recipient. In conclusion, even decades after HCT, there does not appear to be widespread accelerated clonal expansion in the transplanted cells, highlighting the immense regenerative capacity of the human hematopoietic system.}, }
@article {pmid39441819, year = {2024}, author = {Owens, L and Brahme, O and Gulati, R and Etzioni, R}, title = {Trends in age and prostate-specific antigen at prostate cancer diagnosis between 2010 and 2019.}, journal = {JNCI cancer spectrum}, volume = {8}, number = {6}, pages = {}, pmid = {39441819}, issn = {2515-5091}, support = {R50 CA221836/CA/NCI NIH HHS/United States ; U01CA253915/CA/NCI NIH HHS/United States ; //Rosalie and Harold Rea Brown Endowed Chair/ ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms/blood/diagnosis/pathology ; *Prostate-Specific Antigen/blood ; Aged ; United States/epidemiology ; *SEER Program ; *White People/statistics &amp; numerical data ; *Black or African American/statistics &amp; numerical data ; Middle Aged ; Age Factors ; Delayed Diagnosis/statistics &amp; numerical data ; Early Detection of Cancer ; Aged, 80 and over ; Incidence ; White ; }, abstract = {Recent studies have shown that de novo metastatic prostate cancer incidence in the United States increased from 2010 to 2019. Plausible explanations include delayed detection after recommendations against prostate cancer screening or upstaging associated with use of more sensitive imaging technologies. Using Surveillance, Epidemiology, and End Results patient cases and controlling for aging of the population, we found the median age and prostate-specific antigen (PSA) level at prostate cancer diagnosis increased by 1.4 years of age (95% CI = 1.3 to 1.5 years) and 1.4 ng/mL (95% CI = 1.4 to 1.5 ng/mL) over this period, consistent with the delayed detection hypothesis. Racial differences were noted, with 75th percentiles of PSA at diagnosis increasing by 4.3 ng/mL (95% CI = 3.7 to 4.8 ng/mL) over this time period for non-Hispanic Black men compared with 3.0 ng/mL (95% CI = 2.8 to 3.2 ng/mL) for non-Hispanic White men. Overall, patient characteristics at diagnosis suggest that delayed detection contributed at least in part to increases in de novo metastatic disease.}, }
@article {pmid39439295, year = {2024}, author = {Colonne, CK and Kimble, EL and Turtle, CJ}, title = {Evolving strategies to overcome barriers in CAR-T cell therapy for acute myeloid leukemia.}, journal = {Expert review of hematology}, volume = {17}, number = {11}, pages = {797-818}, doi = {10.1080/17474086.2024.2420614}, pmid = {39439295}, issn = {1747-4094}, mesh = {Humans ; *Leukemia, Myeloid, Acute/therapy/immunology ; *Immunotherapy, Adoptive/methods ; *Tumor Microenvironment/immunology ; *Receptors, Chimeric Antigen/immunology/therapeutic use/metabolism ; Antigens, Neoplasm/immunology ; T-Lymphocytes/immunology/metabolism/transplantation ; Clinical Trials as Topic ; Treatment Outcome ; }, abstract = {INTRODUCTION: Acute myeloid leukemia (AML) is a complex and heterogeneous disease characterized by an aggressive clinical course and limited efficacious treatment options in the relapsed/refractory (R/R) setting. Chimeric antigen receptor (CAR)-modified T (CAR-T) cell immunotherapy is an investigational treatment strategy for R/R AML that has shown some promise. However, obstacles to successful CAR-T cell immunotherapy for AML remain.<br><br>AREAS COVERED: In analyses of clinical trials of CAR-T cell therapy for R/R AML, complete responses without measurable residual disease have been reported, but the durability of those responses remains unclear. Significant barriers to successful CAR-T cell therapy in AML include the scarcity of suitable tumor-target antigens (TTA), inherent T cell functional deficits, and the immunoinhibitory and hostile tumor microenvironment (TME). This review will focus on these barriers to successful CAR-T cell therapy in AML, and discuss scientific advancements and evolving strategies to overcome them.<br><br>EXPERT OPINION: Achieving durable remissions in R/R AML will likely require a multifaceted approach that integrates advancements in TTA selection, enhancement of the intrinsic quality of CAR-T cells, and development of strategies to overcome inhibitory mechanisms in the AML TME.}, }
@article {pmid39438074, year = {2024}, author = {McGillivray, E and Ashouri, K and Chatziioannou, E and Gallegos, JAO and Zarka, J and Kechter, J and Hwang, AS and Zhang, K and Barros, M and Yeh, J and Okazaki, I and Crocker, AB and Maeda, T and Park, SJ and Choi, J and Andreoli, M and Darwish, T and Savage, DJ and Kim, KB and Gupta, J and Shen, J and Shirai, K and Choi, A and Pai, L and de Lima Vazquez, V and Moser, J and Amaral, T and Hernandez Aya, LF and Lutzky, J and Najjar, YG and Costello, CM and Mangold, AR and Bhatia, S and Gibney, GT and Farma, JM and Daniels, GA and Sosman, J and Chandra, S and Mangla, A and Bollin, K and Abrão Possik, P and Robles Espinoza, CD and Ito, F and In, GK}, title = {Combined PD-1 and CTLA-4 Blockade in an International Cohort of Patients with Acral Lentiginous Melanoma.}, journal = {The British journal of dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1093/bjd/ljae401}, pmid = {39438074}, issn = {1365-2133}, abstract = {BACKGROUND: Combination immune checkpoint blockade targeting PD-1 and CTLA-4 leads to high response rates and improved survival in advanced cutaneous melanoma (CM). Less is known about the efficacy of this combination in acral lentiginous melanoma (ALM).<br><br>OBJECTIVES: To determine the efficacy of combination immune checkpoint blockade targeting PD-1 and CTLA-4 in a real-world, diverse population of ALM.<br><br>METHODS: This multi-institutional retrospective study analyzed patients with histologically confirmed ALM treated with the combination of PD-1 and CTLA-4 inhibitors between 2010-2022. The primary objective of the study was objective response rate (ORR) per RECIST criteria. The secondary objectives were progression-free survival (PFS) and overall survival (OS).<br><br>RESULTS: In total, 109 patients with advanced ALM treated with combined PD-1 and CTLA-4 blockade in any line of treatment were included. The majority of patients had stage IV disease (n=81, 74.2%). The ORR for the entire cohort was 18.3% (95% CI 11.6-26.9%), with 9 (8.3%) complete responses (CR) and 11 (10.1%) partial responses (PR). An additional 22 patients (20.2%) had stable disease (SD), and the disease control rate (DCR) was 38.5%. The median PFS was 4.2 months [95% CI 3.25-5.62], while the median OS was 17 months [95% CI 12.4%-23.1%]. A total of 95 patients (87.2%) had a treatment-related adverse event, with 40.4% (n=44/109) experiencing at least one grade 3 or 4 toxicity. Elevated LDH (p=.04), 2+ lines of prior therapy (p=.03), and Asian race/ethnicity (p=.04) were associated with worse OS, while Hispanic/Latino race/ethnicity was associated with better OS (p=.02).<br><br>CONCLUSIONS: Combination of PD-1 and CTLA-4 blockade is less effective for ALM, as compared to CM, despite similar toxicity. Asian patients, in particular, appear to derive lower benefit from this regimen. Novel treatment approaches are needed for this rare melanoma subtype.}, }
@article {pmid39437647, year = {2024}, author = {Wickline, MM and Carpenter, PA and Harris, JR and Iribarren, SJ and Reding, KW and Pike, KC and Lee, SJ and Salit, RB and Oshima, MU and Vo, PT and Berry, DL}, title = {Vaccine hesitancy and routine revaccination among adult HCT survivors in the United States: A convergent mixed methods analysis.}, journal = {Vaccine}, volume = {42}, number = {26}, pages = {126374}, doi = {10.1016/j.vaccine.2024.126374}, pmid = {39437647}, issn = {1873-2518}, abstract = {Revaccination to restore immunity to vaccine-preventable diseases (VPDs) is essential risk mitigation in the prevention of infectious morbidity and mortality after hematopoietic cell transplantation (HCT). However, revaccination rates have been shown to be insufficient and to what extent vaccine hesitancy contributes to survivors not becoming fully revaccinated is unknown. We performed a cross-sectional, mixed methods survey-based study to explore how vaccine hesitancy influences revaccination among US adult HCT survivors who were 2 to 8 years after transplant. Participants were asked to complete the Vaccination Confidence Scale (VCS) and open-ended survey items regarding vaccine confidence. The survey response rate was 30 %; among 332 respondents, vaccine confidence was high in 69 %, medium in 20 %, and low in 11 %. On multivariable analysis, four factors associated with high vaccine confidence were: predominantly Democrat zip codes (per 2020 election results), ability to pay for revaccination out of pocket, receipt of pre-HCT adult vaccines, and receipt of COVID-19 vaccines. From 189 participants who also answered open-ended items, 14 themes associated with vaccine confidence were identified and collapsed into 4 categories based on the VCS: Benefits, Harms, Trust, and Other. Merged analysis showed congruence between VCS scores and open-ended survey responses and created a narrative about the relative importance of the constructs when approaching revaccination by vaccine confidence level. These findings significantly expand our knowledge of how vaccine hesitancy influences revaccination uptake among US adult HCT survivors. Population-specific interventions to approach vaccine-hesitant survivors should be developed and tested.}, }
@article {pmid39436293, year = {2024}, author = {Partridge, SC and Xu, J}, title = {Cellular Characterization of Breast Cancer Using Microstructural Diffusion MRI.}, journal = {Radiology}, volume = {313}, number = {1}, pages = {e242268}, pmid = {39436293}, issn = {1527-1315}, support = {R01 CA190299/CA/NCI NIH HHS/United States ; R01 CA207290/CA/NCI NIH HHS/United States ; R01 CA269620/CA/NCI NIH HHS/United States ; R21 CA270731/CA/NCI NIH HHS/United States ; }, }
@article {pmid39433652, year = {2024}, author = {Adesina, OO and Jenkins, IC and Galvão, F and de Moura, AC and Fertrin, KY and Zemel, BS and Saad, STO}, title = {Alendronate preserves bone mineral density in adults with sickle cell disease and osteoporosis.}, journal = {Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA}, volume = {}, number = {}, pages = {}, pmid = {39433652}, issn = {1433-2965}, support = {5K23HL148310-02/HL/NHLBI NIH HHS/United States ; CSDA 2020095/DDCF/Doris Duke Charitable Foundation/United States ; }, abstract = {UNLABELLED: Low bone mineral density is highly prevalent in sickle cell disease (SCD); whether bisphosphonates can safely preserve or increase bone mass in SCD adults remains unknown. In this study, lumbar spine bone density remained stable with alendronate use, and treatment-related side effects were mostly mild and self-limited.<br><br>PURPOSE: To describe the effects of alendronate in adults with sickle cell disease (SCD) and osteoporosis.<br><br>METHODS: We reviewed retrospective clinical data from adults with SCD and osteoporosis treated with alendronate at a single center in Brazil (2009-2019). Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA) of the lumbar spine, femoral neck, and total hip. We analyzed BMD changes by alendronate treatment duration (months), stratified by sex, skeletal site, and SCD genotype.<br><br>RESULTS: Sixty-four SCD adults with osteoporosis (69% females, 73% HbSS, mean age&#x2009;&#xb1;&#x2009;standard deviation 42.4&#x2009;&#xb1;&#x2009;10.9&#xa0;years) received alendronate for a median (interquartile range) of 48 (29, 73) months. Compared with males, females had significantly lower baseline BMD (g/cm[2]) at the femoral neck (0.72 vs 0.85, p&#x2009;=&#x2009;&#x2009;<&#x2009;0.001) and total hip (0.79 vs 0.88, p&#x2009;=&#x2009;0.009). The between-sex differences in BMD changes were insignificant. Mean lumbar spine BMD significantly changed by 0.0357&#xa0;g/cm[2] (p&#x2009;=&#x2009;0.028) in those on alendronate for&#x2009;>&#x2009;5&#xa0;years. Four adults (6.3%) reported mild therapy-related side effects. An atypical femoral diaphysis fracture, attributed to alendronate, was incidentally noted in a 37-year-old man on treatment for 4&#xa0;years.<br><br>CONCLUSION: In this retrospective cohort of adults with SCD and osteoporosis on alendronate for a median of 48&#xa0;months, we found no significant interactions between sex and changes in lumbar spine, femoral neck, or total hip BMD with alendronate. Lumbar spine BMD was stable in those on alendronate for&#x2009;<&#x2009;5&#xa0;years. Side effects of alendronate were mild, though one patient developed an atypical femoral fracture.}, }
@article {pmid39432443, year = {2024}, author = {Molstad, AJ and Cai, Y and Reiner, AP and Kooperberg, C and Sun, W and Hsu, L}, title = {Heterogeneity-aware integrative regression for ancestry-specific association studies.}, journal = {Biometrics}, volume = {80}, number = {4}, pages = {}, pmid = {39432443}, issn = {1541-0420}, support = {75N92021D00001/HL/NHLBI NIH HHS/United States ; /HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; R01 HL145806/NH/NIH HHS/United States ; //WHI/ ; }, mesh = {Humans ; *Polymorphism, Single Nucleotide ; *Quantitative Trait Loci ; Genome-Wide Association Study/statistics &amp; numerical data ; Regression Analysis ; Likelihood Functions ; Black People/genetics/statistics &amp; numerical data ; Proteome ; Computer Simulation ; Models, Statistical ; Biometry/methods ; }, abstract = {Ancestry-specific proteome-wide association studies (PWAS) based on genetically predicted protein expression can reveal complex disease etiology specific to certain ancestral groups. These studies require ancestry-specific models for protein expression as a function of SNP genotypes. In order to improve protein expression prediction in ancestral populations historically underrepresented in genomic studies, we propose a new penalized maximum likelihood estimator for fitting ancestry-specific joint protein quantitative trait loci models. Our estimator borrows information across ancestral groups, while simultaneously allowing for heterogeneous error variances and regression coefficients. We propose an alternative parameterization of our model that makes the objective function convex and the penalty scale invariant. To improve computational efficiency, we propose an approximate version of our method and study its theoretical properties. Our method provides a substantial improvement in protein expression prediction accuracy in individuals of African ancestry, and in a downstream PWAS analysis, leads to the discovery of multiple associations between protein expression and blood lipid traits in the African ancestry population.}, }
@article {pmid39431098, year = {2024}, author = {Rodarte, J and Baehr, C and Hicks, D and McGovern, M and Zhang, Y and Silva-Ortiz, P and Hannon, B and Duddu, S and Pancera, M and Pravetoni, M}, title = {Structure-Based Engineering of Monoclonal Antibodies for Improved Binding to Counteract the Effects of Fentanyl and Carfentanil.}, journal = {ACS omega}, volume = {9}, number = {41}, pages = {42506-42519}, pmid = {39431098}, issn = {2470-1343}, support = {U01 DA051658/DA/NIDA NIH HHS/United States ; UG3 DA057850/DA/NIDA NIH HHS/United States ; }, abstract = {The opioid overdose epidemic is a growing and evolving public health crisis fueled by the widespread presence of fentanyl and fentanyl analogues (F/FAs) in both street mixtures and counterfeit pills. To expand current treatment options, drug-targeting monoclonal antibodies (mAbs) offer a viable therapeutic for both pre- and postexposure clinical scenarios. This study reports the isolation, in vitro characterization, and in vivo efficacy of two murine mAb families targeting fentanyl, carfentanil, or both. Because humanization of the mAbs by CDR grafting negatively impacted affinity for both fentanyl and carfentanil, crystal structures of mAbs in complex with fentanyl or carfentanil were analyzed to identify key residues involved in ligand binding in murine versus humanized structures, and site-directed mutagenesis was used to verify their functional importance. The structural analysis identified a framework residue, Tyr36, present in the murine germline sequence of two mAbs, which was critical for binding to fentanyl and carfentanil. These studies emphasize the importance of structural considerations in mAb engineering to optimize mAbs targeting small molecules including opioids and other drugs of public health interest.}, }
@article {pmid39430319, year = {2024}, author = {Ye, L and Ryu, H and Granadier, D and Nguyen, LT and Simoni, Y and Dick, I and Firth, T and Rouse, E and Chiang, P and Lee, YCG and Robinson, BW and Creaney, J and Newell, EW and Redwood, AJ}, title = {Stem-like exhausted CD8 T cells in pleural effusions predict improved survival in non-small cell lung cancer (NSCLC) and mesothelioma.}, journal = {Translational lung cancer research}, volume = {13}, number = {9}, pages = {2352-2372}, pmid = {39430319}, issn = {2218-6751}, abstract = {BACKGROUND: Anti-tumor CD8 T cells are important for immunity but can become 'exhausted' and hence ineffective. Tumor-infiltrating exhausted CD8[+] T cells include less differentiated stem-like exhausted T (Tex[stem]) cells and terminally exhausted T (Tex[term]) cells. Both subsets have been proposed as prognostic biomarkers in cancer patients. In this study, we retrospectively investigated their prognostic significance in patients with metastatic non-small cell lung cancer (NSCLC) and validated our findings in a mesothelioma cohort.<br><br>METHODS: Pre-treatment malignant pleural effusions (PEs) from 43 NSCLC (41 non-squamous, 2 squamous) patients were analyzed by flow cytometry. The percentages of Tex[stem] and Tex[term] CD8 T cells were correlated with overall survival (OS) after adjusting for clinicopathological variables. Findings were validated using a mesothelioma cohort (n=49). Mass cytometry was performed on 16 pre-treatment PE samples from 5 mesothelioma and 3 NSCLC patients for T-cell phenotyping. Single-cell multi-omics analysis was performed on 4 pre-treatment PE samples from 2 NSCLC patients and 2 mesothelioma patients for analysis of the transcriptomic profiles, surface markers and T cell receptor (TCR) repertoire.<br><br>RESULTS: Higher frequency of Tex[stem] was associated with significantly increased OS [median 9.9 vs. 3.4 months, hazard ratio (HR) 0.36, 95% CI: 0.16-0.79, P=0.01]. The frequency of Tex[term] was not associated with OS. These findings were validated in the mesothelioma cohort (high vs. low Tex[stem], median OS 32.1 vs. 19.8 months, HR 0.31, 95% CI: 0.10-0.96, P=0.04). Detailed single-cell sequencing and mass cytometry profiling revealed that exhausted T cells from NSCLC expressed greater stem-likeness and less inhibitory markers than those from mesothelioma and that Tex[stem] cells also contained 'bystander' virus-specific T cells.<br><br>CONCLUSIONS: This study demonstrates that PE CD8 Tex[stem] cell abundance is associated with better survival outcomes, and thus may be a useful prognostic biomarker.}, }
@article {pmid39429723, year = {2024}, author = {Georgakopoulou, A and Li, C and Kiem, HP and Lieber, A}, title = {In vitro and in vivo expansion of CD33/HBG promoter-edited HSPCs with Mylotarg.}, journal = {Molecular therapy. Methods &amp; clinical development}, volume = {32}, number = {4}, pages = {101343}, pmid = {39429723}, issn = {2329-0501}, abstract = {We developed an in vivo HSC gene therapy approach that consists of HSC mobilization and intravenous injection of HSC-tropic HDAd vectors. To achieve therapeutically relevant numbers of corrected cells, we incorporated in vivo expansion of transduced cells. We used an HDAd vector for a multiplex adenine base editing approach to (1) remove the region within CD33 that is recognized by gemtuzumab ozogamicin (GO) (Mylotarg), and (2) create therapeutic edits within the HBG1/2 promoters to reactivate γ-globin/HbF. In vitro studies with HDAd-transduced human CD34[+] cells showed editing of both targeted sites and a 2- to 3-fold GO-mediated expansion of edited erythroid/myeloid progenitors. After erythroid in vitro differentiation, up to 40% of erythrocytes were HbF positive. For in vivo studies, mice were transplanted with human CD34[+] cells. After engraftment, HSCs were mobilized with G-CSF/AMD3100 followed by an intravenous HDAd injection and GO-mediated in vivo selection. Two months later, editing in human cells within the bone marrow was significantly higher in GO-treated mice. The percentage of HbF[+] human erythroid cells was 2.5-fold greater compared with untreated mice. These data indicate that in vivo GO selection can increase edited erythroid cells.}, }
@article {pmid39428758, year = {2024}, author = {Minot, SS and Mayer-Blackwell, K and Fiore-Gartland, A and Johnson, A and Self, S and Bhatti, P and Yao, L and Liu, L and Sun, X and Jinfa, Y and Kublin, J}, title = {Species- and subspecies-level characterization of health-associated bacterial consortia that colonize the human gut during infancy.}, journal = {Gut microbes}, volume = {16}, number = {1}, pages = {2414975}, pmid = {39428758}, issn = {1949-0984}, support = {R01 AI127100/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Gastrointestinal Microbiome ; Infant ; *Feces/microbiology ; *Bacteria/classification/genetics/isolation &amp; purification ; Male ; Female ; Metagenomics ; Microbial Consortia ; Metagenome ; Infant, Newborn ; Cohort Studies ; Cystic Fibrosis/microbiology ; }, abstract = {BACKGROUND: The human gut microbiome develops rapidly during infancy, a key window of development coinciding with the maturation of the adaptive immune system. However, little is known about the microbiome growth dynamics over the first few months of life and whether there are any generalizable patterns across human populations. We performed metagenomic sequencing on stool samples (n = 94) from a cohort of infants (n = 15) at monthly intervals in the first 6 months of life, augmenting our dataset with seven published studies for a total of 4,441 metagenomes from 1,162 infants.<br><br>RESULTS: Strain-level de novo analysis was used to identify 592 of the most abundant organisms in the infant gut microbiome. Previously unrecognized consortia were identified which exhibited highly correlated abundances across samples and were composed of diverse species spanning multiple genera. Analysis of a published cohort of infants with cystic fibrosis identified one such novel consortium of diverse Enterobacterales which was positively correlated with weight gain. While all studies showed an increased community stability during the first year of life, microbial dynamics varied widely in the first few months of life, both by study and by individual.<br><br>CONCLUSION: By augmenting published metagenomic datasets with data from a newly established cohort, we were able to identify novel groups of organisms that are correlated with measures of robust human development. We hypothesize that the presence of these groups may impact human health in aggregate in ways that individual species may not in isolation.}, }
@article {pmid39428129, year = {2024}, author = {Samorodnitsky, S and Wu, MC}, title = {Statistical analysis of multiple regions-of-interest in multiplexed spatial proteomics data.}, journal = {Briefings in bioinformatics}, volume = {25}, number = {6}, pages = {}, pmid = {39428129}, issn = {1477-4054}, support = {U10 CA180819/GF/NIH HHS/United States ; //Hope Foundation for Cancer Research/ ; }, mesh = {Humans ; *Proteomics/methods ; Neoplasms/metabolism/genetics ; Carcinoma, Non-Small-Cell Lung/metabolism/pathology/genetics ; Triple Negative Breast Neoplasms/pathology/metabolism/genetics ; Colorectal Neoplasms/metabolism/pathology/genetics ; Lung Neoplasms/metabolism/pathology/genetics ; Data Interpretation, Statistical ; Algorithms ; }, abstract = {Multiplexed spatial proteomics reveals the spatial organization of cells in tumors, which is associated with important clinical outcomes such as survival and treatment response. This spatial organization is often summarized using spatial summary statistics, including Ripley's K and Besag's L. However, if multiple regions of the same tumor are imaged, it is unclear how to synthesize the relationship with a single patient-level endpoint. We evaluate extant approaches for accommodating multiple images within the context of associating summary statistics with outcomes. First, we consider averaging-based approaches wherein multiple summaries for a single sample are combined in a weighted mean. We then propose a novel class of ensemble testing approaches in which we simulate random weights used to aggregate summaries, test for an association with outcomes, and combine the $P$-values. We systematically evaluate the performance of these approaches via simulation and application to data from non-small cell lung cancer, colorectal cancer, and triple negative breast cancer. We find that the optimal strategy varies, but a simple weighted average of the summary statistics based on the number of cells in each image often offers the highest power and controls type I error effectively. When the size of the imaged regions varies, incorporating this variation into the weighted aggregation may yield additional power in cases where the varying size is informative. Ensemble testing (but not resampling) offered high power and type I error control across conditions in our simulated data sets.}, }
@article {pmid39424451, year = {2024}, author = {Li, T and Isautier, J and Lee, JM and Marinovich, ML and Houssami, N}, title = {Performance of Digital Breast Tomosynthesis Versus Digital Mammography in Women With a Family History of Breast Cancer: A Systematic Review.}, journal = {Clinical breast cancer}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.clbc.2024.09.013}, pmid = {39424451}, issn = {1938-0666}, abstract = {BACKGROUND: There is limited evidence on the performance of digital breast tomosynthesis (DBT) in populations at increased risk of breast cancer. Our objective was to systematically review evidence on the performance of DBT versus digital mammography (DM) in women with a family history of breast cancer (FHBC).<br><br>METHODS: We searched 5 databases (2011-January 2024) for studies comparing DBT and DM in women with a FHBC that reported any measure of cancer detection, recall, sensitivity and specificity. Findings were presented using a descriptive and narrative approach. Risk of bias was assessed using QUADAS-2/C.<br><br>RESULTS: Five (4 screening, 1 diagnostic) studies were included (total 3089 DBT, 3024 DM) with most (4/5) being prospective including 1 RCT. All studies were assessed as being at high risk of bias or applicability concern. Four screening studies reported recall rate (range: DBT: 2.7%-4.5%, DM: 2.8%-11.5%) with 3 reporting DBT had lower rates than DM. Cancer detection rates (CDR) were reported in the same studies (DBT: 5.1-11.6 per 1000, DM: 3.8-8.3); 3 reported higher CDR for DBT (vs. DM), and 1 reported same CDR for both. Compared with DM, higher values for sensitivity, specificity and PPV for DBT were reported in 2 studies.<br><br>CONCLUSION: This review provides early evidence that DBT may outperform DM for screening women with a FHBC. Our findings support further evaluation of DBT in this population. However, summarized findings were based on few studies and participants, and high-quality studies with improved methodology are needed to address biases identified in our review.}, }
@article {pmid39424273, year = {2024}, author = {Liese, AD and Julceus, EF and Brown, AD and Pihoker, C and Frongillo, EA and Sauder, KA and Malik, FS and Bellatorre, A and Reboussin, BA and Mendoza, JA}, title = {Reassessing the Burden of Food Insecurity in Youth and Young Adults With Youth-onset Diabetes: The Importance of Marginal Food Security.}, journal = {Canadian journal of diabetes}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jcjd.2024.10.006}, pmid = {39424273}, issn = {2352-3840}, abstract = {INTRODUCTION: Whereas marginal food insecurity has been recognized as important in Canadian food security policy, the category of marginal food security (MFS) is often ignored in US food security research.<br><br>METHODS: Prevalence of FI was estimated according to the conventional and an alternate classification of MFS with food insecurity among 938 youth and young adults (YYA) with youth-onset type 1 diabetes (T1D) and 156 with youth-onset of type 2 diabetes (T2D) from the SEARCH Food Security Cohort Study (2018-2021). Multivariable regression was used to estimate the association of MFS and conventionally defined food insecurity (FI) ascertained with diabetes-related outcomes, including acute diabetes complications, health care utilization, and diabetes self-management among YYA with T1D.<br><br>RESULTS: MFS affected 10% of participants with T1D diabetes and 20% of participants with T2D. Classifying MFS with FI increased FI prevalence from 18.0% to 27.8% in participants with T1D and 34.6% to 55.1% in participants with T2D. Compared to T1D with high food security, YYA with T1D who were FI had higher odds hypoglycemia (2.1, 95% CI 1.2 to 3.6) and ketoacidosis (1.6, 95% CI 1.0 to 2.6), but no association was seen in MFS. The FI group also had higher odds of emergency department use and hospitalization (2.3, 95% CI 1.5 to 3.4; 2.4, 95% CI 1.5 to 3.9) and lower odds of technology use and checking glucose (0.6, 95% CI 0.4 to 0.9; 0.3, 95% CI 0.1 to 0.6). The MFS group exhibited associations of similar directions.<br><br>DISCUSSION AND CONCLUSION: Health care providers should consider care of patients with T1D and MFS the same way they care for patients with FI.}, }
@article {pmid39422615, year = {2024}, author = {Lazarchuk, P and Nguyen, MM and Curca, CM and Pavlova, MN and Oshima, J and Sidorova, JM}, title = {Werner syndrome RECQ helicase participates in and directs maintenance of the protein complexes of constitutive heterochromatin in proliferating human cells.}, journal = {Aging}, volume = {16}, number = {20}, pages = {12977-13011}, pmid = {39422615}, issn = {1945-4589}, support = {R01 CA210916/CA/NCI NIH HHS/United States ; R01 GM115482/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Werner Syndrome Helicase/metabolism/genetics ; *Heterochromatin/metabolism ; *Werner Syndrome/genetics/metabolism ; *Fibroblasts/metabolism ; *Cell Proliferation ; Chromobox Protein Homolog 5/metabolism ; Histone Deacetylase 2/metabolism/genetics ; DNA Replication ; Cellular Senescence ; RecQ Helicases/metabolism/genetics ; }, abstract = {Werner syndrome of premature aging is caused by mutations in the WRN RECQ helicase/exonuclease, which functions in DNA replication, repair, transcription, and telomere maintenance. How the loss of WRN accelerates aging is not understood in full. Here we show that WRN is necessary for optimal constitutive heterochromatin levels in proliferating human fibroblasts. Locally, WRN deficiency derepresses SATII pericentromeric satellite repeats but does not reduce replication fork progression on SATII repeats. Globally, WRN loss reduces a subset of protein-protein interactions responsible for the organization of constitutive heterochromatin in the nucleus, namely, the interactions involving Lamin B1 and Lamin B receptor, LBR. Both the mRNA level and subcellular distribution of LBR are affected by WRN deficiency, and unlike the former, the latter phenotype does not require WRN catalytic activities. The phenotypes of heterochromatin disruption seen in WRN-deficient proliferating fibroblasts are also observed in WRN-proficient fibroblasts undergoing replicative or oncogene-induced senescence. WRN interacts with histone deacetylase 2, HDAC2; WRN/HDAC2 association is mediated by heterochromatin protein alpha, HP1α, and WRN complexes with HP1α and HDAC2 are downregulated in senescing cells. The data suggest that the effect of WRN loss on heterochromatin is separable from senescence program, but mimics at least some of the heterochromatin changes associated with it.}, }
@article {pmid39422601, year = {2024}, author = {Samorodnitsky, S and Othus, M and LeBlanc, M and Wu, MC}, title = {Reverse Selection Designs for Accommodating Multiple Control Arms.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-24-1282}, pmid = {39422601}, issn = {1557-3265}, abstract = {Evaluating a novel treatment in a randomized controlled trial requires comparison against existing therapies. If several existing therapies of similar benefit exist, the identification of a single control regimen may be difficult. For this situation, we propose a reverse selection design which, in its simplest form, includes a single experimental treatment arm and two control arms. Rather than carrying both control arms through the entire trial, the control arms are compared at an early interim analysis, ideally while accrual is ongoing. At this time, the worst-performing control arm is dropped and randomization continues to the remaining arms. At the end of the study, we compare the treatment to the remaining control arm. When no head-to-head comparison of the extant therapies is available or feasible, this design requires a smaller sample size than a traditional three-arm design or two sequential trials in which the extant therapies are compared and the better treatment is used in a subsequent trial as the control arm. This is because the final comparison is only between two arms and because the early interim analysis occurs prior to the end of accrual - yet with enough information such that any substantially better control arm will be selected. We evaluate the operating characteristics of a reverse selection design via simulation and show that it reduces the required sample size needed to compare the treatment against the best control, controls type I error, and likely selects the right control arm to use in the final analysis.}, }
@article {pmid39420548, year = {2024}, author = {Kelly, JP and Runco, DV and Slaven, JE and Niehaus, JZ}, title = {Healthcare Utilization in Pediatric Cancer Patients Near the End-of-Life.}, journal = {The American journal of hospice &amp; palliative care}, volume = {}, number = {}, pages = {10499091241294055}, doi = {10.1177/10499091241294055}, pmid = {39420548}, issn = {1938-2715}, abstract = {Objective: Describe the healthcare utilization in the last 60 days of life in pediatric patients with cancer who died at home under hospice care and those that died in the hospital. Methods: Retrospective chart review of the medical records of those children with cancer diagnosis with palliative care consult and died either under hospice care at home or in the hospital. Results: Patients dying under hospice care spent a median of 44 days at home. Patients dying in the hospital spent a median of 30.5 days in the hospital, 10.5 days in the intensive care unit, and underwent 3.5 procedures requiring anesthesia. 45% of those that died in the hospital were compassionately extubated. Conclusion: For those dying with a cancer diagnosis, hospice care can allow for significant time at home with minimal healthcare while those dying in the hospital do spend a significant time in the hospital. This provides more information to both providers and families about end-of-life healthcare utilization.}, }
@article {pmid39420192, year = {2024}, author = {Wallis, W and Gulbis, AM and Wang, T and Lee, CJ and Sharma, A and Williams, KM and Nishihori, T and Prestidge, T and Gowda, L and Byrne, M and Krem, MM and MacMillan, ML and Kitko, CL and Pidala, J and Spellman, SR and Lee, SJ and Alousi, AM}, title = {Incidence of bacterial blood stream infections in patients with acute GVHD.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, pmid = {39420192}, issn = {1476-5365}, support = {U24 CA076518/CA/NCI NIH HHS/United States ; }, abstract = {Bacterial bloodstream infections (BSI) can be a substantial contributor to complications of GVHD treatment. The aim of this study was to determine the risk for BSI from neutrophil engraftment through day 100 post transplant in patients with acute GVHD (AGVHD) based on organ involvement and severity. Patients (n = 4064) who underwent an allogeneic hematopoietic stem cell transplant (HCT) reported to the CIBMTR registry were analyzed. Grade II-IV AGVHD occurred in 1607 (39.5%) patients and was associated with a greater day-100 incidence of post engraftment BSI than with grade 0/I (24.9 vs. 15.3%). Patients with grade III/IV AGVHD had the highest BSI risk (HR 2.45; 95% CI 1.99-3.0; p < 0.0001). Lower GI involvement increased BSI risk (HR 1.54; 95% CI 1.17-2.02; p = 0.0019). BSI post-engraftment through day 100 was associated with worse survival (HR 1.64, 95% CI 1.43-1.87; p < 0.001) and higher non-relapse mortality (NRM), (HR 2.22; 95% CI 1.91-2.59; p < 0.001). Those with stage III/IV GI involvement are at highest risk for BSI. Future studies evaluating novel methods for preventing BSI in these high risk populations are needed to reduce mortality associated with AGVHD.}, }
@article {pmid39419747, year = {2024}, author = {Lehrbach, N}, title = {Anything you can do, glycans do better: deglycosylation and noncanonical ubiquitination vie to rule the proteasome.}, journal = {Trends in biochemical sciences}, volume = {49}, number = {12}, pages = {1033-1035}, pmid = {39419747}, issn = {0968-0004}, support = {R35 GM142728/GM/NIGMS NIH HHS/United States ; }, mesh = {*Ubiquitination ; *Proteasome Endopeptidase Complex/metabolism ; Glycosylation ; Humans ; *Polysaccharides/metabolism/chemistry ; Animals ; Nuclear Respiratory Factor 1/metabolism ; }, abstract = {The Nrf1/Nfe2L1 transcription factor is a master regulator of proteasome biogenesis. New work by Yoshida and colleagues reveals a surprising mechanism by which ubiquitination of N-glycosylated Nrf1 controls its function.}, }
@article {pmid39418644, year = {2024}, author = {Uy, GL and Pullarkat, VA and Baratam, P and Stuart, RK and Walter, RB and Winer, ES and Wang, Q and Faderl, S and Chakravarthy, D and Menno, D and Cheung, RS and Lin, TL}, title = {Lower-intensity CPX-351 plus venetoclax induction for adults with newly diagnosed AML unfit for intensive chemotherapy.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024013687}, pmid = {39418644}, issn = {2473-9537}, abstract = {Preclinical data suggest a rationale for combining CPX-351, a dual-drug liposomal encapsulation of daunorubicin and cytarabine, with venetoclax, a B-cell lymphoma-2 (BCL-2) inhibitor. This phase 1b study evaluated lower-intensity CPX-351 combined with venetoclax in adults with acute myeloid leukemia (AML) considered unfit/ineligible for intensive chemotherapy. In a dose-exploration phase using a 3+3 design, patients received stepwise dosing of CPX‑351 intravenously on days 1 and 3 plus venetoclax 400 mg orally on days 2-21 per cycle to determine the recommended phase 2 dose (RP2D) for this combination. During the expansion phase, additional patients received CPX-351 plus venetoclax at the identified RP2D. The primary endpoints were the RP2D and safety of CPX‑351 combined with venetoclax. Secondary endpoints included preliminary efficacy and pharmacokinetics. Overall, 35 patients were enrolled in the study. A RP2D of CPX-351 30 units/m2 (daunorubicin 13.2 mg/m2 and cytarabine 30 mg/m2) plus venetoclax 400 mg was established. The safety profile of the combination was consistent with the known safety profiles of CPX-351 and venetoclax. Complete remission (CR)/CR with incomplete hematologic recovery (CRi) was achieved by 17/35 (49%) patients, all after cycle 1; of these, 14 were negative for measurable residual disease. CR was achieved by 1/8 (13%) patients with a mutation in TP53, and CR/CRi was achieved by 15/26 (58%) patients with wild-type TP53. This study highlights that lower-intensity therapy of CPX-351 plus venetoclax as induction therapy provides a well-tolerated treatment option in adults with AML deemed unfit for intensive chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT04038437.}, }
@article {pmid39417692, year = {2024}, author = {Chae, YK and Othus, M and Patel, SP and Wilkinson, KJ and Whitman-Purves, EM and Lea, J and Schallenkamp, JM and Adra, N and Appleman, LJ and Alden, M and Thomes Pepin, J and Ellerton, JA and Poklepovic, A and Walter, A and Rampurwala, MM and Robinson, WR and Kim, HS and Chung, LI and McLeod, CM and Lopez, G and Chen, HX and Sharon, E and Streicher, H and Ryan, CW and Blanke, CD and Kurzrock, R}, title = {SWOG/NCI Phase II Dual Anti-CTLA-4/PD-1 Blockade in Rare Tumors (DART): Non-Epithelial Ovarian Cancer.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-24-0606}, pmid = {39417692}, issn = {1557-3265}, support = {U10 CA180868/CA/NCI NIH HHS/United States ; UG1 CA233320/CA/NCI NIH HHS/United States ; U10 CA180821/CA/NCI NIH HHS/United States ; UG1 CA233198/CA/NCI NIH HHS/United States ; U10 CA180820/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: The role of dual checkpoint inhibition in advanced rare/ultra-rare non-epithelial ovarian cancers (NEOCs) is yet to be explored.<br><br>METHODS: DART is a prospective, multicenter (1,016 US sites), multi-cohort, single-arm phase II trial conducted through the Early Therapeutics and Rare Cancer SWOG/NCI Committee, assessing ipilimumab (anti-CTLA-4) (1mg/kg every 6 weeks) and nivolumab (anti-PD-1) (240mg every 2 weeks) in adults with advanced NEOCs who lack beneficial standard therapy. Primary outcome was overall response rate [ORR; complete response (CR)/partial response (PR)]; secondary outcomes were progression-free survival (PFS), overall survival (OS), clinical benefit rate [CBR; stable disease (SD) &#x2265;6 months plus ORR], and toxicity.<br><br>RESULTS: Seventeen patients (median age: 64; number of prior therapies ranged from 0-8 with no immunotherapy exposure; 8 granulosa, 6 carcinosarcomas, 1 Sertoli-Leydig, 1 yolk sac, 1 Wolffian) were evaluated. In granulosa cell tumors, ORR was 25% (n=2/8; 1 CR, 1 PR) and CBR, 50% (n=4/8); PFS of 58.3 (CR), 50.7+ (PR), 30.4 (SD), and 8.7 (SD) months. Median PFS was 3.5 months (95% confidence intervals (CI) 1.7-11.2 months); median OS, 42.5 months (95% CI 10.1 months-not reached). One Sertoli-Leydig cell tumor showed a 22% regression (PFS 11.2 months). Carcinosarcomas had no response. Three participants (18%) discontinued treatment due to grade 3-4 adverse events.<br><br>CONCLUSIONS: Ipilimumab-nivolumab shows activity in treatment-refractory granulosa cell tumors, with 25% (n=2/8) of patients experiencing either CR or PR lasting over 4 years.&#x200b;.}, }
@article {pmid39416221, year = {2024}, author = {Geiger, RA and Khera, D and Tenthorey, JL and Kochs, G and Graf, L and Emerman, M and Malik, HS}, title = {Heterozygous and generalist MxA super-restrictors overcome breadth-specificity tradeoffs in antiviral restriction.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39416221}, issn = {2692-8205}, support = {T32 HG000035/HG/NHGRI NIH HHS/United States ; U54 AI170792/AI/NIAID NIH HHS/United States ; }, abstract = {Antiviral restriction factors such as MxA (myxovirus resistance protein A) inhibit a broad range of viruses. However, they face the challenge of maintaining this breadth as viruses evolve to escape their defense. Viral escape drives restriction factors to evolve rapidly, selecting for amino acid changes at their virus-binding interfaces to regain defense. How do restriction factors balance the breadth of antiviral functions against the need to evolve specificity against individual escaping viruses? We explored this question in human MxA, which uses its rapidly evolving loop L4 as the specificity determinant for orthomyxoviruses such as THOV and IAV. Previous combinatorial mutagenesis of rapidly evolving residues in human MxA loop L4 revealed variants with a ten-fold increase in potency against THOV. However, this strategy did not yield improved IAV restriction, suggesting a strong tradeoff between antiviral specificity and breadth. Here, using a modified combinatorial mutagenesis strategy, we find 'super-restrictor' MxA variants with over ten-fold enhanced restriction of the avian IAV strain H5N1 but reduced THOV restriction. Analysis of super-restrictor MxA variants reveals that the identity of residue 561 explains most of MxA's breadth-specificity tradeoff in H5N1 versus THOV restriction. However, rare 'generalist' super-restrictors with enhanced restriction of both viruses allow MxA to overcome the breadth-specificity tradeoff. Finally, we show that a heterozygous combination of two 'specialist' super-restrictors, one against THOV and the other against IAV, enhances restriction against both viruses. Thus, two strategies enable restriction factors such as MxA to increase their restriction of diverse viruses to overcome breadth-specificity tradeoffs that may be pervasive in host-virus conflicts.}, }
@article {pmid39416011, year = {2024}, author = {Haack, AJ and Brown, LG and Goldstein, AJ and Mulimani, P and Berthier, J and Viswanathan, AR and Kopyeva, I and Whitten, JM and Lin, A and Nguyen, SH and Leahy, TP and Bouker, EE and Padgett, RM and Mazzawi, NA and Tokihiro, JC and Bretherton, RC and Wu, A and Tapscott, SJ and DeForest, CA and Popowics, TE and Berthier, E and Sniadecki, NJ and Theberge, AB}, title = {Suspended Tissue Open Microfluidic Patterning (STOMP).}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39416011}, issn = {2692-8205}, support = {F30 HL158030/HL/NHLBI NIH HHS/United States ; R01 HL149734/HL/NHLBI NIH HHS/United States ; R90 DE023059/DE/NIDCR NIH HHS/United States ; R35 GM128648/GM/NIGMS NIH HHS/United States ; TL1 TR002318/TR/NCATS NIH HHS/United States ; R03 DE029827/DE/NIDCR NIH HHS/United States ; R35 GM138036/GM/NIGMS NIH HHS/United States ; T32 CA080416/CA/NCI NIH HHS/United States ; P50 AR065139/AR/NIAMS NIH HHS/United States ; }, abstract = {Cell-laden hydrogel constructs suspended between pillars are powerful tools for modeling tissue structure and physiology, though current fabrication techniques often limit them to uniform compositions. In contrast, tissues are complex in nature with spatial arrangements of cell types and extracellular matrices. Thus, we present Suspended Tissue Open Microfluidic Patterning (STOMP), which utilizes a removable, open microfluidic patterning channel to pattern multiple spatial regions across a single suspended tissue. The STOMP platform contains capillary pinning features along the open channel that controls the fluid front, allowing multiple cell and extracellular matrix precursors to be pipetted into one tissue. We have used this technique to pattern suspended tissues with multiple regional components using a variety of native and synthetic extracellular matrices, including fibrin, collagen, and poly(ethylene glycol). Here, we demonstrate that STOMP models a region of fibrosis in a functional heart tissue and a bone-ligament junction in periodontal tissues. Additionally, the STOMP platform can be customized to allow patterning of suspended cores and more spatial configurations, enhancing its utility in complex tissue modeling. STOMP is a versatile technique for generating suspended tissue models with increased control over cell and hydrogel composition to model interfacial tissue regions in a suspended tissue.}, }
@article {pmid39415317, year = {2024}, author = {Purice, MD and Lago-Baldaia, I and Fernandes, VM and Singhvi, A}, title = {Molecular profiling of invertebrate glia.}, journal = {Glia}, volume = {}, number = {}, pages = {}, doi = {10.1002/glia.24623}, pmid = {39415317}, issn = {1098-1136}, support = {5T32CA080416-25/NH/NIH HHS/United States ; NS114222/NH/NIH HHS/United States ; 227823//Esther A. and Joseph Klingenstein Fund/ ; BRFSG-2023-10//Brain Research Foundation/ ; 225986/Z/22/Z/WT_/Wellcome Trust/United Kingdom ; //Washington Research Foundation/ ; }, abstract = {Caenorhabditis elegans and Drosophila melanogaster are powerful experimental models for uncovering fundamental tenets of nervous system organization and function. Findings over the last two decades show that molecular and cellular features are broadly conserved between invertebrates and vertebrates, indicating that insights derived from invertebrate models can broadly inform our understanding of glial operating principles across diverse species. In recent years, these model systems have led to exciting discoveries in glial biology and mechanisms of glia-neuron interactions. Here, we summarize studies that have applied current state-of-the-art "-omics" techniques to C. elegans and D. melanogaster glia. Coupled with the remarkable acceleration in the pace of mechanistic studies of glia biology in recent years, these indicate that invertebrate glia also exhibit striking molecular complexity, specificity, and heterogeneity. We provide an overview of these studies and discuss their implications as well as emerging questions where C. elegans and D. melanogaster are well-poised to fill critical knowledge gaps in our understanding of glial biology.}, }
@article {pmid39414943, year = {2024}, author = {Wang, T and Roach, MJ and Harvey, K and Morlanes, JE and Kiedik, B and Al-Eryani, G and Greenwald, A and Kalavros, N and Dezem, FS and Ma, Y and Pita-Juarez, YH and Wise, K and Degletagne, C and Elz, A and Hadadianpour, A and Johanneson, J and Pakiam, F and Ryu, H and Newell, EW and Tonon, L and Kohlway, A and Drennon, T and Abousoud, J and Stott, R and Lund, P and Durruthy, J and Vallejo, AF and Li, W and Salomon, R and Kaczorowski, D and Warren, J and Butler, LM and O'Toole, S and Plummer, J and Vlachos, IS and Lundeberg, J and Swarbrick, A and Martelotto, LG}, title = {snPATHO-seq, a versatile FFPE single-nucleus RNA sequencing method to unlock pathology archives.}, journal = {Communications biology}, volume = {7}, number = {1}, pages = {1340}, pmid = {39414943}, issn = {2399-3642}, support = {APP2004774//Department of Health | National Health and Medical Research Council (NHMRC)/ ; }, mesh = {*Paraffin Embedding/methods ; Humans ; *Sequence Analysis, RNA/methods ; *Tissue Fixation/methods ; *Single-Cell Analysis/methods ; Formaldehyde/chemistry ; Transcriptome ; Gene Expression Profiling/methods ; Workflow ; }, abstract = {Formalin-fixed paraffin-embedded (FFPE) samples are valuable but underutilized in single-cell omics research due to their low RNA quality. In this study, leveraging a recent advance in single-cell genomic technology, we introduce snPATHO-seq, a versatile method to derive high-quality single-nucleus transcriptomic data from FFPE samples. We benchmarked the performance of the snPATHO-seq workflow against existing 10x 3' and Flex assays designed for frozen or fresh samples and highlighted the consistency in snRNA-seq data produced by all workflows. The snPATHO-seq workflow also demonstrated high robustness when tested across a wide range of healthy and diseased FFPE tissue samples. When combined with FFPE spatial transcriptomic technologies such as FFPE Visium, the snPATHO-seq provides a multi-modal sampling approach for FFPE samples, allowing more comprehensive transcriptomic characterization.}, }
@article {pmid39414769, year = {2024}, author = {Fortuna, GG and Banerjee, R and Savid-Frontera, C and Song, J and Morán-Segura, CM and Nguyen, JV and Lekakis, L and Fernandez-Pol, S and Samraj, AN and Naresh, KN and Vazquez-Martinez, M and Baz, RC and Spiegel, JY and Mikkilineni, L and Gubatan, JM and Sidana, S and de Menezes Silva Corraes, A and Kalariya, NM and Patel, KK and Shim, KG and Fonseca, R and Ferreri, C and Voorhees, PM and Richard, S and Valdes, CR and Sireesha Asoori,  and Wolf, JL and Cowan, AJ and Sborov, DW and Locke, FL and Lin, Y and Wang, Y and Hansen, DK}, title = {Immune effector cell-associated enterocolitis following chimeric antigen receptor T-cell therapy in multiple myeloma.}, journal = {Blood cancer journal}, volume = {14}, number = {1}, pages = {180}, pmid = {39414769}, issn = {2044-5385}, support = {P30 CA076292/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Multiple Myeloma/therapy/immunology/drug therapy ; *Enterocolitis/etiology/therapy/immunology ; Male ; Middle Aged ; Female ; Aged ; *Immunotherapy, Adoptive/adverse effects ; Adult ; Receptors, Chimeric Antigen/therapeutic use/immunology ; }, abstract = {We report 14 cases of immune effector cell (IEC)-associated enterocolitis following chimeric antigen receptor T-cell (CAR-T) therapy in multiple myeloma, with a 1.2% incidence overall (0.2% for idecabtagene vicleucel and 2.2% for ciltacabtagene autoleucel). Patients developed acute-onset symptoms (typically non-bloody Grade 3+ diarrhea) with negative infectious workup beginning a median of 92.5 days (range: 22-210 days) after CAR-T therapy and a median of 85 days after cytokine release syndrome resolution. Gut biopsies uniformly demonstrated inflammation, including intra-epithelial lymphocytosis and villous blunting. In one case where CAR-specific immunofluorescence stains were available, CAR T-cell presence was confirmed within the lamina propria. Systemic corticosteroids were initiated in 10 patients (71%) a median of 25.5 days following symptom onset, with symptom improvement in 40%. Subsequent infliximab or vedolizumab led to improvement in 50% and 33% of corticosteroid-refractory patients, respectively. Five patients (36%) have died from bowel perforation or treatment-emergent sepsis. In conclusion, IEC-associated enterocolitis is a distinct but rare complication of CAR-T therapy typically beginning 1-3 months after infusion. Thorough diagnostic workup is essential, including evaluation for potential T-cell malignancies. The early use of infliximab or vedolizumab may potentially hasten symptom resolution and lower reliance on high-dose corticosteroids during the post-CAR-T period.}, }
@article {pmid39414027, year = {2024}, author = {Wong, WW and Speakman, JR and Ainslie, PN and Anderson, LJ and Arab, L and Baddou, I and Bedu-Addo, K and Blaak, EE and Blanc, S and Bonomi, AG and Bouten, CV and Bovet, P and Buchowski, MS and Butte, NF and Camps, SG and Casper, R and Close, GL and Colbert, LH and Cooper, JA and Das, SK and Davies, PS and Eaton, S and Ekelund, U and Hambly, C and El Hamdouchi, A and Entringer, S and Fudge, BW and Gillingham, M and Goris, AH and Gurven, M and Hoos, MB and Hu, S and Joosen, A and Katzmarzyk, PT and Kempen, KP and Kimura, M and Kraus, WE and Kushner, RF and Larsson, CL and Morehen, JC and Morton, JP and Neuhouser, ML and Nicklas, TA and Ojiambo, RM and Pietilainen, KH and Pitsiladis, YP and Plasqui, G and Prentice, RL and Rabinovich, R and Racette, SB and Raichen, DA and Redman, L and Ravussin, E and Reilly, JJ and Roberts, S and Scuitt, AJ and Sjödin, AM and Stice, E and Urlacher, SS and Valenti, G and van Etten, LM and Van Mil, EA and Verbunt, JA and Wells, JC and Wilson, G and Yoshida, T and Zhang, X and Loechl, CU and Luke, A and Murphy-Alford, AJ and Pontzer, H and Sagayama, H and Rood, JC and Schoeller, DA and Westerterp, KR and Yamada, Y and , }, title = {Decline in Isotope Dilution Space Ratio Above Age 60 Could Affect Energy Estimates Using the Doubly Labeled Water Method.}, journal = {The Journal of nutrition}, volume = {154}, number = {12}, pages = {3824-3831}, doi = {10.1016/j.tjnut.2024.10.016}, pmid = {39414027}, issn = {1541-6100}, mesh = {Humans ; Female ; Male ; Middle Aged ; *Body Composition ; *Energy Metabolism ; Aged ; Adult ; *Oxygen Isotopes ; Deuterium ; Indicator Dilution Techniques ; Water ; Young Adult ; Age Factors ; Aged, 80 and over ; Deuterium Oxide ; Anthropometry ; }, abstract = {BACKGROUND: Doubly labeled water is gold standard for measuring total energy expenditure (TEE). Measurements using the method are sensitive to the isotope dilution space ratio (DSR). Accuracy and precision of the method might be improved if we could identify factors influencing DSR.<br><br>OBJECTIVES: We evaluated the potential associations of age, sex, ethnicity, anthropometry, body composition, turnover rates of the isotopes, and geographical elevation with DSR.<br><br>METHODS: We used univariate regression analysis to explore the relationships between the continuous variables and analysis of variance to test the relationships between the categorical variables with DSR. Subsequently, we used general linear model (GLM) and 1-way analysis of variance to evaluate the simultaneous associations of age, sex, ethnicity, fat-free mass (FFM) and fat mass (FM) on DSR.<br><br>RESULTS: From 5678 measurements complied from studies around the world with diverse ethnicity and living at various elevations, the mean DSR was 1.0364 &#xb1; 0.0141. No meaningful physiologic effect of any of the continuous and categorical variable on DSR was detected. General linear model analysis revealed no effect of FFM and FM (P > 0.33) on DSR, but DSR decreased with age (P < 0.001) among those aged 60 y and older regardless of sex. Among the Whites who were younger than 60 y, DSR was not related to FFM and FM (P = 0.73) but was affected by both age and sex (P < 0.001).<br><br>CONCLUSIONS: Previous estimates of age-related decline in TEE may have overestimated TEE at age 90 y. Validation studies on older participants are required to confirm this finding.}, }
@article {pmid39413835, year = {2024}, author = {Liu, J and Berchuck, A and Backes, FJ and Cohen, J and Grisham, R and Leath, CA and Martin, L and Matei, D and Miller, DS and Robertson, S and Barroilhet, L and Uppal, S and Hendrickson, AW and Gershenson, DM and Gray, HJ and Hakam, A and Jain, A and Konecny, GE and Moroney, J and Ratner, E and Schorge, J and Thaker, PH and Werner, TL and Zsiros, E and Behbakht, K and Chen, LM and DeRosa, M and Eisenhauer, EL and Leiserowitz, G and Litkouhi, B and McHale, M and Percac-Lima, S and Rodabaugh, K and Vargas, R and Jones, F and Kovach, E and Hang, L and Ramakrishnan, S and Alvarez, RD and Armstrong, DK}, title = {NCCN Guidelines® Insights: Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer, Version 3.2024.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {8}, pages = {512-519}, doi = {10.6004/jnccn.2024.0052}, pmid = {39413835}, issn = {1540-1413}, mesh = {Humans ; Female ; *Ovarian Neoplasms/diagnosis/therapy/pathology ; *Peritoneal Neoplasms/therapy/diagnosis ; *Fallopian Tube Neoplasms/diagnosis/therapy/pathology ; Medical Oncology/standards/methods ; Neoplasm Staging ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; }, abstract = {The NCCN Guidelines for Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer provide multidisciplinary diagnostic workup, staging, and treatment recommendations for this disease. These NCCN Guidelines Insights detail how the evolution of the use of PARP inhibitors as maintenance and single-agent regimens for the treatment of ovarian cancer informed panel recommendations in the guidelines.}, }
@article {pmid39413812, year = {2024}, author = {Shah, B and Mattison, RJ and Abboud, R and Abdelmessieh, P and Aldoss, I and Burke, PW and DeAngelo, DJ and Dinner, S and Fathi, AT and Gauthier, J and Haddadin, M and Jain, N and Jonas, B and Kirby, S and Liedtke, M and Litzow, M and Logan, A and Long, M and Luger, S and Mangan, JK and Massaro, S and May, W and Oluwole, O and Park, J and Przespolewski, A and Rangaraju, S and Saygin, C and Schwartz, M and Shami, P and Tomlinson, B and Webster, J and Awotiwon, A and Stehman, K}, title = {Acute Lymphoblastic Leukemia, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {8}, pages = {563-576}, doi = {10.6004/jnccn.2024.0051}, pmid = {39413812}, issn = {1540-1413}, mesh = {Humans ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy/diagnosis ; Medical Oncology/standards/methods ; Adult ; Philadelphia Chromosome ; Adolescent ; }, abstract = {The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for acute lymphoblastic leukemia (ALL) provide recommendations for management of ALL, with a focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. This selection from the NCCN Guidelines for ALL focuses on treatment recommendations for adults with newly diagnosed Ph-negative ALL based on current evidence.}, }
@article {pmid39413375, year = {2024}, author = {Herrera, AF and LeBlanc, M and Castellino, SM and Li, H and Rutherford, SC and Evens, AM and Davison, K and Punnett, A and Parsons, SK and Ahmed, S and Casulo, C and Bartlett, NL and Tuscano, JM and Mei, MG and Hess, BT and Jacobs, R and Saeed, H and Torka, P and Hu, B and Moskowitz, C and Kaur, S and Goyal, G and Forlenza, C and Doan, A and Lamble, A and Kumar, P and Chowdhury, S and Brinker, B and Sharma, N and Singh, A and Blum, KA and Perry, AM and Kovach, A and Hodgson, D and Constine, LS and Shields, LK and Prica, A and Dillon, H and Little, RF and Shipp, MA and Crump, M and Kahl, B and Leonard, JP and Smith, SM and Song, JY and Kelly, KM and Friedberg, JW}, title = {Nivolumab+AVD in Advanced-Stage Classic Hodgkin's Lymphoma.}, journal = {The New England journal of medicine}, volume = {391}, number = {15}, pages = {1379-1389}, pmid = {39413375}, issn = {1533-4406}, support = {UG1CA189955/NH/NIH HHS/United States ; U10 CA180821/CA/NCI NIH HHS/United States ; U10CA180819/NH/NIH HHS/United States ; UG1 CA189955/CA/NCI NIH HHS/United States ; U10 CA180863/CA/NCI NIH HHS/United States ; U10CA180863/NH/NIH HHS/United States ; U10CA180888/NH/NIH HHS/United States ; U10 CA180819/CA/NCI NIH HHS/United States ; U10 CA180820/CA/NCI NIH HHS/United States ; U10CA180821/NH/NIH HHS/United States ; U10CA180820/NH/NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Aged ; Child ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Antineoplastic Combined Chemotherapy Protocols/administration &amp; dosage/adverse effects ; *Brentuximab Vedotin/administration &amp; dosage/adverse effects ; *Dacarbazine/administration &amp; dosage/adverse effects ; *Doxorubicin/administration &amp; dosage/adverse effects ; *Hodgkin Disease/drug therapy/mortality/radiotherapy/pathology ; Intention to Treat Analysis ; Kaplan-Meier Estimate ; Neoplasm Staging ; *Nivolumab/administration &amp; dosage/adverse effects ; Progression-Free Survival ; *Vinblastine/administration &amp; dosage/adverse effects ; Aged, 80 and over ; Treatment Outcome ; }, abstract = {BACKGROUND: Incorporating brentuximab vedotin into the treatment of advanced-stage classic Hodgkin's lymphoma improves outcomes in adult and pediatric patients. However, brentuximab vedotin increases the toxic effects of treatment in adults, more than half of pediatric patients who receive the drug undergo consolidative radiation, and relapse remains a challenge. Programmed death 1 blockade is effective in Hodgkin's lymphoma, including in preliminary studies involving previously untreated patients.<br><br>METHODS: We conducted a phase 3, multicenter, open-label, randomized trial involving patients at least 12 years of age with stage III or IV newly diagnosed Hodgkin's lymphoma. Patients were randomly assigned to receive brentuximab vedotin with doxorubicin, vinblastine, and dacarbazine (BV+AVD) or nivolumab with doxorubicin, vinblastine, and dacarbazine (N+AVD). Prespecified patients could receive radiation therapy directed to residual metabolically active lesions. The primary end point was progression-free survival, defined as the time from randomization to the first observation of progressive disease or death from any cause.<br><br>RESULTS: Of 994 patients who underwent randomization, 970 were included in the intention-to-treat population for efficacy analyses. At the second planned interim analysis, with a median follow-up of 12.1 months, the threshold for efficacy was crossed, indicating that N+AVD significantly improved progression-free survival as compared with BV+AVD (hazard ratio for disease progression or death, 0.48; 99% confidence interval [CI], 0.27 to 0.87; two-sided P&#x2009;=&#x2009;0.001). Owing to the short follow-up time, we repeated the analysis with longer follow-up; with a median follow-up of 2.1 years (range, 0 to 4.2 years), the 2-year progression-free survival was 92% (95% CI, 89 to 94) with N+AVD, as compared with 83% (95% CI, 79 to 86) with BV+AVD (hazard ratio for disease progression or death, 0.45; 95% CI, 0.30 to 0.65). Overall, 7 patients received radiation therapy. Immune-related adverse events were infrequent with nivolumab; brentuximab vedotin was associated with more treatment discontinuation.<br><br>CONCLUSIONS: N+AVD resulted in longer progression-free survival than BV+AVD in adolescents and adults with stage III or IV advanced-stage classic Hodgkin's lymphoma and had a better side-effect profile. (Funded by the National Cancer Institute of the National Institutes of Health and others; S1826 ClinicalTrials.gov number, NCT03907488.).}, }
@article {pmid39412842, year = {2024}, author = {Fabens, I and Makhele, C and Igaba, NK and Hlongwane, S and Phohole, M and Waweru, E and Oni, F and Khwepeya, M and Sardini, M and Moyo, K and Tweya, H and Wafula, MB and Pienaar, J and Ndebele, F and Setswe, G and Dong, TQ and Feldacker, C}, title = {WhatsApp Versus SMS for 2-Way, Text-Based Follow-Up After Voluntary Medical Male Circumcision in South Africa: Exploration of Messaging Platform Choice.}, journal = {JMIR formative research}, volume = {8}, number = {}, pages = {e62762}, pmid = {39412842}, issn = {2561-326X}, support = {P30 AI027757/AI/NIAID NIH HHS/United States ; R01 NR019229/NR/NINR NIH HHS/United States ; }, mesh = {Humans ; Male ; *Circumcision, Male/psychology ; *Text Messaging ; South Africa ; Adult ; Adolescent ; *Mobile Applications ; Telemedicine ; Young Adult ; Patient Satisfaction ; Middle Aged ; Aftercare/methods ; }, abstract = {BACKGROUND: Telehealth is growing, especially in areas where access to health facilities is difficult. We previously used 2-way texting (2wT) via SMS to improve the quality of postoperative care after voluntary medical male circumcision in South Africa. In this study, we offered males aged 15 years and older WhatsApp or SMS as their message delivery and interaction platform to explore user preferences and behaviors.<br><br>OBJECTIVE: The objectives of this process evaluation embedded within a larger 2wT expansion trial were to (1) explore 2wT client preferences, including client satisfaction, with WhatsApp or SMS; (2) examine response rates (participation) by SMS and WhatsApp; and (3) gather feedback from the 2wT implementation team on the WhatsApp approach.<br><br>METHODS: Males aged 15 years and older undergoing voluntary medical male circumcision in program sites could choose their follow-up approach, selecting 2wT via SMS or WhatsApp or routine care (in-person postoperative visits). The 2wT system provided 1-way educational messages and an open 2-way communication channel between providers and clients. We analyzed quantitative data from the 2wT database on message delivery platforms (WhatsApp vs SMS), response rates, and user behaviors using chi-square tests, z tests, and t tests. The team conducted short phone calls with WhatsApp and SMS clients about their perceptions of this 2wT platform using a short, structured interview guide. We consider informal reflections from the technical team members on the use of WhatsApp. We applied an implementation science lens using the RE-AIM (reach, effectiveness, adoption, implementation, and maintenance) framework to focus results on practice and policy improvement.<br><br>RESULTS: Over a 2-month period-from August to October, 2023-337 males enrolled in 2wT and were offered WhatsApp or SMS and were included in the analysis. For 2wT reach, 177 (53%) participants chose WhatsApp as their platform (P=.38). Mean client age was 30 years, and 253 (75%) participants chose English for automated messages. From quality assurance calls, almost all respondents (87/89, 98%) were happy with the way they were followed up. For effectiveness, on average for the days on which responses were requested, 58 (33%) WhatsApp clients and 44 (28%) SMS clients responded (P=.50). All 2wT team members believed WhatsApp limited the automated message content, language choices, and inclusivity as compared with the SMS-based 2wT approach.<br><br>CONCLUSIONS: When presented with a choice of 2wT communication platform, clients appear evenly split between SMS and WhatsApp. However, WhatsApp requires a smartphone and data plan, potentially reducing reach at scale. Clients using both platforms responded to 2wT interactive prompts, demonstrating similar effectiveness in engaging clients in follow-up. For telehealth interventions, digital health designers should maintain an SMS-based platform and carefully consider adding WhatsApp as an option for clients, using an implementation science approach to present evidence that guides the best implementation approach for their setting.}, }
@article {pmid39410956, year = {2024}, author = {Parker, SA and Weygand, J and Bernat, BG and Jackson, AM and Mawlawi, O and Barreto, I and Hao, Y and Khan, R and Yorke, AA and Swanson, W and Huq, MS and Lief, E and Biancia, CD and Njeh, CF and Al-Basheer, A and Chau, OW and Avery, S and Ngwa, W and Sandwall, PA}, title = {Assessing Radiology and Radiation Therapy Needs for Cancer Care in Low-and-Middle-Income Countries: Insight From a Global Survey of Departmental and Institutional Leaders.}, journal = {Advances in radiation oncology}, volume = {9}, number = {11}, pages = {101615}, pmid = {39410956}, issn = {2452-1094}, abstract = {PURPOSE: The global cancer burden and mortality rates are increasing, with significant disparities in access to care in low- and middle-income countries (LMICs). This study aimed to identify radiology and radiation therapy needs in LMICs from the perspective of departmental and institutional leaders.<br><br>METHODS AND MATERIALS: A survey was developed and conducted by the American Association of Physicists in Medicine Global Needs Assessment Committee and the American Association of Physicists in Medicine International Council. The survey, organized into 5 sections (Introduction, Infrastructure Needs, Education Needs, Research Needs, and General Information), was open to respondents from March 1, to August 16, 2022.<br><br>RESULTS: A total of 175 responses were received from 6 global regions: Africa (31.4%), the Americas (17.7%), the Eastern Mediterranean (14.3%), Europe (9.1%), Southeast Asia (23.4%), and the Western Pacific (4.0%). The greatest reported need was for new or updated equipment, particularly positron emission tomography/computed tomography imaging technology. There was also a high demand for clinical and equipment training. Approximately 25% of institutions reported a lack of radiology-based cancer screening programs because of high health care costs and a shortage of specialized equipment. Many institutions that expressed interest in research face funding and grant challenges.<br><br>CONCLUSIONS: The findings highlight critical areas where organizations can support LMICs in enhancing radiology and radiation therapy services to mitigate the growing cancer burden.}, }
@article {pmid39406835, year = {2024}, author = {Li, Z and Li, R and Ganan-Gomez, I and Abbas, HA and Garcia-Manero, G and Sun, W}, title = {Accurate identification of locally aneuploid cells by incorporating cytogenetic information in single cell data analysis.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {24152}, pmid = {39406835}, issn = {2045-2322}, support = {R01 GM105785/GM/NIGMS NIH HHS/United States ; U24 CA274212/CA/NCI NIH HHS/United States ; R03CA270725/NH/NIH HHS/United States ; R01GM105785/NH/NIH HHS/United States ; }, mesh = {Humans ; *Single-Cell Analysis/methods ; *Aneuploidy ; *Algorithms ; Cytogenetic Analysis/methods ; Markov Chains ; Sequence Analysis, RNA/methods ; Leukemia, Myeloid, Acute/genetics/pathology ; Data Analysis ; }, abstract = {Single-cell RNA sequencing is a powerful tool to investigate the cellular makeup of tumor samples. However, due to the sparse data and the complex tumor microenvironment, it can be challenging to identify neoplastic cells that play important roles in tumor growth and disease progression. This is especially relevant for blood cancers, where neoplastic cells may be highly similar to normal cells. To address this challenge, we have developed partCNV and partCNVH, two methods for rapid and accurate detection of aneuploid cells with local copy number deletion or amplification. PartCNV uses an expectation-maximization (EM) algorithm with mixtures of Poisson distributions and incorporates cytogenetic information to guide the classification. PartCNVH further improves partCNV by integrating a hidden Markov model for feature selection. We have thoroughly evaluated the performance of partCNV and partCNVH through simulation studies and real data analysis using three scRNA-seq datasets from blood cancer patients. Our results show that partCNV and partCNVH have favorable accuracy and provide more interpretable results compared to existing methods. In the real data analysis, we have identified multiple biological processes involved in the oncogenesis of myelodysplastic syndromes and acute myeloid leukemia.}, }
@article {pmid39405343, year = {2024}, author = {Hamilton, E and Galsky, MD and Ochsenreither, S and Del Conte, G and Martín, M and de Miguel, MJ and Yu, EY and Williams, A and Gion, M and Tan, AR and Agrawal, L and Rutten, A and Machiels, JP and Cresta, S and Debruyne, PR and Hennequin, A and Moreno, V and Minchom, A and Valdes-Albini, F and Petrylak, D and Li, L and Tsuchihashi, Z and Suto, F and Cheng, FC and Kandil, M and Barrios, D and Hurvitz, S}, title = {Trastuzumab Deruxtecan With Nivolumab in HER2-Expressing Metastatic Breast or Urothelial Cancer: Analysis of the Phase Ib DS8201-A-U105 Study.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-24-1513}, pmid = {39405343}, issn = {1557-3265}, abstract = {PURPOSE: This multicenter phase Ib study investigated trastuzumab deruxtecan (T-DXd) plus nivolumab in patients with HER2-expressing metastatic breast cancer (mBC) and metastatic urothelial cancer (mUC).<br><br>PATIENTS AND METHODS: Part 1 determined the recommended dose for expansion (RDE) of T-DXd plus nivolumab. Part 2 evaluated efficacy and safety; the primary endpoint was confirmed objective response rate (cORR) by independent central review.<br><br>RESULTS: Seven patients with mBC were enrolled in part 1 and received T-DXd 3.2 mg/kg (4 patients) or 5.4 mg/kg (3 patients) plus nivolumab. The RDE for T-DXd was 5.4 mg/kg plus nivolumab 360 mg intravenously/3 weeks. In part 2, 32 patients with HER2-positive mBC (cohort 1; inclusive of 3 administered 5.4 mg/kg in part 1), 16 with HER2-low mBC (cohort 2), 30 with HER2-high mUC (cohort 3), and 4 with HER2-low mUC (cohort 4) were enrolled. At data cutoff (July 22, 2021), the cORR (95% CI) for cohorts 1-4 was 65.6% (46.8%-81.4%), 50.0% (24.7%-75.3%), 36.7% (19.9%-56.1%), and not assessed due to small sample size, respectively. Median treatment duration (range) with T-DXd in cohorts 1-4 was 8.9 (1-23), 6.9 (1-21), 3.9 (1-21) months, and not assessed; most common treatment-emergent adverse event was nausea (55.2%, 62.5%, 73.3%, 75.0%). Adjudicated drug-related ILD/pneumonitis rates (cohorts 1-3) were 20.7%, 0%, and 20.0% (1 grade 5 each, cohorts 1 and 3).<br><br>CONCLUSION: T-DXd plus nivolumab demonstrated promising antitumor activity in HER2-expressing mBC or mUC and safety consistent with the known profile of T&#x2011;DXd. ILD/pneumonitis is an important risk and requires careful monitoring and prompt intervention.}, }
@article {pmid39404767, year = {2024}, author = {Li, Y and Lee, T and Marin, K and Hua, X and Srinivasan, S and Fredricks, DN and Lee, JR and Ling, W}, title = {SurvBal: compositional microbiome balances for survival outcomes.}, journal = {Bioinformatics (Oxford, England)}, volume = {40}, number = {10}, pages = {}, doi = {10.1093/bioinformatics/btae612}, pmid = {39404767}, issn = {1367-4811}, support = {R01 GM129512/GM/NIGMS NIH HHS/United States ; }, mesh = {*Microbiota ; *Software ; Humans ; Proportional Hazards Models ; Survival Analysis ; Bacteria/classification ; }, abstract = {SUMMARY: Identification of balances of bacterial taxa in relation to continuous and dichotomous outcomes is an increasingly frequent analytic objective in microbiome profiling experiments. SurvBal enables the selection of balances in relation to censored survival or time-to-event outcomes which are of considerable interest in many biomedical studies. The most commonly used survival models-the Cox proportional hazards and parametric survival models are included in the package, which are used in combination with step-wise selection procedures to identify the optimal associated balance of microbiome, i.e. the ratio of the geometric means of two groups of taxa's relative abundances.<br><br>The SurvBal R package and Shiny app can be accessed at https://github.com/yinglia/SurvBal and https://yinglistats.shinyapps.io/shinyapp-survbal/.}, }
@article {pmid39403956, year = {2024}, author = {Young, CL and Beichman, AC and Mas-Ponte, D and Hemker, SL and Zhu, L and Kitzman, JO and Shirts, BH and Harris, K}, title = {A maternal germline mutator phenotype in a family affected by heritable colorectal cancer.}, journal = {Genetics}, volume = {228}, number = {4}, pages = {}, pmid = {39403956}, issn = {1943-2631}, abstract = {Variation in DNA repair genes can increase cancer risk by elevating the rate of oncogenic mutation. Defects in one such gene, MUTYH, are known to elevate the incidence of colorectal cancer in a recessive Mendelian manner. Recent evidence has also linked MUTYH to a mutator phenotype affecting normal somatic cells as well as the female germline. Here, we use whole genome sequencing to measure germline de novo mutation rates in a large extended family containing both mothers and fathers who are affected by pathogenic MUTYH variation. By developing novel methodology that uses siblings as "surrogate parents" to identify de novo mutations, we were able to include mutation data from several children whose parents were unavailable for sequencing. In the children of mothers affected by the pathogenic MUTYH genotype p.Y179C/V234M, we identify an elevation of the C>A mutation rate that is weaker than mutator effects previously reported to be caused by other pathogenic MUTYH genotypes, suggesting that mutation rates in normal tissues may be useful for classifying cancer-associated variation along a continuum of severity. Surprisingly, we detect no significant elevation of the C>A mutation rate in children born to a father with the same MUTYH genotype, and we similarly find that the mutator effect of the mouse homolog Mutyh appears to be localized to embryonic development, not the spermatocytes. Our results suggest that maternal MUTYH variants can cause germline mutations by attenuating the repair of oxidative DNA damage in the early embryo.}, }
@article {pmid39403932, year = {2024}, author = {Zhang, P and Minnie, SA and Hill, GR}, title = {Calcineurin inhibition rescues alloantigen-specific central memory T cell subsets that promote chronic GVHD. Reply.}, journal = {The Journal of clinical investigation}, volume = {134}, number = {20}, pages = {}, pmid = {39403932}, issn = {1558-8238}, mesh = {Animals ; Humans ; Mice ; Calcineurin/metabolism/immunology/genetics ; *Calcineurin Inhibitors ; Chronic Disease ; *Graft vs Host Disease/immunology/pathology ; Immunologic Memory ; *Isoantigens/immunology ; Memory T Cells/immunology ; T-Lymphocyte Subsets/immunology/metabolism ; }, }
@article {pmid39402405, year = {2024}, author = {Bologna, E and Licari, LC and Badani, KK and Razdan, S and Psutka, SP and Ditonno, F and Ramos-Carpinteyro, R and Soputro, NA and Jackson, JC and Nelson, R and Rais-Bahrami, S and White, WM and Djaladat, H and Pierorazio, PM and Eun, DD and Kutikov, A and Margulis, V and Kovac, E and Kim, IY and Anele, UA and Mehrazin, R and Ben-David, R and Viers, BR and Su, LM and Rogers, CG and Abdollah, F and Ghazi, A and Cherullo, EE and Vourganti, S and Coogan, CL and Raman, JD and Sundaram, CP and Stifelman, M and Link, RE and Kaouk, J and Crivellaro, S and Autorino, R}, title = {The impact of single-port robotic surgery: a survey among urology residents and fellows in the United States.}, journal = {Journal of robotic surgery}, volume = {18}, number = {1}, pages = {369}, pmid = {39402405}, issn = {1863-2491}, mesh = {*Robotic Surgical Procedures/education/statistics &amp; numerical data ; *Internship and Residency ; United States ; Humans ; Surveys and Questionnaires ; *Urology/education ; *Fellowships and Scholarships ; Urologic Surgical Procedures/education ; Male ; Female ; Clinical Competence ; }, abstract = {Our aim was to investigate the perception and future expectations of Single-Port (SP) surgery among urology trainees in the United States. A 34-item online survey was distributed to urological residency and fellowship programs across the US, covering demographic profiles, SP training opportunities, perceived educational impact, and future perspectives. Descriptive analysis and multivariable linear regression were used to assess predictors of SP adoption. 201 surveys were completed (28.6% completion rate). Among institutions with an SP platform, about 50% have used it regularly for over 2 years, though often in less than 50% of procedures. While robotic simulators are commonly available, only 17% offer both multi-port and SP simulators, and structured pre-clinical SP training is limited. Approximately 30% of respondents expressed concerns over limited hands-on experience and a steeper learning curve with SP. Around 40% felt that their robotic surgery exposure was negatively impacted by SP's introduction. SP surgery's benefits are seen mostly in the immediate post-operative period and a significant number of respondents foresee a major role for SP in urology. However, proficiency in SP surgery is not seen as crucial for career advancement or job opportunities. Academic job aspirations, SP platform availability, and SP surgery workload are predictors of future SP implementation. Trainees increasingly recognize the clinical benefits of SP procedures but express concerns about the potential negative impact on hands-on experience. Training programs should more systematically integrate SP technology into curricula. There is a correlation between training in high-volume SP centers and future SP adoption.}, }
@article {pmid39401968, year = {2024}, author = {Pulliam, T and Jani, S and Goff, PH and Bhakuni, R and Tabachnick-Cherny, S and Smythe, K and Seaton, BW and Tachiki, L and Kulikauskas, R and Church, C and Koelle, DM and Nghiem, P and Bhatia, S}, title = {Intratumoral STING agonist reverses immune evasion in PD-(L)1-refractory Merkel cell carcinoma: mechanistic insights from detailed biomarker analyses.}, journal = {Journal for immunotherapy of cancer}, volume = {12}, number = {10}, pages = {}, pmid = {39401968}, issn = {2051-1426}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; P01 CA225517/CA/NCI NIH HHS/United States ; F30 CA254168/CA/NCI NIH HHS/United States ; T32 CA080416/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Carcinoma, Merkel Cell/drug therapy/immunology ; *Membrane Proteins/metabolism ; Skin Neoplasms/drug therapy/immunology/pathology ; Biomarkers, Tumor/metabolism ; Male ; B7-H1 Antigen/metabolism ; Aged ; Programmed Cell Death 1 Receptor/antagonists &amp; inhibitors ; Immune Checkpoint Inhibitors/pharmacology/therapeutic use ; }, abstract = {BACKGROUND: Antibodies blocking programmed death (PD)-1 or its ligand (PD-L1) have revolutionized cancer care, but many patients do not experience durable benefits. Novel treatments to stimulate antitumor immunity are needed in the PD-(L)1 refractory setting. The stimulator of interferon genes (STING) protein, an innate sensor of cytoplasmic DNA, is a promising target with several agonists in development. However, response rates in most recent clinical trials have been low and mechanisms of response remain unclear. We report detailed biomarker analyses in a patient with anti-PD-L1 refractory, Merkel cell polyomavirus (MCPyV)-positive, metastatic Merkel cell carcinoma (MCC) who was treated with an intratumoral (IT) STING agonist (ADU-S100) plus intravenous anti-PD-1 antibody (spartalizumab) and experienced a durable objective response with regression of both injected and non-injected lesions.<br><br>METHODS: We analyzed pretreatment and post-treatment tumor and peripheral blood samples from our patient with single-cell RNA sequencing, 30-parameter flow cytometry, T cell receptor sequencing, and multiplexed immunohistochemistry. We analyzed cancer-specific CD8 T cells using human leukocyte antigen (HLA)-I tetramers loaded with MCPyV peptides. We also analyzed STING expression and signaling in the tumor microenvironment (TME) of 88 additional MCC tumor specimens and in MCC cell lines.<br><br>RESULTS: We observed high levels of MCPyV-specific T cells (12% of T cells) in our patient's tumor at baseline. These cancer-specific CD8 T cells exhibited characteristics of exhaustion including high TOX and low TCF1 proteins. Following treatment with STING-agonist plus anti-PD-1, IT CD8 T cells expanded threefold. We also observed evidence of likely improved antigen presentation in the MCC TME (greater than fourfold increase of HLA-I-positive cancer cells). STING expression was not detected in any cancer cells within our patient's tumor or in 88 other MCC tumors, however high STING expression was observed in immune and stromal cells within all 89 MCC tumors.<br><br>CONCLUSIONS: Our results suggest that STING agonists may be able to work indirectly in MCC via signaling through immune and stromal cells in the TME, and may not necessarily need STING expression in the cancer cells. This approach may be particularly effective in tumors that are already infiltrated by inflammatory cells in the TME but are evading immune detection via HLA-I downregulation.}, }
@article {pmid39398350, year = {2024}, author = {Chen, Z and Li, X and Zhang, B}, title = {The role of randomization inference in unraveling individual treatment effects in early phase vaccine trials.}, journal = {Statistical communications in infectious diseases}, volume = {16}, number = {1}, pages = {}, pmid = {39398350}, issn = {2194-6310}, support = {UM1 AI068635/AI/NIAID NIH HHS/United States ; }, abstract = {Randomization inference is a powerful tool in early phase vaccine trials when estimating the causal effect of a regimen against a placebo or another regimen. Randomization-based inference often focuses on testing either Fisher's sharp null hypothesis of no treatment effect for any participant or Neyman's weak null hypothesis of no sample average treatment effect. Many recent efforts have explored conducting exact randomization-based inference for other summaries of the treatment effect profile, for instance, quantiles of the treatment effect distribution function. In this article, we systematically review methods that conduct exact, randomization-based inference for quantiles of individual treatment effects (ITEs) and extend some results to a special case where naïve participants are expected not to exhibit responses to highly specific endpoints. These methods are suitable for completely randomized trials, stratified completely randomized trials, and a matched study comparing two non-randomized arms from possibly different trials. We evaluate the usefulness of these methods using synthetic data in simulation studies. Finally, we apply these methods to HIV Vaccine Trials Network Study 086 (HVTN 086) and HVTN 205 and showcase a wide range of application scenarios of the methods. R code that replicates all analyses in this article can be found in first author's GitHub page at https://github.com/Zhe-Chen-1999/ITE-Inference.}, }
@article {pmid39396254, year = {2024}, author = {Petersdorf, EW}, title = {HLA structure and function in hematopoietic-cell transplantation.}, journal = {Best practice &amp; research. Clinical haematology}, volume = {37}, number = {3}, pages = {101564}, doi = {10.1016/j.beha.2024.101564}, pmid = {39396254}, issn = {1532-1924}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation ; *HLA Antigens/immunology/genetics ; Killer Cells, Natural/immunology ; Polymorphism, Genetic ; Donor Selection ; Allografts ; Histocompatibility Testing ; Transplantation, Homologous ; }, abstract = {The degree of HLA compatibility between a patient and donor has formed the basis of donor selection since the development of allogeneic hematopoietic cell transplantation over 50 years ago and has advanced understanding of the basic immunobiology of HLA. New evidence supports a role for germline variation in the patient and the donor that do not require HLA matching for their effects to have clinical consequences. The discovery of novel non-coding polymorphisms, structural features of HLA molecules, and expression provide new models for donor selection and inspire the development of tools for clinical translation. Pairwise effects of HLA ligand/donor NK receptors may play an important role in transplant outcomes and showcase the value of understanding the role played by each constituent of the NK pathway in modulating donor responses to target antigens.}, }
@article {pmid39396092, year = {2024}, author = {Denos, M and Sun, YQ and Brumpton, BM and Li, Y and Albanes, D and Burnett-Hartman, A and Campbell, PT and Küry, S and Li, CI and White, E and Samadder, JN and Jenkins, MA and Mai, XM}, title = {Sex hormones and risk of lung and colorectal cancers in women: a Mendelian randomization study.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {23891}, pmid = {39396092}, issn = {2045-2322}, mesh = {Humans ; *Colorectal Neoplasms/genetics/epidemiology ; Female ; *Mendelian Randomization Analysis ; *Lung Neoplasms/genetics/epidemiology ; *Genome-Wide Association Study ; *Gonadal Steroid Hormones/metabolism ; Sex Hormone-Binding Globulin/genetics/metabolism ; Risk Factors ; Testosterone/blood ; Polymorphism, Single Nucleotide ; Middle Aged ; White People/genetics ; }, abstract = {The roles of sex hormones such as estradiol, testosterone, and sex hormone-binding globulin (SHBG) in the etiology of lung and colorectal cancers in women, among the most common cancers after breast cancer, are unclear. This Mendelian randomization (MR) study evaluated such potential causal associations in women of European ancestry. We used summary statistics data from genome-wide association studies on sex hormones and from the Trøndelag Health Study (HUNT) and large consortia on cancers. There was suggestive evidence of 1-standard deviation increase in total testosterone levels being associated with a lower risk of lung non-adenocarcinoma (hazard ratio 0.60, 95% confidence interval 0.37-0.98) in the HUNT Study. However, this was not confirmed by using data from a larger consortium. In general, we did not find convincing evidence to support a causal role of sex hormones on risk of lung and colorectal cancers in women of European ancestry.}, }
@article {pmid39396053, year = {2024}, author = {Marcink, TC and Zipursky, G and Sobolik, EB and Golub, K and Herman, E and Stearns, K and Greninger, AL and Porotto, M and Moscona, A}, title = {How a paramyxovirus fusion/entry complex adapts to escape a neutralizing antibody.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8831}, pmid = {39396053}, issn = {2041-1723}, support = {R01 AI160953/AI/NIAID NIH HHS/United States ; R01 AI114736/AI/NIAID NIH HHS/United States ; U19 AI181984/AI/NIAID NIH HHS/United States ; AI121349//Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)/ ; R01 AI160961/AI/NIAID NIH HHS/United States ; AI160961//Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)/ ; AI160953//Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)/ ; AI152275//Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)/ ; AI114736//Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)/ ; F32 AI152275/AI/NIAID NIH HHS/United States ; R01 AI121349/AI/NIAID NIH HHS/United States ; }, mesh = {*Antibodies, Neutralizing/immunology ; *Viral Fusion Proteins/immunology/metabolism/chemistry ; Humans ; *Virus Internalization ; *Parainfluenza Virus 3, Human/immunology ; Antibodies, Viral/immunology ; Cryoelectron Microscopy ; HN Protein/metabolism/immunology/chemistry/genetics ; Antibodies, Monoclonal/immunology ; Animals ; Mutation ; Models, Molecular ; }, abstract = {Paramyxoviruses including measles, Nipah, and parainfluenza viruses are public health threats with pandemic potential. Human parainfluenza virus type 3 (HPIV3) is a leading cause of illness in pediatric, older, and immunocompromised populations. There are no approved vaccines or therapeutics for HPIV3. Neutralizing monoclonal antibodies (mAbs) that target viral fusion are a potential strategy for mitigating paramyxovirus infection, however their utility may be curtailed by viral evolution that leads to resistance. Paramyxoviruses enter cells by fusing with the cell membrane in a process mediated by a complex consisting of a receptor binding protein (HN) and a fusion protein (F). Existing atomic resolution structures fail to reveal physiologically relevant interactions during viral entry. We present cryo-ET structures of pre-fusion HN-F complexes in situ on surfaces of virions that evolved resistance to an anti-HPIV3 F neutralizing mAb. Single mutations in F abolish mAb binding and neutralization. In these complexes, the HN protein that normally restrains F triggering has shifted to uncap the F apex. These complexes are more readily triggered to fuse. These structures shed light on the adaptability of the pre-fusion HN-F complex and mechanisms of paramyxoviral resistance to mAbs, and help define potential barriers to resistance for the design of mAbs.}, }
@article {pmid39395534, year = {2024}, author = {Henry, NL and Unger, JM and Vaidya, R and Darke, AK and Skaar, TC and Fisch, MJ and Hershman, DL}, title = {Active symptom monitoring for premenopausal women with breast cancer initiating adjuvant endocrine therapy: Protocol for the SWOG S2010 randomized controlled efficacy trial.}, journal = {Contemporary clinical trials}, volume = {147}, number = {}, pages = {107712}, pmid = {39395534}, issn = {1559-2030}, support = {R01 CA266012/CA/NCI NIH HHS/United States ; UG1 CA189974/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Breast Neoplasms/drug therapy ; Female ; *Premenopause ; *Antineoplastic Agents, Hormonal/therapeutic use/administration &amp; dosage/adverse effects ; *Tamoxifen/therapeutic use/administration &amp; dosage/adverse effects ; *Aromatase Inhibitors/therapeutic use/adverse effects/administration &amp; dosage ; Chemotherapy, Adjuvant/methods ; Adult ; Patient Education as Topic ; Middle Aged ; Hot Flashes/chemically induced ; Quality of Life ; Anxiety ; Arthralgia ; Self Efficacy ; Medication Adherence ; Estradiol/administration &amp; dosage ; }, abstract = {BACKGROUND: Premenopausal women with early stage, high risk hormone receptor positive breast cancer are at risk of early discontinuation of adjuvant endocrine therapy (ET), primarily because of toxicity, which can increase the risk of disease recurrence and death. We hypothesize that identification of bothersome symptoms between clinic visits, and automated notification of clinicians about symptoms, will result in improved persistence with ET.<br><br>METHODS: Pre- and perimenopausal women planning to receive adjuvant treatment with tamoxifen or an aromatase inhibitor plus ovarian function suppression or ablation for treatment of breast cancer are eligible. A total of 540 participants will be enrolled and randomized 1:1 to patient education with or without Active Symptom Monitoring (ASM). The ASM intervention includes 6 symptom questions (hot flashes, sadness, anxiety, insomnia, vaginal dryness, joint pain) that will be completed via text, email, or telephone weekly for 24&#xa0;weeks, then every 4&#xa0;weeks for 48&#xa0;weeks. All participants will complete a battery of questionnaires every 12&#xa0;weeks to examine symptoms, beliefs about medicine, self-efficacy, and ET adherence. Optional blood draws will be collected at baseline and after 12, 48, and 72&#xa0;weeks of therapy to examine estradiol and ET concentrations. The primary endpoint is time to nonpersistence with initially prescribed ET within the first 72&#xa0;weeks, evaluated using Kaplan-Meier plots and multivariable Cox regression.<br><br>CONCLUSION: We expect early identification and management of ET-related toxicities to improve persistence with breast cancer therapy, breast cancer outcomes, and quality of life for premenopausal women at high risk of breast cancer recurrence.<br><br>CLINICALTRIALS: govNCT05568472.}, }
@article {pmid39395448, year = {2024}, author = {Zhu, A and Psutka, SP}, title = {Editorial Comment on "Comparing Frailty Indices for Risk Stratifi cation in Urologic Oncology: Which Index to Choose?".}, journal = {Urology}, volume = {194}, number = {}, pages = {163-164}, doi = {10.1016/j.urology.2024.10.009}, pmid = {39395448}, issn = {1527-9995}, }
@article {pmid39387238, year = {2024}, author = {Khanijow, K and Rosendale, N and Wright, S and Lee, RS and Nass, S and Keniston, A and Dalal, M and Jager, LR and Anstett, T}, title = {Characterizing hospitalists' comfort and familiarity with LGBTQ clinical topics.}, journal = {Hospital practice (1995)}, volume = {}, number = {}, pages = {}, doi = {10.1080/21548331.2024.2414734}, pmid = {39387238}, issn = {2154-8331}, support = {UL1 TR003098/TR/NCATS NIH HHS/United States ; }, abstract = {OBJECTIVES: Evidence has shown that lesbian, gay, bisexual, queer (LGBQ) and transgender patients (LGBTQ) experience disparities in health care delivery and clinical outcomes. As the predominant U.S. inpatient provider workforce, this paper's objective was to understand hospitalists' comfort with LGBTQ health.<br><br>METHODS: A 58-question anonymous online survey was distributed in 2019 to practicing hospitalists through the Society of Hospital Medicine regarding their experiences in caring for hospitalized LGBTQ patients.<br><br>RESULTS: Two hundred and eighteen hospitalist providers completed the entire survey. While hospitalists reported high levels of comfort in caring for these populations (LGBQ: 90.6%, Transgender: 77.8%), they acknowledged feeling less confident in their clinical competence (LGBQ: 71.6%, Transgender: 51.2%). Hospitalist providers who were themselves LGBQ reported more comfort with most aspects of LGBQ patient clinical care than heterosexual respondents (p&#x2009;<&#x2009;0.05 for 4 of 6 comfort variables). Seventy-four percent of hospitalists wanted training to advance their knowledge and skills in working with LGBTQ patients.<br><br>CONCLUSIONS: Hospitalist clinicians are regularly exposed to LGBTQ patients yet their comfort and expertise in caring for this vulnerable population is highly variable. Educational interventions that include reflective practice may serve to optimize hospitalists' ability to more confidently and competently serve LGBTQ patients.}, }
@article {pmid39394376, year = {2024}, author = {Ogimi, C and Xie, H and Waghmare, A and Jerome, KR and Leisenring, WM and Ueda Oshima, M and Carpenter, PA and Englund, JA and Boeckh, M}, title = {Correction: Novel factors to predict respiratory viral disease progression in allogeneic hematopoietic cell transplant recipients.}, journal = {Bone marrow transplantation}, volume = {59}, number = {12}, pages = {1790}, doi = {10.1038/s41409-024-02418-9}, pmid = {39394376}, issn = {1476-5365}, }
@article {pmid39394013, year = {2024}, author = {Gillessen, S and Turco, F and Davis, ID and Efstathiou, JA and Fizazi, K and James, ND and Shore, N and Small, E and Smith, M and Sweeney, CJ and Tombal, B and Zilli, T and Agarwal, N and Antonarakis, ES and Aparicio, A and Armstrong, AJ and Bastos, DA and Attard, G and Axcrona, K and Ayadi, M and Beltran, H and Bjartell, A and Blanchard, P and Bourlon, MT and Briganti, A and Bulbul, M and Buttigliero, C and Caffo, O and Castellano, D and Castro, E and Cheng, HH and Chi, KN and Clarke, CS and Clarke, N and de Bono, JS and De Santis, M and Duran, I and Efstathiou, E and Ekeke, ON and El Nahas, TIH and Emmett, L and Fanti, S and Fatiregun, OA and Feng, FY and Fong, PCC and Fonteyne, V and Fossati, N and George, DJ and Gleave, ME and Gravis, G and Halabi, S and Heinrich, D and Herrmann, K and Hofman, MS and Hope, TA and Horvath, LG and Hussain, MHA and Jereczek-Fossa, BA and Jones, RJ and Joshua, AM and Kanesvaran, R and Keizman, D and Khauli, RB and Kramer, G and Loeb, S and Mahal, BA and Maluf, FC and Mateo, J and Matheson, D and Matikainen, MP and McDermott, R and McKay, RR and Mehra, N and Merseburger, AS and Morgans, AK and Morris, MJ and Mrabti, H and Mukherji, D and Murphy, DG and Murthy, V and Mutambirwa, SBA and Nguyen, PL and Oh, WK and Ost, P and O'Sullivan, JM and Padhani, AR and Parker, C and Poon, DMC and Pritchard, CC and Rabah, DM and Rathkopf, D and Reiter, RE and Renard-Penna, R and Ryan, CJ and Saad, F and Sade, JP and Sandhu, S and Sartor, OA and Schaeffer, E and Scher, HI and Sharifi, N and Skoneczna, IA and Soule, HR and Spratt, DE and Srinivas, S and Sternberg, CN and Suzuki, H and Taplin, ME and Thellenberg-Karlsson, C and Tilki, D and Türkeri, LN and Uemura, H and Ürün, Y and Vale, CL and Vapiwala, N and Walz, J and Yamoah, K and Ye, D and Yu, EY and Zapatero, A and Omlin, A}, title = {Management of Patients with Advanced Prostate Cancer. Report from the 2024 Advanced Prostate Cancer Consensus Conference (APCCC).}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2024.09.017}, pmid = {39394013}, issn = {1873-7560}, abstract = {BACKGROUND AND OBJECTIVE: Innovations have improved outcomes in advanced prostate cancer (PC). Nonetheless, we continue to lack high-level evidence on a variety of topics that greatly impact daily practice. The 2024 Advanced Prostate Cancer Consensus Conference (APCCC) surveyed experts on key questions in clinical management in order to supplement evidence-based guidelines. Here we present voting results for questions from APCCC 2024.<br><br>METHODS: Before the conference, a panel of 120 international PC experts used a modified Delphi process to develop 183 multiple-choice consensus questions on eight different topics. Before the conference, these questions were administered via a web-based survey to the voting panel members ("panellists").<br><br>KEY FINDINGS AND LIMITATIONS: Consensus was a priori defined as &#x2265;75% agreement, with strong consensus defined as &#x2265;90% agreement. The voting results show varying degrees of consensus, as discussed in this article and detailed in the Supplementary material. These findings do not include a formal literature review or meta-analysis.<br><br>The voting results can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers in prioritising areas for future research. Diagnostic and treatment decisions should always be individualised on the basis of patient and cancer characteristics, and should incorporate current and emerging clinical evidence, guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2024 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials.}, }
@article {pmid39392812, year = {2024}, author = {Sharma, V and Fadel, A and Tollefson, MK and Psutka, SP and Blezek, DJ and Frank, I and Thapa, P and Tarrell, R and Viers, LD and Potretzke, AM and Hartman, RP and Boorjian, SA and Viers, BR}, title = {Artificial Intelligence-Based Assessment of Preoperative Body Composition is Associated With Early Complications After Radical Cystectomy.}, journal = {The Journal of urology}, volume = {}, number = {}, pages = {101097JU0000000000004292}, doi = {10.1097/JU.0000000000004292}, pmid = {39392812}, issn = {1527-3792}, abstract = {PURPOSE: We aimed to use a validated artificial intelligence (AI) algorithm to extract muscle and adipose areas from CT images before radical cystectomy (RCx) and then correlate these measures with 90-day post-RCx complications.<br><br>MATERIALS AND METHODS: A tertiary referral center's cystectomy registry was queried for patients who underwent RCx between 2009 and 2017 for bladder cancer. Eight hundred forty-three RCx patients with CT imaging within 90 days of preceding surgery were included, to allow for extraction of body composition parameters by AI. We assessed complications within 90 days of surgery including wound, infectious, and major complications; readmission; and death. Multivariable logistic regressions associated pre-RCx measures with post-RCx complications.<br><br>RESULTS: Increasing subcutaneous adipose tissue was associated with more wound complications, while patients with increasing visceral adipose tissue had greater odds of infectious-related complications. After adjusting for patient characteristics, every 10 cm[2] increases in fat mass index were associated with more infectious (OR, 1.04; P = .002) and wound (OR, 1.06; P < .001) complications. On multivariable analysis, a higher preoperative skeletal muscle index was associated with lower odds of major complications (OR, 0.75 for every 10 cm[2]; P = .008), while higher intramuscular adipose was associated with higher odds of major complications (OR, 1.93; P = .008).<br><br>CONCLUSIONS: Automated AI body composition measurements preoperatively are associated with post-RCx complications. These measurements, in addition to patient (ECOG performance status and smoking status) and surgical (robotic approach and continent diversion) characteristics, can then be used to individualize patient counseling and facilitate triage of nutritional and rehabilitation efforts.}, }
@article {pmid39391570, year = {2024}, author = {Brown, MC and Snidarich, M and Budak, JZ and Murphy, N and Giustini, N and Romine, PE and Weiner, BJ and Caverly, T and Crothers, K and Triplette, M}, title = {Adaptation of a Tailored Lung Cancer Screening Decision Aid for People With HIV.}, journal = {CHEST pulmonary}, volume = {2}, number = {3}, pages = {}, pmid = {39391570}, issn = {2949-7892}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: People with HIV are both at elevated risk of lung cancer and at high risk of multimorbidity, which makes shared decision-making (SDM) for lung cancer screening (LCS) in people with HIV complex. Currently no known tools have been adapted for SDM in people with HIV.<br><br>RESEARCH QUESTION: Can an SDM decision aid be adapted to include HIV-specific measures with input from both people with HIV and their providers?<br><br>STUDY DESIGN AND METHODS: This study used qualitative methods including focus groups of people with HIV and interviews with HIV care providers to adapt and iterate an SDM tool for people with HIV. Eligible participants were those with HIV enrolled in an HIV primary care clinic who met age and smoking eligibility criteria for LCS and HIV care providers at the clinic. Both the focus groups and interviews included semistructured discussions of SDM and decision aid elements for people with HIV. We used a framework-guided thematic analysis, mapping themes onto the Health Equity Implementation framework.<br><br>RESULTS: Forty-three people with HIV participated in eight focus groups; 10 providers were interviewed. Key themes from patients included broad interest in adapting LCS SDM specifically for people with HIV, a preference for clear LCS recommendations, and the need for positive framing emphasizing survival. Providers were enthusiastic about personalized LCS risk assessments and point-of-care tools. Both patients and providers gave mixed views on the usefulness of HIV-specific risk measures in patient-facing tools. Themes were used to adapt a personalized and flexible SDM tool for LCS in people with HIV.<br><br>INTERPRETATION: People with HIV and providers were enthusiastic about specific tools for SDM that are personalized and tailored for people with HIV, that make recommendations, and that inform LCS decision-making. Divergent views on presenting patient-facing quantitative risk assessments suggests that these elements could be optional but available for review. This tool may have usefulness in complex decision-making for LCS in this population and currently is being evaluated in a pilot prospective trial.}, }
@article {pmid39389851, year = {2024}, author = {Swank, Z and Borberg, E and Chen, Y and Senussi, Y and Chalise, S and Manickas-Hill, Z and Yu, XG and Li, JZ and Alter, G and Henrich, TJ and Kelly, JD and Hoh, R and Goldberg, SA and Deeks, SG and Martin, JN and Peluso, MJ and Talla, A and Li, X and Skene, P and Bumol, TF and Torgerson, TR and Czartoski, JL and McElrath, MJ and Karlson, EW and Walt, DR and , }, title = {Measurement of circulating viral antigens post-SARS-CoV-2 infection in a multicohort study.}, journal = {Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases}, volume = {30}, number = {12}, pages = {1599-1605}, pmid = {39389851}, issn = {1469-0691}, support = {R01 AI158013/AI/NIAID NIH HHS/United States ; K23 AI157875/AI/NIAID NIH HHS/United States ; R01 AI176287/AI/NIAID NIH HHS/United States ; R01 NS136197/NS/NINDS NIH HHS/United States ; R01 AI141003/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *COVID-19/diagnosis/blood/immunology/epidemiology ; Male ; Female ; *SARS-CoV-2/immunology ; Middle Aged ; *Antigens, Viral/blood/immunology ; Adult ; *Spike Glycoprotein, Coronavirus/immunology ; Aged ; Coronavirus Nucleocapsid Proteins/immunology ; Cohort Studies ; Phosphoproteins/blood/immunology ; }, abstract = {OBJECTIVES: To determine the proportion of individuals with detectable antigen in plasma or serum after SARS-CoV-2 infection and the association of antigen detection with postacute sequelae of COVID-19 (PASC) symptoms.<br><br>METHODS: Plasma and serum samples were collected from adults participating in four independent studies at different time points, ranging from several days up to 14&#xa0;months post-SARS-CoV-2 infection. The primary outcome measure was to quantify SARS-CoV-2 antigens, including the S1 subunit of spike, full-length spike, and nucleocapsid, in participant samples. The presence of 34 commonly reported PASC symptoms during the postacute period was determined from participant surveys or chart reviews of electronic health records.<br><br>RESULTS: Of the 1569 samples analysed from 706 individuals infected with SARS-CoV-2, 21% (95% CI, 18-24%) were positive for either S1, spike, or nucleocapsid. Spike was predominantly detected, and the highest proportion of samples was spike positive (20%; 95% CI, 18-22%) between 4 and 7&#xa0;months postinfection. In total, 578 participants (82%) reported at least one of the 34 PASC symptoms included in our analysis &#x2265;1&#xa0;month postinfection. Cardiopulmonary, musculoskeletal, and neurologic symptoms had the highest reported prevalence in over half of all participants, and among those participants, 43% (95% CI, 40-45%) on average were antigen-positive. Among the participants who reported no ongoing symptoms (128, 18%), antigen was detected in 28 participants (21%). The presence of antigen was associated with the presence of one or more PASC symptoms, adjusting for sex, age, time postinfection, and cohort (OR, 1.8; 95% CI, 1.4-2.2).<br><br>DISCUSSION: The findings of this multicohort study indicate that SARS-CoV-2 antigens can be detected in the blood of a substantial proportion of individuals up to 14&#xa0;months after infection. While approximately one in five asymptomatic individuals was antigen-positive, roughly half of all individuals reporting ongoing cardiopulmonary, musculoskeletal, and neurologic symptoms were antigen-positive.}, }
@article {pmid39388026, year = {2024}, author = {Chen, JG and Zhang, YH and Lu, JH and Kensler, TW}, title = {Liver Cancer Etiology: Old Issues and New Perspectives.}, journal = {Current oncology reports}, volume = {26}, number = {11}, pages = {1452-1468}, pmid = {39388026}, issn = {1534-6269}, mesh = {Humans ; Aflatoxins/adverse effects/toxicity ; Alcohol Drinking/adverse effects ; Diet/adverse effects ; Genetic Predisposition to Disease ; Life Style ; *Liver Neoplasms/epidemiology/etiology ; Risk Factors ; }, abstract = {PURPOSE OF REVIEW: This review aims to synthesize the old issues and current understandings of the etiology of liver cancer, focusing on the diverse causative factors influenced by geographical, socioeconomic, and lifestyle variations across different regions.<br><br>RECENT FINDINGS: We highlight significant geographic disparities in liver cancer risk factors. While hepatitis B and C viruses, aflatoxin exposure, and alcohol consumption remain globally established contributors; metabolic dysfunction-associated steatotic liver disease and metabolic syndromes are increasingly prominent in the West. Chronic HBV and aflatoxin continue to dominate as risk factors in Asia and Africa. Dietary factors, metabolic diseases like diabetes and obesity, genetic predispositions, environmental risk factors and lifestyle choices such as smoking and alcohol use play substantial roles in specific populations. Protective factors like coffee and tea consumption, along with aspirin use, vegetables and fruits have shown potential in reducing HCC risk, although findings vary by population and dietary habits. Liver cancer etiology is influenced by various factors that differ by region. Established risk factors include hepatitis B and C, aflatoxin, and alcohol. Emerging risks, such as metabolic dysfunction-associated steatotic liver disease, are more prevalent in Western countries, while aflatoxin and HBV remains significant in Asia and Africa. Diet, metabolic conditions like diabetes and obesity, genetic predispositions, and lifestyle choices also play crucial roles. Coffee, tea, aspirin, vegetables, and fruits may reduce HCC risk, but effectiveness varies. Future research should integrate epidemiology, genetics, and nutrition, with global cooperation and data sharing essential for effective cancer control strategies.}, }
@article {pmid39388304, year = {2024}, author = {Bryce, Y and Whitton, JA and Stratton, KL and Leisenring, WM and Chow, EJ and Armstrong, G and Weil, B and Dieffenbach, B and Howell, RM and Oeffinger, KC and Nathan, PC and Tonorezos, ES}, title = {Prevalence of carotid ultrasound screening in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.35591}, pmid = {39388304}, issn = {1097-0142}, support = {U24 CA055727/CA/NCI NIH HHS/United States ; U24 CA55727//Childhood Cancer Survivor Study/ ; P30 CA 008748//Vickers/ ; }, abstract = {INTRODUCTION: Many childhood cancer survivors are at risk for cardiovascular disease and stroke. The North American Children's Oncology Group long-term follow-up guidelines recommend carotid ultrasound in cancer survivors 10 years after neck radiation therapy (RT) ≥40 Gy. The use of carotid ultrasound in this population has not been described.<br><br>METHODS: Survivors of childhood cancer diagnosed 1970-1999 (N&#xa0;=&#xa0;8693) and siblings (N&#xa0;=&#xa0;1989) enrolled in the Childhood Cancer Survivor Study were asked if they had ever had a carotid ultrasound. Prevalence of carotid ultrasound was evaluated. Prevalence ratios (PR) and 95% confidence intervals (CIs) were evaluated in multivariate Poisson regression models.<br><br>RESULTS: Among participants with no reported cardiovascular condition, prevalence of carotid ultrasound among survivors with RT&#xa0;&#x2265;40 Gy to the neck (N&#xa0;=&#xa0;172) was 29.7% (95% CI, 22.5-36.8), significantly higher than those with <40 Gy (prevalence 10.7%; 95% CI, 9.9%-11.4%). Siblings without a cardiovascular condition (N&#xa0;=&#xa0;1621) had the lowest prevalence of carotid ultrasound (4.7%; 95% CI, 3.6%-5.7%). In a multivariable models among survivors with no reported cardiovascular condition and RT&#xa0;&#x2265;40 Gy to the neck, those who were over age 50 (vs. 18-49) at follow-up (PR&#xa0;=&#xa0;1.82; 95% CI, 1.09-3.05), with a history of seeing a cancer specialist in the last 2 years (PR&#xa0;=&#xa0;2.58; 95% CI, 1.53-4.33), or having a colonoscopy (PR&#xa0;=&#xa0;2.02; 95% CI, 1.17-3.48) or echocardiogram (PR&#xa0;=&#xa0;6.42; 95% CI, 1.54-26.85) were more likely to have had a carotid ultrasound.<br><br>CONCLUSION: Many survivors do not undergo carotid ultrasound despite meeting existing guidelines. Health care delivery features such as having seen a cancer specialist or having other testing are relevant.}, }
@article {pmid39386724, year = {2024}, author = {Alassaf, M and Rajan, A}, title = {Adipocyte metabolic state regulates glial phagocytic function.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39386724}, issn = {2692-8205}, support = {P40 OD018537/OD/NIH HHS/United States ; R35 GM124593/GM/NIGMS NIH HHS/United States ; S10 OD021562/OD/NIH HHS/United States ; }, abstract = {Obesity and type 2 diabetes are well-established risk factors for neurodegenerative disorders[1-4], yet the underlying mechanisms remain poorly understood. The adipocyte-brain axis is crucial for brain function, as adipocytes secrete signaling molecules, including lipids and adipokines, that impinge on neural circuits to regulate feeding and energy expenditure[5]. Disruptions in the adipocyte-brain axis are associated with neurodegenerative conditions[6], but the causal links are not fully understood. Neural debris accumulates with age and injury, and glial phagocytic function is crucial for clearing this debris and maintaining a healthy brain microenvironment[7-9]. Using adult Drosophila, we investigate how adipocyte metabolism influences glial phagocytic activity in the brain. We demonstrate that a prolonged obesogenic diet increases adipocyte fatty acid oxidation and ketogenesis. Genetic manipulations that mimic obesogenic diet-induced changes in adipocyte lipid and mitochondrial metabolism unexpectedly reduce the expression of the phagocytic receptor Draper in Drosophila microglia-like cells in the brain. We identify Apolpp-the Drosophila equivalent of human apolipoprotein B (ApoB)-as a critical adipocyte-derived signal that regulates glial phagocytosis. Additionally, we show that Lipoprotein Receptor 1 (LpR1), the LDL receptor on phagocytic glia, is required for glial capacity to clear injury-induced neuronal debris. Our findings establish that adipocyte-brain lipoprotein signaling regulates glial phagocytic function, revealing a novel pathway that links adipocyte metabolic disorders with neurodegeneration.}, }
@article {pmid39386474, year = {2024}, author = {Freie, B and Ibrahim, AH and Carroll, PA and Bronson, RT and Augert, A and MacPherson, D and Eisenman, RN}, title = {MAX inactivation deregulates the MYC network and induces neuroendocrine neoplasia in multiple tissues.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39386474}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA248762/CA/NCI NIH HHS/United States ; R35 CA231989/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, abstract = {The MYC transcription factor requires MAX for DNA binding and widespread activation of gene expression in both normal and neoplastic cells. Surprisingly, inactivating mutations in MAX are associated with a subset of neuroendocrine cancers including pheochromocytoma, pituitary adenoma and small cell lung cancer. Neither the extent nor the mechanisms of MAX tumor suppression are well understood. Delet-ing Max across multiple mouse neuroendocrine tissues, we find Max inactivation alone produces pituitary adenomas while Max loss cooperates with Rb1/Trp53 loss to accelerate medullary thyroid C-cell and pituitary adenoma development. In the thyroid tumor cell lines, MAX loss triggers a striking shift in genomic occupancy by other members of the MYC network (MNT, MLX, MondoA) supporting metabolism, survival and proliferation of neoplastic neuroendocrine cells. Our work reveals MAX as a broad suppressor of neuroendocrine tumorigenesis through its ability to maintain a balance of genomic occupancies among the diverse transcription factors in the MYC network.}, }
@article {pmid39386462, year = {2024}, author = {Wellington, R and Cheng, X and Campbell, CA and Trapnell, C and Espin-Palazon, R and Hadland, B and Doulatov, S}, title = {Developmental regulation of endothelial-to-hematopoietic transition from induced pluripotent stem cells.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39386462}, issn = {2692-8205}, support = {RC2 DK127989/DK/NIDDK NIH HHS/United States ; R01 HL169156/HL/NHLBI NIH HHS/United States ; R01 DK131162/DK/NIDDK NIH HHS/United States ; DP2 HL147126/HL/NHLBI NIH HHS/United States ; R01 HL168110/HL/NHLBI NIH HHS/United States ; R01 HL151651/HL/NHLBI NIH HHS/United States ; }, abstract = {Hematopoietic stem cells (HSCs) arise in embryogenesis from a specialized hemogenic endothelium (HE). In this process, HE cells undergo a unique fate change termed endothelial-to-hematopoietic transition, or EHT. While induced pluripotent stem cells (iPSCs) give rise to HE with robust hemogenic potential, the generation of bona fide HSCs from iPSCs remains a challenge. Here, we map single cell dynamics of EHT during embryoid body differentiation from iPSCs and integrate it with human embryo datasets to identify key transcriptional differences between in vitro and in vivo cell states. We further map ligand-receptor interactions associated with differential expression of developmental programs in the iPSC system. We found that the expression of endothelial genes was incompletely repressed during iPSC EHT. Elevated FGF signaling by FGF23, an endothelial pathway ligand, was associated with differential gene expression between in vitro and in vivo EHT. Chemical inhibition of FGF signaling during EHT increased HSPC generation in the zebrafish, while an FGF agonist had the opposite effect. Consistently, chemical inhibition of FGF signaling increased hematopoietic output from iPSCs. In summary, we map the dynamics of EHT from iPSCs at single cell resolution and identify ligand-receptor interactions that can be modulated to improve iPSC differentiation protocols. We show, as proof of principle, that chemical inhibition of FGF signaling during EHT improves hematopoietic output in zebrafish and the iPSC system.}, }
@article {pmid39386436, year = {2024}, author = {Nguyen, TNH and Horowitz, LF and Nguyen, B and Lockhart, E and Zhu, S and Gujral, TS and Folch, A}, title = {Microfluidic Modulation of Microvasculature in Microdissected Tumors.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39386436}, issn = {2692-8205}, support = {R01 CA181445/CA/NCI NIH HHS/United States ; R01 CA272677/CA/NCI NIH HHS/United States ; }, abstract = {The microvasculature within the tumor microenvironment (TME) plays an essential role in cancer signaling beyond nutrient delivery. However, it has been challenging to control the generation and/or maintenance of microvasculature in ex vivo systems, a critical step for establishing cancer models of high clinical biomimicry. There have been great successes in engineering tissues incorporating microvasculature de novo (e.g., organoids and organs-on-chip), but these reconstituted tissues are formed with non-native cellular and molecular components that can skew certain outcomes such as drug efficacy. Microdissected tumors, on the other hand, show promise in preserving the TME, which is key for creating cancer models that can bridge the gap between bench and bedside. However, microdissected tumors are challenging to perfuse. Here, we developed a microfluidic platform that allows for perfusing the microvasculature of microdissected tumors. We demonstrate that, compared to diffusive transport, microfluidically perfused tissues feature larger and longer microvascular structures, with a better expression of CD31, a marker for endothelial cells, as analyzed by 3D imaging. This study also explores the effects of nitric oxide pathway-related drugs on endothelial cells, which are sensitive to shear stress and can activate endothelial nitric oxide synthase, producing nitric oxide. Our findings highlight the critical role of controlled perfusion and biochemical modulation in preserving tumor microvasculature, offering valuable insights for developing more effective cancer treatments.}, }
@article {pmid39385741, year = {2024}, author = {Mosna, F and Borlenghi, E and Litzow, M and Byrd, JC and Papayannidis, C and Tecchio, C and Ferrara, F and Marcucci, G and Cairoli, R and Morgan, EA and Gurrieri, C and Yeung, CCS and Deeg, HJ and Capelli, D and Candoni, A and Gotlib, JR and Lunghi, M and Pullarkat, S and Lanza, F and Galimberti, S and Forghieri, F and Venditti, A and Festuccia, M and Audisio, E and Marvalle, D and Rigolin, GM and Roti, G and DiBona, E and Visani, G and Albano, F and Eisfeld, AK and Valent, P and Huls, G and Borthakur, G and Krampera, M and Martinelli, G and Kröger, N and Sperotto, A and Gottardi, M}, title = {Long-term survival can be achieved in a significant fraction of older patients with core binding factor acute myeloid leukemia treated with intensive chemotherapy.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2024.285448}, pmid = {39385741}, issn = {1592-8721}, abstract = {Acute Myeloid Leukemia is mainly a disease of the elderly: however, the knowledge on the outcomes of treatment in core binding factor AML (CBFAML) in older population, is limited. We retrospectively collected data on 229 patients with CBF- AML followed long-term in the last two decades. A 5-year overall survival (OS) of 44.2% (95%CI, 39.9-47.5) and a 5-year event - free survival (EFS) of 32.9% (95%CI, 25.5-40.1) was observed. In a subgroup of >70-year patients who completed intensive therapy (induction + >3 courses of consolidation including autologous stem cell transplant: 10 patients) the median EFS was 11.8 months (95%CI, 9.4 - 15.2) and OS was 40.0% (95%CI, 36.4 - 44.1) at 5yr. In univariate analysis, age >70 (hazard ratio (HR) 1.78, [95%CI, 1.15 - 2.54], p=.008), failure to achieve remission following induction (HR, 8.96 [95%CI, 5.5 - 13.8], p=<.0001), no consolidation therapy (HR, 0.75 [95%CI, 0.47 - 1.84], p=.04) and less than 3 cycles of consolidation (HR, 1.48 [95%CI, 0.75 - 3.2], p=.0004), predicted poorer EFS. Our study shows that intensive therapy, in selected older CBF-AML patients, leads to longer survival. Achieving a CR seems to be the most important first step and at least 3 cycles of consolidation, an important second one. The analysis suggests that these patients should not be excluded from studies with intensive therapies.}, }
@article {pmid39385266, year = {2024}, author = {Saldarriaga, EM and Chen, Y and Montaño, MA and Thuo, N and Kiptinness, C and Terris-Prestholt, F and Stergachis, A and Mugambi, ML and Ngure, K and Ortblad, KF and Sharma, M}, title = {Preferences for pre-exposure prophylaxis delivery via online pharmacy among potential users in Kenya: a discrete choice experiment.}, journal = {Journal of the International AIDS Society}, volume = {27}, number = {10}, pages = {e26356}, pmid = {39385266}, issn = {1758-2652}, support = {INV-037646/GATES/Bill &amp; Melinda Gates Foundation/United States ; INV 035424//Bill and Melinda Gates Foundation/ ; INV-035932/GATES/Bill &amp; Melinda Gates Foundation/United States ; INV-038498/GATES/Bill &amp; Melinda Gates Foundation/United States ; }, mesh = {Humans ; *Pre-Exposure Prophylaxis/methods ; Kenya ; Male ; Female ; *HIV Infections/prevention &amp; control ; Adult ; Young Adult ; Adolescent ; Middle Aged ; Anti-HIV Agents/therapeutic use/administration &amp; dosage ; Pharmaceutical Services, Online ; Patient Preference ; Surveys and Questionnaires ; }, abstract = {INTRODUCTION: Oral pre-exposure prophylaxis (PrEP) is highly effective, but coverage remains low in high HIV prevalence settings. Initiating and continuing PrEP remotely via online pharmacies is a promising strategy to expand PrEP uptake, but little is known about potential users' preferences.<br><br>METHODS: We conducted a discrete choice experiment (DCE) to assess preferences for online pharmacy PrEP services. We partnered with MYDAWA, an online pharmacy in Nairobi, Kenya. Eligibility criteria were: &#x2265;18 years, not known HIV positive, interested in PrEP. The DCE contained four attributes: PrEP eligibility assessment (online self-assessed, guided), HIV test type (provider administered, oral HIV self-test [HIVST], blood-based HIVST), clinical consultation (remote, in-person) and user support options (text messages, phone/video call, email). Additionally, participants indicated whether they were willing to uptake their selected service. The survey was advertised on MYDAWA's website; interested participants met staff in-person at a convenient location to complete the survey from 1 June to 20 November 2022. We used conditional logit modelling with an interaction by current PrEP use to estimate overall preferences and latent class analysis (LCA) to assess preference heterogeneity.<br><br>RESULTS: Overall, 772 participants completed the DCE; the mean age was 25 years and 54% were female. Most participants indicated a willingness to acquire online PrEP services, with particularly high demand among PrEP-naive individuals. Overall, participants preferred remote clinical consultation, HIV self-testing, online self-assessment and phone call user support. The LCA identified three subgroups: the "prefer online PrEP with remote components" group (60.3% of the sample) whose preferences aligned with the main analysis, the "prefer online PrEP with in-person components" group (20.7%), who preferred in-person consultation, provider-administered HIV testing, and guided assessment, and the "prefer remote PrEP (18.9%)" group who preferred online PrEP services only if they were remote.<br><br>CONCLUSIONS: Online pharmacy PrEP is highly acceptable and may expand PrEP coverage to those interested in PrEP but not accessing services. Most participants valued privacy and autonomy, preferring HIVST and remote provider interactions. However, when needing support for questions regarding PrEP, participants preferred phone/SMS contact with a provider. One-fifth of participants preferred online PrEP with in-person components, suggesting that providing multiple options can increase uptake.}, }
@article {pmid39385257, year = {2024}, author = {Edwards, LA and Yang, C and Sharma, S and Chen, ZH and Gorantla, L and Joshi, SA and Longhi, NJ and Worku, N and Yang, JS and Martinez Di Pietro, B and Armenian, S and Bhat, A and Border, W and Buddhe, S and Blythe, N and Stratton, K and Leger, KJ and Leisenring, WM and Meacham, LR and Nathan, PC and Narasimhan, S and Sachdeva, R and Sadak, K and Chow, EJ and Boyle, PM}, title = {Building a machine learning-assisted echocardiography prediction tool for children at risk for cancer therapy-related cardiomyopathy.}, journal = {Cardio-oncology (London, England)}, volume = {10}, number = {1}, pages = {66}, pmid = {39385257}, issn = {2057-3804}, support = {R21 CA277746/CA/NCI NIH HHS/United States ; CA277746//National Cancer Institute of the National Institutes of Health/ ; }, abstract = {BACKGROUND: Despite routine echocardiographic surveillance for childhood cancer survivors, the ability to predict cardiomyopathy risk in individual patients is limited. We explored the feasibility and optimal processes for machine learning-enhanced cardiomyopathy prediction in survivors using serial echocardiograms from five centers.<br><br>METHODS: We designed a series of deep convolutional neural networks (DCNNs) for prediction of cardiomyopathy (shortening fraction&#x2009;&#x2264;&#x2009;28% or ejection fraction&#x2009;&#x2264;&#x2009;50% on two occasions) for at-risk survivors&#x2009;&#x2265;&#x2009;1-year post initial cancer therapy. We built DCNNs with four subsets of echocardiographic data differing in timing relative to case (survivor who developed cardiomyopathy) index diagnosis and two input formats (montages) with differing image selections. We used holdout subsets in a 10-fold cross-validation framework and standard metrics to assess model performance (e.g., F1-score, area under the precision-recall curve [AUPRC]). Performance of the input formats was compared using a combined 5&#x2009;&#xd7;&#x2009;2 cross-validation F-test.<br><br>RESULTS: The dataset included 542 pairs of montages: 171 montage pairs from 45 cases at time of cardiomyopathy diagnosis or pre-diagnosis and 371 pairs from 70 at-risk survivors who didn't develop cardiomyopathy during follow-up (non-case). The DCNN trained to distinguish between non-case and time of cardiomyopathy diagnosis or pre-diagnosis case montages achieved an AUROC of 0.89&#x2009;&#xb1;&#x2009;0.02, AUPRC 0.83&#x2009;&#xb1;&#x2009;0.03, and F1-score: 0.76&#x2009;&#xb1;&#x2009;0.04. When limited to smaller subsets of case data (e.g., &#x2265;&#x2009;1 or 2 years pre-diagnosis), performance worsened. Model input format did not impact performance accuracy across models.<br><br>CONCLUSIONS: This methodology is a promising first step toward development of a DCNN capable of accurately differentiating pre-diagnosis versus non-case echocardiograms to predict survivors more likely to develop cardiomyopathy.}, }
@article {pmid39384953, year = {2024}, author = {Appelbaum, FR}, title = {Offering patients a second chance: what is the minimum cure rate needed to justify allogeneic hematopoietic cell transplantation?.}, journal = {Leukemia}, volume = {38}, number = {12}, pages = {2515-2516}, pmid = {39384953}, issn = {1476-5551}, }
@article {pmid39384951, year = {2024}, author = {Anczukow, O and Allain, FH and Angarola, BL and Black, DL and Brooks, AN and Cheng, C and Conesa, A and Crosse, EI and Eyras, E and Guccione, E and Lu, SX and Neugebauer, KM and Sehgal, P and Song, X and Tothova, Z and Valcárcel, J and Weeks, KM and Yeo, GW and Thomas-Tikhonenko, A}, title = {Steering research on mRNA splicing in cancer towards clinical translation.}, journal = {Nature reviews. Cancer}, volume = {24}, number = {12}, pages = {887-905}, pmid = {39384951}, issn = {1474-1768}, support = {R01 CA248317/CA/NCI NIH HHS/United States ; R21 AG080243/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Neoplasms/genetics ; *RNA Splicing ; RNA, Messenger/genetics ; Spliceosomes/genetics ; Translational Research, Biomedical ; }, abstract = {Splicing factors are affected by recurrent somatic mutations and copy number variations in several types of haematologic and solid malignancies, which is often seen as prima facie evidence that splicing aberrations can drive cancer initiation and progression. However, numerous spliceosome components also 'moonlight' in DNA repair and other cellular processes, making their precise role in cancer difficult to pinpoint. Still, few would deny that dysregulated mRNA splicing is a pervasive feature of most cancers. Correctly interpreting these molecular fingerprints can reveal novel tumour vulnerabilities and untapped therapeutic opportunities. Yet multiple technological challenges, lingering misconceptions, and outstanding questions hinder clinical translation. To start with, the general landscape of splicing aberrations in cancer is not well defined, due to limitations of short-read RNA sequencing not adept at resolving complete mRNA isoforms, as well as the shallow read depth inherent in long-read RNA-sequencing, especially at single-cell level. Although individual cancer-associated isoforms are known to contribute to cancer progression, widespread splicing alterations could be an equally important and, perhaps, more readily actionable feature of human cancers. This is to say that in addition to 'repairing' mis-spliced transcripts, possible therapeutic avenues include exacerbating splicing aberration with small-molecule spliceosome inhibitors, targeting recurrent splicing aberrations with synthetic lethal approaches, and training the immune system to recognize splicing-derived neoantigens.}, }
@article {pmid39384807, year = {2024}, author = {Minot, SS and Li, N and Srinivasan, H and Ayers, JL and Yu, M and Koester, ST and Stangis, MM and Dominitz, JA and Halberg, RB and Grady, WM and Dey, N}, title = {Colorectal cancer-associated bacteria are broadly distributed in global microbiomes and drivers of precancerous change.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {23646}, pmid = {39384807}, issn = {2045-2322}, support = {K08 DK111941/DK/NIDDK NIH HHS/United States ; R50 CA233042/CA/NCI NIH HHS/United States ; U54 CA274374/CA/NCI NIH HHS/United States ; R50CA233042//U.S. Department of Health and Human Services | NIH | National Cancer Institute (NCI)/ ; }, mesh = {*Colorectal Neoplasms/microbiology/genetics ; *Gastrointestinal Microbiome/genetics ; Animals ; Humans ; Mice ; *Bacteria/genetics/classification ; *Precancerous Conditions/microbiology ; Metagenomics/methods ; }, abstract = {The gut microbiome is implicated in the pathogenesis of colorectal cancer (CRC), but the full scope of this dialogue is unknown. Here we aimed to define the scale and membership of the body of CRC- and health-associated gut bacteria in global populations. We performed a microbiome-CRC correlation analysis of published ultra-deep shotgun metagenomic sequencing data from global microbiome surveys, utilizing a de novo (reference-agnostic) gene-level clustering approach to identify protein-coding co-abundant gene (CAGs) clusters. We link an unprecedented ~ 23-40% of gut bacteria to CRC or health, split nearly evenly as CRC- or health-associated. These microbes encode 2319 CAGs encompassing 427,261 bacterial genes significantly enriched or depleted in CRC. We identified many microbes that had not previously been linked to CRC, thus expanding the scope of "known unknowns" of CRC-associated microbes. We performed an agnostic CAG-based screen of bacterial isolates and validated predicted effects of previously unimplicated bacteria in preclinical models, in which we observed differential induction of precancerous adenomas and field effects. Single-cell RNA sequencing disclosed microbiome-induced senescence-associated gene expression signatures in discrete colonic populations including fibroblasts. In organoid co-cultures, primary colon fibroblasts from mice with microbiomes promoted significantly greater growth than fibroblasts from microbiome-depleted mice. These results offer proof-of-principle for gene-level metagenomic analysis enabling discovery of microbiome links to health and demonstrate that the microbiome can drive precancer states, thereby potentially revealing novel cancer prevention opportunities.}, }
@article {pmid39384761, year = {2024}, author = {Rocheleau, G and Clarke, SL and Auguste, G and Hasbani, NR and Morrison, AC and Heath, AS and Bielak, LF and Iyer, KR and Young, EP and Stitziel, NO and Jun, G and Laurie, C and Broome, JG and Khan, AT and Arnett, DK and Becker, LC and Bis, JC and Boerwinkle, E and Bowden, DW and Carson, AP and Ellinor, PT and Fornage, M and Franceschini, N and Freedman, BI and Heard-Costa, NL and Hou, L and Chen, YI and Kenny, EE and Kooperberg, C and Kral, BG and Loos, RJF and Lutz, SM and Manson, JE and Martin, LW and Mitchell, BD and Nassir, R and Palmer, ND and Post, WS and Preuss, MH and Psaty, BM and Raffield, LM and Regan, EA and Rich, SS and Smith, JA and Taylor, KD and Yanek, LR and Young, KA and ,  and Hilliard, AT and Tcheandjieu, C and Peyser, PA and Vasan, RS and Rotter, JI and Miller, CL and Assimes, TL and de Vries, PS and Do, R}, title = {Rare variant contribution to the heritability of coronary artery disease.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8741}, pmid = {39384761}, issn = {2041-1723}, support = {R01 HL139731/HL/NHLBI NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; R35 GM124836/GM/NIGMS NIH HHS/United States ; R01 HL092577/HL/NHLBI NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; S10 OD026880/OD/NIH HHS/United States ; R35-GM124836//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01 HL146860/HL/NHLBI NIH HHS/United States ; HHSN268201500014C/HL/NHLBI NIH HHS/United States ; S10 OD030463/OD/NIH HHS/United States ; R01 HL157635/HL/NHLBI NIH HHS/United States ; HHSN268201600033C/HL/NHLBI NIH HHS/United States ; R01 HL055673/HL/NHLBI NIH HHS/United States ; HHSN268201100037C/HL/NHLBI NIH HHS/United States ; R01 HL112064/HL/NHLBI NIH HHS/United States ; U54 HG003067/HG/NHGRI NIH HHS/United States ; R01 HL121007/HL/NHLBI NIH HHS/United States ; R01-HL139865, R01-HL155915//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01 HL139865/HL/NHLBI NIH HHS/United States ; R01 HL089856/HL/NHLBI NIH HHS/United States ; U54 HG003273/HG/NHGRI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; UM1 HG008853/HG/NHGRI NIH HHS/United States ; HHSN268201500015C/HL/NHLBI NIH HHS/United States ; R01 HL164577/HL/NHLBI NIH HHS/United States ; UL1 TR004419/TR/NCATS NIH HHS/United States ; R01 HL148239/HL/NHLBI NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; R01 HL155915/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Coronary Artery Disease/genetics ; *Genetic Predisposition to Disease ; *Linkage Disequilibrium ; *Polymorphism, Single Nucleotide ; Male ; Female ; Gene Frequency ; Genome-Wide Association Study ; White People/genetics ; Case-Control Studies ; Whole Genome Sequencing ; Genetic Variation ; Middle Aged ; }, abstract = {Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.}, }
@article {pmid39384759, year = {2024}, author = {Crook, ZR and Sevilla, GP and Young, P and Girard, EJ and Phi, TD and Howard, ML and Price, J and Olson, JM and Nairn, NW}, title = {CYpHER: catalytic extracellular targeted protein degradation with high potency and durable effect.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8731}, pmid = {39384759}, issn = {2041-1723}, support = {R01 CA223674/CA/NCI NIH HHS/United States ; R01-CA223674//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; }, mesh = {Humans ; *Proteolysis/drug effects ; *Receptors, Transferrin/metabolism ; Animals ; Cell Line, Tumor ; *ErbB Receptors/metabolism ; *Lysosomes/metabolism ; Mice ; Carcinoma, Non-Small-Cell Lung/metabolism/drug therapy/genetics/pathology ; Hydrogen-Ion Concentration ; B7-H1 Antigen/metabolism ; Female ; Lung Neoplasms/metabolism/drug therapy/genetics ; Catalysis ; Endosomes/metabolism ; Xenograft Model Antitumor Assays ; }, abstract = {Many disease-causing proteins have multiple pathogenic mechanisms, and conventional inhibitors struggle to reliably disrupt more than one. Targeted protein degradation (TPD) can eliminate the protein, and thus all its functions, by directing a cell's protein turnover machinery towards it. Two established strategies either engage catalytic E3 ligases or drive uptake towards the endolysosomal pathway. Here we describe CYpHER (CatalYtic pH-dependent Endolysosomal delivery with Recycling) technology with potency and durability from a catalytic mechanism that shares the specificity and straightforward modular design of endolysosomal uptake. By bestowing pH-dependent release on the target engager and using the rapid-cycling transferrin receptor as the uptake receptor, CYpHER induces endolysosomal delivery of surface and extracellular targets while re-using drug, potentially yielding increased potency and reduced off-target tissue exposure risks. The TfR-based approach allows targeting to tumors that overexpress this receptor and offers the potential for transport to the CNS. CYpHER function was demonstrated in vitro with EGFR and PD-L1, and in vivo with EGFR in a model of EGFR-driven non-small cell lung cancer.}, }
@article {pmid39383036, year = {2024}, author = {Scharffenberger, SC and Wan, YH and Homad, LJ and Kher, G and Haynes, AM and Poudel, B and Sinha, IR and Aldridge, N and Pai, A and Bibby, M and Chhan, CB and Davis, AR and Moodie, Z and Palacio, MB and Escolano, A and McElrath, MJ and Boonyaratanakornkit, J and Pancera, M and McGuire, AT}, title = {Targeting RSV-neutralizing B cell receptors with anti-idiotypic antibodies.}, journal = {Cell reports}, volume = {43}, number = {10}, pages = {114811}, pmid = {39383036}, issn = {2211-1247}, mesh = {*Antibodies, Neutralizing/immunology ; Animals ; *Receptors, Antigen, B-Cell/immunology/metabolism ; Humans ; *Antibodies, Anti-Idiotypic/immunology/pharmacology ; Mice ; B-Lymphocytes/immunology ; Respiratory Syncytial Virus Infections/immunology ; Respiratory Syncytial Viruses/immunology ; Antibodies, Monoclonal/immunology ; Antibodies, Viral/immunology ; Female ; Respiratory Syncytial Virus, Human/immunology ; Mice, Inbred BALB C ; }, abstract = {Respiratory syncytial virus (RSV) causes lower respiratory tract infections with significant morbidity and mortality at the extremes of age. Vaccines based on the viral fusion protein are approved for adults over 60, but infant protection relies on passive immunity via antibody transfer or maternal vaccination. An infant vaccine that rapidly elicits protective antibodies would fulfill a critical unmet need. Antibodies arising from the VH3-21/VL1-40 gene pairing can neutralize RSV without the need for affinity maturation, making them attractive to target through vaccination. Here, we develop an anti-idiotypic monoclonal antibody (ai-mAb) immunogen that is specific for unmutated VH3-21/VL1-40 B cell receptors (BCRs). The ai-mAb efficiently engages B cells with bona fide target BCRs and does not activate off-target non-neutralizing B cells, unlike recombinant pre-fusion (preF) protein used in current RSV vaccines. These results establish proof of concept for using an ai-mAb-derived vaccine to target B cells hardwired to produce RSV-neutralizing antibodies.}, }
@article {pmid39382296, year = {2024}, author = {Stearns, K and Lampe, G and Hanan, R and Marcink, T and Niewiesk, S and Sternberg, SH and Greninger, AL and Porotto, M and Moscona, A}, title = {Human parainfluenza virus 3 field strains undergo extracellular fusion protein cleavage to activate entry.}, journal = {mBio}, volume = {15}, number = {11}, pages = {e0232724}, pmid = {39382296}, issn = {2150-7511}, support = {R01 AI114736/AI/NIAID NIH HHS/United States ; R01AI031971, R01AI114736, R01AI175362//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; F31 AI176760/AI/NIAID NIH HHS/United States ; R01 AI175362/AI/NIAID NIH HHS/United States ; //Sharon Golub Fund at Columbia University Vagelos College of Physicians &amp; Surgeons/ ; R01AI175362//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; R01 AI031971/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Virus Internalization ; *Viral Fusion Proteins/metabolism/genetics ; *Parainfluenza Virus 3, Human/genetics/physiology/metabolism ; HEK293 Cells ; Furin/metabolism/genetics ; HN Protein/metabolism/genetics ; Animals ; Cell Line ; Proteolysis ; }, abstract = {UNLABELLED: Human parainfluenza virus 3 (HPIV3) infection is driven by the coordinated action of viral surface glycoproteins hemagglutinin-neuraminidase (HN) and fusion protein (F). Receptor-engaged HN activates F to insert into the target cell membrane and drive virion-cell membrane fusion. For F to mediate entry, its precursor (F0) must first be cleaved by host proteases. F0 cleavage has been thought to be executed during viral glycoprotein transit through the trans-Golgi network by the ubiquitously expressed furin because F0 proteins of laboratory-adapted viruses contain a furin recognition dibasic cleavage motif RXKR around residue 108. Here, we show that the F proteins of field strains have a different cleavage motif from laboratory-adapted strains and are cleaved by unidentified proteases expressed in only a narrow subset of cell types. We demonstrate that extracellular serine protease inhibitors block HPIV3 F0 cleavage for field strains, suggesting F0 cleavage occurs at the cell surface facilitated by transmembrane proteases. Candidate proteases that may process HPIV3 F in vivo were identified by a genome-wide CRISPRa screen in HEK293/dCas9-VP64 + MPH cells. The lung-expressed extracellular serine proteases TMPRSS2 and TMPRSS13 are both sufficient to cleave HPIV3 F and enable infectious virus release by otherwise non-permissive cells. Our findings support an alternative mechanism of F activation in vivo, reliant on extracellular membrane-bound serine proteases expressed in a narrow subset of cells. The proportion of HPIV3 F proteins cleaved and infectious virus release is determined by host cell expression of requisite proteases, allowing just-in-time activation of F and positioning F cleavage as another key regulator of HPIV3 spread.<br><br>IMPORTANCE: Enveloped viruses cause a wide range of diseases in humans. At the first step of infection, these viruses must fuse their envelope with a cell membrane to initiate infection. This fusion is mediated by viral proteins that require a critical activating cleavage event. It was previously thought that for parainfluenza virus 3, an important cause of respiratory disease and a representative of a group of important pathogens, this cleavage event was mediated by furin in the cell secretory pathways prior to formation of the virions. We show that this is only true for laboratory strain viruses, and that clinical viruses that infect humans utilize extracellular proteases that are only made by a small subset of cells. These results highlight the importance of studying authentic clinical viruses that infect human tissues for understanding natural infection.}, }
@article {pmid39381003, year = {2024}, author = {Fiore-Gartland, A and Srivastava, H and Seese, A and Day, T and Penn-Nicholson, A and Luabeya, AKK and Du Plessis, N and Loxton, AG and Bekker, LG and Diacon, A and Walzl, G and Sagawa, ZK and Reed, SG and Scriba, TJ and Hatherill, M and Coler, R}, title = {Co-regulation of innate and adaptive immune responses induced by ID93+GLA-SE vaccination in humans.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1441944}, pmid = {39381003}, issn = {1664-3224}, mesh = {Humans ; *Immunity, Innate ; *Adaptive Immunity ; Female ; Male ; *Tuberculosis Vaccines/immunology/administration &amp; dosage ; *Vaccination ; Adult ; Tuberculosis/prevention &amp; control/immunology ; Mycobacterium tuberculosis/immunology ; CD4-Positive T-Lymphocytes/immunology ; Antibodies, Bacterial/blood/immunology ; Vaccines, Subunit/immunology/administration &amp; dosage ; }, abstract = {INTRODUCTION: Development of an effective vaccine against tuberculosis is a critical step towards reducing the global burden of disease. A therapeutic vaccine might also reduce the high rate of TB recurrence and help address the challenges of drug-resistant strains. ID93+GLA-SE is a candidate subunit vaccine that will soon be evaluated in a phase 2b efficacy trial for prevention of recurrent TB among patients undergoing TB treatment. ID93+GLA-SE vaccination was shown to elicit robust CD4+ T cell and IgG antibody responses among recently treated TB patients in the TBVPX-203 Phase 2a study (NCT02465216), but the mechanisms underlying these responses are not well understood.<br><br>METHODS: In this study we used specimens from TBVPX-203 participants to describe the changes in peripheral blood gene expression that occur after ID93+GLA-SE vaccination.<br><br>RESULTS: Analyses revealed several distinct modules of co-varying genes that were either up- or down-regulated after vaccination, including genes associated with innate immune pathways at 3 days post-vaccination and genes associated with lymphocyte expansion and B cell activation at 7 days post-vaccination. Notably, the regulation of these gene modules was affected by the dose schedule and by participant sex, and early innate gene signatures were correlated with the ID93-specific CD4+ T cell response.<br><br>DISCUSSION: The results provide insight into the complex interplay of the innate and adaptive arms of the immune system in developing responses to vaccination with ID93+GLA-SE and demonstrate how dosing and schedule can affect vaccine responses.}, }
@article {pmid39380691, year = {2024}, author = {Parrish, AG and Arora, S and Thirimanne, HN and Rudoy, D and Schmid, S and Sievers, P and Sahm, F and Holland, EC and Szulzewsky, F}, title = {Aggressive high-grade NF2 mutant meningiomas downregulate oncogenic YAP signaling via the upregulation of VGLL4 and FAT3/4.}, journal = {Neuro-oncology advances}, volume = {6}, number = {1}, pages = {vdae148}, pmid = {39380691}, issn = {2632-2498}, abstract = {BACKGROUND: Meningiomas are the most common primary central nervous system tumors in adults. Although generally benign, a subset is of higher grade and ultimately fatal. Around half of all meningiomas harbor inactivating mutations in NF2, leading to deregulation of oncogenic YAP1 activity. While benign NF2 mutant meningiomas exhibit few genetic events in addition to NF2 inactivation, aggressive high-grade NF2 mutant meningiomas frequently harbor a highly aberrant genome. It is unclear if NF2 mutant meningiomas of different grades are equally reliant on YAP activity.<br><br>METHODS: We analyzed bulk and single-cell RNA-Seq data from a large cohort of human meningiomas for the expression of YAP1 target genes and Hippo effectors as well as in vitro cell line experiments.<br><br>RESULTS: Aggressive NF2 mutant meningiomas harbor decreased expression levels of YAP1 target genes and increased expression levels of the YAP1 antagonist VGLL4 and the upstream regulators FAT3/4 compared to their benign counterparts. Decreased expression of YAP1 target genes as well as high expression of VGLL4 and FAT3/4 is significantly associated with an increased risk of recurrence. In vitro, overexpression of VGLL4 resulted in the downregulation of YAP activity in benign NF2 mutant meningioma cells, confirming the direct link between VGLL4 expression and decreased levels of YAP activity observed in aggressive NF2 mutant meningiomas.<br><br>CONCLUSIONS: Our results shed new insight into the biology of benign and aggressive NF2 mutant meningiomas and may have important implications for the efficacy of therapies targeting oncogenic YAP1 activity in NF2 mutant meningiomas.}, }
@article {pmid39379736, year = {2024}, author = {Bloom, A and Springer, R and Angier, H and Heintzman, J and Likumahuwa-Ackman, S and Huguet, N and Moreno, L and DeVoe, J}, title = {Association Between a Mother's Cervical Cancer Screening and Child's Human Papillomavirus (HPV) Vaccination Status.}, journal = {Maternal and child health journal}, volume = {28}, number = {12}, pages = {2137-2146}, pmid = {39379736}, issn = {1573-6628}, support = {R01HS025962//Agency for Healthcare Research and Quality/ ; }, mesh = {Humans ; Female ; *Uterine Cervical Neoplasms/prevention &amp; control/diagnosis ; *Papillomavirus Vaccines/administration &amp; dosage ; *Early Detection of Cancer/methods/statistics &amp; numerical data ; *Papillomavirus Infections/prevention &amp; control/diagnosis ; Child ; *Mothers/psychology/statistics &amp; numerical data ; Adult ; Adolescent ; Vaccination/statistics &amp; numerical data ; Male ; United States/epidemiology ; Mass Screening/methods/statistics &amp; numerical data ; Cohort Studies ; Human Papillomavirus Viruses ; }, abstract = {OBJECTIVES: To investigate the association between maternal cervical cancer (CC) screening status and child human papillomavirus (HPV) vaccination uptake. To understand if child sex or social deprivation index (SDI) modify this association.<br><br>METHODS: We used a national cohort of children linked to at least one parent using electronic health record (EHR) data from a network of community health centers across the United States. We used SDI scores and child sex as moderating variables. We performed the analysis (1) for the whole sample (with SDI and child sex added as covariates), (2) stratified by SDI quartile (with child sex added as a covariate), and (3) stratified by SDI quartile and child sex, to examine whether associations vary by SDI quartile and by child sex.<br><br>RESULTS: N&#x2009;=&#x2009;52,919 linked mother-child pairs. Mother's receipt of CC screening was positively associated with the linked child's odds of receiving HPV vaccination [adjusted odds ratio (AOR) 1.39, 95% confidence interval (CI) 1.32, 1.47]. Neither sex or SDI modified this association. There were no significant differences in odds of HPV vaccination in children between SDI quartiles or between male and female children.<br><br>CONCLUSIONS FOR PRACTICE: An effective way to improve rates of HPV vaccination among children and adolescents may be to target attention towards increasing CC screening rates among mothers. Further, focusing resources and efforts on CC screenings and care of both mothers and their children may be more worthwhile than isolated efforts targeting HPV vaccination for children and adolescents.}, }
@article {pmid39379678, year = {2024}, author = {Akhiwu, TO and Adewunmi, C and Bilalaga, M and Atarere, JO and Gaddipati, G and Chido-Amajuoyi, OG and Eziuche, DK and Onyeaka, H and Amonoo, HL}, title = {Clinical trial knowledge among cancer survivors in the United States: the role of health information technology.}, journal = {Cancer causes &amp; control : CCC}, volume = {}, number = {}, pages = {}, pmid = {39379678}, issn = {1573-7225}, support = {K08CA251654/NH/NIH HHS/United States ; }, abstract = {PURPOSE: Clinical trials are essential to the advancement of cancer care. However, clinical trial knowledge and participation remain critically low among adult patients with cancer. Health information technology (HIT) could play an important role in improving clinical trial knowledge and engagement among cancer survivors.<br><br>METHODS: We used data from 3,794 adults who completed the 2020 Health Information National Trends Survey, 626 (16.2%) of whom were cancer survivors. We examined the prevalence of HIT use in the study population and by cancer history using chi-squared tests. We used multivariable logistic regression models to examine the impact of HIT use on clinical trial knowledge for cancer survivors and respondents with no cancer history, respectively.<br><br>RESULTS: Approximately 63.8% of cancer survivors reported having some knowledge of clinical trials. Almost half of the cancer survivors used HIT to communicate with doctors (47.1%) and make health appointments (49.4%), 68.0% used HIT to look up health information online and 42.2% used it to check test results. In the adjusted models, the use of HIT in communicating with doctors [OR 2.79; 95% CI (1.41, 5.54)], looking up health information online [OR 2.84; 95% CI (1.04, 7.77)], and checking test results [OR 2.47; 95% CI (1.12, 5.43)] was associated with having some knowledge of clinical trials.<br><br>CONCLUSION: HIT use for engaging with the healthcare team and health information gathering is associated with higher clinical trial knowledge in cancer survivors. Given the rapid increase in mobile technology access globally and the increased use of HIT, digital technology can be leveraged to improve clinical trial knowledge and engagement among cancer survivors.}, }
@article {pmid39377755, year = {2024}, author = {Montaño, M and Shapiro, AE and Whitney, BM and Bamford, L and Burkholder, G and Cachay, ER and Christopoulos, KA and Crane, HM and Delaney, JAC and Eron, JJ and Fredericksen, RJ and Hunt, PW and Jacobson, JM and Keruly, JC and Kim, HN and Mayer, KH and Moore, RD and Napravnik, S and Pettit, A and Saag, MS and Yendewa, GA and Kitahata, MM and Bender Ignacio, RA}, title = {Mpox in People With Human Immunodeficiency Virus: Predictors of Diagnosis, Outcomes, and Vaccine Effectiveness in a Multisite Cohort.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciae464}, pmid = {39377755}, issn = {1537-6591}, support = {P30 AI027763/AI/NIAID NIH HHS/United States ; //National Institute of Allergy and Infectious Diseases/ ; P30 AI073961/AI/NIAID NIH HHS/United States ; //CFAR/ ; P30 AI110527/AI/NIAID NIH HHS/United States ; R24 AI067039/AI/NIAID NIH HHS/United States ; P30 AI50410//University of North Carolina Chapel Hill/ ; P30 AI094189/AI/NIAID NIH HHS/United States ; //University of Washington/ ; //Vanderbilt Univ/ ; P30 AI027767/AI/NIAID NIH HHS/United States ; P30 AI036214/AI/NIAID NIH HHS/United States ; }, abstract = {INTRODUCTION: Since its global reemergence in 2022, monkeypox (mpox) has demonstrated increased incidence and severity among people with human immunodeficiency virus (HIV [PWH]). Predictors of mpox diagnosis, vaccination, and outcomes among PWH are limited.<br><br>METHODS: We included PWH with primary care visits after 1 January 2022 at 9 US sites participating in the Centers for AIDS Research Network of Integrated Clinic Systems Network. We identified mpox diagnosed between 1 June 2022 and 31 May 2023, through a combination of polymerase chain reaction result, diagnosis code, and/or tecovirimat receipt. We examined validated clinical diagnoses, laboratory results, vaccine data, and patient reported outcomes. We evaluated relative risks (RR) of mpox diagnosis, hospitalization, tecovirimat treatment, and vaccine receipt.<br><br>FINDINGS: Among 19 777 PWH in care, 413 mpox cases (all male sex at birth) occurred (2.2 cases/100 person-years). Age <40 years, geographic region, Hispanic/Latine ethnicity, lack of antiretroviral therapy, detectable HIV viral load, and recent bacterial sexually transmitted infection predicted mpox diagnosis. PWH with CD4 200-349&#x2005;cells/mm3 were most likely to be hospitalized (adjusted RR, 3.20; 95% confidence interval: 1.44-7.09) compared to CD4 &#x2265;500, but half as likely as those with CD4 <200 to receive tecovirimat. Overall, smallpox/mpox vaccine effectiveness of &#x2265;1 vaccine was 71% (adjusted RR, 0.29; 95% confidence interval: .14-.47) at preventing mpox, and 86% or better with CD4 &#x2265;350 or HIV viral suppression. Non-Hispanic Black PWH were less likely to be vaccinated than other racial/ethnic identities.<br><br>INTERPRETATION: PWH not on antiretroviral therapy or with unsuppressed HIV were more likely to be diagnosed with, and hospitalized for, mpox. Mpox/smallpox vaccine effectiveness was high, inclusive of those with low CD4 count and HIV viremia.}, }
@article {pmid39377586, year = {2024}, author = {Belmont, L and Contreras, M and Cartwright-Acar, CH and Marceau, CD and Agrawal, A and Levoir, LM and Lubow, J and Goo, L}, title = {Functional genomics screens reveal a role for TBC1D24 and SV2B in antibody-dependent enhancement of dengue virus infection.}, journal = {Journal of virology}, volume = {98}, number = {11}, pages = {e0158224}, pmid = {39377586}, issn = {1098-5514}, support = {T32 AI007509/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; //Chan Zuckerberg Biohub - San Francisco/ ; T32 AI083203/AI/NIAID NIH HHS/United States ; //Fred Hutchinson Cancer Center Diverse Trainee Fund/ ; //Hypothesis Fund/ ; S10 OD028685/OD/NIH HHS/United States ; }, mesh = {*Dengue Virus/immunology/genetics/physiology ; Humans ; *Dengue/immunology/virology/genetics ; *GTPase-Activating Proteins/genetics/metabolism ; *Antibodies, Viral/immunology ; *Immunoglobulin G/immunology ; Receptors, IgG/metabolism/genetics/immunology ; Cell Line ; Genomics/methods ; Gene Knockout Techniques ; Animals ; Host-Pathogen Interactions/immunology/genetics ; Virus Internalization ; HEK293 Cells ; }, abstract = {Under some conditions, dengue virus (DENV) can hijack IgG antibodies to facilitate its uptake into target cells expressing Fc gamma receptors (FcgR)-a process known as antibody-dependent enhancement (ADE) of infection. Beyond a requirement for FcgR, host dependency factors for this unusual IgG-mediated infection route remain unknown. To identify cellular factors exclusively required for ADE, here, we performed CRISPR knockout (KO) screens in an in vitro system poorly permissive to infection in the absence of IgG antibodies. Validating our approach, a top hit was FcgRIIa, which facilitates the binding and internalization of IgG-bound DENV but is not required for canonical infection. Additionally, we identified host factors with no previously described role in DENV infection, including TBC1D24 and SV2B, which have known functions in regulated secretion. Using genetic knockout and trans-complemented cells, we validated a functional requirement for these host factors in ADE assays performed with monoclonal antibodies and polyclonal sera in multiple cell lines and using all four DENV serotypes. We show that knockout of TBC1D24 or SV2B impaired the binding of IgG-DENV complexes to cells without affecting FcgRIIa expression levels. Thus, we identify cellular factors beyond FcgR that promote efficient ADE of DENV infection. Our findings represent a first step toward advancing fundamental knowledge behind the biology of a non-canonical infection route implicated in disease.IMPORTANCEAntibodies can paradoxically enhance rather than inhibit dengue virus (DENV) infection in some cases. To advance knowledge of the functional requirements of antibody-dependent enhancement (ADE) of infection beyond existing descriptive studies, we performed a genome-scale CRISPR knockout (KO) screen in an optimized in vitro system permissive to efficient DENV infection only in the presence of IgG. In addition to FcgRIIa, a known receptor that facilitates IgG-mediated uptake of IgG-bound, but not naked DENV particles, our screens identified TBC1D24 and SV2B, cellular factors with no known role in DENV infection. We validated a functional role for TBC1D24 and SV2B in mediating ADE of all four DENV serotypes in different cell lines and using various antibodies. Thus, we identify cellular factors beyond Fc gamma receptors that promote ADE mechanisms. This study represents a first step toward advancing fundamental knowledge beyond a poorly understood non-canonical viral entry mechanism.}, }
@article {pmid39375704, year = {2024}, author = {Gabel, AM and Belleville, AE and Thomas, JD and Pineda, JMB and Bradley, RK}, title = {APC mutations dysregulate alternative polyadenylation in cancer.}, journal = {Genome biology}, volume = {25}, number = {1}, pages = {255}, pmid = {39375704}, issn = {1474-760X}, mesh = {*Polyadenylation ; Humans ; *Adenomatous Polyposis Coli Protein/genetics/metabolism ; *3' Untranslated Regions ; Mutation ; Colorectal Neoplasms/genetics/metabolism ; Gene Expression Regulation, Neoplastic ; Animals ; Mice ; Neoplasms/genetics/metabolism ; Poly A/metabolism ; Adenocarcinoma/genetics/metabolism/pathology ; }, abstract = {BACKGROUND: Alternative polyadenylation (APA) affects most human genes and is recurrently dysregulated in all studied cancers. However, the mechanistic origins of this dysregulation are incompletely understood.<br><br>RESULTS: We describe an unbiased analysis of molecular regulators of poly(A) site selection across The Cancer Genome Atlas and identify that colorectal adenocarcinoma is an outlier relative to all other cancer subtypes. This distinction arises from the frequent presence of loss-of-function APC mutations in colorectal adenocarcinoma, which are strongly associated with long 3' UTR expression relative to tumors lacking APC mutations. APC knockout similarly dysregulates APA in human colon organoids. By mining previously published APC eCLIP data, we show that APC preferentially binds G- and C-rich motifs just upstream of proximal poly(A) sites. Lastly, we find that reduced APC expression is associated with APA dysregulation in tumor types lacking recurrent APC mutations.<br><br>CONCLUSIONS: As APC has been previously identified as an RNA-binding protein that preferentially binds 3' UTRs during mouse neurogenesis, our results suggest that APC promotes proximal poly(A) site use and that APC loss and altered expression contribute to pervasive APA dysregulation in cancers.}, }
@article {pmid39375464, year = {2024}, author = {Crespillo-Casado, A and Pothukuchi, P and Naydenova, K and Yip, MCJ and Young, JM and Boulanger, J and Dharamdasani, V and Harper, C and Hammoudi, PM and Otten, EG and Boyle, K and Gogoi, M and Malik, HS and Randow, F}, title = {Recognition of phylogenetically diverse pathogens through enzymatically amplified recruitment of RNF213.}, journal = {EMBO reports}, volume = {25}, number = {11}, pages = {4979-5005}, pmid = {39375464}, issn = {1469-3178}, support = {P400PB_191083//the&#xa0;Swiss National Science Foundation (SNSF)/ ; U54 AI170792 (PI: Nevan Krogan)//the National Institutes of Health/ ; BI31336//Diamond Light Source (Diamond)/ ; U105170648//UK Research and Innovation (UKRI)/ ; /WT_/Wellcome Trust/United Kingdom ; U54 AI170792/AI/NIAID NIH HHS/United States ; 222503/Z/21/Z//Wellcome Trust (WT)/ ; }, mesh = {*Ubiquitin-Protein Ligases/metabolism/genetics ; *Phylogeny ; Humans ; Toxoplasma/genetics/metabolism ; Listeria/genetics ; Cryoelectron Microscopy ; Salmonella/genetics/metabolism ; Protein Binding ; Immunity, Innate ; Adenosine Triphosphate/metabolism ; Host-Pathogen Interactions/genetics ; }, abstract = {Innate immunity senses microbial ligands known as pathogen-associated molecular patterns (PAMPs). Except for nucleic acids, PAMPs are exceedingly taxa-specific, thus enabling pattern recognition receptors to detect cognate pathogens while ignoring others. How the E3 ubiquitin ligase RNF213 can respond to phylogenetically distant pathogens, including Gram-negative Salmonella, Gram-positive Listeria, and eukaryotic Toxoplasma, remains unknown. Here we report that the evolutionary history of RNF213 is indicative of repeated adaptation to diverse pathogen target structures, especially in and around its newly identified CBM20 carbohydrate-binding domain, which we have resolved by cryo-EM. We find that RNF213 forms coats on phylogenetically distant pathogens. ATP hydrolysis by RNF213's dynein-like domain is essential for coat formation on all three pathogens studied as is RZ finger-mediated E3 ligase activity for bacteria. Coat formation is not diffusion-limited but instead relies on rate-limiting initiation events and subsequent cooperative incorporation of further RNF213 molecules. We conclude that RNF213 responds to evolutionarily distant pathogens through enzymatically amplified cooperative recruitment.}, }
@article {pmid39374582, year = {2024}, author = {Ali, N and Othus, M and Rodríguez-Arbolí, E and Orvain, C and Milano, F and Sandmaier, BM and Davis, C and Basom, R and Appelbaum, FR and Walter, RB}, title = {Measurable Residual Disease as Predictor of Post-Day +100 Relapses Following Allografting in Adult AML.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024013214}, pmid = {39374582}, issn = {2473-9537}, abstract = {Measurable residual disease (MRD) by multiparametric flow cytometry (MFC) before allogeneic hematopoietic cell transplantation (HCT) identifies patients at high risk of acute myeloid leukemia (AML) relapse, often occurring early after allografting. To examine the role of MFC MRD testing for the prediction of later relapses, we examined 935 adults with AML or myelodysplastic neoplasm (MDS)/AML transplanted in first or second morphologic remission who underwent bone marrow restaging studies between day 70 and 100 post-HCT and were alive and without relapse by day +100. Of these 136 (15%) had MRD before HCT, whereas only 11 (1%) had MRD at day +70-100. In day +100 landmark analyses, pre-HCT and day +70-100 MFC MRD were both associated with relapse (both P<0.001), relapse-free survival (RFS; both P<0.001) overall survival (OS; both P<0.001), and, for post-HCT MRD, non-relapse mortality (P=0.001) after multivariable adjustment. Importantly, while 126 of the 136 patients (92%) with MRD before HCT tested negative for MRD at day +70-100, their outcomes were inferior to those without MRD before HCT and at day +70-100, with 3-year relapse risk of 40% vs. 15% (P<0.001), 3-year RFS of 50% vs. 72% (P<0.001), and 3-year OS of 56% vs. 76% (P<0.001), whereas 3-year NRM estimates were similar (P=0.53). Thus, despite high MRD conversion rates, outcomes for MRDpos/MRDneg patients are inferior to MRDneg/MRDneg patients, suggesting all patients with pre-HCT MRD should be considered for pre-emptive therapeutic strategies after allografting.}, }
@article {pmid39374522, year = {2024}, author = {Coffey, DG and Atilla, PA and Atilla, E and Landgren, O and Cowan, AJ and Simon, S and Pont, M and Comstock, ML and Hill, GR and Riddell, SR and Green, DJ}, title = {Single-cell analysis of the multiple myeloma microenvironment after gamma-secretase inhibition and CAR T-cell therapy.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024025231}, pmid = {39374522}, issn = {1528-0020}, support = {P01 CA018029/CA/NCI NIH HHS/United States ; }, abstract = {Chimeric antigen receptor (CAR) T-cells and bispecific antibodies (BsAb) targeting B-cell maturation antigen (BCMA) have significantly advanced the treatment of relapsed and refractory multiple myeloma (MM). Resistance to BCMA-targeting therapies, nonetheless, remains a significant challenge. BCMA shedding by gamma-secretase is a known resistance mechanism, and preclinical studies suggest that inhibition may improve anti-BCMA therapy. Leveraging a phase I clinical trial of the gamma-secretase inhibitor (GSI), crenigacestat, with anti-BCMA CAR T-cells (FCARH143), we utilized single-nuclei RNA sequencing and Assay for Transposase-Accessible Chromatin (ATAC) sequencing to characterize the effects of GSI on the tumor microenvironment. The most significant impacts of GSI involved effects on monocytes, which are known to promote tumor growth. In addition to observing a reduction in the frequency of non-classical monocytes, we also detected significant changes in gene expression, chromatin accessibility, and inferred cell-cell interactions following exposure to GSI. Although many genes with altered expression are associated with gamma-secretase-dependent signaling, such as Notch, other pathways were affected, indicating GSI has far-reaching effects. Finally, we detected monoallelic deletion of the BCMA locus in some patients with prior exposure to anti-BCMA therapy, which significantly correlated with reduced progression-free survival (median PFS 57 days versus 861 days). GSIs are being explored in combination with the full spectrum of BCMA targeting agents, and our results reveal widespread effects of GSI on both tumor and immune cell populations, providing insight into mechanisms for enhancing BCMA-directed therapies.}, }
@article {pmid39374449, year = {2024}, author = {Dizman, N and Bakouny, Z and Haykal, T and Riano, I and Desai, A and Butt, A and Basu, A and Zhao, D and Saad, E and Saliby, RM and Gosain, R and Gosain, R and Ardeshir, F and Deng, L and Matt-Amaral, L and Arnaoutakis, K and Bekaii-Saab, T and Manochakian, R and Marshall, A and Forde, P and Murphy, M and Subbiah, V and Chavez-MacGregor, M and Owonikoko, TK and Lopes, G and Aggarwal, C and Lee, AI and Choueiri, TK}, title = {Guide to Understanding and Supporting International Medical Graduates in Hematology/Oncology by the ASCO International Medical Graduates Community of Practice.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2400565}, doi = {10.1200/OP-24-00565}, pmid = {39374449}, issn = {2688-1535}, abstract = {PURPOSE: International medical graduates (IMGs) are an essential component of the oncology workforce in the United States, comprising a third of all practicing oncologists and almost half of hematology/oncology fellows. In this article, we discuss the contributions of IMGs in the US oncology workforce, review unique challenges faced by IMGs, and propose potential solutions to overcome these challenges.<br><br>METHODS: ASCO's IMG Community of Practice was established with the mission to connect, mentor, guide, raise awareness, and overcome the challenges unique to IMGs interested in pursuing medical oncology in the United States. The content of this article is based on discussions at the IMG Community of Practice meetings at ASCO's 2023 and 2024 Annual Meetings.<br><br>RESULTS: IMGs bring an inherent diversity of thought and experience to the oncology workforce. They provide high-quality, culture- and language-concordant care to a diverse population of patients with cancer. However, IMGs in oncology face significant hardships throughout their careers, including visa-related restrictions, psychosocial and cultural struggles, as well as differential treatment while applying for residency and fellowship training, and early career positions. Greater awareness of these challenges among the members of the hematology/oncology community, along with institutional and individual efforts to support IMGs, is warranted.<br><br>CONCLUSION: We encourage oncology professionals and institutions to join our efforts in recognizing the unique paths of IMGs and providing support and advocacy to maximize the potential of IMGs in the US oncology workforce.}, }
@article {pmid39374015, year = {2024}, author = {Goldkorn, A and Tangen, C and Plets, M and Bsteh, D and Xu, T and Pinski, JK and Ingles, S and Triche, TJ and MacVicar, GR and Vaena, DA and Crispino, AW and McConkey, DJ and Lara, PN and Hussain, MHA and Quinn, DI and Dorff, TB and Lerner, SP and Thompson, I and Agarwal, N}, title = {Circulating Tumor Cell Count and Overall Survival in Patients With Metastatic Hormone-Sensitive Prostate Cancer.}, journal = {JAMA network open}, volume = {7}, number = {10}, pages = {e2437871}, pmid = {39374015}, issn = {2574-3805}, mesh = {Male ; Humans ; *Neoplastic Cells, Circulating ; Aged ; Prognosis ; Middle Aged ; Prospective Studies ; Prostatic Neoplasms/mortality/pathology/blood/drug therapy ; Prostatic Neoplasms, Castration-Resistant/blood/mortality/drug therapy/pathology ; Aged, 80 and over ; Biomarkers, Tumor/blood ; Neoplasm Metastasis ; Prostate-Specific Antigen/blood ; }, abstract = {IMPORTANCE: In metastatic hormone-sensitive prostate cancer (mHSPC), new first-line combination therapies have enhanced overall survival (OS), but clinical outcomes for individual patients vary greatly and are difficult to predict. Peripheral blood circulating tumor cell (CTC) count is the most extensively validated prognostic liquid biomarker in metastatic castration-resistant prostate cancer (mCRPC), and recent studies have suggested that it may also be informative in mHSPC.<br><br>OBJECTIVE: To examine the prognostic value of CTC count in men with mHSPC.<br><br>In this prognostic study, peripheral blood was drawn at registration (baseline) and at progression to mCRPC in the S1216 study (March 1, 2013, to July 15, 2017), a phase 3, prospective, randomized clinical trial in men with mHSPC. The CTCs were enumerated using a US Food and Drug Administration-cleared isolation platform. Counts were categorized as 0, 1 to 4, or 5 or more CTCs per 7.5 mL based on the prognostic value of these cut points in prior studies. The data analysis was performed between October 28, 2022, and June 15, 2023.<br><br>EXPOSURE: Metastatic hormone-sensitive prostate cancer.<br><br>MAIN OUTCOMES AND MEASURES: Circulating tumor cell count was evaluated for an association with 3 prespecified trial end points: OS, progression-free survival, and 7-month prostate-specific antigen, after adjusting for other baseline covariates using proportional hazards and logistic regression models.<br><br>RESULTS: Of 1313 S1216 participants (median [IQR] age, 68 [44-92] years), evaluable samples from 503 (median [IQR] age, 69 [46-90] years) with newly diagnosed mHSPC were collected at baseline, and 93 samples were collected at progression. Baseline counts were 5 or more CTCs per 7.5 mL in 60 samples (11.9%), 1 to 4 CTCs per 7.5 mL in 107 samples (21.3%), and 0 CTCs per 7.5 mL in 336 samples (66.8%). Median OS for men with 5 or more CTCs per 7.5 mL was 27.9 months (95% CI, 24.1-31.2 months) compared with 56.2 months (95% CI, 45.7-69.8 months) for men with 1 to 4 CTCs per 7.5 mL and not reached at 78.0 months follow-up for men with 0 CTCs per 7.5 mL. After adjusting for baseline clinical covariates, men with 5 or more CTCs per 7.5 mL at baseline had a significantly higher hazard of death (hazard ratio, 3.22; 95% CI, 2.22-4.68) and disease progression (hazard ratio, 2.46; 95% CI, 1.76-3.43) and a lower likelihood of prostate-specific antigen complete response (odds ratio, 0.26; 95% CI, 0.12-0.54) compared with men with 0 CTCs per 7.5 mL at baseline. Adding baseline CTC count to other known prognostic factors (covariates only: area under the curve, 0.73; 95% CI, 0.67-0.79) resulted in an increased prognostic value for 3-year survival (area under the curve, 0.79; 95% CI, 0.73-0.84).<br><br>CONCLUSIONS AND RELEVANCE: In this prognostic study, the findings validate CTC count as a prognostic biomarker that improved upon existing prognostic factors and estimated vastly divergent survival outcomes regardless of subsequent lines of therapy. As such, baseline CTC count in mHSPC may serve as a valuable noninvasive biomarker to identify men likely to have poor survival who may benefit from clinical trials of intensified or novel regimens.}, }
@article {pmid39373644, year = {2024}, author = {Wickline, M and Carpenter, PA and Harris, JR and Iribarren, SJ and Reding, KW and Pike, KC and Lee, SJ and Salit, RB and Oshima, MU and Vo, PT and Berry, DL}, title = {Barriers and facilitators to routine revaccination among adult Hematopoietic Cell Transplant survivors in the United States: A convergent mixed methods analysis.}, journal = {Transplant infectious disease : an official journal of the Transplantation Society}, volume = {}, number = {}, pages = {e14388}, doi = {10.1111/tid.14388}, pmid = {39373644}, issn = {1399-3062}, support = {//Oncology Nursing Society Foundation/ ; //School of Nursing, University of Washington/ ; //Hester McLaws Nursing Scholarship/ ; }, abstract = {BACKGROUND: Hematopoietic cell transplant (HCT) survivorship care includes recommendations for post-HCT revaccination to restore immunity to vaccine-preventable diseases (VPDs). However, not all survivors agree to be vaccinated. No existing studies have comprehensively reported barriers and facilitators to adult HCT survivors completing revaccination.<br><br>METHODS: A cross-sectional survey of 194 adult HCT survivors was analyzed using convergent mixed methods. The analysis used various statistical methods to determine the prevalence of barriers and facilitators and the association between revaccination and the number and specific type of barriers and facilitators. Content analysis was applied to open-ended item responses. Integrated analysis merged quantitative and qualitative findings.<br><br>RESULTS: The most frequent barriers included the inability to receive live vaccines because of immunosuppression, identifying a suitable community location for administering childhood vaccines to adults, and delayed immune recovery. The most frequent facilitators were having healthcare insurance and a clear calendar of the revaccination schedule. Complete revaccination rates were lower with each additional reported barrier (OR = 0.58; 95% CI 0.459-0.722) and higher with each additional reported facilitator (OR = 1.31; 95% CI 1.05-1.63). Content analysis suggested that most barriers were practical issues. One significant facilitator highlighted by respondents was for the transplant center to coordinate and serve as the vaccination location for revaccination services. Merged analysis indicated convergence between quantitative and qualitative data.<br><br>CONCLUSION: Practical barriers and facilitators played a consequential role in revaccination uptake, and survivors would like to be revaccinated at the transplant center.}, }
@article {pmid39373623, year = {2024}, author = {Loroña, NC and Himbert, C and Ose, J and Cohen, SA and Strehli, I and Ulrich, CM and Cobos, S and Jean-Baptiste, E and Bloomer, AM and Figueiredo, JC and Gigic, B and Hardikar, S and Karchi, M and Mutch, M and Peoples, AR and Schneider, M and Shibata, D and Siegel, EM and Toriola, AT and Wood, EH and Li, CI}, title = {Alcohol consumption and smoking history at time of diagnosis, and risk of colorectal cancer recurrence and mortality: Results from the ColoCare Study.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-24-0834}, pmid = {39373623}, issn = {1538-7755}, support = {R01 CA254108/CA/NCI NIH HHS/United States ; T32 CA009168/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Findings from studies investigating the impacts of alcohol use and smoking on colorectal cancer (CRC) outcomes are inconclusive. This study aimed to investigate associations between alcohol use and smoking status at the time of diagnosis on recurrence and overall mortality among patients with CRC.<br><br>METHODS: The present study included 2,216 stage I-IV patients with CRC from the longitudinal multi-center ColoCare study, with available data on recurrence and CRC-specific mortality. Cox proportional hazards models adjusted for age, sex, race, ethnicity, stage, tumor site, treatment, comorbidities, body mass index, and study site were fit, with imputations for missing data.<br><br>RESULTS: We observed 235 recurrences and 308 CRC-specific deaths over an average of 3 years of follow-up. After adjusting for confounders, current alcohol consumption and ever smoking, relative to not current consumption and never smoking, respectively, were not statistically significantly associated with CRC recurrence (Alcohol - HR: 0.95. 95% CI: 0.71-1.29; Ever smoking - HR: 0.98, 95% CI: 0.75-1.29) or CRC-specific mortality (Alcohol - HR: 0.95. 95% CI: 0.74-1.22; Ever smoking - HR: 0.98, 95% CI: 0.77-1.24).<br><br>CONCLUSIONS: No associations were observed between alcohol and smoking at diagnosis and clinical outcomes in this well-annotated longitudinal cohort.<br><br>IMPACT: Our cohort study reports no significant associations; however, limiting alcohol use and avoiding smoking are health behaviors recommended for CRC survivors for prevention of other cancers and chronic conditions.}, }
@article {pmid39373353, year = {2024}, author = {Amonoo, HL and Daskalakis, E and Lam, JA and Wolfe, ED and Guo, M and Onyeaka, HK and Newcomb, RA and Barata, A and Ghanime, PM and Keane, EP and Boardman, AC and Cutler, C and Pirl, WF and Peteet, JR and Gudenkauf, LM and Lee, SJ and Huffman, JC and El-Jawahri, A}, title = {Association between positive affect, flourishing, quality of life, and psychological distress in allogeneic hematopoietic stem cell transplantation.}, journal = {Journal of psychosocial oncology}, volume = {}, number = {}, pages = {1-16}, doi = {10.1080/07347332.2024.2410929}, pmid = {39373353}, issn = {1540-7586}, abstract = {PURPOSE: To examine the associations between state positive psychological well-being (PPWB) constructs, mood, and quality of life (QOL) in hematopoietic stem cell transplantation (HSCT) survivors.<br><br>DESIGN: The study was a secondary analysis of cross-sectional data.<br><br>SAMPLE/METHODS: We analyzed self-report data assessing positive affect, flourishing, QOL, depression and anxiety, and PTSD symptoms from 158 allogeneic HSCT recipients at day-100 post-transplant enrolled in supportive care studies.<br><br>FINDINGS: Univariate analysis showed that factors associated with greater levels of various state PPWB constructs include older age, disability status, greater social support, and presence of graft-versus-host disease. Multivariate analysis showed that state PPWB constructs-greater levels of positive affect and flourishing-were significantly associated with better QOL and lower PTSD, anxiety, and depression symptomatology.<br><br>IMPLICATIONS: Our findings suggest that longitudinal studies are needed to examine the links between state PPWB constructs and HSCT outcomes, which may inform population specific interventions and opportunities to improve outcomes.}, }
@article {pmid39373106, year = {2024}, author = {Poston, JN and Brown, SP and Ginsburg, AS and Ilich, A and Herren, H and El Kassar, N and Triulzi, DJ and Key, NS and May, S and Gernsheimer, TB}, title = {Analysis of bleeding outcomes in patients with hypoproliferative thrombocytopenia in the A-TREAT clinical trial.}, journal = {Transfusion}, volume = {64}, number = {11}, pages = {2055-2062}, doi = {10.1111/trf.18028}, pmid = {39373106}, issn = {1537-2995}, support = {HL122272/HL/NHLBI NIH HHS/United States ; HL122894/HL/NHLBI NIH HHS/United States ; HL143403/HL/NHLBI NIH HHS/United States ; HL146226/HL/NHLBI NIH HHS/United States ; HL122272/HL/NHLBI NIH HHS/United States ; HL122894/HL/NHLBI NIH HHS/United States ; HL143403/HL/NHLBI NIH HHS/United States ; HL146226/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Thrombocytopenia/drug therapy/therapy ; Male ; Middle Aged ; *Hemorrhage/etiology ; Aged ; *Tranexamic Acid/therapeutic use ; Adult ; Platelet Transfusion ; Risk Factors ; Hematologic Neoplasms/complications/therapy ; Antifibrinolytic Agents/therapeutic use ; Platelet Count ; }, abstract = {BACKGROUND: Despite prophylactic platelet transfusions, hypoproliferative thrombocytopenia is associated with bleeding; historical risk factors include hematocrit (HCT) ≤ 25%, activated partial thromboplastin time ≥ 30 s, international normalized ratio ≥ 1.2, and platelets ≤ 5000/μL.<br><br>METHODS: We performed a post hoc analysis of bleeding outcomes and risk factors in participants with hematologic malignancy and hypoproliferative thrombocytopenia enrolled in the American Trial to Evaluate Tranexamic Acid Therapy in Thrombocytopenia (A-TREAT) and randomized to receive either tranexamic acid (TXA) or placebo.<br><br>RESULTS: World Health Organization (WHO) grade 2+ bleeding occurred in 46% of 330 participants, with no difference between the TXA (44%) and placebo (47%) groups (p&#x2009;=&#x2009;0.66). Overall, the most common sites of bleeding were oronasal (18%), skin (17%), gastrointestinal (11%), and genitourinary (11%). Among participants of childbearing potential, 28% experienced vaginal bleeding. Platelets &#x2264;5000/&#x3bc;L and HCT&#x2009;<&#x2009;21% (after adjusting for severe thrombocytopenia) were independently associated with increased bleeding risk (HR 3.78, 95% CI 2.16-6.61; HR 2.67, 95% CI 1.35-5.27, respectively). Allogeneic stem cell transplant was associated with nonsignificant increased risk of bleeding versus chemotherapy alone (HR 1.34, 95% CI 0.94-1.91).<br><br>DISCUSSION: The overall rate of WHO grade 2+ bleeding was similar to previous reports, albeit with lower rates of gastrointestinal bleeding. Vaginal bleeding was common in participants of childbearing potential. Platelets &#x2264;5000/&#x3bc;L remained a risk factor for bleeding. Regardless of platelet count, bleeding risk increased with HCT&#x2009;<&#x2009;21%, suggesting a red blood cell transfusion threshold above 21% should be considered to mitigate bleeding. More investigation is needed on strategies to reduce bleeding in this population.}, }
@article {pmid39371366, year = {2024}, author = {Krantz, EM and Mutyaba, I and Nankoma, J and Okuku, F and Casper, C and Orem, J and Swan, DA and Phipps, W and Schiffer, JT}, title = {Highly Heterogeneous Kaposi Sarcoma-Associated Herpesvirus Oral Shedding Kinetics Among People With and Without Kaposi Sarcoma and Human Immunodeficiency Virus Coinfection.}, journal = {Open forum infectious diseases}, volume = {11}, number = {10}, pages = {ofae548}, pmid = {39371366}, issn = {2328-8957}, support = {P30 AI027757/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: An improved understanding of oral Kaposi sarcoma-associated herpesvirus (KSHV) viral dynamics could provide insights into transmission risk and guide vaccine development.<br><br>METHODS: We evaluated KSHV oral shedding dynamics in Ugandan adults stratified by Kaposi sarcoma (KS) and human immunodeficiency virus (HIV) status. Participants were followed for &#x2265;4 weeks, with daily home oral swab collection to quantify KSHV using polymerase chain reaction. Shedding rates were defined by number of days with KSHV DNA detected divided by total days with swabs and compared by group using hurdle models.<br><br>RESULTS: Two hundred ninety-five participants were enrolled; median age was 35 years (range, 18-71 years), and 134 (45%) were male. KSHV was detected more frequently among participants with KS (HIV positive [HIV[+]]/KS[+], 56/76 [74%]; HIV negative [HIV[-]]/KS[+], 9/18 [50%]) than those without KS (HIV[+]/KS[-], 36/125 [29%]; HIV[-]/KS[-], 16/76 [21%]); odds of shedding did not differ significantly by HIV status. Among participants with KSHV detected, shedding rates did not differ significantly by group. Median per-participant viral loads among positive samples were lowest in HIV[+]/KS[+] (3.1 log10 copies/mL) and HIV[-]/KS[+] (3.3 log10 copies/mL) participants relative to HIV[+]/KS[-] (3.8 log10 copies/mL) and HIV[-]/KS[-] (4.0 log10 copies/mL) participants. All groups had participants with low viral load intermittent shedding and participants with high viral load persistent shedding. Within each group, individual KSHV shedding rate positively correlated with median KSHV log10 copies/mL, and episode duration positively correlated with peak viral load.<br><br>CONCLUSIONS: Oral KSHV shedding is highly heterogeneous across Ugandan adults with and without KS and HIV. Persistent shedding is associated with higher median viral loads regardless of HIV and KS status.}, }
@article {pmid39371123, year = {2024}, author = {Dehn, JG and Logan, B and Shaw, BE and Devine, S and Ciurea, SO and Horowitz, M and He, N and Pusic, I and Srour, SA and Arai, S and Juckett, M and Uberti, J and Hill, L and Vasu, S and Hogan, WJ and Hayes-Lattin, B and Westervelt, P and Bashey, A and Farhadfar, N and Grunwald, MR and Leifer, E and Symons, H and Saad, A and Vogel, J and Erickson, C and Buck, K and Lee, SJ and Pidala, J}, title = {Access to Allogeneic Cell Transplantation Based on Donor Search Prognosis: An Interventional Trial.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39371123}, support = {U10 HL069294/HL/NHLBI NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; U24 HL138660/HL/NHLBI NIH HHS/United States ; }, abstract = {IMPORTANCE: Patients requiring allogeneic hematopoietic cell transplantation have variable likelihoods of identifying an 8/8 HLA-matched unrelated donor. A Search Prognosis calculator can estimate the likelihood.<br><br>OBJECTIVE: To determine if using a search algorithm based on donor search prognosis can result in similar incidence of transplant between patients Very Likely (>90%) vs Very Unlikely (<10%) to have a matched unrelated donor.<br><br>DESIGN: This interventional trial utilized a Search Prognosis-based biologic assignment algorithm to guide donor selection. Trial enrollment from June 13, 2019-May 13, 2022; analysis of data as of September 7, 2023 with median follow-up post-evaluability of 14.5 months.<br><br>SETTINGS: National multi-center Blood and Marrow Transplantation Clinical Trials Network 1702 study of US participating transplant centers.<br><br>PARTICIPANTS: Acute myeloid and lymphoid leukemias, myelodysplastic syndrome, Hodgkin's and non-Hodgkin's lymphomas, severe aplastic anemia, and sickle cell disease patients referred to participating transplant centers were invited to participate. 2225 patients were enrolled and 1751 were declared evaluable for this study. Patients were declared evaluable once it was determined no suitable HLA-matched related donor was available.<br><br>INTERVENTION: Patients assigned to the Very Likely arm were to proceed with matched unrelated donor, while Very Unlikely were to utilize alternative donors. A third stratum, Less Likely (~25%) to find a matched unrelated donor, were observed under standard center practices, but were not part of the primary objective.<br><br>MAIN OUTCOME: Cumulative incidence of transplantation by Search Prognosis arm.<br><br>RESULTS: Evaluable patients included 1751 of which 413 (24%) were from racial/ethnic minorities. Search prognosis was 958 (55%) Very Likely, 517 (30%) Less Likely and 276 (16%) Very Unlikely. 1171 (67%) received HCT, 384 (22%) died without HCT, and 196 (11%) remained alive without HCT. Among the 1,234 patients, the adjusted cumulative incidence (95% CI) of HCT at 6-months was 59.8% (56.7-62.8) in the Very Likely group versus 52.3% (46.1-58.5) in the Very Unlikely (P=0.113).<br><br>CONCLUSIONS: A prospective Search Prognosis-based algorithm can be effectively implemented in a national multicenter clinical trial. This approach resulted in rapid alternative donor identification and comparable rates of HCT in patients Very Likely and Very Unlikely to find a matched unrelated donor.}, }
@article {pmid39370355, year = {2024}, author = {Choe, M and Summers, C}, title = {The Road More or Less Traveled- Examining the Role of Consolidative Allogeneic Hematopoietic Stem Cell Transplantation After Chimeric Antigen Receptor T Cell Therapy in B-cell ALL.}, journal = {Seminars in hematology}, volume = {61}, number = {5}, pages = {314-320}, doi = {10.1053/j.seminhematol.2024.08.004}, pmid = {39370355}, issn = {1532-8686}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/methods ; *Immunotherapy, Adoptive/methods ; *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/therapy/immunology ; Transplantation, Homologous/methods ; Receptors, Chimeric Antigen/immunology ; Antigens, CD19/immunology ; }, abstract = {Treatment with CD19-targeted chimeric antigen receptor T cell therapy (CD19-CART) has improved salvage rates in children and adults with relapsed and/or refractory B-cell acute lymphoblastic leukemia (ALL). However, not all patients treated with CD19-CAR T cells achieve long-term remission. The role of allogeneic hematopoietic stem cell transplantation as consolidative therapy remains undefined. We aim to review the current literature published to date regarding prognostic markers indicating durable ALL response to CD19-CART and risk factors for relapse after CD19-CART to identify patient cohorts who may benefit from consolidative hematopoietic stem cell transplantation.}, }
@article {pmid39369160, year = {2024}, author = {Zhu, W and Lusk, JA and Pascua, V and Djukovic, D and Raftery, D}, title = {Combination of low glucose and SCD1 inhibition impairs cancer metabolic plasticity and growth in MCF-7 cancer cells: a comprehensive metabolomic and lipidomic analysis.}, journal = {Metabolomics : Official journal of the Metabolomic Society}, volume = {20}, number = {5}, pages = {112}, pmid = {39369160}, issn = {1573-3890}, mesh = {Humans ; *Stearoyl-CoA Desaturase/metabolism/antagonists &amp; inhibitors ; *Glucose/metabolism ; MCF-7 Cells ; *Lipidomics/methods ; *Metabolomics/methods ; Lipid Metabolism/drug effects ; Female ; Cell Proliferation/drug effects ; Breast Neoplasms/metabolism/drug therapy ; Metabolome/drug effects ; }, abstract = {BACKGROUND: Cancer cells exhibit remarkable metabolic plasticity, enabling them to adapt to fluctuating nutrient conditions. This study investigates the impact of a combination of low glucose levels and inhibition of stearoyl-CoA desaturase 1 (SCD1) using A939572 on cancer metabolic plasticity and growth.<br><br>METHODS: A comprehensive metabolomic and lipidomic analysis was conducted to unravel the intricate changes in cellular metabolites and lipids. MCF-7 cells were subjected to low glucose conditions, and SCD1 was inhibited using A939572. The resulting alterations in metabolic pathways and lipid profiles were explored to elucidate the synergistic effects on cancer cell physiology.<br><br>RESULTS: The combination of low glucose and A939572-induced SCD1 inhibition significantly impaired cancer cell metabolic plasticity. Metabolomic analysis highlighted shifts in key glycolytic and amino acid pathways, indicating the cells' struggle to adapt to restricted glucose availability. Lipidomic profiling revealed alterations in lipid composition, implying disruptions in membrane integrity and signaling cascades.<br><br>CONCLUSION: Our findings underscore the critical roles of glucose availability and SCD1 activity in sustaining cancer metabolic plasticity and growth. Simultaneously targeting these pathways emerges as a promising strategy to impede cancer progression. The comprehensive metabolomic and lipidomic analysis provides a detailed roadmap of molecular alterations induced by this combination treatment, that may help identify potential therapeutic targets.}, }
@article {pmid39369133, year = {2024}, author = {Basin, MF and Miguel, CM and Jacob, JM and Goldberg, H and Grivas, P and Spiess, PE and Necchi, A and Kamat, AM and Pavlick, DC and Huang, RSP and Lin, DI and Danziger, N and Sokol, ES and Sivakumar, S and Graf, R and Cheng, L and Vasan, N and Ross, J and Basnet, A and Bratslavsky, G}, title = {Single-Hit and Multi-hit PIK3CA Short Variant Genomic Alterations in Clinically Advanced Prostate Cancer: A Genomic Landscape Study.}, journal = {Targeted oncology}, volume = {19}, number = {6}, pages = {981-990}, pmid = {39369133}, issn = {1776-260X}, mesh = {Humans ; Male ; *Class I Phosphatidylinositol 3-Kinases/genetics ; *Prostatic Neoplasms/genetics/pathology ; *Genomics/methods ; Aged ; Middle Aged ; Mutation ; }, abstract = {BACKGROUND: Tumors harboring two or more PIK3CA short variant (SV) ("multi-hit") mutations have been linked to improved outcomes with anti-PIK3CA-targeted therapies in breast cancer. The landscape and clinical implications of multi-hit PIK3CA alterations in clinically advanced prostate cancer (CAPC) remains elusive.<br><br>OBJECTIVE: To evaluate the genomic landscape of single-hit and multi-hit PIK3CA genomic alterations in CAPC.<br><br>PATIENTS AND METHODS: The Foundation Medicine FoundationCore database was used to identify 19,978 CAPC tumors that underwent hybrid capture-based comprehensive genomic profiling to evaluate all classes of genomic alterations (GA) and determine tumor mutational burden (TMB), microsatellite instability (MSI), genomic ancestry, single-base substitution mutational signatures, and homologous recombination deficiency signature (HRDsig). Tumor cell PD-L1 expression was determined by IHC (Dako 22C3).<br><br>RESULTS: 18,741 (93.8%) tumors were PIK3CA wild type (WT), 1155 (5.8%) featured single PIK3CA SV, and 82 (0.4%) featured multi-hit PIK3CA SVs. Single-hit (6.6 versus 3.8; p < 0.0001) and multi-hit (12.8 versus 3.8; p < 0.0001) featured more driver GA per tumor than PIK3CA WT CAPC, as well as higher prevalence of MMR mutational signature, MSI high status, and TMB levels versus PIK3CA WT (p < 0.0001). Other differences in GA included higher frequencies of GA in BRCA2 in multi-hit versus WT (18.3% versus 8.5%; p = 0.0191), ATM in multi-hit versus WT (13.4% versus 5.6%; p = 0.02) and PTEN in single-hit versus WT (40.2% versus 30.1%; p < 0.0001). Homologous recombination deficiency signatures were higher in PIK3CA WT versus single-hit (11.2% versus 7.6%; p = 0.0002). There were no significant differences in PD-L1 expression among the three groups.<br><br>CONCLUSIONS: Identification of multi-hit PIK3CA GA in CAPC highlights a potentially unique phenotype that may be associated with response to anti-PIK3CA targeted therapy and checkpoint inhibition, supporting relevant clinical trial designs.}, }
@article {pmid39368804, year = {2024}, author = {Pal, KV and Othus, M and Ali, Z and Russell, K and Shaw, C and Percival, MM and Hendrie, PC and Appelbaum, JS and Walter, RB and Halpern, AB}, title = {Identification of factors predicting low-risk febrile neutropenia admissions in adults with acute myeloid leukemia (AML).}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024014291}, pmid = {39368804}, issn = {2473-9537}, abstract = {Febrile neutropenia (FN) is the most common reason for hospital readmission following chemotherapy for AML and is a major driver of healthcare resource utilization. While FN risk models exist, these have largely been developed and validated in solid tumors. We therefore examined whether baseline characteristics could predict which AML patients with FN have a lower risk of progression to severe illness. We identified adults with high-grade myeloid neoplasm ([3]10% blasts in blood/marrow) who received intensive chemotherapy and were admitted for FN from 2016-2023. We collected baseline clinical and disease variables. Outcomes were: infections identified, hospital length of stay (LOS), intensive care unit (ICU) admission, and survival. A "lower-risk [LR]" outcome was defined as LOS <72hrs without ICU admission or inpatient death. Univariate and multivariable (MV) logistic regression models were used to assess covariate associations with outcomes. We identified 397 FN admissions in 248 patients (median age 61 [range: 29-77] years). The median hospital LOS was 6 (range: 1-56) days; 10% required ICU admission and 3.5% died inpatient. Only 15% of admissions were LR. Infection was identified in 59% of admissions. Physiologic parameters including heart rate, blood pressure and fever height were the best predictors of LR admission and infection. We developed MV models to predict LR admission and infection with AUCs of 0.82 and AUC 0.72, respectively. Established FN and critical illness models were not predictive of outcomes in AML, where we could not identify a lower risk group; thus an AML-specific FN risk model requires further development and validation.}, }
@article {pmid39368130, year = {2024}, author = {Pascoe, KM and Bishop, S and Ci, X and Ramirez, M and Perez, G and Ibarra, G and Garza, L and Linde, S and Duran, MC and Chae, HY and Quigley, T and Hassell, L and Garrison, MM and Drain, PK and Shah, PD and Ko, LK}, title = {Factors that shape COVID-19 pediatric vaccine decision-making in rural agricultural communities: A qualitative study.}, journal = {Vaccine}, volume = {42}, number = {26}, pages = {126389}, doi = {10.1016/j.vaccine.2024.126389}, pmid = {39368130}, issn = {1873-2518}, support = {OT2 HD107544/HD/NICHD NIH HHS/United States ; }, abstract = {While COVID-19 immunizations can improve outcomes from SARS-CoV-2, vaccine rates in the United States have been lowest among children under age 11 and among rural agricultural communities. This study examined factors influencing pediatric COVID-19 vaccine uptake among rural agricultural and predominantly Hispanic communities in Washington State. We conducted in-depth interviews with school district employees and students and held English and Spanish focus group discussions with parents, all of which were audio-recorded and transcribed. We used inductive coding with constant comparison approach to capture emergent themes. We identified five factors that influenced pediatric COVID-19 vaccine uptake in a rural community, including: 1) concerns and misinformation surrounding the new vaccine; 2) witnessing others' vaccine and pandemic experiences; 3) participation in social activities; 4) politicization of and political climate surrounding the vaccine; and 5) health education surrounding the vaccines. To increase pediatric COVID-19 vaccine uptake in rural communities, school districts, students, and parents should receive accurate information and reassurance to dispel health concerns and misinformation, without politicization of the vaccine and fears surrounding vaccine regulations. Social networks can be leveraged to encourage vaccine uptake by sharing positive vaccination vignettes. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT04859699https://clinicaltrials.gov/ct2/show/NCT04859699.}, }
@article {pmid39366729, year = {2024}, author = {, }, title = {Forecasting the effects of smoking prevalence scenarios on years of life lost and life expectancy from 2022 to 2050: a systematic analysis for the Global Burden of Disease Study 2021.}, journal = {The Lancet. Public health}, volume = {9}, number = {10}, pages = {e729-e744}, pmid = {39366729}, issn = {2468-2667}, support = {IA/CPHE/17/1/503345/WTDBT_/DBT-Wellcome Trust India Alliance/India ; T32 AG049676/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Life Expectancy/trends ; *Forecasting ; *Smoking/epidemiology ; Prevalence ; Female ; Male ; *Global Burden of Disease ; Adult ; Middle Aged ; Global Health/statistics &amp; numerical data ; Aged ; Young Adult ; Adolescent ; }, abstract = {BACKGROUND: Smoking is the leading behavioural risk factor for mortality globally, accounting for more than 175 million deaths and nearly 4·30 billion years of life lost (YLLs) from 1990 to 2021. The pace of decline in smoking prevalence has slowed in recent years for many countries, and although strategies have recently been proposed to achieve tobacco-free generations, none have been implemented to date. Assessing what could happen if current trends in smoking prevalence persist, and what could happen if additional smoking prevalence reductions occur, is important for communicating the effect of potential smoking policies.<br><br>METHODS: In this analysis, we use the Institute for Health Metrics and Evaluation's Future Health Scenarios platform to forecast the effects of three smoking prevalence scenarios on all-cause and cause-specific YLLs and life expectancy at birth until 2050. YLLs were computed for each scenario using the Global Burden of Disease Study 2021 reference life table and forecasts of cause-specific mortality under each scenario. The reference scenario forecasts what could occur if past smoking prevalence and other risk factor trends continue, the Tobacco Smoking Elimination as of 2023 (Elimination-2023) scenario quantifies the maximum potential future health benefits from assuming zero percent smoking prevalence from 2023 onwards, whereas the Tobacco Smoking Elimination by 2050 (Elimination-2050) scenario provides estimates for countries considering policies to steadily reduce smoking prevalence to 5%. Together, these scenarios underscore the magnitude of health benefits that could be reached by 2050 if countries take decisive action to eliminate smoking. The 95% uncertainty interval (UI) of estimates is based on the 2&#xb7;5th and 97&#xb7;5th percentile of draws that were carried through the multistage computational framework.<br><br>FINDINGS: Global age-standardised smoking prevalence was estimated to be 28&#xb7;5% (95% UI 27&#xb7;9-29&#xb7;1) among males and 5&#xb7;96% (5&#xb7;76-6&#xb7;21) among females in 2022. In the reference scenario, smoking prevalence declined by 25&#xb7;9% (25&#xb7;2-26&#xb7;6) among males, and 30&#xb7;0% (26&#xb7;1-32&#xb7;1) among females from 2022 to 2050. Under this scenario, we forecast a cumulative 29&#xb7;3 billion (95% UI 26&#xb7;8-32&#xb7;4) overall YLLs among males and 22&#xb7;2 billion (20&#xb7;1-24&#xb7;6) YLLs among females over this period. Life expectancy at birth under this scenario would increase from 73&#xb7;6 years (95% UI 72&#xb7;8-74&#xb7;4) in 2022 to 78&#xb7;3 years (75&#xb7;9-80&#xb7;3) in 2050. Under our Elimination-2023 scenario, we forecast 2&#xb7;04 billion (95% UI 1&#xb7;90-2&#xb7;21) fewer cumulative YLLs by 2050 compared with the reference scenario, and life expectancy at birth would increase to 77&#xb7;6 years (95% UI 75&#xb7;1-79&#xb7;6) among males and 81&#xb7;0 years (78&#xb7;5-83&#xb7;1) among females. Under our Elimination-2050 scenario, we forecast 735 million (675-808) and 141 million (131-154) cumulative YLLs would be avoided among males and females, respectively. Life expectancy in 2050 would increase to 77&#xb7;1 years (95% UI 74&#xb7;6-79&#xb7;0) among males and 80&#xb7;8 years (78&#xb7;3-82&#xb7;9) among females.<br><br>INTERPRETATION: Existing tobacco policies must be maintained if smoking prevalence is to continue to decline as forecast by the reference scenario. In addition, substantial smoking-attributable burden can be avoided by accelerating the pace of smoking elimination. Implementation of new tobacco control policies are crucial in avoiding additional smoking-attributable burden in the coming decades and to ensure that the gains won over the past three decades are not lost.<br><br>FUNDING: Bloomberg Philanthropies and the Bill &amp; Melinda Gates Foundation.}, }
@article {pmid39365992, year = {2024}, author = {DeFilipp, Z and Kim, HT and Cheng, GS and Hamilton, BK and Chhabra, S and Hamadani, M and Sandhu, KS and Perez, LE and Lee, C and Brennan, TL and Garrelts, C and Brown, BM and Gallagher, KME and Newcomb, RA and El-Jawahri, A and Chen, YB}, title = {A phase 2 multicenter trial of ruxolitinib to treat bronchiolitis obliterans syndrome after allogeneic HCT.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024014000}, pmid = {39365992}, issn = {2473-9537}, abstract = {Bronchiolitis obliterans syndrome (BOS) occurring after allogeneic hematopoietic cell transplantation (HCT) is a high-risk manifestation of chronic graft-versus-host disease. In this prospective, multicenter phase 2 trial (ClinicalTrials.gov, NCT03674047), adult participants with BOS were treated with ruxolitinib 10mg twice daily, continuously in 28-day cycles for up to 12 cycles. Participants enrolled into newly diagnosed (<6 months since BOS diagnosis, cohort A) or established (≥6 months since BOS diagnosis, cohort B) disease cohorts, respectively. The primary objective was to evaluate the early treatment effect of ruxolitinib, assessed by the change in forced expiratory volume in 1 second (FEV1) at 3 months compared to enrollment. The primary endpoint differed according to cohort (Cohort A: improvement, defined as [3]10% increase in FEV1; Cohort B: stabilization, defined as absence of [3]10% decrease in FEV1). Between 2019 and 2022, 49 participants meeting criteria for BOS were enrolled and treated (cohort A, n=36; cohort B, n=13). The primary endpoint was achieved by 27.8% of participants with new BOS and 92.3% of participants with established BOS. According to the 2014 NIH Consensus Criteria, the best lung-specific overall response rate on ruxoltinib for the 49 participants was 34.7% (16.3% complete response, 18.4% partial response), with most responses occurring in mild or moderate disease. Non-infectious severe (grade ≥3) treatment-emergent adverse events were infrequent. Nine severe infectious events occurred and were largely respiratory in nature. These results support the use of ruxolitinib in the management of BOS after allogeneic HCT.}, }
@article {pmid39365700, year = {2024}, author = {Schmid, S and Russell, ZR and Yamashita, AS and West, ME and Parrish, AG and Walker, J and Rudoy, D and Yan, JZ and Quist, DC and Gessesse, BN and Alvinez, N and Hill, KD and Anderson, LW and Cimino, PJ and Kumasaka, DK and Parchment, RE and Holland, EC and Szulzewsky, F}, title = {ERK signaling promotes resistance to TRK kinase inhibition in NTRK fusion-driven glioma mouse models.}, journal = {Cell reports}, volume = {43}, number = {10}, pages = {114829}, pmid = {39365700}, issn = {2211-1247}, support = {R35 CA253119/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; U54 CA243125/CA/NCI NIH HHS/United States ; S10 OD026919/OD/NIH HHS/United States ; 75N91019D00024/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; *Glioma/genetics/pathology/drug therapy ; *Protein Kinase Inhibitors/pharmacology/therapeutic use ; Mice ; *Disease Models, Animal ; *MAP Kinase Signaling System/drug effects/genetics ; *Receptor, trkA/metabolism/genetics/antagonists &amp; inhibitors ; Humans ; Drug Resistance, Neoplasm/genetics ; Oncogene Proteins, Fusion/metabolism/genetics ; Receptor, trkC/genetics/metabolism/antagonists &amp; inhibitors ; Receptor, trkB/metabolism/genetics ; }, abstract = {Pediatric-type high-grade gliomas frequently harbor gene fusions involving receptor tyrosine kinase genes, including neurotrophic tyrosine kinase receptor (NTRK) fusions. Clinically, these tumors show high initial response rates to tyrosine kinase inhibition but ultimately recur due to the accumulation of additional resistance-conferring mutations. Here, we develop a series of genetically engineered mouse models of treatment-naive and -experienced NTRK1/2/3 fusion-driven gliomas. All tested NTRK fusions are oncogenic in vivo. The NTRK variant, N-terminal fusion partners, and resistance-associated point mutations all influence tumor histology and aggressiveness. Additional tumor suppressor losses greatly enhance tumor aggressiveness. Treatment with TRK kinase inhibitors significantly extends the survival of NTRK fusion-driven glioma mice, but fails to fully eradicate tumors, leading to recurrence upon treatment discontinuation. Finally, we show that ERK activation promotes resistance to TRK kinase inhibition and identify MEK inhibition as a potential combination therapy. These models will be invaluable tools to study therapy resistance of NTRK fusion tumors.}, }
@article {pmid39363864, year = {2024}, author = {Shah, NN and Wang, M and Roeker, LE and Patel, K and Woyach, JA and Wierda, WG and Ujjani, CS and Eyre, TA and Zinzani, PL and Alencar, AJ and Ghia, P and Lamanna, N and Hoffmann, MS and Patel, MR and Flinn, I and Gerson, JN and Ma, S and Coombs, CC and Cheah, CY and Lech-Maranda, E and Fakhri, B and Kim, WS and Barve, MA and Cohen, JB and Jurczak, W and Munir, T and Thompson, MC and Tsai, DE and Bao, K and Cangemi, NA and Kherani, JF and Walgren, RA and Han, H and Ruppert, AS and Brown, JR}, title = {Pirtobrutinib monotherapy in Bruton tyrosine kinase inhibitor-intolerant patients with B-cell malignancies: results of the phase I/II BRUIN trial.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2024.285754}, pmid = {39363864}, issn = {1592-8721}, support = {P30 CA016672/CA/NCI NIH HHS/United States ; }, abstract = {Bruton tyrosine kinase inhibitors (BTKi) have transformed the treatment of B-cell malignancies, but intolerance has often led to their discontinuation. The phase 1/2 BRUIN study evaluated pirtobrutinib, a highly selective non-covalent (reversible) BTKi, in patients with R/R B-cell malignancies (NCT03740529). Pirtobrutinib was investigated in 127 patients with intolerance to at least one prior BTKi therapy in the absence of progressive disease. The most common adverse event (AE) leading to BTKi discontinuation was cardiac disorders (n=40, 31.5%), specifically atrial fibrillation (n=30, 23.6%). The median follow-up was 17.4 months and the median time on pirtobrutinib was 15.3 months. The most common reasons for pirtobrutinib discontinuation were progressive disease (26.8%), AE (10.2%), or death (5.5%). The most frequent treatment-emergent AEs were fatigue (39.4%) and neutropenia (37.0%). Among patients who discontinued a prior BTKi for a cardiac issue, 75% had no recurrence of their cardiac AE. No patient discontinued pirtobrutinib for the same AE that led to discontinuation of the prior BTKi. In 78 CLL/SLL and 21 MCL patients intolerant to prior BTKi, ORR to pirtobrutinib was 76.9% and 81.0%, respectively. Median PFS for CLL/SLL was 28.4 months and was not estimable for MCL. These results suggest that pirtobrutinib was safe, well-tolerated, and an efficacious option in patients with prior BTKi-intolerance.}, }
@article {pmid39363105, year = {2024}, author = {Itell, HL and Guenthoer, J and Humes, D and Baumgarten, NE and Overbaugh, J}, title = {Host cell glycosylation selects for infection with CCR5- versus CXCR4-tropic HIV-1.}, journal = {Nature microbiology}, volume = {9}, number = {11}, pages = {2985-2996}, pmid = {39363105}, issn = {2058-5276}, support = {R01HD103571//U.S. Department of Health &amp; Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)/ ; T32GM007270//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; F31AI165168//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; }, mesh = {Humans ; *HIV-1/physiology/genetics/metabolism ; *Receptors, CXCR4/metabolism ; *Receptors, CCR5/metabolism ; Glycosylation ; *HIV Infections/virology/metabolism ; *Viral Tropism ; *CD4-Positive T-Lymphocytes/virology/metabolism ; CRISPR-Cas Systems ; Virus Internalization ; HEK293 Cells ; Polysaccharides/metabolism ; Host-Pathogen Interactions ; }, abstract = {Human immunodeficiency virus type 1 (HIV-1) infection involves a selection bottleneck that leads to transmission of one or a few variants. C-C motif chemokine receptor 5 (CCR5) or C-X-C motif chemokine receptor 4 (CXCR4) can act as coreceptors for HIV-1 viral entry. However, initial infection mostly occurs via CCR5, despite abundant expression of CXCR4 on target cells. The host factors that influence HIV-1 susceptibility and selection during transmission are unclear. Here we conduct CRISPR-Cas9 screens and identify SLC35A2 (a transporter of UDP-galactose expressed in target cells in blood and mucosa) as a potent and specific CXCR4-tropic restriction factor in primary target CD4[+] T cells. SLC35A2 inactivation, which resulted in truncated glycans, not only increased CXCR4-tropic infection levels but also decreased those of CCR5-tropic strains consistently. Single-cycle infections demonstrated that the effect is cell-intrinsic. These data support a role for a host protein that influences glycan structure in regulating HIV-1 infection. Host cell glycosylation may, therefore, affect HIV-1 selection during transmission in vivo.}, }
@article {pmid39363100, year = {2024}, author = {Chu, VT and Glascock, A and Donnell, D and Grabow, C and Brown, CE and Ward, R and Love, C and Kalantar, KL and Cohen, SE and Cannon, C and Woodworth, MH and Kelley, CF and Celum, C and Luetkemeyer, AF and Langelier, CR}, title = {Impact of doxycycline post-exposure prophylaxis for sexually transmitted infections on the gut microbiome and antimicrobial resistome.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {39363100}, issn = {1546-170X}, support = {K23 AI144036/AI/NIAID NIH HHS/United States ; R01 AI143439/AI/NIAID NIH HHS/United States ; }, abstract = {Doxycycline post-exposure prophylaxis (doxy-PEP) reduces bacterial sexually transmitted infections among men who have sex with men and transgender women. Although poised for widespread clinical implementation, the impact of doxy-PEP on antimicrobial resistance remains a primary concern as its effects on the gut microbiome and resistome, or the antimicrobial resistance genes (ARGs) present in the gut microbiome, are unknown. To investigate these effects, we studied participants from the DoxyPEP trial, a randomized clinical trial comparing doxy-PEP use, a one-time doxycycline 200-mg dose taken after condomless sex (DP arm, n = 100), to standard of care (SOC arm, n = 50) among men who have sex with men and transgender women. From self-collected rectal swabs at enrollment (day-0) and after 6 months (month-6), we performed metagenomic DNA sequencing (DNA-seq) or metatranscriptomic RNA sequencing (RNA-seq). DNA-seq data were analyzable from 127 samples derived from 89 participants, and RNA-seq data were analyzable from 86 samples derived from 70 participants. We compared the bacterial microbiome and resistome between the two study arms and over time. The median number of doxycycline doses taken since enrollment by participants with DNA-seq data was zero (interquartile range (IQR): 0-7 doses) for the SOC arm and 42 (IQR: 27-64 doses) for the DP arm. Tetracycline ARGs were detected in all day-0 DNA-seq samples and in 85% of day-0 RNA-seq samples. The proportional mass of tetracycline ARGs in the resistome increased between day-0 and month-6 in DP participants from 46% to 51% in the metagenome (P = 2.3 × 10[-2]) and from 4% to 15% in the metatranscriptome (P = 4.5 × 10[-6]), but no statistically significant increases in other ARG classes were observed. Exposure to a higher number of doxycycline doses correlated with proportional enrichment of tetracycline ARGs in the metagenome (Spearman's ρ = 0.23, P = 9.0 × 10[-3]) and metatranscriptome (Spearman's ρ = 0.55, P = 3.7 × 10[-8]). Bacterial microbiome alpha diversity, beta diversity and total bacterial mass did not differ between day-0 and month-6 samples from DP participants when assessed by either DNA-seq or RNA-seq. In an abundance-based correlation analysis, we observed an increase over time in the strength of the correlation between tetracycline ARGs and specific bacterial taxa, including some common human pathogens. In sum, doxy-PEP use over a 6-month period was associated with an increase in the proportion of tetracycline ARGs comprising the gut resistome and an increase in the expression of tetracycline ARGs. At 6 months of doxy-PEP use, no residual differences were observed in alpha and beta diversity or taxonomic composition of the gut microbiome. As doxy-PEP is implemented as a public health strategy, further studies and population-level surveillance of doxycycline-resistant pathogens are needed to understand the implications of these findings. ClinicalTrials.gov registration number: NCT03980223 .}, }
@article {pmid39362880, year = {2024}, author = {Hawkes, G and Beaumont, RN and Li, Z and Mandla, R and Li, X and Albert, CM and Arnett, DK and Ashley-Koch, AE and Ashrani, AA and Barnes, KC and Boerwinkle, E and Brody, JA and Carson, AP and Chami, N and Chen, YI and Chung, MK and Curran, JE and Darbar, D and Ellinor, PT and Fornage, M and Gordeuk, VR and Guo, X and He, J and Hwu, CM and Kalyani, RR and Kaplan, R and Kardia, SLR and Kooperberg, C and Loos, RJF and Lubitz, SA and Minster, RL and Naseri, T and Viali, S and Mitchell, BD and Murabito, JM and Palmer, ND and Psaty, BM and Redline, S and Shoemaker, MB and Silverman, EK and Telen, MJ and Weiss, ST and Yanek, LR and Zhou, H and ,  and Liu, CT and North, KE and Justice, AE and Locke, JM and Owens, N and Murray, A and Patel, K and Frayling, TM and Wright, CF and Wood, AR and Lin, X and Manning, A and Weedon, MN}, title = {Whole-genome sequencing in 333,100 individuals reveals rare non-coding single variant and aggregate associations with height.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8549}, pmid = {39362880}, issn = {2041-1723}, support = {/WT_/Wellcome Trust/United Kingdom ; MR/M008924/1/MRC_/Medical Research Council/United Kingdom ; P30 ES010126/ES/NIEHS NIH HHS/United States ; 875534//Innovative Medicines Initiative (IMI)/ ; }, mesh = {Humans ; *Whole Genome Sequencing ; *Body Height/genetics ; *Polymorphism, Single Nucleotide ; *Genome-Wide Association Study ; Male ; Female ; Gene Frequency ; Genome, Human ; Genetic Variation ; Phenotype ; }, abstract = {The role of rare non-coding variation in complex human phenotypes is still largely unknown. To elucidate the impact of rare variants in regulatory elements, we performed a whole-genome sequencing association analysis for height using 333,100 individuals from three datasets: UK Biobank (N = 200,003), TOPMed (N = 87,652) and All of Us (N = 45,445). We performed rare (< 0.1% minor-allele-frequency) single-variant and aggregate testing of non-coding variants in regulatory regions based on proximal-regulatory, intergenic-regulatory and deep-intronic annotation. We observed 29 independent variants associated with height at P < 6 × 10 - 10 after conditioning on previously reported variants, with effect sizes ranging from -7cm to +4.7 cm. We also identified and replicated non-coding aggregate-based associations proximal to HMGA1 containing variants associated with a 5 cm taller height and of highly-conserved variants in MIR497HG on chromosome 17. We have developed an approach for identifying non-coding rare variants in regulatory regions with large effects from whole-genome sequencing data associated with complex traits.}, }
@article {pmid39362248, year = {2024}, author = {Wang, ES and Issa, GC and Erba, HP and Altman, JK and Montesinos, P and DeBotton, S and Walter, RB and Pettit, K and Savona, MR and Shah, MV and Kremyanskaya, M and Baer, MR and Foran, JM and Schiller, G and Adès, L and Heiblig, M and Berthon, C and Peterlin, P and Rodríguez-Arbolí, E and Salamero, O and Patnaik, MM and Papayannidis, C and Grembecka, J and Cierpicki, T and Clegg, B and Ray, J and Linhares, BM and Nie, K and Mitra, A and Ahsan, JM and Tabachri, M and Soifer, HS and Corum, D and Leoni, M and Dale, S and Fathi, AT}, title = {Ziftomenib in relapsed or refractory acute myeloid leukaemia (KOMET-001): a multicentre, open-label, multi-cohort, phase 1 trial.}, journal = {The Lancet. Oncology}, volume = {25}, number = {10}, pages = {1310-1324}, doi = {10.1016/S1470-2045(24)00386-3}, pmid = {39362248}, issn = {1474-5488}, mesh = {Humans ; *Leukemia, Myeloid, Acute/drug therapy/genetics/pathology ; Middle Aged ; Male ; Female ; *Nucleophosmin ; Aged ; Adult ; Neoplasm Recurrence, Local/drug therapy ; Maximum Tolerated Dose ; Drug Resistance, Neoplasm ; Dose-Response Relationship, Drug ; Aged, 80 and over ; }, abstract = {BACKGROUND: Ziftomenib (KO-539) is an oral selective menin inhibitor with known preclinical activity in menin-dependent acute myeloid leukaemia models. The primary objective of this study was to determine the recommended phase 2 dose in patients with relapsed or refractory acute myeloid leukaemia based on safety, pharmacokinetics, pharmacodynamics, and preliminary activity.<br><br>METHODS: KOMET-001 is a multicentre, open-label, multi-cohort, phase 1/2 clinical trial of ziftomenib in adults with relapsed or refractory acute myeloid leukaemia. Results of the phase 1 study, conducted at 22 hospitals in France, Italy, Spain, and the USA, are presented here and comprise the dose-escalation (phase 1a) and dose-validation and expansion (phase 1b) phases. Eligible patients were aged 18 years or older, had relapsed or refractory acute myeloid leukaemia, and had an Eastern Cooperative Oncology Group performance status of 2 or less. For phase 1a, patients (all molecular subtypes) received ziftomenib (50-1000 mg) orally once daily in 28-day cycles. For phase 1b, patients with NPM1 mutations or with KMT2A rearrangements were randomly assigned (1:1) using third-party interactive response technology to two parallel dose cohorts (200 mg and 600 mg ziftomenib). Primary endpoints were maximum tolerated dose or recommended phase 2 dose in phase 1a, and safety, remission rates, and pharmacokinetics supporting recommended phase 2 dose determination in phase 1b. Analyses were performed in all patients who received at least one dose of ziftomenib (modified intention-to-treat population). Phase 1a/1b is complete. This trial is registered with ClinicalTrials.gov, NCT04067336, and the EU Clinical Trials register, EudraCT 2019-001545-41.<br><br>FINDINGS: From Sept 12, 2019, to Aug 19, 2022, 83 patients received 50-1000 mg ziftomenib (39 [47%] were male and 44 [53%] were female). Median follow-up was 22&#xb7;3 months (IQR 15&#xb7;4-30&#xb7;2). Of 83 patients, the most common grade 3 or worse treatment-emergent adverse events were anaemia (20 [24%]), febrile neutropenia (18 [22%]), pneumonia (16 [19%]), differentiation syndrome (12 [15%]), thrombocytopenia (11 [13%]), and sepsis (ten [12%]). Overall, 68 of 83 patients had serious adverse events, with two reported treatment-related deaths (one differentiation syndrome and one cardiac arrest). Differentiation syndrome rate and severity influenced the decision to halt enrolment of patients with KMT2A rearrangements. In Phase 1b, no responses were reported in patients treated at the 200 mg dose level. At the recommended phase 2 dose of 600 mg, nine (25%) of 36 patients with KMT2A rearrangement or NPM1 mutation had complete remission or complete remission with partial haematologic recovery. Seven (35%) of 20 patients with NPM1 mutation treated at the recommended phase 2 dose had a complete remission.<br><br>INTERPRETATION: Ziftomenib showed promising clinical activity with manageable toxicity in heavily pretreated patients with relapsed or refractory acute myeloid leukaemia. Phase 2 assessment of ziftomenib combination therapy in the upfront and relapsed or refractory setting is ongoing.<br><br>FUNDING: Kura Oncology.}, }
@article {pmid39361354, year = {2024}, author = {Hazelwood, E and Lopez Manzano, C and Vincent, EE and Albanes, D and Bishop, DT and Le Marchand, L and Ulrich, CM and Peters, U and Murphy, G and Samadder, NJ and Anderson, L and Gunter, MJ and Murphy, N and Van Guelpen, B and Papadimitriou, N}, title = {Plasma Ghrelin and Risks of Sex-Specific, Site-Specific, and Early-Onset Colorectal Cancer: A Mendelian Randomization Analysis.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {33}, number = {12}, pages = {1727-1732}, pmid = {39361354}, issn = {1538-7755}, support = {R01 CA042182/CA/NCI NIH HHS/United States ; SAF07-64873//Ministerio de Econom&#xed;a y Competitividad (MEC)/ ; R01 CA067941/CA/NCI NIH HHS/United States ; U01 CA067941/CA/NCI NIH HHS/United States ; R01 CA059045/CA/NCI NIH HHS/United States ; PI08/0024//Federaci&#xf3;n Espa&#xf1;ola de Enfermedades Raras (FEDER)/ ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; R01 CA197350/CA/NCI NIH HHS/United States ; //Herzfelder'sche Familienstiftung (Herzfelder Family Foundation)/ ; R01 CA076366/CA/NCI NIH HHS/United States ; GCB13131592CAST//Fundaci&#xf3;n Cient&#xed;fica Asociaci&#xf3;n Espa&#xf1;ola Contra el C&#xe1;ncer (AECC)/ ; R35 CA197735/CA/NCI NIH HHS/United States ; LE22A10-2//Junta de Castilla y Le&#xf3;n (JCYL)/ ; C18281/A29019//Cancer Research UK (CRUK)/ ; VR 2017-00650//Vetenskapsr&#xe5;det (VR)/ ; U01 HG004438/HG/NHGRI NIH HHS/United States ; IIG_FULL_2021_030//World Cancer Research Fund (WCRF)/ ; U01 HG004446/HG/NHGRI NIH HHS/United States ; JTC2012-MetaboCCC//Transcan (Transcan-3)/ ; //Ontario Ministry of Research and Innovation (MRI)/ ; 75N92021D00005/WH/WHI NIH HHS/United States ; U10 CA037429/CA/NCI NIH HHS/United States ; S10OD028685//Office of Research Infrastructure Programs (ORIP)/ ; R01 CA072520/CA/NCI NIH HHS/United States ; 2017SGR723//Agency for Management of University and Research Grants of the Catalan Government/ ; P01 CA087969/CA/NCI NIH HHS/United States ; 1000143//Medical Research Council (MRC)/ ; P30 CA015704/CA/NCI NIH HHS/United States ; 23 3153 Pj//Cancerfonden (Swedish Cancer Society)/ ; P30 CA006973/CA/NCI NIH HHS/United States ; IIG_FULL_2021_030//Wereld Kanker Onderzoek Fonds (WKOF)/ ; //Swedish Cancer Foundation/ ; R01 CA273198/CA/NCI NIH HHS/United States ; K05 CA154337/CA/NCI NIH HHS/United States ; UM 2012-//KWF Kankerbestrijding (DCS)/ ; P01 CA055075/CA/NCI NIH HHS/United States ; R01 CA151993/CA/NCI NIH HHS/United States ; U01 CA152753/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; //Region Sk&#xe5;ne/ ; P30 DK034987/DK/NIDDK NIH HHS/United States ; R01 CA048998/CA/NCI NIH HHS/United States ; U01 CA137088/CA/NCI NIH HHS/United States ; R01 CA189184/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; Z01 CP010200/ImNIH/Intramural NIH HHS/United States ; U24 CA074794/CA/NCI NIH HHS/United States ; //Instituto de Salud Carlos III (ISCIII)/ ; 01KH0404//Bundesministerium f&#xfc;r Bildung und Frauen (BMBF)/ ; MC_UU_00032/03//Medical Research Council (MRC)/ ; //National Research Council (NRC)/ ; //Deutsche Krebshilfe (German Cancer Aid)/ ; R01 CA066635/CA/NCI NIH HHS/United States ; U01 CA206110/CA/NCI NIH HHS/United States ; HCRI15011-1//Chonnam National University Hwasun Hospital (CNUHH)/ ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; R01 CA137178/CA/NCI NIH HHS/United States ; U01 CA074794/CA/NCI NIH HHS/United States ; HHSN268201200008C/HL/NHLBI NIH HHS/United States ; R01 CA242218/CA/NCI NIH HHS/United States ; MCRF18005//Victorian Cancer Agency (VCA)/ ; U01 CA167551/CA/NCI NIH HHS/United States ; //Ligue Contre le Cancer (French League Against Cancer)/ ; P30 CA076292/CA/NCI NIH HHS/United States ; P30 CA014089/CA/NCI NIH HHS/United States ; BM1206 and CA17118//European Cooperation in Science and Technology (COST)/ ; 09BN-13//Florida Department of Health (DOH)/ ; R01 CA081488/CA/NCI NIH HHS/United States ; R01 CA143237/CA/NCI NIH HHS/United States ; PT13/0010/0013//platforma biobancos/ ; //Mutuelle G&#xe9;n&#xe9;rale de l'Education Nationale (MGEN)/ ; 2014SGR135//Ag&#xe8;ncia de Gesti&#xf3; d'Ajuts Universitaris i de Recerca (AGAUR)/ ; R01 CA201407/CA/NCI NIH HHS/United States ; 509348//National Health and Medical Research Council (NHMRC)/ ; R01 CA063464/CA/NCI NIH HHS/United States ; P01 CA033619/CA/NCI NIH HHS/United States ; HHSN268201700006I//National Institutes of Health (NIH)/ ; U01 CA086308/CA/NCI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; //Danish Cancer Society Research Center (DCRC)/ ; UM1 CA186107/CA/NCI NIH HHS/United States ; C18281/A30905//Cancer Research UK (CRUK)/ ; //State of Maryland (Maryland)/ ; 98-10030//ZonMw (Netherlands Organisation for Health Research and Development)/ ; VLL-765961//Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)/ ; //Stockholm l&#xe4;ns landsting (Stockholm County Council)/ ; //VicHealth (Victorian Health Promotion Foundation)/ ; PGIDIT07PXIB9101209PR//Xunta de Galicia (Regional Government of Galicia)/ ; R01 CA207371/CA/NCI NIH HHS/United States ; R03 CA153323/CA/NCI NIH HHS/United States ; R01 CA060987/CA/NCI NIH HHS/United States ; 112746//Canadian Institutes of Health Research (CIHR)/ ; T32 ES013678/ES/NIEHS NIH HHS/United States ; R01 CA136726/CA/NCI NIH HHS/United States ; P30 CA016058/CA/NCI NIH HHS/United States ; //Cancer Council Victoria/ ; UM1 CA167552/CA/NCI NIH HHS/United States ; K05 CA152715/CA/NCI NIH HHS/United States ; U01 CA122839/CA/NCI NIH HHS/United States ; U01 CA074783/CA/NCI NIH HHS/United States ; KL2 TR000421/TR/NCATS NIH HHS/United States ; NCI R01CA136726//Damon Runyon Cancer Research Foundation (DRCRF)/ ; //American Cancer Society (ACS)/ ; 21 0467 FE 01 H//Cancerfonden (Swedish Cancer Society)/ ; //Food Standards Agency (FSA)/ ; P01 CA196569/CA/NCI NIH HHS/United States ; 001/WHO_/World Health Organization/International ; //Institut National de la Sant&#xe9; et de la Recherche M&#xe9;dicale (Inserm)/ ; //Imperial College London (ICL)/ ; UM1 CA182883/CA/NCI NIH HHS/United States ; HHSN268201200008I/HL/NHLBI NIH HHS/United States ; R37 CA054281/CA/NCI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; //Pelotonia/ ; //Canadian Cancer Society (CCS)/ ; SLT002/16/00398//Generalitat de Catalunya (Government of Catalonia)/ ; R01 CA097325/CA/NCI NIH HHS/United States ; NU58DP006333//Centers for Disease Control and Prevention (CDC)/ ; HHSN268201700006C/HL/NHLBI NIH HHS/United States ; PI14-613//FEDER/ ; U01 AG018033/AG/NIA NIH HHS/United States ; U19 CA148107/CA/NCI NIH HHS/United States ; //American Institute for Cancer Research (AICR)/ ; }, mesh = {Humans ; *Colorectal Neoplasms/blood/genetics/epidemiology ; *Ghrelin/blood/genetics ; *Mendelian Randomization Analysis ; Male ; Female ; Genome-Wide Association Study ; Risk Factors ; Polymorphism, Single Nucleotide ; Age of Onset ; Sex Factors ; }, abstract = {BACKGROUND: Epidemiological and laboratory-based studies have provided conflicting evidence for a role of ghrelin in colorectal cancer development. We conducted two-sample Mendelian randomization (MR) analyses to evaluate evidence for an association of circulating ghrelin and colorectal cancer risk overall and by sex, cancer subsite, and age at diagnosis.<br><br>METHODS: Genetic instruments proxying plasma total ghrelin levels were obtained from a recent genome-wide association study of 54,219 participants. Summary data for colorectal cancer risk were obtained from a recent meta-analysis of several genetic consortia (up to 73,673 cases and 86,854 controls). A two-sample MR approach and several sensitivity analyses were applied.<br><br>RESULTS: We found no evidence for an association of genetically predicted plasma total ghrelin levels and colorectal cancer risk (0.95, 95% confidence interval, 0.81-1.12; R2 of ghrelin genetic instruments: 4.6%), with similarly null results observed when stratified by sex, anatomical subsite, and for early-onset colorectal cancer.<br><br>CONCLUSIONS: Our study suggests that plasma ghrelin levels are unlikely to have a causal relationship with overall, early-onset, and sex- and cancer subsite-stratified colorectal cancer risk.<br><br>IMPACT: This large-scale analysis adds to the growing body of evidence that plasma total ghrelin levels are not associated with colorectal cancer risk.}, }
@article {pmid39361286, year = {2024}, author = {Pizzo, A and Leisenring, WM and Stratton, KL and Lamoureux, &#xc9; and Flynn, JS and Alschuler, K and Krull, KR and Jibb, LA and Nathan, PC and Olgin, JE and Stinson, JN and Armstrong, GT and Alberts, NM}, title = {Fear of Cancer Recurrence in Adult Survivors of Childhood Cancer.}, journal = {JAMA network open}, volume = {7}, number = {10}, pages = {e2436144}, pmid = {39361286}, issn = {2574-3805}, support = {P30 CA021765/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; U2C EB021881/EB/NIBIB NIH HHS/United States ; }, mesh = {Humans ; *Cancer Survivors/psychology/statistics &amp; numerical data ; Female ; Male ; *Fear/psychology ; Adult ; Cross-Sectional Studies ; *Neoplasm Recurrence, Local/psychology/epidemiology ; Retrospective Studies ; Neoplasms/psychology/epidemiology ; Risk Factors ; Middle Aged ; Prevalence ; Child ; }, abstract = {IMPORTANCE: Fear of cancer recurrence is common among survivors of adult-onset cancer and associated with increased distress, functional impairment, and health care utilization. However, little is known about the prevalence and risk factors of fear of cancer recurrence among adult survivors of childhood cancer who are also at high risk for subsequent malignant neoplasms.<br><br>OBJECTIVE: To characterize the prevalence of and risk factors for clinically significant fear of cancer recurrence in adult survivors of childhood cancer.<br><br>This cross-sectional investigation included participants recruited from the Childhood Cancer Survivor Study, a retrospective cohort study of long-term childhood cancer survivors treated at 31 institutions between 1970 and 1999 across North America. Participants were recruited and completed psychosocial measures via online survey between October 2018 and April 2019. Cancer and treatment-related variables were abstracted from medical records. Data were analyzed from May 2023 to July 2024.<br><br>MAIN OUTCOMES AND MEASURES: Clinically significant fear of cancer recurrence was assessed via the Fear of Cancer Recurrence Inventory-Short Form. Poisson regression models estimated prevalence ratios (PRs) with 95% CIs adjusted for age and sex to examine the associations of demographic, disease, treatment, and psychosocial variables with fear of cancer recurrence.<br><br>RESULTS: The final sample included 229 adult survivors of childhood cancer (115 female [50.2%]; mean [SD] age, 39.6 [9.9] years; mean [SD] time since diagnosis, 31.7 [8.4] years). Among survivors, 38 (16.6%; 95% CI, 11.6%-21.6%) reported clinically significant fear of cancer recurrence, and an additional 36 (15.7%) reported high fear of cancer recurrence. Clinically significant fear of cancer recurrence was associated with unemployment (PR, 2.5; 95% CI, 1.3-4.8), presence of neurologic chronic health conditions (PR, 3.3; 95% CI, 1.8-6.1), treatment with pelvic radiation (PR, 2.9; 95% CI, 1.5-5.6), and amputation or limb sparing surgery (PR, 2.4; 95% CI, 1.2-4.9). Higher risk of clinically significant fear of cancer recurrence was also associated with having either elevated anxiety or depression (PR, 2.6; 95% CI, 1.2-5.9), having both elevated (PR, 3.2; 95% CI, 1.2-8.4), and perceived poor health status (PR, 3.0; 95% CI, 3.1-9.7).<br><br>CONCLUSIONS AND RELEVANCE: Decades following treatment, one-third of childhood cancer survivors in this study reported elevated fear their cancer will recur or a subsequent malignant neoplasm will develop. Findings suggest that fear of cancer recurrence should be routinely screened, and clinically significant symptoms intervened upon as a part of survivorship care.}, }
@article {pmid39361281, year = {2024}, author = {Gjesvik, J and Moshina, N and Lee, CI and Miglioretti, DL and Hofvind, S}, title = {Artificial Intelligence Algorithm for Subclinical Breast Cancer Detection.}, journal = {JAMA network open}, volume = {7}, number = {10}, pages = {e2437402}, pmid = {39361281}, issn = {2574-3805}, mesh = {Humans ; *Breast Neoplasms/diagnosis/diagnostic imaging ; Female ; Middle Aged ; *Artificial Intelligence ; *Algorithms ; Aged ; Retrospective Studies ; *Early Detection of Cancer/methods ; *Mammography/methods/statistics &amp; numerical data ; Norway/epidemiology ; }, abstract = {IMPORTANCE: Early breast cancer detection is associated with lower morbidity and mortality.<br><br>OBJECTIVE: To examine whether a commercial artificial intelligence (AI) algorithm for breast cancer detection could estimate the development of future cancer.<br><br>This retrospective cohort study of 116&#x202f;495 women aged 50 to 69 years with no prior history of breast cancer before they underwent at least 3 consecutive biennial screening examinations used scores from an AI algorithm (INSIGHT MMG, version 1.1.7.2; Lunit Inc; used September 28, 2022, to April 5, 2023) for breast cancer detection and screening data from multiple, consecutive rounds of mammography performed from September 13, 2004, to December 21, 2018, at 9 breast centers in Norway. The statistical analyses were performed from September 2023 to August 2024.<br><br>EXPOSURE: Artificial intelligence algorithm score indicating suspicion for the presence of breast cancer. The algorithm provided a continuous cancer detection score for each examination ranging from 0 to 100, with increasing values indicating a higher likelihood of cancer being present on the current mammogram.<br><br>MAIN OUTCOMES AND MEASURES: Maximum AI algorithm score for cancer detection and absolute difference in score among breasts of women developing screening-detected cancer, women with interval cancer, and women who screened negative.<br><br>RESULTS: The mean (SD) age at the first study round was 58.5 (4.5) years for 1265 women with screening-detected cancer in the third round, 57.4 (4.6) years for 342 women with interval cancer after 3 negative screening rounds, and 56.4 (4.9) years for 116&#x202f;495 women without breast cancer all 3 screening rounds. The mean (SD) absolute differences in AI scores among breasts of women developing screening-detected cancer were 21.3 (28.1) at the first study round, 30.7 (32.5) at the second study round, and 79.0 (28.9) at the third study round. The mean (SD) differences prior to interval cancer were 19.7 (27.0) at the first study round, 21.0 (27.7) at the second study round, and 34.0 (33.6) at the third study round. The mean (SD) differences among women who did not develop breast cancer were 9.9 (17.5) at the first study round, 9.6 (17.4) at the second study round, and 9.3 (17.3) at the third study round. Areas under the receiver operating characteristic curve for the absolute difference were 0.63 (95% CI, 0.61-0.65) at the first study round, 0.72 (95% CI, 0.71-0.74) at the second study round, and 0.96 (95% CI, 0.95-0.96) at the third study round for screening-detected cancer and 0.64 (95% CI, 0.61-0.67) at the first study round, 0.65 (95% CI, 0.62-0.68) at the second study round, and 0.77 (95% CI, 0.74-0.79) at the third study round for interval cancers.<br><br>CONCLUSIONS AND RELEVANCE: In this retrospective cohort study of women undergoing screening mammography, mean absolute AI scores were higher for breasts developing vs not developing cancer 4 to 6 years before their eventual detection. These findings suggest that commercial AI algorithms developed for breast cancer detection may identify women at high risk of a future breast cancer, offering a pathway for personalized screening approaches that can lead to earlier cancer diagnosis.}, }
@article {pmid39361275, year = {2024}, author = {Kampouri, E and Reynolds, G and Teh, BW and Hill, JA}, title = {Chimeric antigen receptor-T-cell therapies going viral: latent and incidental viral infections.}, journal = {Current opinion in infectious diseases}, volume = {37}, number = {6}, pages = {526-535}, doi = {10.1097/QCO.0000000000001066}, pmid = {39361275}, issn = {1473-6527}, mesh = {Humans ; *Receptors, Chimeric Antigen/immunology ; *Immunotherapy, Adoptive/methods ; *Virus Diseases/prevention &amp; control/immunology/therapy ; }, abstract = {PURPOSE OF REVIEW: Infections are the leading cause of non-relapse mortality following chimeric antigen receptor (CAR)-T-cell therapy, with viral infections being frequent both in the early and late phases post-infusion. We review the epidemiology of viral infections and discuss critical approaches to prevention and management strategies in this setting.<br><br>RECENT FINDINGS: Herpesviruses dominate the early period. herpes simplex virus and varicella zoster virus infections are rare due to widespread antiviral prophylaxis, but cytomegalovirus (CMV) reactivation is increasingly observed, particularly in high-risk groups including B cell maturation antigen (BCMA)-CAR-T-cell therapy recipients and patients receiving corticosteroids. While CMV end-organ disease is rare, CMV is associated with increased mortality, emphasizing the need to evaluate the broader impact of CMV on long-term hematological, infection, and survival outcomes. Human herpesvirus-6 (HHV-6) has also emerged as a concern, with its diagnosis complicated by overlapping symptoms with neurotoxicity, underscoring the importance of considering viral encephalitis in differential diagnoses. Respiratory viruses are the most common late infections with a higher incidence after BCMA CAR-T-cell therapy. Vaccination remains a critical preventive measure against respiratory viruses but may be less immunogenic following CAR-T-cell therapy. The optimal timing, type of vaccine, and dosing schedule require further investigation.<br><br>SUMMARY: A better understanding of viral epidemiology and preventive trials are needed to improve infection prevention practices and outcomes following CAR-T-cell therapies.}, }
@article {pmid39359003, year = {2024}, author = {Halloran, ME and Struchiner, CJ}, title = {Invited Commentary: Thirty-five Years of Leaky Vaccines.}, journal = {American journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/aje/kwae379}, pmid = {39359003}, issn = {1476-6256}, abstract = {Over the past 35 years, the term "leaky vaccine" has gained widespread use in both mathematical modeling and epidemiologic methods for evaluating vaccines. Here we present a short history as we recall it of how the term was coined in the context of the history of sporozoite malaria vaccines that were thought to be possibly leaky in the 1980s. We draw a contrast with the all-or-none vaccine mechanism and review a few consequences for study design and population level effects. We invite readers to contribute information covering the time period preceding our memories in the 1980s as we may have overlooked something.}, }
@article {pmid39357788, year = {2024}, author = {Wisdom, AJ and Yeap, BY and Michalski, JM and Horick, NK and Zietman, AL and Christodouleas, JP and Kamran, SC and Parikh, RR and Vapiwala, N and Mihalcik, S and Miyamoto, DT and Zeng, J and Gay, HA and Pisansky, TM and Mishra, MV and Spratt, DE and Mendenhall, NP and Soffen, EM and Bekelman, JE and Efstathiou, JA}, title = {Setting the Stage: Feasibility and Baseline Characteristics in the PARTIQoL Trial Comparing Proton Therapy Versus Intensity Modulated Radiation Therapy for Localized Prostate Cancer.}, journal = {International journal of radiation oncology, biology, physics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ijrobp.2024.09.043}, pmid = {39357788}, issn = {1879-355X}, abstract = {PURPOSE: Men with localized prostate cancer may receive either photon-based intensity modulated radiation therapy (IMRT) or proton beam therapy (PBT). The PARTIQoL trial (NCT01617161) demonstrates the feasibility of performing a large, multicenter phase 3 randomized trial comparing IMRT with PBT for localized prostate cancer. Here, we report baseline features of patients enrolled on this trial and present strategies to improve feasibility of other similar trials.<br><br>METHODS AND MATERIALS: Patients with low- or intermediate-risk prostate cancer were randomly assigned to either PBT or IMRT with stratification by institution, age, use of rectal spacer, and fractionation schedule (conventional fractionation: 79.2 Gy in 44 fractions vs moderate hypofractionation: 70.0 Gy in 28 fractions). The primary endpoint is a change from baseline bowel health using the Expanded Prostate Index Composite score 24 months after radiation therapy. Secondary objectives include treatment-related differences in urinary and erectile functions, adverse events, and efficacy endpoints.<br><br>RESULTS: Between July 2012 and November 2021, 450 patients were successfully accrued. Patients were randomly assigned to either PBT (N = 226) or to IMRT (N = 224); 13 were ineligible or withdrew before treatment. The median age of 437 analyzed patients was 68 years (range, 46-89 years). A total of 41% of patients had low-risk and 59% had intermediate-risk disease. In total, 49% of patients were treated with conventional fractionation and 51% with moderately hypofractionation. 48% of patients used a rectal spacer. For patients receiving PBT, pencil beam scanning was used in 48%. PBT and IMRT arms were balanced for baseline variables.<br><br>CONCLUSIONS: Despite significant challenges, the PARTIQoL trial demonstrated that, with targeted recruitment approaches, multicenter collaboration, payer engagement, and protocol updates to incorporate contemporary techniques, it is feasible to perform a large phase 3 randomized clinical trial to assess whether PBT improves outcomes. We will separately report primary results and continue to monitor participants for longer follow-up and secondary endpoints.}, }
@article {pmid39357459, year = {2024}, author = {Chappidi, MR and Iravani, A and Stambler, N and Baskaran, S and DiPippo, VA and Denes, BS and Lin, DW}, title = {Impact of Baseline Renal Insufficiency on Piflufolastat F-18 Performance and Investigation of Changes in Renal Function Following Piflufolastat F-18 Administration: Results From the OSPREY Trial.}, journal = {Clinical genitourinary cancer}, volume = {22}, number = {6}, pages = {102223}, doi = {10.1016/j.clgc.2024.102223}, pmid = {39357459}, issn = {1938-0682}, mesh = {Humans ; Male ; Aged ; Middle Aged ; *Glomerular Filtration Rate/drug effects ; *Prostatic Neoplasms/drug therapy/surgery ; *Radiopharmaceuticals/administration &amp; dosage ; Creatinine/blood ; Renal Insufficiency, Chronic ; Positron Emission Tomography Computed Tomography ; Renal Insufficiency ; Fluorine Radioisotopes ; }, abstract = {INTRODUCTION: Piflufolastat F-18, a prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical, is predominantly eliminated via urinary excretion, and the kidneys have one of the highest absorbed doses. Therefore, this subgroup analysis aimed to investigate the impact of piflufolastat F-18 on renal function and its diagnostic performance in patients stratified by baseline renal function.<br><br>PATIENTS AND METHODS: The OSPREY clinical trial enrolled 2 cohorts: A-high-risk patients undergoing radical prostatectomy with pelvic lymphadenectomy, and B-patients with suspected recurrent/metastatic prostate cancer on conventional imaging. Baseline estimated glomerular filtration rates were calculated, and patients were stratified by baseline chronic kidney disease (CKD) stage. Changes in serum creatinine within 28 days postdose and diagnostic performance of piflufolastat F-18 were assessed for each CKD stage group in both cohorts.<br><br>RESULTS: 385 patients (cohort A, n = 268; cohort B, n = 117) underwent piflufolastat F-18-PET/CT. Baseline and postpiflufolastat F-18 median creatinine levels (mg/dL) were similar for patients in cohort A (0.95 [n = 264] vs. 0.95 [n = 252], respectively) and cohort B (0.93 [n = 116] vs. 0.96 [n = 84], respectively). Among 332 men (cohort A, n = 249; cohort B, n = 83) with baseline and postpiflufolastat creatinine measurements, there were minimal changes in creatinine across all baseline CKD stage groups (median change ranged from -0.02 to 0.023 in groups with >1 patient). The diagnostic performance of piflufolastat F-18 showed no meaningful differences when stratified by baseline CKD stage.<br><br>CONCLUSION: Piflufolastat F-18 appears to be safe and effective for imaging prostate cancer, including men with mild/moderate renal insufficiency.}, }
@article {pmid39353277, year = {2024}, author = {Irajizad, E and Fahrmann, JF and Toumazis, I and Vykoukal, J and Dennison, JB and Shen, Y and Do, KA and Ostrin, EJ and Feng, Z and Hanash, S}, title = {Biomarker trajectory for earlier detection of lung cancer.}, journal = {EBioMedicine}, volume = {108}, number = {}, pages = {105377}, pmid = {39353277}, issn = {2352-3964}, support = {U01 CA086368/CA/NCI NIH HHS/United States ; U01 CA194733/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Lung Neoplasms/diagnosis/blood ; *Biomarkers, Tumor/blood ; Male ; Female ; *Early Detection of Cancer/methods ; Middle Aged ; Algorithms ; Aged ; Bayes Theorem ; }, abstract = {BACKGROUND: To determine whether an algorithm based on repeated measurements of a panel of four circulating protein biomarkers (4 MP) for lung cancer risk assessment results in improved performance over a single time measurement.<br><br>METHODS: We conducted data analysis of the 4&#xa0;MP consisting of the precursor form of surfactant protein B, cancer antigen 125, carcinoembryonic antigen, and cytokeratin-19 fragment in pre-diagnostic sera from 2483 ever-smoker participants (389 cases and 2094 randomly selected non-cases) in the Prostate, Lung, Colorectal, Ovarian (PLCO) Study who had at least two sequential blood collections over 6 years. A parametric empirical Bayes (PEB) algorithm, which incorporates participant biomarker history at each time point, was compared to a single-threshold (ST) method.<br><br>FINDINGS: Among ever-smoker participants, the PEB approach yielded an additional 4% improvement in the AUC compared to the ST approach (P-value: 0.009). When considering an &#x2265;10 PY smoking history and at a fixing the specificity corresponding to 1% 6-year lung cancer risk, PEB resulted in significant improvement in the sensitivity (SenPEB:96.3% vs SenST:91.0%; P-value: 6.7e-3). The PEB algorithm identified 17 of the 35 cases that remained ST negative, at an average of 1.26 years before diagnosis. Ten case individuals who were positive based on ST at an average of 1.03 years prior to diagnosis were identified earlier by PEB, at an average of 2.70 years.<br><br>INTERPRETATION: An algorithm based on repeated measurements of the 4&#xa0;MP improves sensitivity and results in an earlier detection of lung cancer compared to a single-threshold method.<br><br>FUNDING: This study was supported by NIH Grant Nos. U01CA271888, U01CA194733, U01CA213285, NCI EDRN U01 CA200468, P30CA016672, and U24CA086368; the Cancer Prevention &amp; Research Institute of Texas RP180505 and RP160693; the SPORE P50CA140388; the CCTS TR000371; and the generous philanthropic contributions to The University of Texas MD Anderson Cancer Center Moon Shots Program and the Lyda Hill Foundation.}, }
@article {pmid39356983, year = {2024}, author = {Lurain, K and Ramaswami, R and Ekwede, I and Eulo, V and Goyal, G and Menon, M and Odeny, TA and Sharon, E and Wagner, MJ and Wang, CJ and Bhardwaj, N and Friedlander, PA and Abdul-Hay, M and Cornejo Castro, EM and Labo, N and Marshall, VA and Miley, W and Moore, K and Roshan, R and Whitby, D and Kask, AS and Kaiser, J and Han, E and Wright, A and Yarchoan, R and Fling, SP and Uldrick, TS}, title = {Cancer Immunotherapy Trials Network 12: Pembrolizumab in HIV-Associated Kaposi Sarcoma.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2400640}, doi = {10.1200/JCO.24.00640}, pmid = {39356983}, issn = {1527-7755}, abstract = {PURPOSE: Cancer Immunotherapy Trials Network 12 demonstrated safety of pembrolizumab in treating advanced cancer in people with HIV. Here, we report results of the Kaposi sarcoma (KS) cohort.<br><br>METHODS: In this multicenter phase I trial, we enrolled participants with HIV-associated KS on antiretroviral therapy with CD4[+] &#x2265;50 cells/&#x3bc;L and HIV plasma RNA <200 copies/mL. Pembrolizumab 200 mg intravenously was administered once every 3 weeks for up to 35 cycles. The primary end point was safety, and the secondary end point was KS response by modified AIDS Clinical Trials Group Criteria.<br><br>RESULTS: Thirty-two cisgender men enrolled with baseline median CD4[+] T-cell count of 274 cells/&#xb5;L. All but nine participants had received previous systemic KS therapy. Participants received a median of 11 cycles of pembrolizumab (range, 1-35). Sixty-six percent had grade &#x2265;1 treatment-emergent adverse events, including one death from polyclonal KS herpesvirus-related B-cell lymphoproliferation. Thirty-one percent had &#x2265;one immune-mediated AEs (imAEs) with 25% requiring systemic steroids. In 29 participants with evaluable KS, the overall response rate (ORR) was 62.1% (95% CI, 42.3 to 79.3) and did not differ by CD4[+] T-cell count. ORR in the eight participants with evaluable disease without previous KS therapy was 87.5% (95% CI, 47.3 to 99.7). Median duration of response (DOR) was not reached, and the Kaplan-Meier estimate of DOR of &#x2265;12 months was 92.3% (95% CI, 56.6 to 98.8). Median progression-free survival was 28.2 months (95% CI, 4.2 to noncalculable).<br><br>CONCLUSION: Pembrolizumab yielded a high rate of durable responses in HIV-associated KS. imAEs were successfully managed with standard guidelines.}, }
@article {pmid39354185, year = {2024}, author = {Armstrong, AJ and Taylor, A and Haffner, MC and Abida, W and Bryce, AH and Karsh, LI and Tagawa, ST and Twardowski, P and Serritella, AV and Lang, JM}, title = {Germline and somatic testing for homologous repair deficiency in patients with prostate cancer (part 1 of 2).}, journal = {Prostate cancer and prostatic diseases}, volume = {}, number = {}, pages = {}, pmid = {39354185}, issn = {1476-5608}, abstract = {BACKGROUND/OBJECTIVES: Unfortunately, not all metastatic castration resistant prostate cancer (mCRPC) patients receive available life-prolonging systemic therapies, emphasizing the need to optimize mCRPC treatment selections. Better guidelines are necessary to determine genetic testing in prostate cancer.<br><br>SUBJECTS/METHODS: In this two-part expert opinion-based guide, we provide an expert consensus opinion on the utilization of germline and somatic testing to detect HRR alterations in patients with mCRPC. This guide was developed by a multidisciplinary expert panel that convened in 2023-2024, including representatives from medical oncology, urology, radiation oncology, pathology, medical genomics, and basic science.<br><br>RESULTS/CONCLUSION: We argue for the widespread adoption of germline testing in all patients with prostate cancer and for somatic mutations testing in patients at the time of recurrent/metastatic disease. In this first part, we review how genomic testing is performed. We also review how to overcome certain barriers to integrate genetic and biomarker testing into clinical practice.}, }
@article {pmid39354095, year = {2024}, author = {Zhao, LP and Papadopoulos, GK and Skyler, JS and Pugliese, A and Parikh, HM and Kwok, WW and Lybrand, TP and Bondinas, GP and Moustakas, AK and Wang, R and Pyo, CW and Nelson, WC and Geraghty, DE and Lernmark, &#xc5;}, title = {Progression to type 1 diabetes in the DPT-1 and TN07 clinical trials is critically associated with specific residues in HLA-DQA1-B1 heterodimers.}, journal = {Diabetologia}, volume = {67}, number = {11}, pages = {2481-2493}, pmid = {39354095}, issn = {1432-0428}, support = {R01 DK132406/DK/NIDDK NIH HHS/United States ; R01 DK132406/DK/NIDDK NIH HHS/United States ; }, mesh = {*Diabetes Mellitus, Type 1/genetics/metabolism/immunology ; Humans ; *HLA-DQ alpha-Chains/genetics/metabolism ; *HLA-DQ beta-Chains/genetics/metabolism ; *Haplotypes/genetics ; *Disease Progression ; Female ; Male ; Genetic Predisposition to Disease ; Genotype ; Protein Multimerization ; }, abstract = {AIMS/HYPOTHESIS: The aim of this work was to explore molecular amino acids (AAs) and related structures of HLA-DQA1-DQB1 that underlie its contribution to the progression from stages 1 or 2 to stage 3 type 1 diabetes.<br><br>METHODS: Using high-resolution DQA1 and DQB1 genotypes from 1216 participants in the Diabetes Prevention Trial-Type 1 and the Diabetes Prevention Trial, we applied hierarchically organised haplotype association analysis (HOH) to decipher which AAs contributed to the associations of DQ with disease and their structural properties. HOH relied on the Cox regression to quantify the association of DQ with time-to-onset of type 1 diabetes.<br><br>RESULTS: By numerating all possible DQ heterodimers of &#x3b1;- and &#x3b2;-chains, we showed that the heterodimerisation increases genetic diversity at the cellular level from 43 empirically observed haplotypes to 186 possible heterodimers. Heterodimerisation turned several neutral haplotypes (DQ2.2, DQ2.3 and DQ4.4) to risk haplotypes (DQ2.2/2.3-DQ4.4 and DQ4.4-DQ2.2). HOH uncovered eight AAs on the &#x3b1;-chain (-16&#x3b1;, -13&#x3b1;, -6&#x3b1;, &#x3b1;22, &#x3b1;23, &#x3b1;44, &#x3b1;72, &#x3b1;157) and six AAs on the &#x3b2;-chain (-18&#x3b2;, &#x3b2;9, &#x3b2;13, &#x3b2;26, &#x3b2;57, &#x3b2;135) that contributed to the association of DQ with progression of type 1 diabetes. The specific AAs concerned the signal peptide (minus sign, possible linkage to expression levels), pockets 1, 4 and 9 in the antigen-binding groove of the &#x3b1;1&#x3b2;1 domain, and the putative homodimerisation of the &#x3b1;&#x3b2; heterodimers.<br><br>CONCLUSIONS/INTERPRETATION: These results unveil the contribution made by DQ to type 1 diabetes progression at individual residues and related protein structures, shedding light on its immunological mechanisms and providing new leads for developing treatment strategies.<br><br>DATA AVAILABILITY: Clinical trial data and biospecimen samples are available through the National Institute of Diabetes and Digestive and Kidney Diseases Central Repository portal (https://repository.niddk.nih.gov/studies).}, }
@article {pmid39352173, year = {2024}, author = {Weinstock, LM and Bishop, TM and Bauer, MS and Benware, J and Bossarte, RM and Bradley, J and Dobscha, SK and Gibbs, J and Gildea, SM and Graves, H and Haas, G and House, S and Kennedy, CJ and Landes, SJ and Liu, H and Luedtke, A and Marx, BP and Miller, A and Nock, MK and Owen, RR and Pigeon, WR and Sampson, NA and Santiago-Colon, A and Shivakumar, G and Urosevic, S and Kessler, RC}, title = {Design of a multicenter randomized controlled trial of a post-discharge suicide prevention intervention for high-risk psychiatric inpatients: The Veterans Coordinated Community Care Study.}, journal = {International journal of methods in psychiatric research}, volume = {33}, number = {4}, pages = {e70003}, pmid = {39352173}, issn = {1557-0657}, support = {EBP 22-104//Department of Veterans Affairs Quality Enhancement Research Initiative/ ; PII 18-195//Department of Veterans Affairs Quality Enhancement Research Initiative/ ; QUE 20-026//Department of Veterans Affairs Quality Enhancement Research Initiative/ ; //Warren Alpert Foundation/ ; 36C24122P0883//National Center for PTSD, U.S. Department of Veterans Affairs/ ; 36C24122P0883//VA Boston Healthcare System/ ; UL1 TR003107/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Suicide Prevention ; *Veterans ; United States ; *Patient Discharge ; *Inpatients ; Mental Disorders/prevention &amp; control/therapy ; United States Department of Veterans Affairs ; Adult ; Female ; Male ; Middle Aged ; Follow-Up Studies ; }, abstract = {BACKGROUND: The period after psychiatric hospital discharge is one of elevated risk for suicide-related behaviors (SRBs). Post-discharge clinical outreach, although potentially effective in preventing SRBs, would be more cost-effective if targeted at high-risk patients. To this end, a machine learning model was developed to predict post-discharge suicides among Veterans Health Administration (VHA) psychiatric inpatients and target a high-risk preventive intervention.<br><br>METHODS: The Veterans Coordinated Community Care (3C) Study is a multicenter randomized controlled trial using this model to identify high-risk VHA psychiatric inpatients (n&#xa0;=&#xa0;850) randomized with equal allocation to either the Coping Long Term with Active Suicide Program (CLASP) post-discharge clinical outreach intervention or treatment-as-usual (TAU). The primary outcome is SRBs over a 6-month follow-up. We will estimate average treatment effects adjusted for loss to follow-up and investigate the possibility of heterogeneity of treatment effects.<br><br>RESULTS: Recruitment is underway and will end September 2024. Six-month follow-up will end and analysis will begin in Summer 2025.<br><br>CONCLUSION: Results will provide information about the effectiveness of CLASP versus TAU in reducing post-discharge SRBs and provide guidance to VHA clinicians and policymakers about the implications of targeted use of CLASP among high-risk psychiatric inpatients in the months after hospital discharge.<br><br>CLINICAL TRIALS REGISTRATION: ClinicalTrials.Gov identifier: NCT05272176 (https://www.<br><br>CLINICALTRIALS: gov/ct2/show/NCT05272176).}, }
@article {pmid39352001, year = {2024}, author = {Shadman, M and Salkar, M and Srivastava, B and Karve, S and Emond, B and Gogna, P and Manceur, AM and Lafeuille, MH and Rava, A and Sun, H and Howarth, A and Tomicki, S and Agatep, B and Jones, B and Franceschini, E and Saifan, C and Bacchus, S and Roeker, L and Stephens, DM}, title = {Real-world outcomes following ibrutinib dose reduction in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma.}, journal = {Leukemia &amp; lymphoma}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/10428194.2024.2402814}, pmid = {39352001}, issn = {1029-2403}, abstract = {This study used real-world data from three separate United States (US) databases to evaluate dosing patterns and time to next treatment (TTNT) following the first-incident adverse event (AE) in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) treated with first-line ibrutinib with and without dose reduction (DR). Median TTNT or death in patients with and without a DR following an AE in each database was as follows: Optum Clinformatics Data Mart (CDM): 59.5 and 30.6 months; ConcertAI: 27.1 and 18.0 months; and Medicare Fee-for-Service (FFS): 49.8 and 22.0 months, respectively. Median TTNT or death in patients with cardiac AEs, with and without a DR, was: Optum CDM: 44.4 and 22.9 months; ConcertAI: 29.9 and 18.3 months; and Medicare FFS: 49.6 and 14.0 months, respectively. Ibrutinib DR was associated with fewer outpatient visits and lower CLL/SLL-related medical costs. These findings suggest that utilizing ibrutinib DR may effectively manage tolerability without compromising clinical efficacy.}, }
@article {pmid39349773, year = {2024}, author = {Liu, S and Zhu, J and Zhong, H and Wu, C and Xue, H and Darst, BF and Guo, X and Durda, P and Tracy, RP and Liu, Y and Johnson, WC and Taylor, KD and Manichaikul, AW and Goodarzi, MO and Gerszten, RE and Clish, CB and Chen, YI and Highland, H and Haiman, CA and Gignoux, CR and Lange, L and Conti, DV and Raffield, LM and Wilkens, L and Marchand, LL and North, KE and Young, KL and Loos, RJ and Buyske, S and Matise, T and Peters, U and Kooperberg, C and Reiner, AP and Yu, B and Boerwinkle, E and Sun, Q and Rooney, MR and Echouffo-Tcheugui, JB and Daviglus, ML and Qi, Q and Mancuso, N and Li, C and Deng, Y and Manning, A and Meigs, JB and Rich, SS and Rotter, JI and Wu, L}, title = {Identification of proteins associated with type 2 diabetes risk in diverse racial and ethnic populations.}, journal = {Diabetologia}, volume = {67}, number = {12}, pages = {2754-2770}, pmid = {39349773}, issn = {1432-0428}, support = {RG/13/13/30194/BHF_/British Heart Foundation/United Kingdom ; RG/18/13/33946/BHF_/British Heart Foundation/United Kingdom ; R01CA263494/BC/NCI NIH HHS/United States ; U54HG013243//NHGRI/NIMHD/ ; }, mesh = {Humans ; *Diabetes Mellitus, Type 2/genetics/epidemiology/ethnology ; *Genome-Wide Association Study ; Female ; *Polymorphism, Single Nucleotide/genetics ; Male ; Genetic Predisposition to Disease ; Hispanic or Latino/genetics ; Middle Aged ; Aged ; Ethnicity/genetics ; White People/genetics ; Risk Factors ; Asian People/genetics ; White ; }, abstract = {AIMS/HYPOTHESIS: Several studies have reported associations between specific proteins and type 2 diabetes risk in European populations. To better understand the role played by proteins in type 2 diabetes aetiology across diverse populations, we conducted a large proteome-wide association study using genetic instruments across four racial and ethnic groups: African; Asian; Hispanic/Latino; and European.<br><br>METHODS: Genome and plasma proteome data from the Multi-Ethnic Study of Atherosclerosis (MESA) study involving 182 African, 69 Asian, 284 Hispanic/Latino and 409 European individuals residing in the USA were used to establish protein prediction models by using potentially associated cis- and trans-SNPs. The models were applied to genome-wide association study summary statistics of 250,127 type 2 diabetes cases and 1,222,941 controls from different racial and ethnic populations.<br><br>RESULTS: We identified three, 44 and one protein associated with type 2 diabetes risk in Asian, European and Hispanic/Latino populations, respectively. Meta-analysis identified 40 proteins associated with type 2 diabetes risk across the populations, including well-established as well as novel proteins not yet implicated in type 2 diabetes development.<br><br>CONCLUSIONS/INTERPRETATION: Our study improves our understanding of the aetiology of type 2 diabetes in diverse populations.<br><br>DATA AVAILABILITY: The summary statistics of multi-ethnic type 2 diabetes GWAS of MVP, DIAMANTE, Biobank Japan and other studies are available from The database of Genotypes and Phenotypes (dbGaP) under accession number phs001672.v3.p1. MESA genetic, proteome and covariate data can be accessed through dbGaP under phs000209.v13.p3. All code is available on GitHub (https://github.com/Arthur1021/MESA-1K-PWAS).}, }
@article {pmid39348623, year = {2024}, author = {Sankaran, S and Banerjee, R}, title = {Smartwatch Biometrics in the Electronic Medical Record: Time for a New Vital Sign?.}, journal = {JCO clinical cancer informatics}, volume = {8}, number = {}, pages = {e2400161}, doi = {10.1200/CCI-24-00161}, pmid = {39348623}, issn = {2473-4276}, mesh = {Humans ; *Electronic Health Records ; *Biometry/methods ; *Smartphone ; Vital Signs ; }, abstract = {Smartphone biometrics in the EMR: is the 5th vital sign here? @JCOCCI_ASCO commentary by Sankaran and @RahulBanerjeeMD here.}, }
@article {pmid39348095, year = {2024}, author = {Harris, HR and Saboda, K and Thomson, CA and Saquib, N and Shadyab, AH and Schnatz, PF and Robles-Morales, R and Qi, L and Roe, DJ and Farland, LV}, title = {History of Infertility and Risk of Endometrial Cancer in the Women's Health Initiative.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {33}, number = {12}, pages = {1683-1689}, pmid = {39348095}, issn = {1538-7755}, support = {R03 HD102403/HD/NICHD NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Endometrial Neoplasms/epidemiology ; Middle Aged ; Risk Factors ; *Women's Health/statistics &amp; numerical data ; Infertility, Female/epidemiology ; Aged ; Body Mass Index ; Incidence ; United States/epidemiology ; }, abstract = {BACKGROUND: Several studies have suggested an association between infertility and risk of endometrial cancer. However, most studies have evaluated this relationship in premenopausal people, yet the mean age of endometrial cancer is 60 years, after the average age of menopause.<br><br>METHODS: Our study included Women's Health Initiative participants who self-reported whether they had a history of infertility. Cox proportional hazards models were used to examine the association between infertility and incident endometrial cancer. Given that all infertility diagnoses occurred prior to study enrollment, we conducted secondary analyses using logistic regression examining prevalent endometrial cancer cases diagnosed before study baseline.<br><br>RESULTS: Approximately 18% of participants reported a history of infertility. No statistically significant association was observed between infertility and risk of incident endometrial cancer overall [incident cases = 1,622; HR = 1.12; 95% confidence interval (CI) = 0.99-1.26]. Although point estimates suggested an increase in risk of endometrial cancer among women with body mass index (BMI) &#x2265;25 (HR = 1.15; 95% CI = 0.99-1.33), none of the associations were statistically significant. There was an association between history of infertility and prevalent endometrial cancer cases (OR = 1.19; 95% CI = 1.06-1.34), with the strongest association for infertility diagnosis due to endometriosis (OR 2.42; 95% CI = 1.83-3.19).<br><br>CONCLUSIONS: In a population of postmenopausal participants, we observed a modest, but not statistically significant, association between overall infertility and incident endometrial cancer, with the suggestion of a higher risk among those with a BMI &#x2265; 25.<br><br>IMPACT: Our findings highlight, as observed in previous studies, that risk factors for endometrial cancer may vary by BMI.}, }
@article {pmid39346961, year = {2024}, author = {Zeller, MA and Chang, J and Trevisan, G and Main, RG and Gauger, PC and Zhang, J}, title = {Rapid PRRSV-2 ORF5-based lineage classification using Nextclade.}, journal = {Frontiers in veterinary science}, volume = {11}, number = {}, pages = {1419340}, pmid = {39346961}, issn = {2297-1769}, abstract = {Porcine reproductive and respiratory syndrome virus (PRRSV) continues to be a global challenge for swine health. Yim-Im et al. 2023 provides a standard genetic nomenclature, extending previously published works to better characterize PRRSV-2 ORF5-based genetic lineages on a global scale. To facilitate the use of this nomenclature, scaffold sequences, including historical and contemporary vaccines, were synthesized into a dataset designed for Nextclade v3.0. Metadata from the scaffold sequences representing year, country, and RFLP typing of the sequence were incorporated into the dataset. These scaffold sequences were processed through the Augur pipeline using DQ478308.1 as a reference strain for rooting and comparison. The resultant classifier can be accessed through the Nextclade website (https://clades.nextstrain.org/) or a link on the PRRSView homepage (https://prrsv.vdl.iastate.edu/). The resultant classifier functions the same as other classifiers hosted by the Nextclade core group and can provide phylogenetic-based PRRSV-2 ORF5 classifications on demand. Nextclade provides additional sequence metrics such as classification quality and notable mutations relative to the reference. The submitted sequences are grafted to the reference tree using phylogenetic placement, allowing for comparison to nearby sequences of reference viruses and vaccine strains. Additional comparisons between sequences can be made with metadata incorporated in the dataset. Although Nextclade is hosted as a webtool, the sequences are not uploaded to a server, and all analysis stay strictly confidential to the user. This work provides a standardized, trivial workflow facilitated by Nextclade to rapidly assign lineage classifications to PRRSV-2, identify mutations of interest, and compare contemporary strains to relevant vaccines.}, }
@article {pmid39345789, year = {2024}, author = {Parraga-Leo, A and Oskotsky, TT and Oskotsky, B and Wibrand, C and Roldan, A and Tang, AS and Ha, CWY and Wong, RJ and Minot, SS and Andreoletti, G and Kosti, I and Theis, KR and Ng, S and Lee, YS and Diaz-Gimeno, P and Bennett, PR and MacIntyre, DA and Lynch, SV and Romero, R and Tarca, AL and Stevenson, DK and Aghaeepour, N and Golob, JL and Sirota, M}, title = {VMAP: Vaginal Microbiome Atlas during Pregnancy.}, journal = {JAMIA open}, volume = {7}, number = {3}, pages = {ooae099}, pmid = {39345789}, issn = {2574-2531}, support = {R01 AG058417/AG/NIA NIH HHS/United States ; }, abstract = {OBJECTIVES: To enable interactive visualization of the vaginal microbiome across the pregnancy and facilitate discovery of novel insights and generation of new hypotheses.<br><br>MATERIAL AND METHODS: Vaginal Microbiome Atlas during Pregnancy (VMAP) was created with R shiny to generate visualizations of structured vaginal microbiome data from multiple studies.<br><br>RESULTS: VMAP (http://vmapapp.org) visualizes 3880 vaginal microbiome samples of 1402 pregnant individuals from 11 studies, aggregated via open-source tool MaLiAmPi. Visualized features include diversity measures, VALENCIA community state types, and composition (phylotypes, taxonomy) that can be filtered by various categories.<br><br>DISCUSSION: This work represents one of the largest and most geographically diverse aggregations of the vaginal microbiome in pregnancy to date and serves as a user-friendly resource to further analyze vaginal microbiome data and better understand pregnancies and associated outcomes.<br><br>CONCLUSION: VMAP can be obtained from https://github.com/msirota/vmap.git and is currently deployed as an online app for non-R users.}, }
@article {pmid39345629, year = {2024}, author = {Takenaka, R and Simmerman, SM and Schmidt, CA and Albanese, EH and Rieder, LE and Malik, HS}, title = {The Drosophila maternal-effect gene abnormal oocyte (ao) does not repress histone gene expression.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39345629}, issn = {2692-8205}, support = {R35 GM142724/GM/NIGMS NIH HHS/United States ; U24 HG013300/HG/NHGRI NIH HHS/United States ; P40 OD010949/OD/NIH HHS/United States ; K12 GM000680/GM/NIGMS NIH HHS/United States ; T32 GM007270/GM/NIGMS NIH HHS/United States ; R01 GM074108/GM/NIGMS NIH HHS/United States ; R00 HD092625/HD/NICHD NIH HHS/United States ; F32 GM140778/GM/NIGMS NIH HHS/United States ; }, abstract = {The abnormal oocyte (ao) gene of Drosophila melanogaster is a maternal-effect lethal gene previously identified as encoding a transcriptional regulator of core histones. However, background genetic mutations in existing ao mutant strains could compromise their utility in manipulating histone levels. To distinguish the true ao phenotype from background effects, we created two new ao reagents: a CRISPR/Cas9-mediated knockout of the ao allele for genetic and molecular analyses and an epitope-tagged ao allele for cytological experiments. Using these reagents, we confirm previous findings that ao exhibits maternal-effect lethality, which can be rescued by either a decrease in the histone gene copy number or by Y chromosome heterochromatin. We also confirm that the Ao protein localizes to the histone locus bodies in ovaries. Our data also suggest that ao genetically interacts with the histone genes and heterochromatin, as previously suggested. However, contrary to prior findings, we find that ao does not repress core histone transcript levels. Thus, the molecular basis for ao-associated maternal-effect lethality remains unknown.}, }
@article {pmid39345457, year = {2024}, author = {Alencar, GF and Rodriguez, HJ and Pulliam, TH and Remington, AJ and Gilmour, MW and Alam, R and Jabbour, AJ and Mullen, LJ and DeBuysscher, BL and Nghiem, P and Taylor, JJ}, title = {Merkel cell carcinoma-derived macrophage migration inhibitory factor (MIF) may promote persistence of Chronic Lymphocytic Leukemia.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39345457}, issn = {2692-8205}, support = {P01 CA225517/CA/NCI NIH HHS/United States ; P30 CA044579/CA/NCI NIH HHS/United States ; }, abstract = {While concurrent diagnoses of Merkel cell carcinoma (MCC) and other cancers, like Chronic lymphocytic leukemia (CLL), are rare, patients with MCC have a 30-fold higher incidence of CLL. While these increases have been attributed to the ability of CLL to suppress immune responses allowing for the emergence of MCC, here we found evidence that MCC could support the persistence of CLL. Using single cell sequencing approaches and computational analyses of MCC and CLL from a patient where both cancers were present in the same lymph node, we found that production of macrophage migration inhibitory factor (MIF) by MCC could promote the persistence of CLL through stimulation of CD74 and CXCR4. These results may explain why blood cell counts rapidly normalized after treatment for MCC and were maintained at normal levels despite the absence of treatment for CLL.}, }
@article {pmid39343510, year = {2024}, author = {Chae, YK and Othus, M and Patel, S and Powers, B and Hsueh, CT and Govindarajan, R and Bucur, S and Kim, HS and Chung, LI and McLeod, C and Chen, HX and Sharon, E and Streicher, H and Ryan, CW and Blanke, C and Kurzrock, R}, title = {Phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: the desmoid tumors.}, journal = {Journal for immunotherapy of cancer}, volume = {12}, number = {9}, pages = {}, pmid = {39343510}, issn = {2051-1426}, support = {U10 CA180819/CA/NCI NIH HHS/United States ; U10 CA180820/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; Middle Aged ; Adult ; *CTLA-4 Antigen/antagonists &amp; inhibitors ; *Fibromatosis, Aggressive/drug therapy ; Aged ; Young Adult ; Prospective Studies ; Ipilimumab/therapeutic use/pharmacology ; Immune Checkpoint Inhibitors/therapeutic use/pharmacology/adverse effects ; Programmed Cell Death 1 Receptor/antagonists &amp; inhibitors ; Nivolumab/therapeutic use/pharmacology ; Adolescent ; }, abstract = {BACKGROUND: Dual inhibition using anti-programmed death-1 (PD-1) and anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) checkpoint inhibitors has proven effective in many cancers. However, its efficacy in rare solid cancers remains unclear. Desmoid tumors are ultrarare soft-tissue tumors, traditionally treated with surgery. This study reviews the first results of using ipilimumab and nivolumab in the desmoid tumor cohort of the SWOG S1609 Dual Anti-CTLA-4 &amp; Anti-PD-1 blockade in Rare Tumors (DART) trial.<br><br>METHODS: DART is a prospective/open-label/multicenter (1,016 US sites)/multicohort phase II trial of ipilimumab (1&#x2009;mg/kg intravenously every 6 weeks) plus nivolumab (240&#x2009;mg intravenously every 2 weeks) that opened at 1,016 US sites. The primary endpoint included overall response rate (ORR) defined as confirmed complete (CR) and partial responses (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1. Secondary endpoints include progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR; stable disease (SD) &#x2265;6 months plus CR and PR) and toxicity.<br><br>RESULTS: Sixteen evaluable patients (median age: 37) with desmoid tumors and a median of 1.5 prior therapies (with no prior exposure to immunotherapy) were analyzed. The tumors varied in location (eight abdomen, three lower limb, two upper limb, two pelvis, and one neck). ORR was 18.8% (3/16; 3 confirmed PR): 40% regression (PFS 30+ months), 83% regression (PFS 16 months) and 71% regression (PFS 8.4 months). Seven additional patients (43.8%) had prolonged SD over 6 months (PFS: 16.5, 22.4+, 22.6, 30.1, 38.2+, 48.3+ and 60.7+ months). Overall CBR was 62.5% (10/16). Median PFS was 19.4 months, with 6-month PFS of 73% and 1-year PFS of 67%. All patients were alive at 1 year; median OS was not assessable, as 13 patients were alive at analysis. Common adverse events included fatigue, nausea and hypothyroidism, with 50% experiencing grade 3-4 events. There were no grade 5 events.<br><br>CONCLUSION: Treatment with ipilimumab and nivolumab in desmoid tumors yielded an ORR of 18.8% and a CBR of 62.5% with durable responses seen. This is the first prospective study exploring the efficacy of this combination in this rare disease. Ongoing studies aim to identify markers for response and resistance. Expanded trials are necessary.<br><br>TRIAL REGISTRATION NUMBER: NCT02834013.}, }
@article {pmid39341639, year = {2024}, author = {Butler, CD and Combs Bowles, D and Hanigan, IC and Harmer, A and Potter, JD}, title = {The Lancet Countdown on health and climate change: competing interests and optimism bias.}, journal = {Lancet (London, England)}, volume = {404}, number = {10459}, pages = {1196-1197}, doi = {10.1016/S0140-6736(24)01491-0}, pmid = {39341639}, issn = {1474-547X}, mesh = {Humans ; Bias ; *Climate Change ; *Global Health ; *Optimism ; }, }
@article {pmid39339842, year = {2024}, author = {Huang, Y and Alam, S and Andersen-Nissen, E and Carpp, LN and Dintwe, OB and Flach, BS and Grunenberg, N and Laher, F and De Rosa, SC and Ferrari, G and Innes, C and Bekker, LG and Kublin, JG and McElrath, MJ and Tomaras, GD and Gray, GE and Gilbert, PB}, title = {Non-HIV Vaccine-Induced Immune Responses as Potential Baseline Immunogenicity Predictors of ALVAC-HIV and AIDSVAX B/E-Induced Immune Responses.}, journal = {Viruses}, volume = {16}, number = {9}, pages = {}, pmid = {39339842}, issn = {1999-4915}, support = {R01 CA277133/CA/NCI NIH HHS/United States ; R37AI054165//National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH)/ ; R01CA277133//National Cancer Institute of the NIH/ ; UM1AI068635//National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH)/ ; }, mesh = {Humans ; *AIDS Vaccines/immunology/administration &amp; dosage ; *HIV Infections/immunology/prevention &amp; control ; *Immunoglobulin G/blood/immunology ; *CD4-Positive T-Lymphocytes/immunology ; Male ; Female ; Adult ; Tetanus Toxoid/immunology/administration &amp; dosage ; Immunogenicity, Vaccine ; HIV Antibodies/blood/immunology ; Hepatitis B Vaccines/immunology/administration &amp; dosage ; HIV-1/immunology ; Young Adult ; Antibodies, Viral/blood/immunology ; Viral Vaccines ; }, abstract = {Identifying correlations between immune responses elicited via HIV and non-HIV vaccines could aid the search for correlates of HIV protection and increase statistical power in HIV vaccine-efficacy trial designs. An exploratory objective of the HVTN 097 phase 1b trial was to assess whether immune responses [focusing on those supported as correlates of risk (CoR) of HIV acquisition] induced via the RV144 pox-prime HIV vaccine regimen correlated with those induced via tetanus toxoid (TT) and/or hepatitis B virus (HBV) vaccines. We measured TT-specific and HBV-specific IgG-binding antibody responses and TT-specific and HBV-specific CD4+ T-cell responses at multiple time points in HVTN 097 participants, and we assessed their correlations at peak time points with HIV vaccine (ALVAC-HIV and AIDSVAX B/E)-induced responses. Four correlations were significant [false discovery rate-adjusted p-value (FDR) ≤ 0.2]. Three of these four were with IgG-binding antibody responses to TT measured one month after TT receipt, with the strongest and most significant correlation [rho = 0.368 (95% CI: 0.096, 0.588; p = 0.008; FDR = 0.137)] being with IgG-binding antibody responses to MN gp120 gDneg (B protein boost) measured two weeks after the second ALVAC-HIV and AIDSVAX B/E boost. The fourth significant correlation [(rho = 0.361; 95% CI: 0.049, 0.609; p = 0.021; FDR = 0.137)] was between CD4+ T-cell responses to a hepatitis B surface antigen peptide pool, measured 2 weeks after the third HBV vaccination, and IgG-binding antibody responses to gp70BCaseAV1V2 (B V1V2 immune correlate), measured two weeks after the second ALVAC-HIV and AIDSVAX B/E boost. These moderate correlations imply that either vaccine, TT or HBV, could potentially provide a moderately useful immunogenicity predictor for the ALVAC-HIV and AIDSVAX B/E HIV vaccine regimen.}, }
@article {pmid39334347, year = {2024}, author = {Michel, AM and Yi, H and Amenta, J and Collins, N and Vaynrub, A and Umakanth, S and Anderson, G and Arnold, K and Law, C and Pruthi, S and Sandoval-Leon, A and Shirley, R and Perdekamp, MG and Colonna, S and Krisher, S and King, T and Yee, LD and Ballinger, TJ and Braun-Inglis, C and Mangino, DA and Wisinski, K and DeYoung, CA and Ross, M and Floyd, J and Kaster, A and VanderWalde, L and Saphner, TJ and Zarwan, C and Lo, S and Graham, C and Conlin, A and Yost, K and Agnese, D and Jernigan, C and Hershman, DL and Neuhouser, ML and Arun, B and Crew, KD and Kukafka, R}, title = {Use of web-based decision support to improve informed choice for chemoprevention: a qualitative analysis of pre-implementation interviews (SWOG S1904).}, journal = {BMC medical informatics and decision making}, volume = {24}, number = {1}, pages = {272}, pmid = {39334347}, issn = {1472-6947}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Chemoprevention ; *Qualitative Research ; *Breast Neoplasms/prevention &amp; control ; Middle Aged ; Adult ; Internet ; Male ; Decision Support Techniques ; Interviews as Topic ; }, abstract = {BACKGROUND: Women with high-risk breast lesions, such as atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS), have a 4- to tenfold increased risk of breast cancer compared to women with non-proliferative breast disease. Despite high-quality data supporting chemoprevention, uptake remains low. Interventions are needed to break down barriers.<br><br>METHODS: The parent trial, MiCHOICE, is a cluster randomized controlled trial evaluating the effectiveness and implementation of patient and provider decision support tools to improve informed choice about chemoprevention among women with AH or LCIS. For this pre-implementation analysis, 25 providers participated in semi-structured interviews prior to accessing decision support tools. Interviews sought to understand attitudes/beliefs and barriers/facilitators to chemoprevention.<br><br>RESULTS: Interviews with 25 providers (18 physicians and 7 advanced practice providers) were included. Providers were predominantly female (84%), white (72%), and non-Hispanic (88%). Nearly all providers (96%) had prescribed chemoprevention for eligible patients. Three themes emerged in qualitative analysis. The first theme describes providers' confidence in chemoprevention and the utility of decision support tools. The second theme elucidates barriers to chemoprevention, including time constraints, risk communication and perceptions of patients' fear of side effects and anxiety. The third theme is the need for early implementation of decision support tools.<br><br>CONCLUSIONS: This qualitative study suggests that providers were interested in the early inclusion of decision aids (DA) in their chemoprevention discussion workflow. The DAs may help overcome certain barriers which were elucidated in these interviews, including patient level concerns about side effects, clinic time constraints and difficulty communicating risk. A multi-faceted intervention with a DA as one active component may be needed.<br><br>TRIAL REGISTRATION: This trial was registered with the NIH clinical trial registry, clinicaltrials.gov, NCT04496739.}, }
@article {pmid39334118, year = {2024}, author = {Ko, LK and Jang, SH and Rodriguez, E and Buta, M and Ibarra, G and Reuland, D}, title = {Dissemination of colorectal cancer information among Hispanic patients and their social network.}, journal = {BMC public health}, volume = {24}, number = {1}, pages = {2616}, pmid = {39334118}, issn = {1471-2458}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Colorectal Neoplasms/ethnology/diagnosis ; Decision Support Techniques ; *Early Detection of Cancer/psychology/statistics &amp; numerical data ; *Hispanic or Latino/psychology/statistics &amp; numerical data ; *Information Dissemination ; Social Support ; Washington ; }, abstract = {BACKGROUND: Colorectal cancer (CRC) screening decision aids can inform patients about CRC screening benefits, costs, and procedures. Patients who receive the decision aid report wanting to share the information with their families and friends. We evaluated a CRC screening decision aid on Hispanic patients' communication to their alters and whether patient-alter communication leads to alters' CRC screening intention.<br><br>METHODS: We conducted a one-arm pre/post study of Hispanic patients and their alters; patients (n&#x2009;=&#x2009;42) and their alters (n&#x2009;=&#x2009;19) were recruited from a clinic site in Yakima County, Washington State. Patients viewed a CRC screening decision aid at the clinic site. Survey data from patients and alters were collected via telephone including patients' communication with their alters about CRC screening after viewing the decision aid and alters' intention to be screened for CRC after talking to the patient.<br><br>RESULTS: Most participants reported sharing CRC information with their alters after viewing the decision aid, and most alters confirmed they had received CRC information from participants (68%). The decision aid was associated with participants' own intention to undergo CRC screening and with alters' intention to be screened for CRC using a fecal occult blood test (p&#x2009;=&#x2009;0.014) and sigmoidoscopy (p&#x2009;=&#x2009;0.011).<br><br>CONCLUSIONS: Patient decision aids have the potential to increase CRC screening behavior beyond the decision aid recipients to their social network.<br><br>TRIAL REGISTRATION: Trials Registration Number: NCT04444232 "Retrospectively registered."}, }
@article {pmid39333696, year = {2024}, author = {Serritella, AV and Taylor, A and Haffner, MC and Abida, W and Bryce, A and Karsh, LI and Tagawa, ST and Twardowski, P and Armstrong, AJ and Lang, JM}, title = {Therapeutic implications of homologous repair deficiency testing in patients with prostate cancer (Part 2 of 2).}, journal = {Prostate cancer and prostatic diseases}, volume = {}, number = {}, pages = {}, pmid = {39333696}, issn = {1476-5608}, abstract = {BACKGROUND/OBJECTIVES: Unfortunately, not all metastatic castration-resistant prostate cancer (mCRPC) patients receive available life-prolonging systemic therapies, emphasizing the need to optimize mCRPC treatment selections. Better guidelines are necessary to determine genetic testing for prostate cancer.<br><br>SUBJECTS/METHODS: In this two-part expert opinion-based guide, we provide an expert consensus opinion on the utilization of germline and somatic testing to detect HRR alterations in patients with mCRPC. This guide was developed by a multidisciplinary expert panel that convened in 2023-2024, including representatives from medical oncology, urology, radiation oncology, pathology, medical genomics, and basic science.<br><br>RESULTS/CONCLUSIONS: In this second part, we highlight how genetic testing can lead to improved, life-prolonging mCRPC therapeutic strategies based on a review of the recent phase III trials and subsequent regulatory approvals for PARP inhibitors in mCRPC.}, }
@article {pmid39333103, year = {2024}, author = {Fiorenza, S and Zheng, Y and Purushe, J and Bock, TJ and Sarthy, J and Janssens, DH and Sheih, AS and Kimble, EL and Kirchmeier, D and Phi, TD and Gauthier, J and Hirayama, AV and Riddell, SR and Wu, Q and Gottardo, R and Maloney, DG and Yang, JYH and Henikoff, S and Turtle, CJ}, title = {Histone marks identify novel transcription factors that parse CAR-T subset-of-origin, clinical potential and expansion.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8309}, pmid = {39333103}, issn = {2041-1723}, support = {K99 HG012797/HG/NHGRI NIH HHS/United States ; Clinical Fellowship Grant//Haematology Society of Australia and New Zealand (HSANZ)/ ; }, mesh = {Humans ; *Receptors, Chimeric Antigen/metabolism/genetics/immunology ; *Immunotherapy, Adoptive/methods ; *Histone Code ; *CD8-Positive T-Lymphocytes/immunology/metabolism ; Kruppel-Like Transcription Factors/metabolism/genetics ; Transcription Factors/metabolism/genetics ; Histones/metabolism ; Lymphoma/genetics/metabolism/therapy ; Cell Proliferation/genetics ; T-Lymphocyte Subsets/immunology/metabolism ; Immunologic Memory ; }, abstract = {Chimeric antigen receptor-modified T cell (CAR-T) immunotherapy has revolutionised blood cancer treatment. Parsing the genetic underpinnings of T cell quality and CAR-T efficacy is challenging. Transcriptomics inform CAR-T state, but the nature of dynamic transcription during activation hinders identification of transiently or minimally expressed genes, such as transcription factors, and over-emphasises effector and metabolism genes. Here we explore whether analyses of transcriptionally repressive and permissive histone methylation marks describe CAR-T cell functional states and therapeutic potential beyond transcriptomic analyses. Histone mark analyses improve identification of differences between naïve, central memory, and effector memory CD8 + T cell subsets of human origin, and CAR-T derived from these subsets. We find important differences between CAR-T manufactured from central memory cells of healthy donors and of patients. By examining CAR-T products from a clinical trial in lymphoma (NCT01865617), we find a novel association between the activity of the transcription factor KLF7 with in vivo CAR-T accumulation in patients and demonstrate that over-expression of KLF7 increases in vitro CAR-T proliferation and IL-2 production. In conclusion, histone marks provide a rich dataset for identification of functionally relevant genes not apparent by transcriptomics.}, }
@article {pmid39332809, year = {2024}, author = {Amonoo, HL and Guo, M and Keane, EP and Boardman, AC and Song, MT and Wolfe, ED and Cutler, C and Jim, HS and Lee, SJ and Huffman, JC and El-Jawahri, A}, title = {A Peer Support Intervention in Patients With Hematologic Malignancies Undergoing Hematopoietic Stem Cell Transplantation (HSCT): The STEPP Proof-of-Concept Trial.}, journal = {Transplantation and cellular therapy}, volume = {30}, number = {12}, pages = {1217.e1-1217.e15}, pmid = {39332809}, issn = {2666-6367}, support = {K08 CA251654/CA/NCI NIH HHS/United States ; R37 CA288557/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/psychology ; *Hematologic Neoplasms/therapy/psychology ; Male ; Female ; *Peer Group ; Middle Aged ; Adult ; Social Support ; Aged ; Proof of Concept Study ; }, abstract = {Although peer support interventions are associated with improved patient-reported outcomes in diverse cancer populations, structured peer support programs tailored to the needs of patients undergoing hematopoietic stem cell transplantation (HSCT) are lacking. This single-arm, proof-of-concept trial aimed to refine the Supporting Transplant Experiences with Peer Program (STEPP), a structured, five-session, manualized, phone-delivered peer support intervention for patients undergoing HSCT, informed by qualitative feedback from patients. Adult patients with hematologic malignancies scheduled to undergo allogeneic or autologous HSCT were eligible to participate in the study approximately two weeks prior to their HSCT hospitalization. Participants received the STEPP intervention, which focused on providing informational, emotional, and practical support. To refine the intervention, we conducted semi-structured qualitative exit interviews to gather feedback on the content of STEPP and to identify facilitators and barriers to engagement. Transcribed interviews were analyzed using rapid analytic methods by two coders. Of the 37 eligible patients, 25 enrolled in the study, 20 completed all intervention sessions and 20 completed exit interviews. Participants highlighted that discussions with peer mentors/STEPP interventionists about the transplant journey and processing information provided by the clinical team were the most valuable aspects of STEPP. Positive experiences during the first intervention session facilitated patient engagement with the program. Potential barriers to engagement included logistical challenges in connecting with interventionists while experiencing physical symptoms during inpatient hospitalization and being paired with an interventionist who had a different cancer diagnosis and/or type of transplant. Patients undergoing HSCT reported positive experiences with the structured five-session, phone-delivered peer support intervention administered before and during the HSCT hospitalization. Patients' descriptions of barriers and facilitators to engagement with the STEPP intervention underscore the importance of patient input and programmatic structure in peer support interventions for this population. Insights from this proof-of-concept trial will be incorporated into future trials of STEPP to improve outcomes in HSCT recipients.}, }
@article {pmid39332390, year = {2024}, author = {Drain, PK and Niu, X and Shapiro, AE and Magcaba, ZP and Ngcobo, Z and Ngwane, MW and Thomas, KK and Dalmat, RR and Morton, JF and Budiawan, E and Pinter, A and Cantera, J and Anderson, C and Buchmann, R and Wilson, D and Grant, B and , }, title = {Real-world diagnostic accuracy of lipoarabinomannan in three non-sputum biospecimens for pulmonary tuberculosis disease.}, journal = {EBioMedicine}, volume = {108}, number = {}, pages = {105353}, pmid = {39332390}, issn = {2352-3964}, support = {R01 AI152157/AI/NIAID NIH HHS/United States ; R56 AI171023/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Lipopolysaccharides/urine/blood ; Male ; Female ; Adult ; *Tuberculosis, Pulmonary/diagnosis/urine/blood ; *HIV Infections/complications/diagnosis ; *Biomarkers/urine/blood ; Middle Aged ; Sensitivity and Specificity ; Prospective Studies ; Mycobacterium tuberculosis/immunology ; Sputum/microbiology ; }, abstract = {BACKGROUND: Development of a non-sputum test using readily-obtainable biospecimens remains a global priority for tuberculosis (TB) control. We quantified lipoarabinomannan (LAM) concentrations, a pathogen biomarker for Mycobacterium tuberculosis, in urine, plasma and serum for real-world diagnostic accuracy of pulmonary TB among people living with and without HIV.<br><br>METHODS: We conducted a prospective diagnostic study among adults with TB symptoms in South Africa. We measured LAM concentrations in time-matched urine, plasma and serum with an electrochemiluminescence immunoassay using two capture antibodies (FIND 28 and S4-20). From the completed cohort, we randomly selected 210 participants (2 cases: 1 control) based on sensitivity estimates, and we compared diagnostic accuracy of LAM measurements against the microbiological reference standard.<br><br>FINDINGS: Urine and blood specimens from 210 of 684 adults enrolled were tested for LAM. Among 138&#xa0;TB-positive adults (41% female), median urine LAM was 137&#xa0;pg/mL and 52&#xa0;pg/mL by FIND 28 and S4-20, respectively. Average LAM concentrations were highest in HIV-positive participants with CD4+ T cells <200&#xa0;cells/mm[3]. Urine LAM by S4-20 achieved diagnostic sensitivity of 62% (95% CI: 53%-70%) and specificity of 99% (95% CI: 96%-100%). Plasma and serum LAM by FIND 28 showed similar sensitivity (70%, 95% CI: 62%-78%) and comparable specificities (90%, 95% CI: 82%-97%; 94%, 95% CI: 88%-99%). Diagnostic sensitivity of urine LAM by S4-20 was higher among participants without HIV (41%, 95% CI: 24%-61%) compared to HIV-positive participants with CD4 &#x2265;200&#xa0;cells/mm[3] (20%, 95% CI: 8%-39%).<br><br>INTERPRETATION: Detection of LAM was achievable in non-sputum specimens for pulmonary TB, but additional analyte concentration or signal amplification may be required to achieve diagnostic accuracy targets.<br><br>FUNDING: Bill and Melinda Gates Foundation.}, }
@article {pmid39331724, year = {2024}, author = {Badros, AZ and Foster, L and Anderson, LD and Chaulagain, CP and Pettijohn, EM and Cowan, AJ and Costello, CL and Larson, S and Sborov, DW and Shain, KH and Silbermann, R and Shah, N and Chung, A and Krevvata, M and Pei, H and Patel, S and Khare, V and Cortoos, A and Carson, R and Lin, T and Voorhees, PM}, title = {Daratumumab with lenalidomide as maintenance after transplant in newly diagnosed multiple myeloma: the AURIGA study.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024025746}, pmid = {39331724}, issn = {1528-0020}, abstract = {No randomized trial has directly compared daratumumab and lenalidomide (D-R) maintenance therapy versus standard-of-care lenalidomide (R) alone post-transplant. Here, we report the primary results of the phase 3 AURIGA study evaluating D-R versus R maintenance in NDMM patients who were in ≥very good partial response, minimal residual disease (MRD; threshold 10-5) positive, and anti-CD38 naïve post-transplant. Patients were randomized 1:1 to D-R or R maintenance for up to 36 cycles. Two hundred patients were randomized (D-R, n=99; R, n=101). The primary endpoint, MRD-negative (10-5) conversion rate by 12 months from start of maintenance, was significantly higher for D-R versus R (50.5% vs 18.8%; odds ratio [OR], 4.51; 95% confidence interval [CI], 2.37-8.57; P<0.0001). MRD-negative (10-6) conversion rate was similarly higher with D-R (23.2% vs 5.0%; OR, 5.97; 95% CI, 2.15-16.58; P=0.0002). At 32.3 months' median follow-up, D-R achieved a higher overall MRD-negative (10-5) conversion rate (D-R, 60.6% vs R, 27.7%; OR, 4.12; 95% CI, 2.26-7.52; P<0.0001) and ≥complete response rate (75.8% vs 61.4%; OR, 2.00; 95% CI, 1.08-3.69; P=0.0255) versus R alone. Progression-free survival (PFS) favored D-R versus R (hazard ratio, 0.53; 95% CI, 0.29-0.97); estimated 30-month PFS rates were 82.7% for D-R and 66.4% for R. Incidences of grade 3/4 cytopenias (54.2% vs 46.9%) and infections (18.8% vs 13.3%) were slightly higher with D-R versus R. In conclusion, D-R maintenance achieved a higher MRD-negative conversion rate and improved PFS post-transplant versus R alone, with no new safety concerns. This trial was registered at www.ClinicalTrials.gov: #NCT03901963.}, }
@article {pmid39331494, year = {2024}, author = {Unger, JM and Xiao, H and Vaidya, R and LeBlanc, M}, title = {Patient Enrollment to Industry-Sponsored Versus Federally-Sponsored Cancer Clinical Trials.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {42}, number = {33}, pages = {3917-3925}, pmid = {39331494}, issn = {1527-7755}, mesh = {Humans ; *Clinical Trials as Topic/statistics &amp; numerical data ; United States ; *Neoplasms/drug therapy/economics ; *Drug Industry/economics ; Research Support as Topic ; Patient Selection ; }, abstract = {PURPOSE: The conduct of cancer clinical research in the United States is supported by both private and public sponsors. Industry aims to obtain new drug approvals. Federally-sponsored trials examine a broad set of research questions that are not typically addressed by industry; these trials, which are also more commonly conducted in diverse populations, were recently shown to have contributed to gains of 14 million life-years for patients with cancer. Despite the different mandates, the proportion of patients who might participate in industry-sponsored versus federally-sponsored cancer studies is unknown.<br><br>METHODS: We evaluated trial enrollment patterns from 2008 to 2022 using ClinicalTrials.gov data. The ratio of enrollments attributable to industry versus federal sponsors was estimated. A large set of estimates on the basis of different combinations of study characteristics were generated. Point estimates were determined as the mean of combinations and confidence limits by the IQR. Five-year intervals were examined to smooth annual variation.<br><br>RESULTS: In total, N = 26,080 studies were examined. The estimated enrollment ratio from 2018 to 2022 for all industry-sponsored versus federally-sponsored trials was 8.1 (IQR, 6.2-9.9). For adult trials, the ratio increased from 4.8 (IQR, 4.4-5.3) during 2008-2012 to 9.6 (IQR, 7.4-11.8) during 2018-2022; for trials in children, the ratio increased from 0.7 (IQR, 0.6-0.7) to 2.3 (IQR, 1.8-2.7). Despite increasing cancer incidence, enrollment counts for federally-sponsored trials were flat over the study period.<br><br>CONCLUSION: In the United States, there is a growing reliance on industry to conduct cancer clinical research. Underinvestment in federally-sponsored research comes at a cost for both patients and researchers, with lost opportunities for scientific, clinical, and population advances.}, }
@article {pmid39326063, year = {2024}, author = {Gritti, I and Wan, J and Weeresekara, V and Vaz, JM and Tarantino, G and Bryde, TH and Vijay, V and Kammula, AV and Kattel, P and Zhu, S and Vu, P and Chan, M and Wu, MJ and Gordan, JD and Patra, KC and Silveira, VS and Manguso, RT and Wein, MN and Ott, CJ and Qi, J and Liu, D and Sakamoto, K and Gujral, TS and Bardeesy, N}, title = {DNAJB1-PRKACA fusion drives fibrolamellar liver cancer through impaired SIK signaling and CRTC2/p300-mediated transcriptional reprogramming.}, journal = {Cancer discovery}, volume = {}, number = {}, pages = {}, doi = {10.1158/2159-8290.CD-24-0634}, pmid = {39326063}, issn = {2159-8290}, support = {P50 CA127003/CA/NCI NIH HHS/United States ; R01 CA215498/CA/NCI NIH HHS/United States ; R01 CA279997/CA/NCI NIH HHS/United States ; }, abstract = {Fibrolamellar carcinoma (FLC) is a liver cancer of adolescents and young adults characterized by fusions of the genes encoding the protein kinase A catalytic subunit, PRKACA, and heat shock protein, DNAJB1. The chimeric DNAJB1-PRKACA protein has increased kinase activity and is essential for FLC xenograft growth. Here, we explore the critical oncogenic pathways controlled by DNAJB1-PRKACA using patient-derived FLC models, engineered systems, and patient samples. We show that a core function of DNAJB1-PRKACA is the phosphorylation and inactivation of Salt-inducible kinases (SIKs). This leads to deregulation of the CRTC2 transcriptional co-activator and p300 acetyltransferase, resulting in transcriptional reprogramming and increased global histone acetylation, driving malignant growth. Our studies establish a central oncogenic mechanism of DNAJB1-PRKACA and suggest the potential of targeting CRTC2/p300 in FLC. Notably, these findings link this rare cancer's signature fusion oncoprotein to more common cancer gene alterations involving STK11 and GNAS, which also function via SIK suppression.}, }
@article {pmid39325616, year = {2024}, author = {Kaneko, T and Boulanger-Weill, J and Isabella, AJ and Moens, CB}, title = {Position-independent functional refinement within the vagus motor topographic map.}, journal = {Cell reports}, volume = {43}, number = {10}, pages = {114740}, doi = {10.1016/j.celrep.2024.114740}, pmid = {39325616}, issn = {2211-1247}, support = {R01 NS109425/NS/NINDS NIH HHS/United States ; R21 NS124191/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Zebrafish/physiology ; *Motor Neurons/physiology ; *Vagus Nerve/physiology ; Synaptic Transmission/physiology ; Axons/physiology ; }, abstract = {Motor neurons in the central nervous system often lie in a continuous topographic map, where neurons that innervate different body parts are spatially intermingled. This is the case for the efferent neurons of the vagus nerve, which innervate diverse muscle and organ targets in the head and viscera for brain-body communication. It remains elusive how neighboring motor neurons with different fixed peripheral axon targets develop the separate somatodendritic (input) connectivity they need to generate spatially precise body control. Here, we show that vagus motor neurons in the zebrafish indeed generate spatially appropriate peripheral responses to focal sensory stimulation even when they are transplanted into ectopic positions within the topographic map, indicating that circuit refinement occurs after the establishment of coarse topography. Refinement depends on motor neuron synaptic transmission, suggesting that an experience-dependent periphery-to-brain feedback mechanism establishes specific input connectivity among intermingled motor populations.}, }
@article {pmid39325506, year = {2024}, author = {Fong, Y and Dang, L and Zhang, B and Fintzi, J and Chen, S and Wang, J and Rouphael, NG and Branche, AR and Diemert, DJ and Falsey, AR and Losada, C and Baden, LR and Frey, SE and Whitaker, JA and Little, SJ and Kamidani, S and Walter, EB and Novak, RM and Rupp, R and Jackson, LA and Yu, C and Magaret, CA and Molitor, C and Borate, B and Babu, TM and Kottkamp, AC and Luetkemeyer, AF and Immergluck, LC and Presti, RM and Bäcker, M and Winokur, PL and Mahgoub, SM and Goepfert, PA and Fusco, DN and Atmar, RL and Posavad, CM and Mu, J and Makowski, M and Makhene, MK and Nayak, SU and Roberts, PC and Follmann, D and Gilbert, PB and , }, title = {Neutralizing Antibody Immune Correlates for a Recombinant Protein Vaccine in the COVAIL Trial.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciae465}, pmid = {39325506}, issn = {1537-6591}, support = {UM1 AI148685/AI/NIAID NIH HHS/United States ; }, abstract = {For COVAIL recipients of a COVID-19 Sanofi booster vaccine, neutralizing antibody titers were assessed as a correlate of risk (CoR) of COVID-19. Peak and exposure-proximal titers were inverse CoRs with covariate-adjusted hazard ratios (95% confidence intervals) 0.30 (0.11, 0.78) and 0.25 (0.07, 0.85) per 10-fold increase in weighted average titer.}, }
@article {pmid39324163, year = {2024}, author = {McGowan, M and Wairimu, N and Reedy, AM and Mogere, P and Culquichicon, C and Njeru, I and Malen, RC and Jahn, A and Bärnighausen, T and Roche, SD and Ngure, K and Ortblad, KF}, title = {Formalized peer referral to HIV pre-exposure prophylaxis supported with self-testing: a mixed-methods pilot study among young Kenyan women.}, journal = {Frontiers in public health}, volume = {12}, number = {}, pages = {1428609}, pmid = {39324163}, issn = {2296-2565}, mesh = {Humans ; Female ; Kenya ; *Pre-Exposure Prophylaxis ; Pilot Projects ; *HIV Infections/prevention &amp; control/diagnosis ; *Peer Group ; Adolescent ; *Referral and Consultation ; Young Adult ; *Self-Testing ; Anti-HIV Agents/therapeutic use/administration &amp; dosage ; }, abstract = {BACKGROUND: The uptake of daily oral HIV pre-exposure prophylaxis (PrEP)-a highly effective intervention-remains low among African adolescent girls and young women (AGYW) who could benefit. AGYW who initiate PrEP often do so through informal peer referral, which may be enhanced with formalized peer referral and peer-delivered HIV self-testing (HIVST). To understand the feasibility of this PrEP referral model among AGYW, we conducted a pilot study in Kenya.<br><br>METHOD: From March to May 2022, we recruited AGYW (&#x2265;16-24&#x2009;years) using PrEP (i.e., "peer providers") from public healthcare clinics in Kiambu County and trained them on HIV prevention, HIVST use, and peer-supported linkage to clinic-based HIV services. Following training, peer providers received eight HIVST kits and were encouraged to refer four peers (i.e., "peer clients") to PrEP. We completed surveys with peer providers and clients one month following intervention delivery to assess PrEP initiation among peer clients. Later, we conducted focus group discussions (FGDs) with peer providers and clients to identify factors that facilitated or challenged intervention outcomes.<br><br>RESULTS: We trained 16 peer providers (median age: 23&#x2009;years, IQR 21-24) who reported delivering the intervention to 56 peer clients; 30 peer clients (median age: 21&#x2009;years, IQR 19-22) contacted the study team and were enrolled. Most of the enrolled peer clients reported behaviors associated with HIV risk (e.g., condomless sex; 80%, 24/30) and were PrEP-na&#xef;ve (87%, 26/30). At one-month, PrEP initiation among eligible PrEP-na&#xef;ve peer clients was high, as reported by providers (78%, 43/55) and clients (85%, 22/26); recent HIVST use was also high among peer clients (provider report: 95%, 53/56; client report: 97%, 29/30). In the FGDs, participants reported that intervention outcomes were facilitated by close preexisting relationships, HIVST assistance, and being escorted to clinic-based HIV services by peer providers; intervention barriers included conflicting priorities and limited HIVST experience.<br><br>CONCLUSION: A formalized model of peer referral with HIVST delivery supported PrEP initiation among Kenyan AGYW. These findings demonstrate the potential for peer-delivered interventions to engage AGYW in HIV prevention services; however, more research is needed on the effectiveness and sustainability of this approach at scale.}, }
@article {pmid39322372, year = {2024}, author = {Issaka, RB and Bell-Brown, A and Jewell, T and Jackson, SL and Weiner, BJ}, title = {Interventions to Increase Follow-Up of Abnormal Stool-Based Colorectal Cancer Screening Tests in Safety Net Settings: A Systematic Review.}, journal = {Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association}, volume = {22}, number = {10}, pages = {1967-1974.e3}, doi = {10.1016/j.cgh.2024.07.001}, pmid = {39322372}, issn = {1542-7714}, support = {K08 CA241296/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Colorectal Neoplasms/diagnosis ; *Early Detection of Cancer/methods ; Feces/chemistry ; Occult Blood ; Safety-net Providers ; }, }
@article {pmid39321924, year = {2024}, author = {Rosen, EA and Liu, C}, title = {Author Response to "COVID-19 Outcomes Among Hematopoietic Cell Transplant and Chimeric Antigen Receptor T-cell Recipients: Correspondence".}, journal = {Transplantation and cellular therapy}, volume = {30}, number = {12}, pages = {1227-1228}, doi = {10.1016/j.jtct.2024.09.019}, pmid = {39321924}, issn = {2666-6367}, }
@article {pmid39321347, year = {2024}, author = {Banerjee, R and Sexton, R and Cowan, AJ and Rosenberg, AS and Ailawadhi, S and Rajkumar, SV and Kumar, SK and Dispenzieri, A and Lonial, S and Durie, BGM and Richardson, PG and Usmani, SZ and Hoering, A and Orlowski, RZ}, title = {Dexamethasone dose intensity does not impact outcomes in newly diagnosed multiple myeloma: a secondary SWOG analysis.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024025939}, pmid = {39321347}, issn = {1528-0020}, abstract = {Dexamethasone is a key component of induction for newly diagnosed multiple myeloma (NDMM) despite common toxicities including hyperglycemia and insomnia. In the randomized ECOG E4A03 trial, dexamethasone 40 milligrams (mg) once weekly was associated with lower mortality than higher doses of dexamethasone. However, the performance of dexamethasone dose reductions below this threshold with regard to progression-free survival (PFS) and overall survival (OS) in NDMM have not been fully characterized. We conducted a secondary pooled analysis of the S0777 and S1211 SWOG studies of NDMM, which employed lenalidomide-dexamethasone (Rd) alone with or without bortezomib (VRd) and with or without elotuzumab (Elo-VRd). Planned dexamethasone intensity was 40-60 mg weekly in all arms. Patients were categorized into FD-DEX (full-dose dexamethasone maintained throughout induction) or LD-DEX (lowered-dose dexamethasone or discontinuation; only permitted for Grade 3+ toxicities per both study protocols). Of 541 evaluated patients, the LD-DEX group comprised 373 patients (69%). There was no difference in PFS or OS between the FD-DEX or LD-DEX groups, which were balanced in terms of age, stage, and performance status. Predictors of PFS and OS in multivariate models were treatment arm, age ≥70, and thrombocytopenia; FD-DEX did not significantly improve either outcome. Our study suggests that dexamethasone dose reductions are common in multiple myeloma, even within clinical trials. Given dexamethasone's many toxicities and unclear benefit in the era of modern treatment regimens, dexamethasone dose reduction during NDMM induction warrants further prospective study. NCT00644228, NCT01668719.}, }
@article {pmid39320863, year = {2024}, author = {Kennedy, CJ and Kearns, JC and Geraci, JC and Gildea, SM and Hwang, IH and King, AJ and Liu, H and Luedtke, A and Marx, BP and Papini, S and Petukhova, MV and Sampson, NA and Smoller, JW and Wolock, CJ and Zainal, NH and Stein, MB and Ursano, RJ and Wagner, JR and Kessler, RC}, title = {Predicting Suicides Among US Army Soldiers After Leaving Active Service.}, journal = {JAMA psychiatry}, volume = {81}, number = {12}, pages = {1215-1224}, pmid = {39320863}, issn = {2168-6238}, support = {K01 MH135131/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; *Military Personnel/statistics &amp; numerical data/psychology ; Male ; Adult ; Female ; United States/epidemiology ; *Suicide/statistics &amp; numerical data ; Young Adult ; *Machine Learning ; Risk Factors ; Prognosis ; }, abstract = {IMPORTANCE: The suicide rate of military servicemembers increases sharply after returning to civilian life. Identifying high-risk servicemembers before they leave service could help target preventive interventions.<br><br>OBJECTIVE: To develop a model based on administrative data for regular US Army soldiers that can predict suicides 1 to 120 months after leaving active service.<br><br>In this prognostic study, a consolidated administrative database was created for all regular US Army soldiers who left service from 2010 through 2019. Machine learning models were trained to predict suicides over the next 1 to 120 months in a random 70% training sample. Validation was implemented in the remaining 30%. Data were analyzed from March 2023 through March 2024.<br><br>MAIN OUTCOME AND MEASURES: The outcome was suicide in the National Death Index. Predictors came from administrative records available before leaving service on sociodemographics, Army career characteristics, psychopathologic risk factors, indicators of physical health, social networks and supports, and stressors.<br><br>RESULTS: Of the 800&#x202f;579 soldiers in the cohort (84.9% male; median [IQR] age at discharge, 26 [23-33] years), 2084 suicides had occurred as of December 31, 2019 (51.6 per 100&#x202f;000 person-years). A lasso model assuming consistent slopes over time discriminated as well over all but the shortest risk horizons as more complex stacked generalization ensemble machine learning models. Test sample area under the receiver operating characteristic curve ranged from 0.87 (SE&#x2009;=&#x2009;0.06) for suicides in the first month after leaving service to 0.72 (SE&#x2009;=&#x2009;0.003) for suicides over 120 months. The 10% of soldiers with highest predicted risk accounted for between 30.7% (SE&#x2009;=&#x2009;1.8) and 46.6% (SE&#x2009;=&#x2009;6.6) of all suicides across horizons. Calibration was for the most part better for the lasso model than the super learner model (both estimated over 120-month horizons.) Net benefit of a model-informed prevention strategy was positive compared with intervene-with-all or intervene-with-none strategies over a range of plausible intervention thresholds. Sociodemographics, Army career characteristics, and psychopathologic risk factors were the most important classes of predictors.<br><br>CONCLUSIONS AND RELEVANCE: These results demonstrated that a model based on administrative variables available at the time of leaving active Army service can predict suicides with meaningful accuracy over the subsequent decade. However, final determination of cost-effectiveness would require information beyond the scope of this report about intervention content, costs, and effects over relevant horizons in relation to the monetary value placed on preventing suicides.}, }
@article {pmid39320295, year = {2024}, author = {Oved, JH and Russell, A and DeZern, A and Prockop, SE and Bonfim, C and Sharma, A and Purtill, D and Lakkaraja, M and Bidgoli, A and Bhoopalan, SV and Soni, S and Boelens, JJ and Abraham, A}, title = {The role of the conditioning regimen for autologous and ex vivo genetically modified hematopoietic stem cell-based therapies: recommendations from the ISCT stem cell engineering committee.}, journal = {Cytotherapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jcyt.2024.09.001}, pmid = {39320295}, issn = {1477-2566}, abstract = {BACKGROUND: The advent of autologous gene modified cell therapies to treat monogenic disorders has been a major step forward for the field of hematopoietic stem cell transplantation (HCT) and cellular therapies. The need for disease-specific conditioning to enable these products to provide a potential cure has required extrapolation from experience in myeloablative and non-myeloablative HCT for these disorders.<br><br>METHODS: In this manuscript, we review the current datasets and clinical experience using different conditioning regimens for autologous gene therapies in hemoglobinopathies, metabolic and lysosomal disorders, inborn errors of immunity (IEI) and bone marrow failure (BMF) syndromes.<br><br>RESULTS: The disease specific and unique conditioning requirements of each disorder are considered in order to achieve maximal benefit while minimizing associated toxicities.<br><br>CONCLUSIONS: Standardized recommendations based on these data are made for each set of disorders to harmonize treatment. Future directions and the possibility of non-genotoxic conditioning regimens for autologous gene therapies are also discussed. Ethical Statement: The authors followed all relevant ethical considerations in writing this manuscript.}, }
@article {pmid39319780, year = {2024}, author = {Perofsky, AC and Huddleston, J and Hansen, CL and Barnes, JR and Rowe, T and Xu, X and Kondor, R and Wentworth, DE and Lewis, N and Whittaker, L and Ermetal, B and Harvey, R and Galiano, M and Daniels, RS and McCauley, JW and Fujisaki, S and Nakamura, K and Kishida, N and Watanabe, S and Hasegawa, H and Sullivan, SG and Barr, IG and Subbarao, K and Krammer, F and Bedford, T and Viboud, C}, title = {Antigenic drift and subtype interference shape A(H3N2) epidemic dynamics in the United States.}, journal = {eLife}, volume = {13}, number = {}, pages = {}, pmid = {39319780}, issn = {2050-084X}, support = {10111800//Ministry of Health, Labour and Welfare/ ; 75N93019C00051/NH/NIH HHS/United States ; FC001030/ARC_/Arthritis Research UK/United Kingdom ; 10110400//Ministry of Health, Labour and Welfare/ ; JP22fk0108118//Japan Agency for Medical Research and Development/ ; HHSN272201400008C/NH/NIH HHS/United States ; F31 AI140714/NH/NIH HHS/United States ; 75N93021C00014/AI/NIAID NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; 75N93019C00051/AI/NIAID NIH HHS/United States ; 75N93021C00014/NH/NIH HHS/United States ; R01 AI165821/AI/NIAID NIH HHS/United States ; R01 AI165821/NH/NIH HHS/United States ; HHSN272201400008C/AI/NIAID NIH HHS/United States ; F31 AI140714/AI/NIAID NIH HHS/United States ; 1354890//National Science Foundation/ ; R35 GM119774/GM/NIGMS NIH HHS/United States ; FC001030/WT_/Wellcome Trust/United Kingdom ; R35 GM119774/NH/NIH HHS/United States ; R01 AI127893/NH/NIH HHS/United States ; FC001030/MRC_/Medical Research Council/United Kingdom ; JP23fk0108662//Japan Agency for Medical Research and Development/ ; FC001030/CRUK_/Cancer Research UK/United Kingdom ; R01 AI127893/AI/NIAID NIH HHS/United States ; }, mesh = {*Influenza A Virus, H3N2 Subtype/genetics/immunology ; United States/epidemiology ; *Influenza, Human/epidemiology/virology/immunology ; Humans ; *Hemagglutinin Glycoproteins, Influenza Virus/genetics/immunology ; *Epidemics ; *Antigenic Drift and Shift/genetics ; Child ; Adult ; Neuraminidase/genetics/immunology ; Adolescent ; Child, Preschool ; Antigens, Viral/immunology/genetics ; Young Adult ; Evolution, Molecular ; Seasons ; Middle Aged ; }, abstract = {Influenza viruses continually evolve new antigenic variants, through mutations in epitopes of their major surface proteins, hemagglutinin (HA) and neuraminidase (NA). Antigenic drift potentiates the reinfection of previously infected individuals, but the contribution of this process to variability in annual epidemics is not well understood. Here, we link influenza A(H3N2) virus evolution to regional epidemic dynamics in the United States during 1997-2019. We integrate phenotypic measures of HA antigenic drift and sequence-based measures of HA and NA fitness to infer antigenic and genetic distances between viruses circulating in successive seasons. We estimate the magnitude, severity, timing, transmission rate, age-specific patterns, and subtype dominance of each regional outbreak and find that genetic distance based on broad sets of epitope sites is the strongest evolutionary predictor of A(H3N2) virus epidemiology. Increased HA and NA epitope distance between seasons correlates with larger, more intense epidemics, higher transmission, greater A(H3N2) subtype dominance, and a greater proportion of cases in adults relative to children, consistent with increased population susceptibility. Based on random forest models, A(H1N1) incidence impacts A(H3N2) epidemics to a greater extent than viral evolution, suggesting that subtype interference is a major driver of influenza A virus infection ynamics, presumably via heterosubtypic cross-immunity.}, }
@article {pmid39319420, year = {2024}, author = {Boyle, GE and Sitko, KA and Galloway, JG and Haddox, HK and Bianchi, AH and Dixon, A and Wheelock, MK and Vandi, AJ and Wang, ZR and Thomson, RES and Garge, RK and Rettie, AE and Rubin, AF and Geck, RC and Gillam, EMJ and DeWitt, WS and Matsen, FA and Fowler, DM}, title = {Deep mutational scanning of CYP2C19 in human cells reveals a substrate specificity-abundance tradeoff.}, journal = {Genetics}, volume = {228}, number = {3}, pages = {}, pmid = {39319420}, issn = {1943-2631}, support = {//NIH/ ; //National Human Genome Research Institute Interdisciplinary Training in Genome Sciences/ ; //National Institute of General Medical Sciences of the National Institutes of Health/ ; //Momental Foundation/ ; //Washington Research Foundation Postdoctoral Fellowship/ ; //Australian Government/ ; /HHMI/Howard Hughes Medical Institute/United States ; }, mesh = {Humans ; *Cytochrome P-450 CYP2C19/genetics/metabolism ; Substrate Specificity ; *Cytochrome P-450 CYP2C9/genetics/metabolism ; HEK293 Cells ; Mutation ; Amino Acid Substitution ; High-Throughput Nucleotide Sequencing ; }, abstract = {The cytochrome P450s enzyme family metabolizes ∼80% of small molecule drugs. Variants in cytochrome P450s can substantially alter drug metabolism, leading to improper dosing and severe adverse drug reactions. Due to low sequence conservation, predicting variant effects across cytochrome P450s is challenging. Even closely related cytochrome P450s like CYP2C9 and CYP2C19, which share 92% amino acid sequence identity, display distinct phenotypic properties. Using variant abundance by massively parallel sequencing, we measured the steady-state protein abundance of 7,660 single amino acid variants in CYP2C19 expressed in cultured human cells. Our findings confirmed critical positions and structural features essential for cytochrome P450 function, and revealed how variants at conserved positions influence abundance. We jointly analyzed 4,670 variants whose abundance was measured in both CYP2C19 and CYP2C9, finding that the homologs have different variant abundances in substrate recognition sites within the hydrophobic core. We also measured the abundance of all single and some multiple wild type amino acid exchanges between CYP2C19 and CYP2C9. While most exchanges had no effect, substitutions in substrate recognition site 4 reduced abundance in CYP2C19. Double and triple mutants showed distinct interactions, highlighting a region that points to differing thermodynamic properties between the 2 homologs. These positions are known contributors to substrate specificity, suggesting an evolutionary tradeoff between stability and enzymatic function. Finally, we analyzed 368 previously unannotated human variants, finding that 43% had decreased abundance. By comparing variant effects between these homologs, we uncovered regions underlying their functional differences, advancing our understanding of this versatile family of enzymes.}, }
@article {pmid39318685, year = {2024}, author = {Tereshchenko, LG and Haq, KT and Howell, SJ and Mitchell, EC and Martínez, J and Hyde, J and Briceno, G and Pena, J and Pocius, E and Khan, A and Soliman, EZ and Lima, JAC and Kapadia, SR and Misra-Hebert, AD and Kattan, MW and Kansal, MM and Daviglus, ML and Kaplan, R}, title = {Latent profiles of global electrical heterogeneity: the Hispanic Community Health Study/Study of Latinos.}, journal = {European heart journal. Digital health}, volume = {5}, number = {5}, pages = {611-621}, pmid = {39318685}, issn = {2634-3916}, support = {R01 HL118277/HL/NHLBI NIH HHS/United States ; R56 HL118277/HL/NHLBI NIH HHS/United States ; }, abstract = {AIMS: Despite the highest prevalence of stroke, obesity, and diabetes across races/ethnicities, paradoxically, Hispanic/Latino populations have the lowest prevalence of atrial fibrillation and major Minnesota code-defined ECG abnormalities. We aimed to use Latent Profile Analysis in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) population to obtain insight into epidemiological discrepancies.<br><br>METHODS AND RESULTS: We conducted a cross-sectional analysis of baseline HCHS/SOL visit. Global electrical heterogeneity (GEH) was measured as spatial QRS-T angle (QRSTa), spatial ventricular gradient azimuth (SVGaz), elevation (SVGel), magnitude (SVGmag), and sum absolute QRST integral (SAIQRST). Statistical analysis accounted for the stratified two-stage area probability sample design. We fitted a multivariate latent profile generalized structural equation model adjusted for age, sex, ethnic background, education, hypertension, diabetes, smoking, dyslipidaemia, obesity, chronic kidney disease, physical activity, diet quality, average RR' interval, median beat type, and cardiovascular disease (CVD) to gain insight into the GEH profiles. Among 15 684 participants (age 41 years; 53% females; 6% known CVD), 17% had an increased probability of likely abnormal GEH profile (QRSTa 80 &#xb1; 27&#xb0;, SVGaz -4 &#xb1; 21&#xb0;, SVGel 72 &#xb1; 12&#xb0;, SVGmag 45 &#xb1; 12 mVms, and SAIQRST 120 &#xb1; 23 mVms). There was a 23% probability for a participant of being in Class 1 with a narrow QRSTa (40.0 &#xb1; 10.2&#xb0;) and large SVG (SVGmag 108.3 &#xb1; 22.6 mVms; SAIQRST 203.4 &#xb1; 39.1 mVms) and a 60% probability of being in intermediate Class 2.<br><br>CONCLUSION: A substantial proportion (17%) in the Hispanic/Latino population had an increased probability of altered, likely abnormal GEH profile, whereas 83% of the population was resilient to harmful risk factors exposures.}, }
@article {pmid39317093, year = {2024}, author = {Jones, SMW and Guthrie, KA and Arnold, K and Krouse, R}, title = {The bowel function instrument for rectal cancer survivors with anastomosis and ostomy.}, journal = {Journal of psychosomatic research}, volume = {187}, number = {}, pages = {111931}, doi = {10.1016/j.jpsychores.2024.111931}, pmid = {39317093}, issn = {1879-1360}, mesh = {Humans ; Female ; *Rectal Neoplasms/surgery ; Male ; Middle Aged ; *Anastomosis, Surgical ; Aged ; *Cancer Survivors ; *Ostomy ; Reproducibility of Results ; Surveys and Questionnaires/standards ; Psychometrics ; Quality of Life ; Adult ; Fecal Incontinence/etiology ; Defecation/physiology ; }, abstract = {OBJECTIVE: Rectal cancer is often treated with surgery such as ostomy or anastomosis. The Bowel Function Instrument (BFI) is a valid and reliable 18-item measure of physical bowel symptoms. Some items on the BFI do not apply to those with ostomies. We reanalyzed data from a previous validation study to inform the best method for scoring the BFI for both people with ostomies and anastomosis.<br><br>METHODS: People (n&#xa0;=&#xa0;575) with rectal cancer treated with ostomy (n&#xa0;=&#xa0;181, 31&#xa0;%) or anastomosis (n&#xa0;=&#xa0;394, 69&#xa0;%) completed the BFI and Short Form 12 (SF12) measure on a mailed survey. The full BFI has three subscales and a total score based on 14 items: soilage/urgency (4 items); frequency of bowel movements (6 items); and dietary changes (4 items). We used confirmatory factor analysis (CFA) to examine two versions (8-item, 11-item) of the BFI adapted for use with both ostomy and anastomosis. We also examined reliability and validity of the version supported by the CFA.<br><br>RESULTS: CFA results supported the 8-item BFI that included only the soilage/urgency items and dietary changes items but not the frequency items. The 8-item BFI was reliable (Cronbach's alpha of 0.788). The 8-item BFI score significantly correlated with all SF12 subscales with Pearson correlations ranging from 0.115 (Vitality) to 0.318 (social function).<br><br>CONCLUSIONS: The 8-item version of the BFI was valid and reliable as a total score for people with ostomy or anastomosis. The 8-item BFI may be useful for monitoring bowel function during and after treatment for rectal cancer.}, }
@article {pmid39316822, year = {2025}, author = {Thomas, CE and Lin, Y and Kim, M and Kawaguchi, ES and Qu, C and Um, CY and Lynch, BM and Van Guelpen, B and Tsilidis, K and Carreras-Torres, R and van Duijnhoven, FJB and Sakoda, LC and Campbell, PT and Tian, Y and Chang-Claude, J and Bézieau, S and Budiarto, A and Palmer, JR and Newcomb, PA and Casey, G and Le Marchandz, L and Giannakis, M and Li, CI and Gsur, A and Newton, C and Obón-Santacana, M and Moreno, V and Vodicka, P and Brenner, H and Hoffmeister, M and Pellatt, AJ and Schoen, RE and Dimou, N and Murphy, N and Gunter, MJ and Castellví-Bel, S and Figueiredo, JC and Chan, AT and Song, M and Li, L and Bishop, DT and Gruber, SB and Baurley, JW and Bien, SA and Conti, DV and Huyghe, JR and Kundaje, A and Su, YR and Wang, J and Keku, TO and Woods, MO and Berndt, SI and Chanock, SJ and Tangen, CM and Wolk, A and Burnett-Hartman, A and Wu, AH and White, E and Devall, MA and Díez-Obrero, V and Drew, DA and Giovannucci, E and Hidaka, A and Kim, AE and Lewinger, JP and Morrison, J and Ose, J and Papadimitriou, N and Pardamean, B and Peoples, AR and Ruiz-Narvaez, EA and Shcherbina, A and Stern, MC and Chen, X and Thomas, DC and Platz, EA and Gauderman, WJ and Peters, U and Hsu, L}, title = {Characterization of Additive Gene-environment Interactions For Colorectal Cancer Risk.}, journal = {Epidemiology (Cambridge, Mass.)}, volume = {36}, number = {1}, pages = {126-138}, doi = {10.1097/EDE.0000000000001795}, pmid = {39316822}, issn = {1531-5487}, support = {001/WHO_/World Health Organization/International ; }, mesh = {Humans ; *Colorectal Neoplasms/genetics/epidemiology ; Male ; Female ; *Gene-Environment Interaction ; Case-Control Studies ; Middle Aged ; *Genetic Predisposition to Disease ; Aged ; Risk Factors ; Logistic Models ; Alcohol Drinking ; Smoking/adverse effects ; Body Mass Index ; Polymorphism, Single Nucleotide ; Diet ; Adult ; }, abstract = {BACKGROUND: Colorectal cancer (CRC) is a common, fatal cancer. Identifying subgroups who may benefit more from intervention is of critical public health importance. Previous studies have assessed multiplicative interaction between genetic risk scores and environmental factors, but few have assessed additive interaction, the relevant public health measure.<br><br>METHODS: Using resources from CRC consortia, including 45,247 CRC cases and 52,671 controls, we assessed multiplicative and additive interaction (relative excess risk due to interaction, RERI) using logistic regression between 13 harmonized environmental factors and genetic risk score, including 141 variants associated with CRC risk.<br><br>RESULTS: There was no evidence of multiplicative interaction between environmental factors and genetic risk score. There was additive interaction where, for individuals with high genetic susceptibility, either heavy drinking (RERI = 0.24, 95% confidence interval [CI] = 0.13, 0.36), ever smoking (0.11 [0.05, 0.16]), high body mass index (female 0.09 [0.05, 0.13], male 0.10 [0.05, 0.14]), or high red meat intake (highest versus lowest quartile 0.18 [0.09, 0.27]) was associated with excess CRC risk greater than that for individuals with average genetic susceptibility. Conversely, we estimate those with high genetic susceptibility may benefit more from reducing CRC risk with aspirin/nonsteroidal anti-inflammatory drugs use (-0.16 [-0.20, -0.11]) or higher intake of fruit, fiber, or calcium (highest quartile versus lowest quartile -0.12 [-0.18, -0.050]; -0.16 [-0.23, -0.09]; -0.11 [-0.18, -0.05], respectively) than those with average genetic susceptibility.<br><br>CONCLUSIONS: Additive interaction is important to assess for identifying subgroups who may benefit from intervention. The subgroups identified in this study may help inform precision CRC prevention.}, }
@article {pmid39316666, year = {2024}, author = {Brown, JR and Eichhorst, B and Lamanna, N and O'Brien, SM and Tam, CS and Qiu, L and Jurczak, W and Zhou, K and Šimkovič, M and Mayer, J and Gillespie-Twardy, A and Ferrajoli, A and Ganly, PS and Weinkove, R and Grosicki, S and Mital, A and Robak, T and Osterborg, A and Yimer, HA and Wang, MY and Salmi, T and Wang, L and Li, J and Wu, K and Cohen, AC and Shadman, M}, title = {Sustained Benefit of Zanubrutinib vs Ibrutinib in Patients With R/R CLL/SLL: Final Comparative Analysis of ALPINE.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024024667}, pmid = {39316666}, issn = {1528-0020}, abstract = {ALPINE (NCT03734016) established the superiority of zanubrutinib over ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma (R/R CLL/SLL); here we present data from the final comparative analysis with extended follow-up. Overall, 652 patients received zanubrutinib (n=327) or ibrutinib (n=325). At an overall median follow-up of 42.5 months, progression-free survival benefit with zanubrutinib vs ibrutinib was sustained (HR: 0.68 [95% CI, 0.54-0.84]), including in patients with del(17p)/TP53 mutation (HR: 0.51 [95% CI, 0.33-0.78]) and across multiple sensitivity analyses. Overall response rate remained higher with zanubrutinib compared with ibrutinib (85.6% vs 75.4%); responses deepened over time with complete response/complete response with incomplete bone marrow recovery rates of 11.6% (zanubrutinib) and 7.7% (ibrutinib). While median overall survival has not been reached in either treatment group, fewer zanubrutinib patients have died than ibrutinib patients (HR: 0.77 [95% CI, 0.55-1.06]). With median exposure time of 41.2 and 37.8 months in zanubrutinib and ibrutinib arms, respectively, the most common non-hematologic adverse events included COVID-19-related infection (46.0% vs 33.3%), diarrhea (18.8% vs 25.6%), upper respiratory tract infection (29.3% vs 19.8%), and hypertension (27.2% vs 25.3%). Cardiac events were lower with zanubrutinib (25.9% vs 35.5%) despite similar rates of hypertension. Incidence of atrial fibrillation/flutter was lower with zanubrutinib vs ibrutinib (7.1% vs 17.0%); no cardiac deaths were reported with zanubrutinib vs six cardiac deaths with ibrutinib. This analysis, at 42.5 months median follow-up, demonstrates that zanubrutinib remains more efficacious than ibrutinib with an improved overall safety/tolerability profile.}, }
@article {pmid39315857, year = {2024}, author = {Ortiz Romero, PL and Kim, YH and Molloy, K and Quaglino, P and Scarisbrick, J and Thornton, S and Sandilands, K and Dent, JE and Nixon, A and Williams, A and Shinohara, MM}, title = {Health-related quality of life in cutaneous T-cell lymphoma: A post hoc analysis of a phase 3 trial in mycosis fungoides and Sézary syndrome.}, journal = {Journal of the European Academy of Dermatology and Venereology : JEADV}, volume = {}, number = {}, pages = {}, doi = {10.1111/jdv.20357}, pmid = {39315857}, issn = {1468-3083}, support = {TD1 1QH//Kyowa Kirin Services Ltd, Galabank Business Park, Galashiels, Scotland/ ; }, abstract = {BACKGROUND: Mycosis fungoides (MF) and Sézary syndrome (SS) are common subtypes of cutaneous T-cell lymphoma that primarily affect the skin but may spread to the lymph nodes, viscera and blood. The symptom burden may compromise health-related quality of life (HRQL). The phase 3 MAVORIC study (ClinicalTrials.gov identifier NCT01728805) in patients with relapsed/refractory MF/SS reported improved HRQL with mogamulizumab compared with vorinostat.<br><br>OBJECTIVES: Use baseline (pre-treatment) data from the MAVORIC study to describe the symptom burden of MF/SS and identify characteristics associated with worse HRQL.<br><br>METHODS: Data were from 372 adults with stage IB-IVB histologically confirmed relapsed/ refractory MF or SS. Associations between demographic and medical history variables and worse HRQL (Skindex-29, ItchyQol and Functional Assessment of Cancer Therapy - General [FACT-G]) were determined by regression models.<br><br>RESULTS: In the cohort of 372 adults, 70% were white; 42% were female; mean age was 63 (SD 13.0) years. Fifty-five per cent had MF and 45% had SS; 77% had advanced (stage IIB-IV) disease, involving the skin in all patients and the blood and/or nodes in 66%. HRQL scores showed impairment versus normative means (where available), with the greatest impact on Symptoms and Emotions in the Skindex-29, Functioning in the ItchyQol, and Functional Wellbeing in the FACT-G. In regression analysis, worse HRQL across all domains and total score was associated with being female and younger, worse mSWAT score and worse itch for the Skindex-29 (n&#x2009;=&#x2009;352), and being female, younger, Black/African American, worse performance status and worse itch for the ItchyQol (n&#x2009;=&#x2009;369). Associations across domains and total score were not found for the FACT-G. Associations between domains and demographic/medical history were seen for all instruments.<br><br>CONCLUSIONS: The symptoms of advanced MF/SS compromise all HRQL domains. Treatment goals and therapeutic choice should be informed by individual patients' disease burden.}, }
@article {pmid39315814, year = {2024}, author = {Loes, AN and Tarabi, RAL and Huddleston, J and Touyon, L and Wong, SS and Cheng, SMS and Leung, NHL and Hannon, WW and Bedford, T and Cobey, S and Cowling, BJ and Bloom, JD}, title = {High-throughput sequencing-based neutralization assay reveals how repeated vaccinations impact titers to recent human H1N1 influenza strains.}, journal = {Journal of virology}, volume = {98}, number = {10}, pages = {e0068924}, pmid = {39315814}, issn = {1098-5514}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; T11-712/19-N//Research Grants Council, University Grants Committee ()/ ; U01AI153700//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; U01 AI153700/AI/NIAID NIH HHS/United States ; 75N93021C00015/AI/NIAID NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; R01AI165821//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; Investigator Support//Howard Hughes Medical Institute (HHMI)/ ; R01 AI165821/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *High-Throughput Nucleotide Sequencing/methods ; *Antibodies, Neutralizing/immunology/blood ; *Influenza A Virus, H1N1 Subtype/immunology/genetics ; *Influenza Vaccines/immunology/administration &amp; dosage ; *Antibodies, Viral/blood/immunology ; *Influenza, Human/prevention &amp; control/immunology/virology ; *Neutralization Tests/methods ; *Vaccination ; *Hemagglutinin Glycoproteins, Influenza Virus/immunology/genetics ; Adult ; Female ; }, abstract = {UNLABELLED: The high genetic diversity of influenza viruses means that traditional serological assays have too low throughput to measure serum antibody neutralization titers against all relevant strains. To overcome this challenge, we developed a sequencing-based neutralization assay that simultaneously measures titers against many viral strains using small serum volumes using a workflow similar to traditional neutralization assays. The key innovation is to incorporate unique nucleotide barcodes into the hemagglutinin (HA) genomic segment, and then pool viruses with numerous different barcoded HA variants and quantify the infectivity of all of them simultaneously using next-generation sequencing. With this approach, a single researcher performed the equivalent of 2,880 traditional neutralization assays (80 serum samples against 36 viral strains) in approximately 1 month. We applied the sequencing-based assay to quantify the impact of influenza vaccination on neutralization titers against recent human H1N1 strains for individuals who had or had not also received a vaccine in the previous year. We found that the viral strain specificities of the neutralizing antibodies elicited by vaccination vary among individuals and that vaccination induced a smaller increase in titers for individuals who had also received a vaccine the previous year-although the titers 6 months after vaccination were similar in individuals with and without the previous-year vaccination. We also identified a subset of individuals with low titers to a subclade of recent H1N1 even after vaccination. We provide an experimental protocol (dx.doi.org/10.17504/protocols.io.kqdg3xdmpg25/v1) and computational pipeline (https://github.com/jbloomlab/seqneut-pipeline) for the sequencing-based neutralization assays to facilitate the use of this method by others.<br><br>IMPORTANCE: We describe a new approach that can rapidly measure how the antibodies in human serum inhibit infection by many different influenza strains. This new approach is useful for understanding how viral evolution affects antibody immunity. We apply the approach to study the effect of repeated influenza vaccination.}, }
@article {pmid39315598, year = {2024}, author = {Kwendakwema, CN and Hopkins, T and Bell-Brown, A and Simianu, VV and Shankaran, V and Issaka, RB}, title = {Clinician perceptions on barriers and facilitators to 1-year surveillance colonoscopy completion in survivors of colorectal cancer.}, journal = {Cancer medicine}, volume = {13}, number = {18}, pages = {e70244}, pmid = {39315598}, issn = {2045-7634}, support = {K08 CA241296/CA/NCI NIH HHS/United States ; K08CA241296/RC/CCR NIH HHS/United States ; T32CA009515/CA/NCI NIH HHS/United States ; P30 CA015704/RC/CCR NIH HHS/United States ; }, mesh = {Humans ; *Colorectal Neoplasms/psychology/surgery ; *Colonoscopy/psychology ; *Cancer Survivors/psychology ; Male ; Female ; Middle Aged ; Attitude of Health Personnel ; Early Detection of Cancer/psychology ; Health Services Accessibility ; }, abstract = {INTRODUCTION: Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States. Surveillance colonoscopy is recommended 1-year after surgical resection for patients with stage I-III CRC; however, only 18%-61% of CRC survivors complete this test. This study describes clinician-identified barriers and facilitators to surveillance colonoscopy among CRC survivors.<br><br>METHODS: We conducted semi-structured interviews with clinicians until thematic saturation was achieved. Interviews were analyzed using the social cognitive theory.<br><br>RESULTS: Thirteen clinicians were interviewed, and all identified health system-level barriers to surveillance colonoscopy completion; the most common being fragmented care due to patients receiving care across many health systems. Clinicians also identified social determinants of health barriers (e.g., geographical distance between patients and health systems) to 1-year surveillance colonoscopy completion.<br><br>CONCLUSIONS: Clinicians identified several potentially modifiable barriers to 1-year surveillance colonoscopy completion which, if addressed, could improve post-treatment care and outcomes among stage I-III CRC survivors.}, }
@article {pmid39315597, year = {2024}, author = {Rosenthal, EA and Hsu, L and Thomas, M and Peters, U and Kachulis, C and Patterson, K and Jarvik, GP}, title = {Comparing Ancestry Standardization Approaches for a Transancestry Colorectal Cancer Polygenic Risk Score.}, journal = {Genetic epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1002/gepi.22590}, pmid = {39315597}, issn = {1098-2272}, support = {//This work was funded by the Office of the Director at the National Institute of Health, under award notice 1OT2OD002748-01 and by the NHGRI through the grant U01HG008657./ ; }, abstract = {Colorectal cancer (CRC) is a complex disease with monogenic, polygenic and environmental risk factors. Polygenic risk scores (PRSs) aim to identify high polygenic risk individuals. Due to differences in genetic background, PRS distributions vary by ancestry, necessitating standardization. We compared four post-hoc methods using the All of Us Research Program Whole Genome Sequence data for a transancestry CRC PRS. We contrasted results from linear models trained on A. the entire data or an ancestrally diverse subset AND B. covariates including principal components of ancestry or admixture. Standardization with the training subset also adjusted the variance. All methods performed similarly within ancestry, OR (95% C.I.) per s.d. change in PRS: African 1.5 (1.02, 2.08), Admixed American 2.2 (1.27, 3.85), European 1.6 (1.43, 1.89), and Middle Eastern 1.1 (0.71, 1.63). Using admixture and an ancestrally diverse training set provided distributions closest to standard Normal. Training a model on ancestrally diverse participants, adjusting both the mean and variance using admixture as covariates, created standard Normal z-scores, which can be used to identify patients at high polygenic risk. These scores can be incorporated into comprehensive risk calculation including other known risk factors, allowing for more precise risk estimates.}, }
@article {pmid39314963, year = {2024}, author = {Huddleston, J and Bedford, T}, title = {Timely vaccine strain selection and genomic surveillance improves evolutionary forecast accuracy of seasonal influenza A/H3N2.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39314963}, support = {R01 AI165821/AI/NIAID NIH HHS/United States ; }, abstract = {For the last decade, evolutionary forecasting models have influenced seasonal influenza vaccine design. These models attempt to predict which genetic variants circulating at the time of vaccine strain selection will be dominant 12 months later in the influenza season targeted by vaccination campaign. Forecasting models depend on hemagglutinin (HA) sequences from the WHO's Global Influenza Surveillance and Response System to identify currently circulating groups of related strains (clades) and estimate clade fitness for forecasts. However, the average lag between collection of a clinical sample and the submission of its sequence to the Global Initiative on Sharing All Influenza Data (GISAID) EpiFlu database is ~3 months. Submission lags complicate the already difficult 12-month forecasting problem by reducing understanding of current clade frequencies at the time of forecasting. These constraints of a 12-month forecast horizon and 3-month average submission lags create an upper bound on the accuracy of any long-term forecasting model. The global response to the SARS-CoV-2 pandemic revealed that modern vaccine technology like mRNA vaccines can reduce how far we need to forecast into the future to 6 months or less and that expanded support for sequencing can reduce submission lags to GISAID to 1 month on average. To determine whether these recent advances could also improve long-term forecasts for seasonal influenza, we quantified the effects of reducing forecast horizons and submission lags on the accuracy of forecasts for A/H3N2 populations. We found that reducing forecast horizons from 12 months to 6 or 3 months reduced average absolute forecasting errors to 25% and 50% of the 12-month average, respectively. Reducing submission lags provided little improvement to forecasting accuracy but decreased the uncertainty in current clade frequencies by 50%. These results show the potential to substantially improve the accuracy of existing influenza forecasting models by modernizing influenza vaccine development and increasing global sequencing capacity.}, }
@article {pmid39314956, year = {2024}, author = {Burns, AC and Zellers, S and Windred, DP and Daghlas, I and Sinnott-Armstrong, N and Rutter, M and Hublin, C and Friligkou, E and Polimanti, R and Phillips, AJK and Cain, SW and Kaprio, J and Ollila, HM and Saxena, R and Lane, JM}, title = {Sleep inertia drives the association of evening chronotype with psychiatric disorders: epidemiological and genetic evidence.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39314956}, support = {R01 HG012810/HG/NHGRI NIH HHS/United States ; }, abstract = {Evening chronotypes (a.k.a. "night-owls") are held to be at greater risk for psychiatric disorders. This is postulated to be due to delayed circadian timing increasing the likelihood of circadian misalignment in an early-oriented society. Circadian misalignment is known to heighten sleep inertia, the difficulty transitioning from sleep to wake characterized by low arousal and cognitive impairment, and evening chronotypes experience greater sleep inertia. Therefore, difficulty awakening may explain the relationship between evening chronotype and psychiatric disorders by acting as a biomarker of circadian misalignment. In analyzing the longitudinal incidence of psychiatric disorders in the UK Biobank (n = 496,820), we found that evening chronotype predicted increased incidence of major depressive disorder, schizophrenia, generalized anxiety disorder and bipolar disorder. Crucially, this effect was dependent on sleep inertia, which was a much stronger predictor of these disorders, such that evening types without sleep inertia were at no higher risk as compared to morning types. Longitudinal analyses of suicide and depressed mood (CES-D score) in the Older Finnish Twin Cohort (n = 23,854) replicated this pattern of results. Twin and genome-wide association analyses of difficulty awakening identified the trait to be heritable (Twin H [2] = 0.40; SNP h [2] = 0.08), enriched for circadian rhythms genes and have substantial shared genetic architecture with chronotype. Marginal and conditional Mendelian randomization analyses mirrored the epidemiological results, such that the causal effect of evening chronotype on psychiatric disorders was driven by shared genetic architecture with difficulty awakening. In contrast, difficult awakening was strongly causally associated with psychiatric disorders independently of chronotype. Psychiatric disorders were only weakly reverse causally linked to difficult awakening. Collectively, these results challenge the notion that evening chronotype is a risk factor for psychiatric disorders per se, suggesting instead that evening types are at greater risk for psychiatric disorders due to circadian misalignment, for which sleep inertia may be acting as a biomarker.}, }
@article {pmid39311908, year = {2024}, author = {Wang, L and Chao, M and Han, RR and Li, L and Dong, L and Chen, F and Jin, MZ and Gao, L and Wang, Y and Feng, DY and Zhu, G and Guo, W and Zhao, WJ and Jin, SJ and Wei, DP and Sun, W and Dai, JX and Jin, WL}, title = {Single-cell map of diverse immune phenotypes in the metastatic brain tumor microenvironment of non-small-cell lung cancer.}, journal = {International journal of surgery (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.1097/JS9.0000000000002088}, pmid = {39311908}, issn = {1743-9159}, }
@article {pmid39311597, year = {2024}, author = {Marzinke, MA and Han, K and Hanscom, B and Guo, X and Piwowar-Manning, E and Hendrix, CW and Rose, S and Spooner, E and Mathew, C and Innes, S and Sekabira, R and Mutambanengwe, M and Rooney, JF and Rinehart, AR and Adeyeye, A and Cohen, MS and Hosseinipour, M and Ford, SL and Delany-Moretlwe, S}, title = {Pharmacologic evaluation of delayed long-acting cabotegravir administration among cisgender women in HPTN 084.}, journal = {Antimicrobial agents and chemotherapy}, volume = {68}, number = {11}, pages = {e0099424}, pmid = {39311597}, issn = {1098-6596}, support = {UM1 AI069423/AI/NIAID NIH HHS/United States ; UM1AI068617//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; UM1AI068613//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; UM1 AI068619/AI/NIAID NIH HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; OPP1154174//Bill and Melinda Gates Foundation (GF)/ ; UM1AI068619//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; UM1 AI068613/AI/NIAID NIH HHS/United States ; NA//ViiV Healthcare (ViiV Healthcare Limited)/ ; }, mesh = {Humans ; Female ; *Anti-HIV Agents/pharmacokinetics/administration &amp; dosage ; Adult ; *HIV Infections/drug therapy ; *Pyridones/pharmacokinetics/administration &amp; dosage ; Delayed-Action Preparations ; Tenofovir/pharmacokinetics ; Drug Administration Schedule ; Middle Aged ; Diketopiperazines ; }, abstract = {UNLABELLED: HPTN 084 demonstrated the superiority of long-acting injectable cabotegravir (CAB-LA) compared with daily oral tenofovir disoproxil fumarate-emtricitabine (F/TDF) for HIV prevention in women. CAB-LA (600 mg) or placebo injections were administered 4 weeks after an initial dose (loading dose) and every 2 months (Q2M) thereafter; this is the approved regimen. Participants experienced both loading dose and Q2M delays during the trial. CAB concentrations were evaluated before a delay, at the visit associated with the delay, and the visit after a delayed injection was administered. During the blinded phase of the trial, 194 participants randomized to CAB-LA experienced at least one injection delay. Plasma CAB concentrations were maintained above the 4× protein adjusted 90% inhibitory concentration (4× PA-IC90; protocol-specific threshold) for all loading dose and 98% of Q2M delays when injections were administered up to 6 weeks late. The feasibility of shifting to an every 3-month (Q3M) regimen in females was interrogated via simulation studies using a population pharmacokinetic model. Q3M injections in both CAB-naïve (with a loading dose) and previously CAB-exposed females were predicted to yield higher steady-state exposures than in males on the approved Q2M regimen. Although there is observed forgiveness following an isolated delayed CAB-LA injection and simulations suggest acceptable CAB-LA exposures in women with a 600 mg CAB-LA Q3M regimen, empirical efficacy of this regimen has not been established, and transitioning to this dosing schema is not recommended. Future pharmacokinetic bridging studies are aimed at evaluating higher dose CAB-LA formulations administered less frequently.<br><br>CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT03164564.}, }
@article {pmid39308420, year = {2025}, author = {Damerell, V and Klaassen-Dekker, N and Brezina, S and Ose, J and Ulvik, A and van Roekel, EH and Holowatyj, AN and Baierl, A and Böhm, J and Bours, MJL and Brenner, H and de Wilt, JHW and Grady, WM and Habermann, N and Hoffmeister, M and Keski-Rahkonen, P and Lin, T and Schirmacher, P and Schrotz-King, P and Ulrich, AB and van Duijnhoven, FJB and Warby, CA and Shibata, D and Toriola, AT and Figueiredo, JC and Siegel, EM and Li, CI and Gsur, A and Kampman, E and Schneider, M and Ueland, PM and Weijenberg, MP and Ulrich, CM and Kok, DE and Gigic, B and , }, title = {Circulating tryptophan-kynurenine pathway metabolites are associated with all-cause mortality among patients with stage I-III colorectal cancer.}, journal = {International journal of cancer}, volume = {156}, number = {3}, pages = {552-565}, pmid = {39308420}, issn = {1097-0215}, support = {2014/1179//Wereld Kanker Onderzoek Fonds/ ; U01 CA20//NIH/NCI/ ; MetaboCCC I 1578-B19//Transcan/ ; //VLAG Graduate School/ ; T32 HG008962/HG/NHGRI NIH HHS/United States ; //Rahel-Goitein-Straus-Program, Medical Faculty, Heidelberg University/ ; UM 2012-5653//Dutch Cancer Society/ ; //Listwin Family Foundation/ ; //Matthias-Lackas Foundations/ ; 2016/1620//Wereld Kanker Onderzoek Fonds/ ; R01 CA189184/CA/NCI NIH HHS/United States ; UW 2013-5927//Dutch Cancer Society/ ; //Fred Hutchinson Cancer Center/ ; U01 CA152756/CA/NCI NIH HHS/United States ; //Seattle Translational Tumor Research program/ ; //Research Council Norway/Norwegian Cancer Society/ ; 01KD2101D//Bundesministerium f&#xfc;r Bildung und Forschung/ ; //Netherlands Organization for Health Research and Development/ ; //Cottrell Family Fund/ ; //Stichting Alpe d'HuZes/ ; 00005739//Health Foundation Limburg/ ; //Heidelberger Stiftung Chirurgie/ ; UW2014-6877//Dutch Cancer Society/ ; 01KT1503//Bundesministerium f&#xfc;r Bildung und Forschung/ ; //Stiftung LebensBlicke/ ; R01 CA220//National Insitutes of Health/ ; U01 CA206110/CA/NCI NIH HHS/United States ; //R.A.C.E. Charities/ ; P30 CA15704//National Insitutes of Health/ ; R01 CA207371/CA/NCI NIH HHS/United States ; API02104FW//Austrian Science Fund/ ; //Rodger C. Haggitt Endowed Chair/ ; FOCUS I2104-B26//Transcan/ ; R01 CA194663/CA/NCI NIH HHS/United States ; UW 2015-7//Dutch Cancer Society/ ; 001/WHO_/World Health Organization/International ; //Huntsman Cancer Foundation/ ; }, mesh = {Humans ; *Kynurenine/blood/analogs &amp; derivatives ; *Tryptophan/blood/metabolism ; Male ; Female ; *Colorectal Neoplasms/mortality/blood/pathology ; Middle Aged ; Aged ; Prospective Studies ; Neoplasm Staging ; Prognosis ; 3-Hydroxyanthranilic Acid/metabolism ; Biomarkers, Tumor/blood ; Xanthurenates/blood ; Quinolinic Acid/blood ; Kynurenic Acid/blood ; Metabolic Networks and Pathways ; ortho-Aminobenzoates ; }, abstract = {Alterations within the tryptophan-kynurenine metabolic pathway have been linked to the etiology of colorectal cancer (CRC), but the relevance of this pathway for prognostic outcomes in CRC patients needs further elucidation. Therefore, we investigated associations between circulating concentrations of tryptophan-kynurenine pathway metabolites and all-cause mortality among CRC patients. This study utilizes data from 2102 stage I-III CRC patients participating in six prospective cohorts involved in the international FOCUS Consortium. Preoperative circulating concentrations of tryptophan, kynurenine, kynurenic acid (KA), 3-hydroxykynurenine (HK), xanthurenic acid (XA), 3-hydroxyanthranilic acid (HAA), anthranilic acid (AA), picolinic acid (PA), and quinolinic acid (QA) were measured by liquid chromatography-tandem mass spectrometry. Using Cox proportional hazards regression, we examined associations of above-mentioned metabolites with all-cause mortality, adjusted for potential confounders. During a median follow-up of 3.2 years (interquartile range: 2.2-4.9), 290 patients (13.8%) deceased. Higher blood concentrations of tryptophan, XA, and PA were associated with a lower risk of all-cause mortality (per doubling in concentrations: tryptophan: HR = 0.56; 95%CI:0.41,0.76, XA: HR = 0.74; 95%CI:0.64,0.85, PA: HR = 0.76; 95%CI:0.64,0.92), while higher concentrations of HK and QA were associated with an increased risk of death (per doubling in concentrations: HK: HR = 1.80; 95%CI:1.47,2.21, QA: HR = 1.31; 95%CI:1.05,1.63). A higher kynurenine-to-tryptophan ratio, a marker of cell-mediated immune activation, was associated with an increased risk of death (per doubling: HR = 2.07; 95%CI:1.52,2.83). In conclusion, tryptophan-kynurenine pathway metabolites may be prognostic markers of survival in CRC patients.}, }
@article {pmid39307421, year = {2024}, author = {Iftikhar, R and DeFilipp, Z and DeZern, AE and Pulsipher, MA and Bejanyan, N and Burroughs, LM and Kharfan-Dabaja, MA and Arai, S and Kassim, A and Nakamura, R and Saldaña, BJD and Aljurf, M and Hamadani, M and Carpenter, PA and Antin, JH}, title = {Allogeneic Hematopoietic Cell Transplantation for the Treatment of Severe Aplastic Anemia: Evidence-Based Guidelines From the American Society for Transplantation and Cellular Therapy.}, journal = {Transplantation and cellular therapy}, volume = {30}, number = {12}, pages = {1155-1170}, doi = {10.1016/j.jtct.2024.09.017}, pmid = {39307421}, issn = {2666-6367}, mesh = {*Anemia, Aplastic/therapy ; *Hematopoietic Stem Cell Transplantation ; Humans ; *Transplantation, Homologous ; *Transplantation Conditioning/methods ; Evidence-Based Medicine ; Child ; Adult ; Immunosuppressive Agents/therapeutic use ; Antilymphocyte Serum/therapeutic use ; Animals ; United States ; Graft vs Host Disease/prevention &amp; control ; }, abstract = {Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment for severe aplastic anemia (SAA). Existing guidance about HCT in SAA is primarily derived from expert reviews, registry data and societal guidelines; however, transplant-specific guidelines for SAA are lacking. A panel of SAA experts, both pediatric and adult transplant physicians, developed consensus recommendations using Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology employing a GRADE guideline development tool. The panel agrees with previous recommendations for the preferential use of bone marrow as a graft source and the use of rabbit over horse antithymocyte globulin (ATG) for HCT conditioning. Fludarabine containing regimens are preferred for patients at high risk of graft failure and those receiving matched unrelated or haploidentical donor transplant. Given advancements in HCT, the panel does not endorse the historical 40-year age cut-off for considering upfront HCT in adults, acknowledging that fit older patients may also benefit from HCT. The panel also endorses increased utilization of HCT by prioritizing matched unrelated or haploidentical donor HCT over immunosuppressive therapy in children and adults who lack a matched related donor. Finally, the panel suggests either calcineurin inhibitor plus methotrexate or post-transplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis for matched related or matched unrelated donor recipients. These recommendations reflect a significant advancement in transplant strategies for SAA and highlight the importance of ongoing and further research to revisit current evidence in terms of donor choice, conditioning chemotherapy, GVHD prophylaxis and post-transplant immunosuppression.}, }
@article {pmid39306478, year = {2024}, author = {Francini, E and Agarwal, N and Castro, E and Cheng, HH and Chi, KN and Clarke, N and Mateo, J and Rathkopf, D and Saad, F and Tombal, B}, title = {Intensification Approaches and Treatment Sequencing in Metastatic Castration-resistant Prostate Cancer: A Systematic Review.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2024.09.008}, pmid = {39306478}, issn = {1873-7560}, abstract = {BACKGROUND AND OBJECTIVE: Recently, research on treatment intensification has gathered momentum, and three novel therapy combinations were approved for metastatic castration-resistant prostate cancer (mCRPC). This systematic review summarizes the current and emerging evidence around intensified strategies for mCRPC and provides guidance for an ideal therapeutic sequencing.<br><br>METHODS: Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) guidelines were followed to perform this review. PubMed, EMBASE, Web of Science, Cochrane Library, ClinicalTrials.gov, and major international societies' online proceedings were searched comprehensively until May 15, 2024, for terms related to treatment intensification and sequencing for mCRPC.<br><br>KEY FINDINGS AND LIMITATIONS: Overall, 28 clinical trials and 24 ongoing studies of intensification treatments were included in this review. Algorithms of optimal sequencing of approved treatments for mCRPC were outlined according to the use of androgen receptor pathway inhibitors (ARPIs) with or without docetaxel for earlier disease states. In first line, poly(ADP-ribose) polymerase inhibitor + ARPI combinations improve radiographical progression-free survival (rPFS), particularly for those with BRCA1/2 alterations. The AKT inhibitor combination of ipatasertib + abiraterone extends rPFS in those with PTEN loss or PIK3CA/AKT1/PTEN alterations. In those with two or more risk factors for early progression on enzalutamide, radionuclide 177-Lu-PSMA-617 + enzalutamide prolongs progression-free survival. Ongoing research of intensified approaches for mCRPC, and available and potential predictive and prognostic biomarkers are discussed.<br><br>Recent approvals and ongoing investigations of single agents and intensification approaches will keep transforming the mCRPC treatment landscape. Improvement of patient profiling applying recognized genomic, molecular, and clinical predictive and prognostic indicators is fundamental to optimize sequential use of available therapies.}, }
@article {pmid39306373, year = {2024}, author = {Issaka, RB and Bell-Brown, A and Jewell, T and Jackson, SL and Weiner, BJ}, title = {Interventions to Increase Follow-Up of Abnormal Stool-Based Colorectal Cancer Screening Tests in Safety Net Settings: A Systematic Review.}, journal = {Gastroenterology}, volume = {167}, number = {5}, pages = {826-833.e3}, doi = {10.1053/j.gastro.2024.08.002}, pmid = {39306373}, issn = {1528-0012}, support = {K08 CA241296/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Colorectal Neoplasms/diagnosis ; *Early Detection of Cancer/methods ; *Occult Blood ; *Safety-net Providers ; Feces/chemistry ; Colonoscopy ; Mass Screening/methods ; }, }
@article {pmid39298209, year = {2024}, author = {Langer, SL and Romano, JM and Todd, M and Keefe, FJ and Syrjala, KL and Bricker, JB and Burns, J and Bolger, N and Porter, LS}, title = {Couple communication in cancer: A tale of two conceptual models.}, journal = {Health psychology : official journal of the Division of Health Psychology, American Psychological Association}, volume = {}, number = {}, pages = {}, doi = {10.1037/hea0001396}, pmid = {39298209}, issn = {1930-7810}, support = {/CA/NCI NIH HHS/United States ; }, abstract = {UNLABELLED: Cancer poses significant challenges for patients and caregiving partners. Avoidant communication has been linked to poorer psychosocial adjustment to cancer. Two conceptual models have been proposed to account for this linkage: the social-cognitive processing and relationship intimacy models.<br><br>OBJECTIVE: To examine the utility of these models in explaining patient and partner psychological and relationship adjustment on a day-to-day basis using ecological momentary assessment.<br><br>METHOD: Patients with breast, colorectal, or lung cancer and their partners (286 dyads) were prompted twice daily for 14 days via smartphone to answer questions about communication with their partner, adjustment (psychological distress and relationship satisfaction), and hypothesized mediators (avoidant thoughts and intimacy). Data were collected from 2017 to 2020.<br><br>RESULTS: Participants responded to 92% of prompts and completed 91%. Results supported the relationship intimacy but not the social-cognitive processing model. On afternoons when participants (both patients and caregivers) held back or perceived avoidance or criticism from their partner, they reported less intimacy, as did their partners; this lowered intimacy, in turn, led to participants' (both patients' and caregivers') own lowered relationship satisfaction that evening and to patients' lowered relationship satisfaction through caregivers' lowered intimacy (one-tailed Bayesian ps < .025). When distress was the criterion, patients' holding back or perceived avoidance/criticism led to their own increased distress through their own decreased intimacy, and caregivers' holding back or perceived avoidance/criticism led to patients' increased distress through patients' lowered intimacy (one-tailed Bayesian ps < .005).<br><br>CONCLUSIONS: Findings offer implications for interventions designed to improve communication and enhance closeness. (PsycInfo Database Record (c) 2024 APA, all rights reserved).}, }
@article {pmid39297845, year = {2024}, author = {McGraw, KE and Schilling, K and Glabonjat, RA and Galvez-Fernandez, M and Domingo-Relloso, A and Martinez-Morata, I and Jones, MR and Nigra, A and Post, WS and Kaufman, J and Tellez-Plaza, M and Valeri, L and Brown, ER and Kronmal, RA and Barr, RG and Shea, S and Navas-Acien, A and Sanchez, TR}, title = {Urinary Metal Levels and Coronary Artery Calcification: Longitudinal Evidence in the Multi-Ethnic Study of Atherosclerosis.}, journal = {Journal of the American College of Cardiology}, volume = {84}, number = {16}, pages = {1545-1557}, doi = {10.1016/j.jacc.2024.07.020}, pmid = {39297845}, issn = {1558-3597}, support = {R01 ES028758/ES/NIEHS NIH HHS/United States ; P42 ES010349/ES/NIEHS NIH HHS/United States ; T32 ES007322/ES/NIEHS NIH HHS/United States ; R01 ES029967/ES/NIEHS NIH HHS/United States ; P30 ES009089/ES/NIEHS NIH HHS/United States ; P42 ES033719/ES/NIEHS NIH HHS/United States ; P42 ES023716/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; Middle Aged ; Aged ; *Coronary Artery Disease/urine/epidemiology/ethnology ; *Atherosclerosis/urine/ethnology/epidemiology ; Cadmium/urine ; Vascular Calcification/urine/epidemiology/diagnostic imaging ; Longitudinal Studies ; Aged, 80 and over ; Tungsten/urine/adverse effects ; Cobalt/urine ; Copper/urine ; Risk Factors ; Zinc/urine ; Disease Progression ; United States/epidemiology ; Metals/urine ; Ethnicity ; }, abstract = {BACKGROUND: Exposure to metals, a newly recognized risk factor for cardiovascular disease (CVD), could be related to atherosclerosis progression.<br><br>OBJECTIVES: The authors hypothesized that higher urinary levels of nonessential (cadmium, tungsten, uranium) and essential (cobalt, copper, zinc) metals previously associated with CVD would be associated with baseline and rate of change of coronary artery calcium (CAC) progression, a subclinical marker of CVD in MESA (Multi-Ethnic Study of Atherosclerosis).<br><br>METHODS: We analyzed data from 6,418 MESA participants with spot urinary metal levels at baseline (2000-2002) and 1 to 4 repeated, continuous measures of CAC over a 10-year period. We used linear mixed-effect models to assess the association of baseline urinary metal levels with baseline CAC and cumulative change in CAC over a 10-year period. Urinary metals (&#x3bc;g/g creatinine) and CAC were log transformed. Models were adjusted for baseline sociodemographic factors, estimated glomerular filtration rate, lifestyle factors, and clinical factors.<br><br>RESULTS: At baseline, the median CAC was 6.3 (Q1-Q3: 0.7-58.2). Comparing the highest to lowest quartile of urinary cadmium, CAC levels were 51% (95% CI: 32%, 74%) higher at baseline and 75% (95% CI: 47%, 107%) higher over the 10-year period. For urinary tungsten, uranium, and cobalt, the corresponding CAC levels over the 10-year period were 45% (95% CI: 23%, 71%), 39% (95% CI: 17%, 64%), and 47% (95% CI: 25%, 74%) higher, respectively, with no difference for models with and without adjustment for clinical factors. For copper and zinc, the corresponding estimates dropped from 55% to 33% and from 85% to 57%, respectively, after adjustment for clinical factors. The associations of metals with CAC were comparable in magnitude to those for classical CVD risk factors.<br><br>CONCLUSIONS: Exposure to metals was generally associated with extent of coronary calcification at baseline and follow-up. These findings support that metals are associated with the progression of atherosclerosis, potentially providing a novel strategy for the prevention and treatment of atherosclerosis progression.}, }
@article {pmid39297750, year = {2024}, author = {Kopmar, NE and Qu, X and Liu, Y and Gooley, TA and Ghiuzeli, CM and Mawad, R and Percival, MM and Fang, M and Cassaday, RD}, title = {Prognostic significance of chromosomal genomic array testing in adults with newly-diagnosed acute lymphoblastic leukemia.}, journal = {Leukemia &amp; lymphoma}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/10428194.2024.2404959}, pmid = {39297750}, issn = {1029-2403}, }
@article {pmid39305480, year = {2024}, author = {Chen, JG and Kensler, TW and Zhu, J and Zhu, YR and Wang, JB and Lu, JH and Muñoz, A and Groopman, JD}, title = {Profound primary prevention of liver cancer following a natural experiment in China: A 50-year perspective and public health implications.}, journal = {International journal of cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijc.35198}, pmid = {39305480}, issn = {1097-0215}, support = {MS22019008//Science and Technology Project of Nantong City/ ; P30 CA006973/CA/NCI NIH HHS/United States ; R35 CA197222/CA/NCI NIH HHS/United States ; 2008ZX10002-015//Chinese National Key Projects/ ; 2008ZX10002-017//Chinese National Key Projects/ ; 2012ZX10002009//Chinese National Key Projects/ ; BRA2019030//Project 333 of Jiangsu Province/ ; }, abstract = {Liver cancer causes upwards of 1 million cancer deaths annually and is projected to rise by at least 55% over the next 15 years. Two of the major risk factors contributing to liver cancer have been well documented by multiple epidemiologic studies and the hepatitis B virus (HBV) and aflatoxin show a synergy that increases by more than 8-fold the risk of liver cancer relative to HBV alone. Using the population-based cancer registry established by the Qidong Liver Cancer Institute in 1972 and aflatoxin-specific biomarkers, we document that reduction of aflatoxin exposure has likely contributed to a nearly 70% decline in age-standardized liver cancer incidence over the past 30 years despite an unchanging prevalence of HBV infection in cases. A natural experiment of economic reform in the 1980s drove a rapid switch from consumption of heavily contaminated corn to minimally, if any, contaminated rice and subsequent dietary diversity. Aflatoxin consumption appears to accelerate the time to liver cancer diagnosis; lowering exposure to this carcinogen adds years of life before a cancer diagnosis. Thus, in 1990 the median age of diagnosis was 48 years, while increasing to 67 years by 2021. These findings have important translational public health implications since up to 5 billion people worldwide might be routinely exposed to dietary aflatoxin, especially in societies using corn as the staple food. Interventions against aflatoxin are an achievable outcome leading to a reduction in liver cancer incidence and years of delay of its nearly always fatal diagnosis.}, }
@article {pmid39304265, year = {2024}, author = {, }, title = {Global, regional, and national burden of stroke and its risk factors, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021.}, journal = {The Lancet. Neurology}, volume = {23}, number = {10}, pages = {973-1003}, doi = {10.1016/S1474-4422(24)00369-7}, pmid = {39304265}, issn = {1474-4465}, mesh = {Humans ; *Global Burden of Disease ; Risk Factors ; *Stroke/epidemiology ; *Global Health ; Disability-Adjusted Life Years ; Incidence ; Prevalence ; Quality-Adjusted Life Years ; Male ; Female ; }, abstract = {BACKGROUND: Up-to-date estimates of stroke burden and attributable risks and their trends at global, regional, and national levels are essential for evidence-based health care, prevention, and resource allocation planning. We aimed to provide such estimates for the period 1990-2021.<br><br>METHODS: We estimated incidence, prevalence, death, and disability-adjusted life-year (DALY) counts and age-standardised rates per 100&#x2008;000 people per year for overall stroke, ischaemic stroke, intracerebral haemorrhage, and subarachnoid haemorrhage, for 204 countries and territories from 1990 to 2021. We also calculated burden of stroke attributable to 23 risk factors and six risk clusters (air pollution, tobacco smoking, behavioural, dietary, environmental, and metabolic risks) at the global and regional levels (21 GBD regions and Socio-demographic Index [SDI] quintiles), using the standard GBD methodology. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2&#xb7;5th and 97&#xb7;5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline.<br><br>FINDINGS: In 2021, stroke was the third most common GBD level 3 cause of death (7&#xb7;3 million [95% UI 6&#xb7;6-7&#xb7;8] deaths; 10&#xb7;7% [9&#xb7;8-11&#xb7;3] of all deaths) after ischaemic heart disease and COVID-19, and the fourth most common cause of DALYs (160&#xb7;5 million [147&#xb7;8-171&#xb7;6] DALYs; 5&#xb7;6% [5&#xb7;0-6&#xb7;1] of all DALYs). In 2021, there were 93&#xb7;8 million (89&#xb7;0-99&#xb7;3) prevalent and 11&#xb7;9 million (10&#xb7;7-13&#xb7;2) incident strokes. We found disparities in stroke burden and risk factors by GBD region, country or territory, and SDI, as well as a stagnation in the reduction of incidence from 2015 onwards, and even some increases in the stroke incidence, death, prevalence, and DALY rates in southeast Asia, east Asia, and Oceania, countries with lower SDI, and people younger than 70 years. Globally, ischaemic stroke constituted 65&#xb7;3% (62&#xb7;4-67&#xb7;7), intracerebral haemorrhage constituted 28&#xb7;8% (28&#xb7;3-28&#xb7;8), and subarachnoid haemorrhage constituted 5&#xb7;8% (5&#xb7;7-6&#xb7;0) of incident strokes. There were substantial increases in DALYs attributable to high BMI (88&#xb7;2% [53&#xb7;4-117&#xb7;7]), high ambient temperature (72&#xb7;4% [51&#xb7;1 to 179&#xb7;5]), high fasting plasma glucose (32&#xb7;1% [26&#xb7;7-38&#xb7;1]), diet high in sugar-sweetened beverages (23&#xb7;4% [12&#xb7;7-35&#xb7;7]), low physical activity (11&#xb7;3% [1&#xb7;8-34&#xb7;9]), high systolic blood pressure (6&#xb7;7% [2&#xb7;5-11&#xb7;6]), lead exposure (6&#xb7;5% [4&#xb7;5-11&#xb7;2]), and diet low in omega-6 polyunsaturated fatty acids (5&#xb7;3% [0&#xb7;5-10&#xb7;5]).<br><br>INTERPRETATION: Stroke burden has increased from 1990 to 2021, and the contribution of several risk factors has also increased. Effective, accessible, and affordable measures to improve stroke surveillance, prevention (with the emphasis on blood pressure, lifestyle, and environmental factors), acute care, and rehabilitation need to be urgently implemented across all countries to reduce stroke burden.<br><br>FUNDING: Bill &amp; Melinda Gates Foundation.}, }
@article {pmid39303988, year = {2024}, author = {Taylor, MR and Cole, SW and Bradford, MC and Zhou, C and Fladeboe, KM and Knight, JM and Baker, KS and Yi-Frazier, JP and Rosenberg, AR}, title = {Resilience Intervention Improves Stress-Related Gene Expression in Adolescent and Young Adult HCT Recipients.}, journal = {Transplantation and cellular therapy}, volume = {30}, number = {12}, pages = {1209.e1-1209.e7}, doi = {10.1016/j.jtct.2024.09.014}, pmid = {39303988}, issn = {2666-6367}, mesh = {Humans ; Adolescent ; *Hematopoietic Stem Cell Transplantation/psychology ; Male ; Female ; Young Adult ; *Stress, Psychological/genetics/therapy ; Resilience, Psychological ; Child ; Adult ; }, abstract = {Overactivation of the stress response can influence cancer outcomes through immune-related pathways. Adolescents and young adults (AYAs) undergoing hematopoietic cell transplantation (HCT) are at risk for poor outcomes, yet there are limited behavioral interventions and no psychosocial biomarker data for this population. The Conserved Transcriptional Response to Adversity (CTRA) is an inflammation-related pattern observed in conditions of heightened stress and is associated with HCT outcomes. The objective of the current study was to explore the CTRA gene regulatory impact of Promoting Resilience in Stress Management (PRISM) intervention among AYAs receiving HCT. We hypothesized that patients who received the intervention would have favorable gene expression signatures compared to those in the control arm. This was an ancillary study within a randomized trial testing the PRISM intervention on psychosocial outcomes among AYAs aged 12 to 24 years receiving HCT (NCT03640325). CTRA was quantified through genome-wide transcriptional profiles obtained from whole blood collected at baseline, 1-, and 3-month post-HCT. Group differences in CTRA gene expression were estimated using mixed-effect linear models. There were no baseline group differences in CTRA expression, but PRISM participants showed a greater decline in CTRA at 1 month compared to controls (β -0.301 ± SE 0.114, P = .016), even when controlling for demographic (Group × Time interaction: F(2, 18) = 7.41, P = .004; β -0.386 ± 0.127, P = .007) and clinical covariates (Group × Time interaction: F(2, 20) = 7.03, P = .005; β -0.480 ± 0.144, P = .003). These differences were not detectable at 3 months (β -0.147 ± SE 0.120, P = .235). There was a change in stress-related gene expression among AYAs randomized to a psychosocial intervention. The stress-inflammation axis may be a targetable pathway in the AYA HCT population.}, }
@article {pmid39303986, year = {2024}, author = {Wickline, MM and Carpenter, PA and Harris, JR and Iribarren, SJ and Reding, KW and Pike, KC and Lee, SJ and Lee, CJ and Oshima, MU and Vo, PT and Berry, DL}, title = {Associations Between Demographic Factors, Clinical Variables, Social Determinants of Health, Vaccine Hesitancy, Vaccine Behavior, and Revaccination Status: A Survey of Adult HCT Survivors in the United States.}, journal = {Transplantation and cellular therapy}, volume = {30}, number = {12}, pages = {1221.e1-1221.e13}, doi = {10.1016/j.jtct.2024.09.012}, pmid = {39303986}, issn = {2666-6367}, mesh = {Humans ; Male ; Female ; United States/epidemiology ; Adult ; *Hematopoietic Stem Cell Transplantation/psychology ; Middle Aged ; *Social Determinants of Health ; Vaccination Hesitancy/psychology/statistics &amp; numerical data ; Aged ; Immunization, Secondary/statistics &amp; numerical data ; Cross-Sectional Studies ; Survivors/psychology ; Surveys and Questionnaires ; Vaccination/psychology/statistics &amp; numerical data ; Young Adult ; }, abstract = {Comprehensive survivorship care after hematopoietic cell transplantation (HCT) includes revaccination to restore immunity to vaccine-preventable diseases (VPDs). There is complexity to revaccination in this setting, and revaccination rates are sub-optimal. HCT survivors are at high-risk for morbidity and mortality from infections including VPDs, underscoring the importance of interventions to improve revaccination rates among survivors. Determining associations between survivor characteristics and revaccination uptake may guide interventions. The overall study objective was to advance our understanding of factors influencing revaccination uptake among adult HCT survivors living in the United States The specific study aims were to: (1) determine the prevalence of adult survivors who are completely, partially, or not revaccinated at 2 to 8 years after HCT and (2) examine associations between demographic variables, social determinants of health, clinical variables, past vaccination behaviors, vaccine hesitancy (Vaccination Confidence Scale), and revaccination status in adult HCT survivors. This study employed a one-time cross-sectional revaccination survey of adults who were surviving 2 to 8 years after HCT and living in the United States. The survey was sent to eligible survivors in the Fred Hutchinson Cancer Center Long-term Follow-up research cohort. The point prevalence of revaccination outcomes was determined from all the respondents (n = 338), differences in intent to revaccinate for people not yet fully revaccinated were explored using Fisher's exact test (n = 126), and associations were examined between revaccination outcomes and predictors using multivariable logistic regression (n = 292). Survey response rate was 30%. Among respondents, 62% were completely revaccinated, 33% were partially revaccinated, and 4% were not revaccinated. Most respondents (77%) who were not yet fully revaccinated planned to complete the revaccination protocol. However, fewer not-revaccinated respondents than partially revaccinated respondents planned to complete revaccination (50% versus 80%, P = .032). Factors associated with incomplete revaccination were shorter time from HCT, inadequate immune reconstitution, and not having received all childhood vaccines as a child. Our analysis has identified multiple variables associated with revaccination outcomes, indicating the potential for interventions to enhance post-HCT revaccination rates. Since many survivors cannot be revaccinated promptly due to delayed immune recovery, clinicians should iteratively re-evaluate for revaccination readiness as long as it takes to ensure eventual revaccination. Broader efforts by the healthcare community to increase childhood vaccine uptake might eventually support revaccination uptake. Future research that builds on these findings should focus on intervention testing.}, }
@article {pmid39303435, year = {2024}, author = {Boyd, DT and Jones, KV and Quinn, CR and Hill, M and Nelson, LE and Beauchamp, G and Emel, L and Hightow-Weidman, L and Shoptaw, S and Magnus, M and Piwowar-Manning, E and Mayer, KH and Fields, SD and Wheeler, DP and Dyer, TV and Wilton, L}, title = {Ethnic identity and social support as mediators between childhood sexual abuse and depression among black men who have sex with men.}, journal = {Child abuse &amp; neglect}, volume = {157}, number = {}, pages = {107064}, doi = {10.1016/j.chiabu.2024.107064}, pmid = {39303435}, issn = {1873-7757}, support = {P30 AI117970/AI/NIAID NIH HHS/United States ; }, mesh = {Adult ; Child ; Humans ; Male ; Middle Aged ; Young Adult ; Adult Survivors of Child Abuse/psychology ; *Black or African American/psychology ; *Child Abuse, Sexual/psychology/ethnology ; *Depression/ethnology/psychology ; Social Identification ; *Social Support ; *Sexual and Gender Minorities/psychology ; }, abstract = {BACKGROUND: Survivors of childhood sexual abuse (CSA) often experience long-term adverse mental health effects, a trend that has been observed in research focusing on men who have sex with men (MSM), especially Black MSM.<br><br>OBJECTIVE: The aim of this study was to investigate the direct and indirect effects of childhood sexual abuse on depression symptoms among Black MSM through early sexual debut, histories of incarceration, ethnic identity, and social support. In addition, we examine the role of social support and ethnic identity as mediators of depression symptoms.<br><br>PARTICIPANTS AND SETTING: The HPTN 073 study enrolled and followed 226 HIV-uninfected Black MSM in three US cities (Los Angeles; Washington, DC; and Chapel Hill, North Carolina) from February 2013 to September 2015. Study participants were offered once-daily oral emtricitabine/tenofovir preexposure prophylaxis combined with counseling and followed for 52&#xa0;weeks.<br><br>METHODS: A path analysis was used to examine direct and indirect effects of CSA experiences on depression symptoms through incarceration, early sexual debut ethnic identity, and social support, and to see whether social support and ethnic identity mediated the relationship between incarceration and depression symptoms.<br><br>RESULTS: Our results indicate that childhood sexual abuse was direct and positively associated with early sexual debut (&#x3b2;&#xa0;=&#xa0;0.21, p&#xa0;<&#xa0;.001). Both ethnic identity (&#x3b2;&#xa0;=&#xa0;-0.14, p&#xa0;<&#xa0;.001) and social support (&#x3b2;&#xa0;=&#xa0;-0.82, p&#xa0;<&#xa0;.001) were direct and negatively associated with depressive symptoms.<br><br>CONCLUSION: Our research underscores the significant impact of CSA factors on the life trajectories of some Black MSM, including experiences such as incarceration, sexual debut, and depression symptoms.}, }
@article {pmid39302139, year = {2024}, author = {Zhu, K and Zhao, YQ and Zheng, Y}, title = {Designing cancer screening trials for reduction in late-stage cancer incidence.}, journal = {Biometrics}, volume = {80}, number = {3}, pages = {}, pmid = {39302139}, issn = {1541-0420}, support = {R01 CA236558/NH/NIH HHS/United States ; }, mesh = {Humans ; *Early Detection of Cancer/methods/statistics &amp; numerical data ; Incidence ; *Neoplasms/diagnosis ; Randomized Controlled Trials as Topic ; Models, Statistical ; Research Design ; Biomarkers, Tumor/blood ; Mass Screening/methods/statistics &amp; numerical data ; Computer Simulation ; Biometry/methods ; Sensitivity and Specificity ; }, abstract = {Before implementing a biomarker test for early cancer detection into routine clinical care, the test must demonstrate clinical utility, that is, the test results should lead to clinical actions that positively affect patient-relevant outcomes. Unlike therapeutical trials for patients diagnosed with cancer, designing a randomized controlled trial (RCT) to demonstrate the clinical utility of an early detection biomarker with mortality and related endpoints poses unique challenges. The hurdles stem from the prolonged natural progression of the disease and the lack of information regarding the time-varying screening effect on the target asymptomatic population. To facilitate the study design of screening trials, we propose using a generic multistate disease history model and derive model-based effect sizes. The model links key performance metrics of the test, such as sensitivity, to primary endpoints like the incidence of late-stage cancer. It also incorporates the practical implementation of the biomarker-testing program in real-world scenarios. Based on the chronological time scale aligned with RCT, our method allows the assessment of study powers based on key features of the new program, including the test sensitivity, the length of follow-up, and the number and frequency of repeated tests. The calculation tool from the proposed method will enable practitioners to perform realistic and quick evaluations when strategizing screening trials for specific diseases. We use numerical examples based on the National Lung Screening Trial to demonstrate the method.}, }
@article {pmid39302970, year = {2024}, author = {Cole, JM and Scott, CB and Johnson, MM and Golightly, PR and Carlson, J and Ming, MJ and Harpak, A and Kirkpatrick, M}, title = {The battle of the sexes in humans is highly polygenic.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {39}, pages = {e2412315121}, pmid = {39302970}, issn = {1091-6490}, support = {R01 GM116853/GM/NIGMS NIH HHS/United States ; R35 GM151108/GM/NIGMS NIH HHS/United States ; GM151108//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; GM116853//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; }, mesh = {Humans ; Male ; Female ; *Multifactorial Inheritance/genetics ; *Fertility/genetics ; Selection, Genetic ; Haplotypes ; Alleles ; Sex Characteristics ; Genome-Wide Association Study ; Genome, Human ; }, abstract = {Sex-differential selection (SDS), which occurs when the fitness effects of alleles differ between males and females, can have profound impacts on the maintenance of genetic variation, disease risk, and other key aspects of natural populations. Because the sexes mix their autosomal genomes each generation, quantifying SDS is not possible using conventional population genetic approaches. Here, we introduce a method that exploits subtle sex differences in haplotype frequencies resulting from SDS acting in the current generation. Using data from 300K individuals in the UK Biobank, we estimate the strength of SDS throughout the genome. While only a handful of loci under SDS are individually significant, we uncover highly polygenic signals of genome-wide SDS for both viability and fecundity. Selection coefficients of [Formula: see text] may be typical. Despite its ubiquity, SDS may impose a mortality load of less than 1%. An interesting life-history tradeoff emerges: Alleles that increase viability more strongly in females than males tend to increase fecundity more strongly in males than in females. Finally, we find marginal evidence of SDS on fecundity acting on alleles affecting arm fat-free mass. Taken together, our findings connect the long-standing evidence of SDS acting on human phenotypes with its impact on the genome.}, }
@article {pmid39302924, year = {2024}, author = {Naicker, V and Laher, F and Bekker, LG and Seaton, KE and Allen, M and De Rosa, S and Yates, NL and Mkhize, NN and Saunders, K and Heptinstall, J and Malahleha, M and Mngadi, K and Daniels, B and Innes, C and Yu, C and Modise, T and Bekker, V and Grunenberg, N and Furch, B and Miner, MD and Phogat, S and Diazgranados, CA and Gurunathan, S and Koutsoukos, M and Van Der Meeren, O and Roxby, AC and Ferrari, G and Morris, L and Montefiori, D and McElrath, MJ and Tomaras, GD and Moodie, Z}, title = {Safety and immunogenicity after a 30-month boost of a subtype C ALVAC-HIV (vCP2438) vaccine prime plus bivalent subtype C gp120/MF59 vaccine boost (HVTN 100): A phase 1-2 randomized double-blind placebo-controlled trial.}, journal = {PLOS global public health}, volume = {4}, number = {9}, pages = {e0003319}, pmid = {39302924}, issn = {2767-3375}, abstract = {Induction of broad, durable immune responses is a challenge in HIV vaccine development. HVTN 100 Part A administered subtype C-containing ALVAC-HIV at months 0 and 1, and ALVAC-HIV with bivalent subtype C gp120/MF59 at months 3, 6 and 12. As IgG binding antibody and T-cell responses were similar or greater at month 12.5 vs. month 6.5, but waned by month 18, we investigated vaccine-elicited immune responses after a month 30 boost in this study, HVTN 100 Part B. From 13 September 2017 to 7 August 2018, a subgroup of vaccinees was randomized to receive intramuscular injections of ALVAC+gp120/MF59 (n = 32) or gp120/MF59 alone (n = 31) and a subgroup of placebo recipients was administered placebo (n = 7) at month 30. Primary outcomes were safety, IgG binding antibodies (bAbs) to vaccine-specific and V1V2 Env proteins and vaccine-specific CD4+ T cells at month 30.5. Secondary outcomes included neutralizing and antibody dependent cellular cytotoxicity functions and durability at months 30 and 36. Both vaccine groups had an acceptable safety profile. There were no statistically significant differences in the occurrence or level of IgG bAbs between the vaccine boost groups for any vaccine-specific or V1V2 antigens. IgG responses were higher to vaccine-matched gp120 than to V1V2. The booster vaccination restored the magnitude-breadth IgG bAb response to V1V2 antigens at month 30.5. However, it rapidly waned by month 36. CD4+ T-cell response rates to the 3 vaccine-matched Env antigens for the combined vaccine groups ranged from 37% at month 30, boosted to as high as 91% at month 30.5, and waned by month 36 to as low as 44%, with no significant differences between the vaccine boost groups. Because these responses waned after 6 months, additional strategies may be needed to maintain the durability of prime-boost vaccine regimens and to generate these or other immune responses that confer protection. Trial registration: South African National Clinical Trials Register (SANCTR number: DOH-27-0215-4796) and ClinicalTrials.gov (NCT02404311).}, }
@article {pmid39302431, year = {2024}, author = {Smith, JR and Arellano, AA and Avgousti, DC}, title = {Viral imitation is the sincerest form of epigenetic flattery.}, journal = {Molecular biology of the cell}, volume = {35}, number = {10}, pages = {pe3}, pmid = {39302431}, issn = {1939-4586}, support = {R35 GM133441/GM/NIGMS NIH HHS/United States ; T34 GM136466/GM/NIGMS NIH HHS/United States ; }, mesh = {*Epigenesis, Genetic ; Humans ; *SARS-CoV-2/physiology ; *Histones/metabolism ; Influenza A virus/genetics/physiology ; Chromatin/metabolism ; COVID-19/virology ; Immune Evasion ; Animals ; Host-Pathogen Interactions ; }, abstract = {Viruses use multiple strategies to successfully generate progeny and overcome host defenses. In recent years, it has become increasingly evident that epigenetic mechanisms of host gene regulation are vulnerable to viral manipulation. In the form of histone mimicry, viral invasion of host chromatin is a striking example of how viruses have evolved to invade every aspect of cellular function for viral benefit. In this perspective, we will review how three viruses-influenza A, SARS-CoV-2, and Cotesia plutellae bracovirus-use histone mimicry to promote viral success through immune evasion. These examples highlight the importance of this burgeoning field and point toward the wealth of knowledge we have yet to uncover.}, }
@article {pmid39298738, year = {2024}, author = {Gyurkocza, B and Nath, R and Seropian, S and Choe, H and Litzow, MR and Abboud, C and Koshy, N and Stiff, P and Tomlinson, B and Abhyankar, S and Foran, J and Hari, P and Chen, G and Al-Kadhimi, Z and Kebriaei, P and Sabloff, M and Orozco, JJ and Jamieson, K and Silverman, M and Van Besien, K and Schuster, M and Law, AD and Larkin, K and Pandit-Taskar, N and Rowley, SD and Munshi, P and Cook, R and Levy, MY and Lazarus, HM and Sandmaier, BM and Pagel, JM and Reddy, V and MacDougall, J and McNamara, K and Spross, J and Haeuber, E and Vusirikala, M and Nahar, A and Desai, A and Giralt, S}, title = {Randomized Phase III SIERRA Trial of [131]I-Apamistamab Before Allogeneic Hematopoietic Cell Transplantation Versus Conventional Care for Relapsed/Refractory AML.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2302018}, doi = {10.1200/JCO.23.02018}, pmid = {39298738}, issn = {1527-7755}, abstract = {PURPOSE: Older patients with relapsed or refractory AML (RR AML) have dismal prognoses without allogeneic hematopoietic cell transplantation (alloHCT). SIERRA compared a targeted pretransplant regimen involving the anti-CD45 radioconjugate [131]I-apamistamab with conventional care.<br><br>METHODS: SIERRA (ClinicalTrials.gov identifier: NCT02665065) was a phase III open-label trial. Patients age &#x2265;55 years with active RR AML were randomly assigned 1:1 to either an [131]I-apamistamab-led regimen before alloHCT or conventional care followed by alloHCT if initial complete remission (CR)/CR with incomplete platelet recovery (CRp) occurred. Initial response was assessed 28-56 days after alloHCT in the [131]I-apamistamab group and 28-42 days after salvage chemotherapy initiation; patients without CR/CRp or with AML progression could cross over to receive [131]I-apamistamab followed by alloHCT. The primary end point was durable complete remission (dCR) lasting 180 days after initial CR/CRp. Secondary end points were overall survival (OS) and event-free survival (EFS), assessed hierarchically in the intention-to-treat (ITT) population.<br><br>RESULTS: The ITT population included 153 patients ([131]I-apamistamab [n = 76]; conventional care [n = 77]). In total, 44/77 conventional care arm patients crossed over and 40/77 (52%) received [131]I-apamistamab and alloHCT, with six patients (13.6%) experiencing a dCR. In the ITT population, the dCR rate was significantly higher with [131]I-apamistamab (17.1% [95% CI, 9.4 to 27.5]) than conventional care (0% [95% CI, 0 to 4.7]; P < .0001). The OS hazard ratio (HR) was 0.99 (95% CI, 0.70 to 1.41; P = .96), and the EFS HR was 0.23 (95% CI, 0.15 to 0.34), with HR <1 favoring [131]I-apamistamab. Grade &#x2265;3 treatment-related adverse events occurred in 59.7% and 59.2% of the [131]I-apamistamab and conventional care groups, respectively.<br><br>CONCLUSION: The [131]I-apamistamab-led regimen was associated with a higher dCR rate than conventional care in older patients with RR AML. [131]I-apamistamab was well tolerated and could address an unmet need in this population.}, }
@article {pmid39298390, year = {2024}, author = {Kwan, ML and Pimentel, N and Izano, M and Iribarren, C and Rana, JS and Nguyen-Huynh, M and Cheng, R and Laurent, CA and Lee, VS and Roh, JM and Rillamas-Sun, E and Hershman, DL and Kushi, LH and Greenlee, H and Neugebauer, R}, title = {Adherence to cardiovascular medications and risk of cardiovascular disease in breast cancer patients: A causal inference approach in the Pathways Heart Study.}, journal = {PloS one}, volume = {19}, number = {9}, pages = {e0310531}, pmid = {39298390}, issn = {1932-6203}, mesh = {Humans ; Female ; *Breast Neoplasms/drug therapy/epidemiology ; *Medication Adherence/statistics &amp; numerical data ; Middle Aged ; *Cardiovascular Diseases/drug therapy/epidemiology ; Aged ; Prospective Studies ; Cardiovascular Agents/therapeutic use ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ; Risk Factors ; Heart Failure/drug therapy/epidemiology ; }, abstract = {PURPOSE: Women with breast cancer (BC) are at high risk of developing cardiovascular disease (CVD). We examined adherence to CVD medications and their association with major CVD events over 14 years of follow-up in the Pathways Heart Study, a prospective study of 4,776 stage I-III BC patients diagnosed from 2005-2013.<br><br>METHODS: Eligibility included being alive 6 months post-BC diagnosis, with dyslipidemia, hypertension, or diabetes at diagnosis along with &#x2265;1 prior outpatient order or dispensing for a statin, anti-hypertensive, or diabetes medication, respectively, in the 30 months prior. Medication adherence was measured from pharmacy data to calculate cumulative average adherence (CAA). Incident heart failure (HF), ischemic heart disease (IHD), and stroke were determined via validated diagnosis and procedure codes. Working marginal structural models (MSM) fitted with inverse probability weighting evaluated the effect of adherence regimens on the hazards for each CVD event, while controlling for baseline and time-varying confounders. MSM parameterizations included: 1) CAA<100% versus CAA = 100% (ref), 2) CAA<80% versus CAA&#x2265;80% (ref) and 3) CAA<80% versus 80%&#x2264;CAA<100% versus CAA = 100%.<br><br>RESULTS: Poor statin adherence (CAA<80%) was associated with higher risk of composite CVD (HR = 2.54; 95% CI: 1.09, 5.94) versus CAA&#x2265;80%. Poor statin adherence was also associated with a higher risk of stroke (HR = 8.13; 95% CI: 2.03, 32.51) but not risk of IHD and HF. Further, compared with perfect adherence (CAA = 100%), good adherence (80%&#x2264;CAA<100%) was associated with lower risk (HR = 0.35; 95% CI: 0.13, 0.92) while poor adherence (CAA<80%) was associated with higher risk of composite CVD (HR = 2.45; 95% CI: 1.05, 5.70). Levels of adherence to anti-hypertensives and diabetes medications had mixed or null associations with risk of CVD.<br><br>CONCLUSIONS: Maintaining good adherence (&#x2265;80%) to statins after BC treatment is beneficial for cardiovascular health in patients with dyslipidemia. Future studies should determine factors associated with lower adherence to statins and ways to improve adherence.}, }
@article {pmid39297068, year = {2024}, author = {Guinigundo, A and Baek, G}, title = {Staying Abreast of New Biomarkers in Hematology/Oncology.}, journal = {Journal of the advanced practitioner in oncology}, volume = {15}, number = {3}, pages = {164-169}, pmid = {39297068}, issn = {2150-0878}, abstract = {There has been an increasing number of approvals for targeted therapies in oncology in the past decade, changing the treatment paradigm for many solid tumors and hematologic malignancies. At JADPRO Live 2023, presenters provided an in-depth review of cancer biomarkers, including testing methodology, recommended therapies, and how advanced practitioners can integrate results into clinical decision-making.}, }
@article {pmid39294476, year = {2024}, author = {Luo, K and Zhang, Y and Kaplan, RC and Qi, Q}, title = {Reply to: Milk intake, lactase non-persistence and type 2 diabetes risk in Chinese adults.}, journal = {Nature metabolism}, volume = {6}, number = {11}, pages = {2057-2059}, pmid = {39294476}, issn = {2522-5812}, support = {R01-DK119268//U.S. Department of Health &amp; Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes &amp; Digestive &amp; Kidney Diseases)/ ; R01-DK126698//U.S. Department of Health &amp; Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes &amp; Digestive &amp; Kidney Diseases)/ ; 23POST1020455//American Heart Association (American Heart Association, Inc.)/ ; R01-MD011389//U.S. Department of Health &amp; Human Services | NIH | National Institute on Minority Health and Health Disparities (NIMHD)/ ; }, }
@article {pmid39294453, year = {2024}, author = {Duggan, C and Carosso, E and Ibarra, G and Neuhouser, ML and Thompson, B}, title = {Developing a Dietary Questionnaire for Rural Mexican Americans.}, journal = {Journal of immigrant and minority health}, volume = {}, number = {}, pages = {}, pmid = {39294453}, issn = {1557-1920}, support = {P30 CA015704-39/NH/NIH HHS/United States ; }, abstract = {Latinos form the largest ethnic population in the United States (18.5%), and the majority are Mexican Americans (61.4%). Many Mexican Americans have unique dietary behaviors, yet few food frequency questionnaires explicitly define Mexican American diets. The objective of this work was to engage with a population of rural Mexican Americans to develop a Mexican American food frequency questionnaire. Because acculturation is linked to dietary intake, we also examined acculturation by diet. We used mixed methods with three phases: (1) a qualitative phase in which a sample of rural Mexican-Americans (N = 15) identified and provided rich data about foods they ate; (2) a developmental phase in which 4 day food records were completed sequentially by two new and different samples of Mexican Americans (N = 19); and 3) a preliminary assessment phase where a new sample of Mexican Americans (N = 49) completed the final food frequency questionnaire. The final questionnaire included many traditional Mexican foods and beverages identified by study participants as part of their typical diet. Traditional Mexican foods and beverages were consumed regularly; little variation in diet was seen by level of acculturation. Respondents perceived diets containing commercial sugar-sweetened beverages as unhealthful, but not those with traditional Mexican drinks, which may represent an unappreciated source of added sugar in the diet. Future work includes studies examining dietary patterns in other urban and rural communities with traditional Mexican diets.}, }
@article {pmid39294153, year = {2024}, author = {Wagner, C and Kistler, KE and Perchetti, GA and Baker, N and Frisbie, LA and Torres, LM and Aragona, F and Yun, C and Figgins, M and Greninger, AL and Cox, A and Oltean, HN and Roychoudhury, P and Bedford, T}, title = {Author Correction: Positive selection underlies repeated knockout of ORF8 in SARS-CoV-2 evolution.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8199}, doi = {10.1038/s41467-024-52571-4}, pmid = {39294153}, issn = {2041-1723}, }
@article {pmid39293548, year = {2024}, author = {Marsh, TL and Parikh, ND and Roberts, LR and Schwartz, ME and Nguyen, MH and Befeler, A and Page-Lester, S and Tayob, N and Srivastava, S and Rinaudo, JA and Singal, AG and Reddy, KR and Marrero, JA}, title = {A Phase 3 Biomarker Validation of GALAD for the Detection of Hepatocellular Carcinoma in Cirrhosis.}, journal = {Gastroenterology}, volume = {}, number = {}, pages = {}, doi = {10.1053/j.gastro.2024.09.008}, pmid = {39293548}, issn = {1528-0012}, abstract = {BACKGROUND &amp; AIMS: Better surveillance tests for hepatocellular carcinoma (HCC) are needed. The GALAD score (gender, age, α-fetoprotein [AFP] L3, AFP, and des carboxyprothrombin) has been shown to have excellent sensitivity and specificity for HCC in phase 2 studies. We performed a phase 3 biomarker validation study to compare GALAD with AFP in detecting HCC.<br><br>METHODS: This is a prospective study of patients with cirrhosis enrolled at 7 centers. Surveillance for HCC was performed every 6 months at each site, and HCC diagnosis was confirmed per American Association for the Study of Liver Diseases guidelines. Blood for biomarker research was obtained at each follow-up visit and stored in a biorepository. Measurements of AFP, AFP-L3, and des-&#x3b3; carboxyprothrombin) were performed in a FujiFilm laboratory by staff blinded to clinical data. The performance of GALAD in detecting HCC was retrospectively evaluated within 12 months before the clinical diagnosis. All analyses were conducted by an unblinded statistician in the EDRN data management and coordinating center.<br><br>RESULTS: A total of 1,558 patients with cirrhosis were enrolled and followed for a median of 2.2 years. A total of 109 patients developed HCC (76 very early or early stage), with an annual incident rate of 2.4%. The areas under the curve for AFP and GALAD within 12 months before HCC were 0.66 and 0.78 (P < .001), respectively. Using a cutoff for GALAD of -1.36, the specificity was 82%, and the sensitivity at 12 months before HCC diagnosis was 62%. For comparison, performance of AFP at 82% specificity showed 41% sensitivity at 12 months before HCC diagnosis (P&#xa0;= .001).<br><br>CONCLUSIONS: GALAD score, compared to AFP, improves the detection of HCC within 12 months before the actual diagnosis.}, }
@article {pmid39293545, year = {2024}, author = {Matsumoto, MM and Lee, CI}, title = {Realizing the Potential for Opportunistic Early Detection of Abnormalities on Medical Imaging Using Artificial Intelligence.}, journal = {Journal of the American College of Radiology : JACR}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jacr.2024.09.003}, pmid = {39293545}, issn = {1558-349X}, }
@article {pmid39293515, year = {2024}, author = {Rathkopf, DE and Patel, MR and Choudhury, AD and Rasco, D and Lakhani, N and Hawley, JE and Srinivas, S and Aparicio, A and Narayan, V and Runcie, KD and Emamekhoo, H and Reichert, ZR and Nguyen, MH and Wells, AL and Kandimalla, R and Liu, C and Suryawanshi, S and Han, J and Wu, J and Arora, VK and Pourdehnad, M and Armstrong, AJ}, title = {Safety and clinical activity of BMS-986365 (CC-94676), a dual androgen receptor ligand-directed degrader and antagonist, in heavily pretreated patients with metastatic castration-resistant prostate cancer.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.annonc.2024.09.005}, pmid = {39293515}, issn = {1569-8041}, abstract = {BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) that progresses on androgen receptor pathway inhibitors (ARPIs) may continue to be driven by AR signaling. BMS-986365 is an orally administered ligand-directed degrader targeting the AR via a first-in-class dual mechanism of AR degradation and antagonism. CC-94676-PCA-001 (NCT04428788) is a phase I multicenter study of BMS-986365 in patients with progressive mCRPC.<br><br>PATIENTS AND METHODS: Patients who progressed on androgen deprivation therapy, one or more ARPIs, and taxane chemotherapy (unless declined/ineligible) were enrolled. The study included dose escalation (part A) and expansion (part B) of BMS-986365 up to 900 mg twice daily. Primary objectives were safety and tolerability, and to define maximum tolerated dose and/or recommended phase II dose. Key secondary endpoints included decline in prostate-specific antigen &#x2265;50% (PSA50) and radiographic progression-free survival (rPFS).<br><br>RESULTS: Parts A and B enrolled 27 and 68 patients, respectively. In part B, the median number of prior therapies was 4 (range 2-11). The most common treatment-related adverse events were asymptomatic prolonged corrected QT interval (47%) and bradycardia (34%). Part A maximum tolerated dose was not reached and recommended phase II dose selection is ongoing. Across part B three highest doses (400-900 mg twice daily, n&#xa0;= 60), PSA50 was 32% (n&#xa0;= 19), including 50% (n&#xa0;= 10/20) at 900 mg; median rPFS (95% confidence interval) was 6.3 months (5.3-12.6 months), including 8.3 months (3.8-16.6 months) at 900 mg; and rPFS was longer in patients without versus with prior chemotherapy: 16.5 months (5.5 months-not evaluable) versus 5.5 months (2.7-8.3 months), respectively. Efficacy was observed in patients with mCRPC with AR ligand binding domain (LBD) WT or with AR LBD mutations.<br><br>CONCLUSIONS: BMS-986365 was well tolerated, with a manageable safety profile, and demonstrated activity in heavily pretreated patients with mCRPC with potentially higher benefit in chemotherapy-naive patients. These data show the potential of BMS-986365 to overcome resistance to current ARPIs, regardless of AR LBD mutation status.}, }
@article {pmid39289368, year = {2024}, author = {Walter, M and Haick, AK and Riley, R and Massa, PA and Strongin, DE and Klouser, LM and Loprieno, MA and Stensland, L and Santo, TK and Roychoudhury, P and Aubert, M and Taylor, MP and Jerome, KR and Verdin, E}, title = {Viral gene drive spread during herpes simplex virus 1 infection in mice.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8161}, pmid = {39289368}, issn = {2041-1723}, support = {R21 AI178255/AI/NIAID NIH HHS/United States ; R21AI178255//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; }, mesh = {Animals ; *Herpesvirus 1, Human/genetics/physiology ; Mice ; *Herpes Simplex/virology/genetics ; Humans ; Coinfection/virology ; Gene Drive Technology/methods ; Female ; Vero Cells ; Chlorocebus aethiops ; Encephalitis, Herpes Simplex/genetics/virology ; Mice, Inbred C57BL ; Recombination, Genetic/genetics ; Genes, Viral/genetics ; }, abstract = {Gene drives are genetic modifications designed to propagate efficiently through a population. Most applications rely on homologous recombination during sexual reproduction in diploid organisms such as insects, but we recently developed a gene drive in herpesviruses that relies on co-infection of cells by wild-type and engineered viruses. Here, we report on a viral gene drive against human herpes simplex virus 1 (HSV-1) and show that it propagates efficiently in cell culture and during HSV-1 infection in mice. We describe high levels of co-infection and gene drive-mediated recombination in neuronal tissues during herpes encephalitis as the infection progresses from the site of inoculation to the peripheral and central nervous systems. In addition, we show evidence that a superinfecting gene drive virus could recombine with wild-type viruses during latent infection. These findings indicate that HSV-1 achieves high rates of co-infection and recombination during viral infection, a phenomenon that is currently underappreciated. Overall, this study shows that a viral gene drive could spread in vivo during HSV-1 infection, paving the way toward therapeutic applications.}, }
@article {pmid39292927, year = {2024}, author = {Wolff, D and Cutler, C and Lee, SJ and Pusic, I and Bittencourt, H and White, J and Hamadani, M and Arai, S and Salhotra, A and Perez-Simon, JA and Alousi, A and Choe, H and Kwon, M and Bermúdez, A and Kim, I and Socié, G and Chhabra, S and Radojcic, V and O'Toole, T and Tian, C and Ordentlich, P and DeFilipp, Z and Kitko, CL and , }, title = {Axatilimab in Recurrent or Refractory Chronic Graft-versus-Host Disease.}, journal = {The New England journal of medicine}, volume = {391}, number = {11}, pages = {1002-1014}, doi = {10.1056/NEJMoa2401537}, pmid = {39292927}, issn = {1533-4406}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Antibodies, Monoclonal, Humanized/administration &amp; dosage/adverse effects ; Chronic Disease/drug therapy ; Dose-Response Relationship, Drug ; *Graft vs Host Disease/diagnosis/drug therapy/immunology/metabolism ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Infusions, Intravenous ; *Receptor, Macrophage Colony-Stimulating Factor/antagonists &amp; inhibitors/metabolism ; Recurrence ; Severity of Illness Index ; Treatment Outcome ; }, abstract = {BACKGROUND: Colony-stimulating factor 1 receptor (CSF1R)-dependent monocytes and macrophages are key mediators of chronic graft-versus-host disease (GVHD), a major long-term complication of allogeneic hematopoietic stem-cell transplantation. The CSF1R-blocking antibody axatilimab has shown promising clinical activity in chronic GVHD.<br><br>METHODS: In this phase 2, multinational, pivotal, randomized study, we evaluated axatilimab at three different doses in patients with recurrent or refractory chronic GVHD. Patients were randomly assigned to receive axatilimab, administered intravenously, at a dose of 0.3 mg per kilogram of body weight every 2 weeks (0.3-mg dose group), at a dose of 1 mg per kilogram every 2 weeks (1-mg dose group), or at a dose of 3 mg per kilogram every 4 weeks (3-mg dose group). The primary end point was overall response (complete or partial response) in the first six cycles; the key secondary end point was a patient-reported decrease in chronic GVHD symptom burden, as assessed by a reduction of more than 5 points on the modified Lee Symptom Scale (range, 0 to 100, with higher scores indicating worse symptoms). The primary end point would be met if the lower bound of the 95% confidence interval exceeded 30%.<br><br>RESULTS: A total of 241 patients were enrolled (80 patients in the 0.3-mg dose group, 81 in the 1-mg dose group, and 80 in the 3-mg dose group). The primary end point was met in all the groups; an overall response was observed in 74% (95% confidence interval [CI], 63 to 83) of the patients in the 0.3-mg dose group, 67% (95% CI, 55 to 77) of the patients in the 1-mg dose group, and 50% (95% CI, 39 to 61) of the patients in the 3-mg dose group. A reduction of more than 5 points on the modified Lee Symptom Scale was reported in 60%, 69%, and 41% of the patients in the three dose groups, respectively. The most common adverse events were dose-dependent transient laboratory abnormalities related to CSF1R blockade. Adverse events leading to discontinuation of axatilimab occurred in 6% of the patients in the 0.3-mg dose group, 22% in the 1-mg dose group, and 18% in the 3-mg dose group.<br><br>CONCLUSIONS: Targeting CSF1R-dependent monocytes and macrophages with axatilimab resulted in a high incidence of response among patients with recurrent or refractory chronic GVHD. (Funded by Syndax Pharmaceuticals and Incyte; AGAVE-201 ClinicalTrials.gov number, NCT04710576.).}, }
@article {pmid39292670, year = {2024}, author = {Earnest, JT and Kirstein, OD and Mendoza, AC and Barrera-Fuentes, GA and Puerta-Guardo, H and Parra-Cardeña, M and Yam-Trujillo, K and Collins, MH and Pavia-Ruz, N and Ayora-Talavera, G and Gonzalez-Olvera, G and Medina-Barreiro, A and Bibiano-Marin, W and Lenhart, A and Halloran, ME and Longini, I and Dean, N and Waller, LA and Crisp, AM and Correa-Morales, F and Palacio-Vargas, J and Granja-Perez, P and Villanueva, S and Delfın-Gonzalez, H and Gomez-Dantes, H and Manrique-Saide, P and Vazquez-Prokopec, GM}, title = {The TIRS trial: Enrollment procedures and baseline characterization of a pediatric cohort to quantify the epidemiologic impact of targeted indoor residual spraying on Aedes-borne viruses in Merida, Mexico.}, journal = {PloS one}, volume = {19}, number = {9}, pages = {e0310480}, pmid = {39292670}, issn = {1932-6203}, mesh = {Humans ; Child ; *Aedes/virology ; Animals ; Mexico/epidemiology ; Adolescent ; Child, Preschool ; Female ; *Mosquito Control/methods ; Male ; *Mosquito Vectors/virology ; *Dengue/epidemiology/prevention &amp; control/virology ; *Insecticides ; Seroepidemiologic Studies ; Zika Virus Infection/epidemiology/prevention &amp; control ; Zika Virus/immunology/isolation &amp; purification ; Chikungunya Fever/epidemiology/prevention &amp; control ; Dengue Virus/immunology/isolation &amp; purification ; Chikungunya virus/immunology ; }, abstract = {Aedes mosquito-borne viruses (ABVs) place a substantial strain on public health resources in the Americas. Vector control of Aedes mosquitoes is an important public health strategy to decrease or prevent spread of ABVs. The ongoing Targeted Indoor Residual Spraying (TIRS) trial is an NIH-sponsored clinical trial to study the efficacy of a novel, proactive vector control technique to prevent dengue virus (DENV), Zika virus (ZIKV), and chikungunya virus (CHIKV) infections in the endemic city of Merida, Yucatan, Mexico. The primary outcome of the trial is laboratory-confirmed ABV infections in neighborhood clusters. Despite the difficulties caused by the COVID-19 pandemic, by early 2021 the TIRS trial completed enrollment of 4,792 children aged 2-15 years in 50 neighborhood clusters which were allocated to control or intervention arms via a covariate-constrained randomization algorithm. Here, we describe the makeup and ABV seroprevalence of participants and mosquito population characteristics in both arms before TIRS administration. Baseline surveys showed similar distribution of age, sex, and socio-economic factors between the arms. Serum samples from 1,399 children were tested by commercially available ELISAs for presence of anti-ABV antibodies. We found that 45.1% of children were seropositive for one or more flaviviruses and 24.0% were seropositive for CHIKV. Of the flavivirus-positive participants, most were positive for ZIKV-neutralizing antibodies by focus reduction neutralization testing which indicated a higher proportion of participants with previous ZIKV than DENV infections within the cohort. Both study arms had statistically similar seroprevalence for all viruses tested, similar socio-demographic compositions, similar levels of Ae. aegypti infestation, and similar observed mosquito susceptibility to insecticides. These findings describe a population with a high rate of previous exposure to ZIKV and lower titers of neutralizing antibodies against DENV serotypes, suggesting susceptibility to future outbreaks of flaviviruses is possible, but proactive vector control may mitigate these risks.}, }
@article {pmid39291745, year = {2024}, author = {Nagana Gowda, GA and Pascua, V and Hill, L and Djukovic, D and Wang, D and Raftery, D}, title = {Discovery of Hypoxanthine and Inosine as Robust Biomarkers for Predicting the Preanalytical Quality of Human Plasma and Serum for Metabolomics.}, journal = {Analytical chemistry}, volume = {96}, number = {39}, pages = {15754-15764}, doi = {10.1021/acs.analchem.4c03719}, pmid = {39291745}, issn = {1520-6882}, mesh = {Humans ; *Inosine/blood/metabolism ; *Hypoxanthine/blood ; *Metabolomics/methods ; *Biomarkers/blood ; Plasma/chemistry/metabolism ; }, abstract = {In cold human blood, the anomalous dynamics of adenosine triphosphate (ATP) result in the progressive accumulation of adenosine diphosphate (ADP), adenosine monophosphate (AMP), inosine monophosphate (IMP), inosine, and hypoxanthine. While the ATP, ADP, AMP, and IMP are confined to red blood cells (RBCs), inosine and hypoxanthine are excreted into plasma/serum. The plasma/serum levels of inosine and hypoxanthine depend on the temperature of blood and the plasma/serum contact time with the RBCs, and hence they represent robust biomarkers for evaluating the preanalytical quality of plasma/serum. These biomarkers are highly specific since they are generally absent or at very low levels in fresh plasma/serum and are highly sensitive since they are derived from ATP, one of the most abundant metabolites in blood. Further, whether blood was kept at room temperature or on ice could be predicted based on inosine levels. An analysis of >2000 plasma/serum samples processed for metabolomics-centric analyses showed alarmingly high levels of inosine and hypoxanthine. The results highlight the gravity of sample quality challenges with high risk of grossly inaccurate measurements and incorrect study outcomes. The discovery of these robust biomarkers provides new ways to address the longstanding and underappreciated preanalytical sample quality challenges in the blood metabolomics field.}, }
@article {pmid39290875, year = {2024}, author = {Crotty, EE and Paulson, VA and Ronsley, R and Vitanza, NA and Lee, A and Hauptman, J and Goldstein, HE and Lockwood, CM and Leary, SES and Cole, BL}, title = {Cerebrospinal fluid liquid biopsy by low-pass whole genome sequencing for clinical disease monitoring in pediatric embryonal tumors.}, journal = {Neuro-oncology advances}, volume = {6}, number = {1}, pages = {vdae126}, pmid = {39290875}, issn = {2632-2498}, abstract = {BACKGROUND: Liquid biopsy assays that detect cell-free DNA (cfDNA) in cerebrospinal fluid (CSF) are a promising tool for disease monitoring in pediatric patients with primary central nervous system (CNS) tumors. As a compliment to tissue-derived molecular analyses, CSF liquid biopsy has the potential to transform risk stratification, prognostication, and precision medicine approaches.<br><br>METHODS: In this pilot study, we evaluated a clinical pipeline to determine feasibility and sensitivity of low-pass whole genome sequencing (LP-WGS) of CSF-derived cfDNA from patients with CNS embryonal tumors. Thirty-two longitudinal CSF samples collected from 17 patients with molecularly characterized medulloblastoma (12), embryonal tumor with multilayered rosettes (2), CNS embryonal tumor, not elsewhere classified (NEC) (2), and atypical teratoid/rhabdoid tumor (1) were analyzed.<br><br>RESULTS: Adequate CSF-derived cfDNA for LP-WGS analysis was obtained in 94% of samples (30/32). Copy number variants compatible with neoplasia were detected in 90% (27/30) and included key alterations, such as isodicentric ch17, monosomy 6, and MYCN amplification, among others. Compared to tissue specimens, LP-WGS detected additional aberrations in CSF not previously identified in corresponding primary tumor specimens, suggesting a more comprehensive profile of tumor heterogeneity or evolution of cfDNA profiles over time. Among the 12 CSF samples obtained at initial staging, only 2 (17%) were cytologically positive, compared to 11 (92%) that were copy number positive by LP-WGS.<br><br>CONCLUSIONS: LP-WGS of CSF-derived cfDNA is feasible using a clinical platform, with greater sensitivity for tumor detection compared to conventional CSF cytologic analysis at initial staging. Large prospective studies are needed to further evaluate LP-WGS as a predictive biomarker.}, }
@article {pmid39290639, year = {2024}, author = {Eapen, M and Antin, JH and Tolar, J and Arai, S and Horwitz, ME and Kou, J and Leifer, E and McCarty, JM and Nakamura, R and Pulsipher, MA and Rowley, SD and Horowitz, MM and Deeg, HJ}, title = {Long-term survival after unrelated donor marrow transplantation for aplastic anaemia after optimized conditioning regimen: a retrospective multicentre cohort study.}, journal = {EClinicalMedicine}, volume = {76}, number = {}, pages = {102819}, pmid = {39290639}, issn = {2589-5370}, support = {U10 HL069294/HL/NHLBI NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Almost all acquired severe aplastic anaemia is immune mediated and characterised by hypocellular bone marrow and ≥2 affected haematopoietic lineages. The optimal preparartive regimen for unrelated donor transplantation remains to be established. We aimed to study long-term outcomes after unrelated donor transplantation for severe aplastic anaemia with de-escalation of cyclophosphamide (Cy) dose in steps of 50 mg/kg (150, 100, 50, 0 mg/kg) in combination with total body irradiation (TBI) 2 Gy, anti-thymocyte globulin (ATG) and fludarabine.<br><br>METHODS: Ninety-six patients with severe aplastic anaemia aged &#x2264;65 years with adequate organ function enrolled on a trial of human leukocyte antigen (HLA)-matched or 1 HLA-locus mismatched unrelated donor marrow transplantation conducted between 02/2006 and 12/2013 in the United States (NCT00326417). Exclusion criteria were Karnofsky performance status of less than 60, clonal cytogenetic abnormalities and inherited marrow failure syndormes. The primary outcome was day-100 engraftment (achievement of absolute neutrophil recovery to at least 0.5&#xa0;&#xd7;&#xa0;10[9]/L without subsequent decline) and day-100 survival. The trial determined the lowest effective Cy&#xa0;dose as 50&#xa0;mg/kg (n&#xa0;=&#xa0;38) for day-100 engraftment and survival. Cy dose 100&#xa0;mg/kg (n&#xa0;=&#xa0;41) was also acceptable. Accrual to Cy doses 150&#xa0;mg/kg (n&#xa0;=&#xa0;15) and 0&#xa0;mg/kg (n&#xa0;=&#xa0;3) was terminated early for toxicities. The current study is an extended follow up of patients enrolled on the trial (NCT00326477) and includes 76 of 96 patients alive &#x2265;1 year after transplantation. There were 20 deaths in the first year after transplantation (Cy 0&#xa0;mg/kg [n&#xa0;=&#xa0;2], Cy 50&#xa0;mg/kg [n&#xa0;=&#xa0;1], Cy 100&#xa0;mg/kg [n&#xa0;=&#xa0;10], Cy 150&#xa0;mg/kg [n&#xa0;=&#xa0;7]). Patients were followed prospectively from transplantation and data reported using standardized data collection forms until death, loss to follow up or last contact through November 2023. The incidence of graft failure was calculated using the cumulative incidence estimator and the probability of survival using the Kaplan-Meier estimator.<br><br>FINDINGS: The median follow up of the cohort is 8.02 (IQR) 5.16-10.12) years. With Cy 50&#xa0;mg/kg, there was one graft failure and five deaths &#x2265;1 year after transplantation. With Cy 100&#xa0;mg/kg there was only one late death and no graft failure. The 8-year probabilities of survival were 85.0% (95% CI 67.3-93.5) and 75.6% (95% CI 59.4-86.1) after Cy&#xa0;50&#xa0;mg/kg and 100&#xa0;mg/kg, respectively, P&#xa0;=&#xa0;0.31. With Cy 0&#xa0;mg/kg and 150&#xa0;mg/kg, there were no graft failures or death &#x2265;1 year after transplantation. Regardless of Cy dose 12 of 15 patients aged &#x2265;50 years died.<br><br>INTERPRETATION: Cy 50&#xa0;mg/kg or 100&#xa0;mg/kg with TBI 2&#xa0;Gy, ATG and fludarabine are effective conditioning regimens for unrelated donor marrow transplants for aplastic anaemia. Identification of an optimized transplantation approach for patients aged &#x2265;50 years is needed.<br><br>FUNDING: US National Institutes of Health.}, }
@article {pmid39290356, year = {2024}, author = {Thomson, TJ and Hu, XJ and Nosyk, B}, title = {Estimating effects of time-varying exposures on mortality risk.}, journal = {Journal of applied statistics}, volume = {51}, number = {13}, pages = {2652-2671}, pmid = {39290356}, issn = {0266-4763}, support = {R01 DA050629/DA/NIDA NIH HHS/United States ; }, abstract = {Administrative databases have become an increasingly popular data source for population-based health research. We explore how mortality risk is associated with some health service utilization process via linked administrative data. A generalized Cox regression model is proposed using a time-dependent stratification variable to summarize lifetime service utilization. Recognizing the service utilization over time as an internal covariate in the survival analysis, conventional likelihood methods are inapplicable. We present an estimating function based procedure for estimating model parameters, and provide a testing procedure for updating the stratification levels. The proposed approach is examined both asymptotically and numerically via simulation. We motivate and illustrate the proposed approach using an on-going program pertaining to opioid agonist treatment (OAT) management for individuals identified with opioid use disorders. Our analysis of the OAT data indicates that the OAT effect on mortality risk decreases in successive OAT attempts, in which two risk classes based on an individual's treatment episode number are established: one with 1-3 OAT episodes, and the other with 4+ OAT episodes.}, }
@article {pmid39290203, year = {2024}, author = {Raychaudhuri, S and Dong, ZM and Knowles, S and Graf, S}, title = {EBV-Positive Classic Hodgkin Lymphoma and Primary Nodal T-Cell/NK-Cell Lymphoma Arising in the Background of Follicular Lymphoma.}, journal = {Case reports in hematology}, volume = {2024}, number = {}, pages = {8810646}, pmid = {39290203}, issn = {2090-6560}, support = {T32 HL007093/HL/NHLBI NIH HHS/United States ; }, abstract = {EBV-positive primary nodal T-cell/NK cell lymphoma (TNKL) is a rare diagnosis with a poor prognosis. No relationship with follicular lymphoma (FL), classic Hodgkin lymphoma (cHL), or other non-Hodgkin lymphomas is established. We describe a case of Epstein-Barr virus (EBV)-positive cHL and EBV-positive primary nodal TNKL in the background of an antecedent FL, with all 3 subtypes identified in a single lymph node biopsy from an immunocompetent patient. Intensive frontline therapy achieved only a temporary response, with subsequent rapid progression associated with hemophagocytic lymphohistiocytosis (HLH). We discuss the relationship of the three lymphoma subtypes and the potential roles of EBV and immune dysregulation as contributing factors to this previously undescribed composite lymphoma.}, }
@article {pmid39289635, year = {2024}, author = {Leader, AE and Rebbeck, TR and Oh, WK and Patel, AV and Winer, EP and Bailey, LO and Gomella, LG and Lumpkins, CY and Garraway, IP and Aiello, LB and Baskin, ML and Cheng, HH and Cooney, KA and Ganzak, A and George, DJ and Halabi, S and Hathaway, F and Healy, C and Kim, JW and Leapman, MS and Loeb, S and Maxwell, KN and McNair, C and Morgan, TM and Prindeville, B and Soule, HR and Steward, WL and Suttiratana, SC and Taplin, ME and Yamoah, K and Fortune, T and Bennett, K and Blanding-Godbolt, J and Gross, L and Giri, VN}, title = {Adaptation of the socioecological model to address disparities in engagement of Black men in prostate cancer genetic testing.}, journal = {BMC public health}, volume = {24}, number = {1}, pages = {2533}, pmid = {39289635}, issn = {1471-2458}, mesh = {Humans ; Male ; Africa/ethnology ; Black or African American ; Delphi Technique ; *Genetic Testing ; *Healthcare Disparities ; *Prostatic Neoplasms/diagnosis/genetics ; United States ; *Black People ; }, abstract = {BACKGROUND: Black men consistently have higher rates of prostate cancer (PCA)- related mortality. Advances in PCA treatment, screening, and hereditary cancer assessment center around germline testing (GT). Of concern is the significant under-engagement of Black males in PCA GT, limiting the benefit of precision therapy and tailored cancer screening despite longstanding awareness of these disparities. To address these critical disparities, the Socioecological Model (SEM) was employed to develop comprehensive recommendations to overcome barriers and implement equitable strategies to engage Black males in PCA GT.<br><br>METHODS: Clinical/research experts, national organization leaders, and community stakeholders spanning multiple regions in US and Africa participated in developing a framework for equity in PCA GT grounded in the SEM. A novel mixed-methods approach was employed to generate key areas to be addressed and informed statements for consensus consideration utilizing the modified Delphi model. Statements achieving strong consensus (>&#x2009;=75% agreement) were included in final equity frameworks addressing clinical/community engagement and research engagement.<br><br>RESULTS: All societal levels of the SEM (interpersonal, institutional, community, and policy/advocacy) must deliver information about PCA GT to Black males that address benefits/limitations, clinical impact, hereditary cancer implications, with acknowledgment of mistrust (mean scores [MS] 4.57-5.00). Interpersonal strategies for information delivery included engagement of family/friends/peers/Black role models to improve education/awareness and overcome mistrust (MS 4.65-5.00). Institutional strategies included diversifying clinical, research, and educational programs and integrating community liaisons into healthcare institutions (MS 4.57-5.00). Community strategies included partnerships with healthcare institutions and visibility of healthcare providers/researchers at community events (MS 4.65-4.91). Policy/advocacy included improving partnerships between advocacy and healthcare/community organizations while protecting patient benefits (MS 4.57-5.00). Media strategies were endorsed for the first time at every level (MS 4.56-5.00).<br><br>CONCLUSION: The SEM-based equity frameworks proposed provide the first multidisciplinary strategies dedicated to increase engagement of Black males in PCA GT, which are critical to reduce disparities in PCA-mortality through informing tailored screening, targeted therapy, and cascade testing in families.}, }
@article {pmid39288406, year = {2024}, author = {Chen, X and Soma, L and Murphy, C and Tretiakova, M and Naresh, KN and Fromm, JR}, title = {Utility of CCR7 to differentiate classic Hodgkin lymphoma and other B-cell lymphomas by flow cytometry and immunohistochemistry.}, journal = {American journal of clinical pathology}, volume = {}, number = {}, pages = {}, doi = {10.1093/ajcp/aqae119}, pmid = {39288406}, issn = {1943-7722}, abstract = {OBJECTIVES: Classic Hodgkin lymphoma (CHL) is characterized by infrequent neoplastic Hodgkin and Reed-Sternberg (HRS) cells in an inflammatory background. The diagnostic utility of CC-chemokine receptor 7 (CCR7) in CHL was explored using flow cytometry and immunohistochemistry (IHC).<br><br>METHODS: Neoplastic specimens and non-neoplastic lymph nodes were immunophenotyped and CCR7 expression was measured semiquantitatively by flow cytometry (clone 3D12) and IHC (clone 150503).<br><br>RESULTS: Our results showed that CCR7 was expressed on HRS cells in the vast majority of CHL cases (45/48 by flow cytometry, 57/59 by IHC) but rarely expressed in neoplastic cells in diffuse large B-cell lymphoma, not otherwise specified (1/25 by flow cytometry, 2/40 by IHC) and nodular lymphocyte predominant Hodgkin lymphoma (0/4 by flow cytometry, 1/13 by IHC). Primary mediastinal large B-cell lymphoma (PMLBCL) revealed weak CCR7 expression by flow cytometry in most cases (8/10) but only occasionally by IHC (2/12). Both cases (2/2) of T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) also showed CCR7 expression detected by flow cytometry compared with IHC (0/7). The HRS cells demonstrated a greater percentage of positive cells and greater antigen intensity than the other B-cell lymphomas by IHC. The expression identified by flow cytometry in PMLBCL and THRLBCL but not by IHC suggests that there may be differences in the detection capabilities of the 2 techniques or the&#xa0;2 CCR7 clones used.<br><br>CONCLUSIONS: The expression of CCR7 in HRS cells suggests its potential utility in differentiating CHL from other B-cell lymphomas. Incorporating CCR7 into flow cytometry and IHC panels may further enhance the diagnostic sensitivity of CHL.}, }
@article {pmid39287566, year = {2024}, author = {Neary, J and Njuguna, I and Wagner, AD and Richardson, BA and Chebet, D and Langat, A and Ngugi, E and Benki-Nugent, S and Moraa, H and Hawes, SE and Overbaugh, J and Slyker, JA and Lehman, DA and Wamalwa, D and John-Stewart, G}, title = {Brief Report: Group-Based Trajectory Modeling to Determine Long-Term HIV Viral Load Trends Among Children With HIV in Kenya.}, journal = {Journal of acquired immune deficiency syndromes (1999)}, volume = {96}, number = {4}, pages = {311-317}, pmid = {39287566}, issn = {1944-7884}, support = {R01 AI076105/AI/NIAID NIH HHS/United States ; F31 HD106261/HD/NICHD NIH HHS/United States ; K01MH121124/MH/NIMH NIH HHS/United States ; K24 HD054314/HD/NICHD NIH HHS/United States ; R01HD094718//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P30 AI027757/AI/NIAID NIH HHS/United States ; R25 TW011212/TW/FIC NIH HHS/United States ; K01AI087369//Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ ; K24HD054314//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; K01 AI087369/AI/NIAID NIH HHS/United States ; R01HD23412//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; R01 HD094718/HD/NICHD NIH HHS/United States ; P30AI027757//Center for AIDS Research, University of Washington/ ; K43 TW 011422-01A1/TW/FIC NIH HHS/United States ; F31HD106261//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; R01 HD023412/HD/NICHD NIH HHS/United States ; K43 TW011422/TW/FIC NIH HHS/United States ; K01 MH121124/MH/NIMH NIH HHS/United States ; }, mesh = {Child ; Child, Preschool ; Female ; Humans ; Infant ; Male ; *Anti-HIV Agents/therapeutic use ; *HIV Infections/drug therapy/virology ; Kenya/epidemiology ; Longitudinal Studies ; Medication Adherence/statistics &amp; numerical data ; *Viral Load ; }, abstract = {BACKGROUND: Identifying determinants of longitudinal HIV viral load (VL) trajectories using group-based trajectory modeling (GBTM) can inform clinical strategies and mechanisms of nonadherence among children.<br><br>METHODS: Children under 12 months old who were newly diagnosed with HIV were enrolled in the Optimizing Pediatric HIV therapy cohort (NCT00428116) from 2007 to 2010. Children initiated antiretroviral therapy at enrollment, and VL was assessed every 3 months for 24 months post-antiretroviral therapy and every 6 months thereafter up to 8 years old. VL trajectory groups were defined using GBTM. Fisher's exact and Kruskal-Wallis tests were used to determine the correlates of each trajectory group compared with the sustained-low VL group.<br><br>RESULTS: Five VL trajectory groups were identified among 89 children with 522 VL visits from 6 to 24 months: sustained-low (63% of children), sustained-very-high (16%), sustained-high (9%), low-to-high (7%), and high-with-periods-of-low (6%). Children in the sustained-high group were more frequently on a first-line protease inhibitor (PI)-based regimen (63% vs 38%; P = 0.03) and had younger caregivers (median: 22 vs 28 years; P = 0.02). Among 54 children with 560 VL visits followed from 48 to 96 months, 5 trajectory groups were identified: sustained-low (74%), mid-range (4%), periods-of-low (7%), high-to-low (7%), and sustained-high (7%). Those in the high-to-low group had younger caregivers (21 vs 29 years; P = 0.01).<br><br>CONCLUSIONS: GBTM identified unique VL patterns among children with unsuppressed VL. Caregiver and regimen-related characteristics were associated with patterns of nonsuppression. Younger caregivers may benefit from tailored counseling to help them support child antiretroviral therapy adherence. Palatable regimens are necessary for viral suppression among children with HIV.}, }
@article {pmid39286979, year = {2024}, author = {Westaby, D and Jiménez-Vacas, JM and Figueiredo, I and Rekowski, J and Pettinger, C and Gurel, B and Lundberg, A and Bogdan, D and Buroni, L and Neeb, A and Padilha, A and Taylor, J and Zeng, W and Das, S and Hobern, E and Riisnaes, R and Crespo, M and Miranda, S and Ferreira, A and Hanratty, BP and Nava Rodrigues, D and Bertan, C and Seed, G and Fenor de La Maza, MLD and Guo, C and Carmichael, J and Grochot, R and Chandran, K and Stavridi, A and Varkaris, A and Stylianou, N and Hollier, BG and Tunariu, N and Balk, SP and Carreira, S and Yuan, W and Nelson, PS and Corey, E and Haffner, M and de Bono, J and Sharp, A}, title = {BCL2 expression is enriched in advanced prostate cancer with features of lineage plasticity.}, journal = {The Journal of clinical investigation}, volume = {134}, number = {18}, pages = {}, pmid = {39286979}, issn = {1558-8238}, mesh = {Male ; Humans ; *Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; *Prostatic Neoplasms, Castration-Resistant/genetics/pathology/metabolism ; *Gene Expression Regulation, Neoplastic ; Animals ; Cell Line, Tumor ; Receptors, Androgen/metabolism/genetics ; Mice ; DNA Methylation ; Epithelial-Mesenchymal Transition ; Basic Helix-Loop-Helix Transcription Factors/genetics/metabolism ; Cell Lineage ; Neoplasm Proteins/genetics/metabolism/biosynthesis ; }, abstract = {The widespread use of potent androgen receptor signaling inhibitors (ARSIs) has led to an increasing emergence of AR-independent castration-resistant prostate cancer (CRPC), typically driven by loss of AR expression, lineage plasticity, and transformation to prostate cancers (PCs) that exhibit phenotypes of neuroendocrine or basal-like cells. The anti-apoptotic protein BCL2 is upregulated in neuroendocrine cancers and may be a therapeutic target for this aggressive PC disease subset. There is an unmet clinical need, therefore, to clinically characterize BCL2 expression in metastatic CRPC (mCRPC), determine its association with AR expression, uncover its mechanisms of regulation, and evaluate BCL2 as a therapeutic target and/or biomarker with clinical utility. Here, using multiple PC biopsy cohorts and models, we demonstrate that BCL2 expression is enriched in AR-negative mCRPC, associating with shorter overall survival and resistance to ARSIs. Moreover, high BCL2 expression associates with lineage plasticity features and neuroendocrine marker positivity. We provide evidence that BCL2 expression is regulated by DNA methylation, associated with epithelial-mesenchymal transition, and increased by the neuronal transcription factor ASCL1. Finally, BCL2 inhibition had antitumor activity in some, but not all, BCL2-positive PC models, highlighting the need for combination strategies to enhance tumor cell apoptosis and enrich response.}, }
@article {pmid39286457, year = {2024}, author = {von Berg, J and McArdle, PF and Häppölä, P and Haessler, J and Kooperberg, C and Lemmens, R and Pezzini, A and Thijs, V and Pulit, SL and Kittner, SJ and Mitchell, BD and de Ridder, J and van der Laan, SW}, title = {Evidence of survival bias in the association between APOE-Є4 and age at ischemic stroke onset.}, journal = {Frontiers in genetics}, volume = {15}, number = {}, pages = {1392061}, pmid = {39286457}, issn = {1664-8021}, support = {75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; R01 NS100178/NS/NINDS NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; R01 NS105150/NS/NINDS NIH HHS/United States ; I01 BX004672/BX/BLRD VA/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; }, abstract = {INTRODUCTION: Large genome-wide association studies (GWASs) using case-control study designs have now identified tens of loci associated with ischemic stroke (IS). As a complement to these studies, we performed GWAS in a case-only design to identify loci influencing the age at onset (AAO) of ischemic stroke.<br><br>METHODS: Analyses were conducted in a discovery cohort of 10,857 ischemic stroke cases using a linear regression framework. We meta-analyzed all SNPs with p-value <1 x 10[-5] in a sexcombined or sex-stratified analysis using summary data from two additional replication cohorts.<br><br>RESULTS: In the women-only meta-analysis, we detected significant evidence for the association of AAO with rs429358, an exonic variant in apolipoprotein E (APOE) that encodes for the APOE-&#x404;4 allele. Each copy of the rs429358:T>C allele was associated with a 1.29-year earlier stroke AAO (meta p-value = 2.48 x 10[-11]). This APOE variant has previously been associated with increased mortality and ischemic stroke AAO. We hypothesized that the association with AAO may reflect a survival bias attributable to an age-related decrease in mortality among APOE-&#x404;4 carriers and have no association to stroke AAO per se. A simulation study showed that a variant associated with overall mortality might indeed be detected with an AAO analysis. A variant with a 2-fold increase in mortality risk would lead to an observed effect of AAO that is comparable to what we found.<br><br>DISCUSSION: In conclusion, we detected a robust association of the APOE locus with stroke AAO and provided simulations to suggest that this association may be unrelated to ischemic stroke per se but related to a general survival bias.}, }
@article {pmid39283647, year = {2024}, author = {Church, EC and Bishop, E and Fiore-Gartland, A and Yu, KKQ and Chang, M and Jones, RM and Brache, JK and Ballweber Fleming, L and Phan, JM and Makatsa, MS and Heptinstall, J and Chiong, K and Dintwe, O and Naidoo, A and Voillet, V and Mayer-Blackwell, K and Nwanne, G and Andersen-Nissen, E and Vary, JC and Tomaras, GD and McElrath, MJ and Sherman, DR and Murphy, SC and Kublin, JG and Seshadri, C}, title = {Probing Dermal Immunity to Mycobacteria through a Controlled Human Infection Model.}, journal = {ImmunoHorizons}, volume = {8}, number = {9}, pages = {695-711}, pmid = {39283647}, issn = {2573-7732}, support = {P30 AI168034/AI/NIAID NIH HHS/United States ; 75N92020D00005/HL/NHLBI NIH HHS/United States ; 75N93019C00071/AI/NIAID NIH HHS/United States ; 75N93022D00005/AI/NIAID NIH HHS/United States ; 75N99020D00005/OF/ORFDO NIH HHS/United States ; R01 AI146072/AI/NIAID NIH HHS/United States ; 75N95020D00005/DA/NIDA NIH HHS/United States ; 75N93023D00005/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Mycobacterium bovis/immunology ; *Skin/immunology/microbiology/pathology ; Male ; Adult ; Isoniazid/therapeutic use/pharmacology ; Female ; Tuberculosis/immunology/microbiology ; Young Adult ; Antitubercular Agents/therapeutic use ; }, abstract = {Cutaneous mycobacterial infections cause substantial morbidity and are challenging to diagnose and treat. An improved understanding of the dermal immune response to mycobacteria may inspire new therapeutic approaches. We conducted a controlled human infection study with 10 participants who received 2 × 106 CFUs of Mycobacterium bovis bacillus Calmette-Guérin (Tice strain) intradermally and were randomized to receive isoniazid or no treatment. Peripheral blood was collected at multiple time points for flow cytometry, bulk RNA sequencing (RNA-seq), and serum Ab assessments. Systemic immune responses were detected as early as 8 d postchallenge in this M. bovis bacillus Calmette-Guérin-naive population. Injection-site skin biopsies were performed at days 3 and 15 postchallenge and underwent immune profiling using mass cytometry and single-cell RNA-seq, as well as quantitative assessments of bacterial viability and burden. Molecular viability testing and standard culture results correlated well, although no differences were observed between treatment arms. Single-cell RNA-seq revealed various immune and nonimmune cell types in the skin, and communication between them was inferred by ligand-receptor gene expression. Day 3 communication was predominantly directed toward monocytes from keratinocyte, muscle, epithelial, and endothelial cells, largely via the migration inhibitory factor pathway and HLA-E-KLRK1 interaction. At day 15, communication was more balanced between cell types. These data reveal the potential role of nonimmune cells in the dermal immune response to mycobacteria and the utility of human challenge studies to augment our understanding of mycobacterial infections.}, }
@article {pmid39283236, year = {2024}, author = {Presant, CA and Till, C and Vaidya, R and Ashing, KT and Warren, GW and Sun, V and Salgia, R and Massarelli, E and Mortimer, JE and Pal, S and Dorff, T and Amini, A and Erhunmwunsee, L and Phillips, T and Hershman, DL and Unger, JM}, title = {Smoking prevalence and association with sociodemographic variables in cancer clinical trial participants.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.35560}, pmid = {39283236}, issn = {1097-0142}, support = {UG1 CA189974/CA/NCI NIH HHS/United States ; R01 CA27989/CA/NCI NIH HHS/United States ; UG1CA189974//NIH/NCI/NCORP/ ; //Hope Foundation/ ; P30&#xa0;CA033572/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Tobacco use (smoking) causes adverse clinical outcomes among patients with cancer, including increased cancer-related mortality. In participants in cancer clinical trials, the prevalence of tobacco use and the factors associated with tobacco use are not well described.<br><br>METHODS: Data were examined from participants enrolled in SWOG cancer clinical treatment trials between 2016 and 2022 who reported their smoking status at trial enrollment. Baseline variables (smoking status, insurance type, zip code, and demographic factors) were obtained from patient registration forms. Bivariate and multivariable associations were examined via logistic regression.<br><br>RESULTS: Among 4326 patients enrolled in 29 trials, 48.1% reported currently/previously smoking, including 12.4% currently, 4.9% recently, and 30.7% formerly. Ever smoking was more commonly reported in males, patients aged &#x2265;65 years, patients with Medicaid or no insurance, patients from areas of high socioeconomic deprivation, and rural patients. Patients of Hispanic ethnicity and Asian and Pacific Islander patients were less likely to have ever smoked. In multivariable regression, patients with lung cancer were most likely to report ever smoking compared to patients with breast cancer (odds ratio,&#xa0;4.98; p&#xa0;<&#xa0;.001).<br><br>CONCLUSIONS: In the first comprehensive evaluation of smoking status among trial participants enrolled in National Cancer Institute network group treatment trials, nearly half reported ever smoking and one in six reported current or recent smoking. Smoking was more common among vulnerable population patients defined by demographic and socioeconomic factors. Tobacco use should be routinely assessed and reported in clinical trials to help reduce the negative cancer and overall health effects of persistent tobacco use and to address disparities among patients with cancer.}, }
@article {pmid39283073, year = {2024}, author = {Crawford, KHD and Baniecki, ML and Dushin, EG and Tierney, CA and Guan, S and Stensland, LL and Perez-Osorio, AC and Greninger, AL}, title = {Specimen adequacy assay controls in nucleic acid amplification tests do not correlate with nasopharyngeal swab collection method.}, journal = {Journal of clinical microbiology}, volume = {62}, number = {10}, pages = {e0097524}, pmid = {39283073}, issn = {1098-660X}, mesh = {Humans ; *Nasopharynx/virology/microbiology ; *Specimen Handling/methods ; *Nucleic Acid Amplification Techniques/methods ; COVID-19 Nucleic Acid Testing/methods/standards ; }, }
@article {pmid39282902, year = {2024}, author = {Apolo, AB and Ballman, KV and Sonpavde, G and Berg, S and Kim, WY and Parikh, R and Teo, MY and Sweis, RF and Geynisman, DM and Grivas, P and Chatta, G and Reichert, ZR and Kim, JW and Bilen, MA and McGregor, B and Singh, P and Tripathi, A and Cole, S and Simon, N and Niglio, S and Ley, L and Cordes, L and Srinivas, S and Huang, J and Odegaard, M and Watt, C and Petrylak, D and Hoffman-Censits, J and Wen, Y and Hahn, O and Mitchell, C and Tan, A and Streicher, H and Sharon, E and Moon, H and Woods, M and Halabi, S and Perez Burbano, G and Morris, MJ and Rosenberg, JE}, title = {Adjuvant Pembrolizumab versus Observation in Muscle-Invasive Urothelial Carcinoma.}, journal = {The New England journal of medicine}, volume = {}, number = {}, pages = {}, doi = {10.1056/NEJMoa2401726}, pmid = {39282902}, issn = {1533-4406}, support = {UG1 CA233160/CA/NCI NIH HHS/United States ; UG1 CA233302/CA/NCI NIH HHS/United States ; UG1 CA233373/CA/NCI NIH HHS/United States ; UG1 CA233193/CA/NCI NIH HHS/United States ; UG1 CA233180/CA/NCI NIH HHS/United States ; UG1 CA233191/CA/NCI NIH HHS/United States ; U10 CA180882/CA/NCI NIH HHS/United States ; U10 CA180820/CA/NCI NIH HHS/United States ; UG1 CA233247/CA/NCI NIH HHS/United States ; UG1 CA233253/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; UG1 CA233290/CA/NCI NIH HHS/United States ; UG1 CA233270/CA/NCI NIH HHS/United States ; U10 CA180821/CA/NCI NIH HHS/United States ; UG1 CA233337/CA/NCI NIH HHS/United States ; UG1 CA233196/CA/NCI NIH HHS/United States ; UG1 CA233327/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Muscle-invasive urothelial carcinoma is an aggressive disease with high rates of relapse. Whether pembrolizumab as adjuvant therapy would be effective in patients with high-risk muscle-invasive urothelial carcinoma after radical surgery is unknown.<br><br>METHODS: In this phase 3 trial, we randomly assigned patients, in a 1:1 ratio, to receive pembrolizumab at a dose of 200 mg every 3 weeks for 1 year or to undergo observation. Randomization was stratified according to pathological stage, centrally tested programmed death ligand 1 (PD-L1) status, and previous neoadjuvant chemotherapy. The coprimary end points were disease-free survival and overall survival in the intention-to-treat population. We considered the trial to be successful if either disease-free survival or overall survival was significantly longer with pembrolizumab than with observation.<br><br>RESULTS: A total of 702 patients underwent randomization; 354 were assigned to receive pembrolizumab, and 348 were assigned to observation. As of July 5, 2024, the median duration of follow-up for disease-free survival was 44.8 months. The median disease-free survival was 29.6 months (95% confidence interval [CI], 20.0 to 40.7) with pembrolizumab and 14.2 months (95% CI, 11.0 to 20.2) with observation (hazard ratio for disease progression or death, 0.73; 95% CI, 0.59 to 0.90; two-sided P&#x2009;=&#x2009;0.003). Grade 3 or higher adverse events (regardless of attribution) occurred in 50.7% of the patients in the pembrolizumab group and in 31.6% of the patients in the observation group.<br><br>CONCLUSIONS: Among patients with high-risk muscle-invasive urothelial carcinoma after radical surgery, disease-free survival was significantly longer with adjuvant pembrolizumab than with observation. (Funded by the National Cancer Institute of the National Institutes of Health and others; Alliance A031501 AMBASSADOR ClinicalTrials.gov number, NCT03244384.).}, }
@article {pmid39282531, year = {2024}, author = {Beresford, SAA and Ornelas, IJ and Garrity, G and Bauer, MC and Bishop, SK and Vreeke, A and Garcia, L and Francis, B and Rillamas-Sun, E and Lombard, KA}, title = {Impact of a school-based intervention and the COVID-19 pandemic on healthy eating in Navajo families: Results from the Yéego! Healthy eating and gardening intervention trial.}, journal = {Preventive medicine reports}, volume = {46}, number = {}, pages = {102858}, pmid = {39282531}, issn = {2211-3355}, support = {U54 CA132381/CA/NCI NIH HHS/United States ; U54 CA132383/CA/NCI NIH HHS/United States ; }, abstract = {OBJECTIVES: As part of a group randomized trial of a school-based intervention promoting gardening and healthy eating, health behaviors of adult family members were evaluated. The COVID-19 pandemic hit the Navajo Nation in March 2020 and the ongoing Yéego! collaborative study allowed description of adult response to COVID as an ancillary objective.<br><br>METHODS: Six elementary schools on the Navajo Nation in Arizona or New Mexico had been randomized to intervention or comparison group. One adult family member for each 3rd and 4th grade student completed surveys at baseline, nine-month and 21-month follow-up. Adult outcomes were fruit and vegetable (F&amp;V) intake, obesogenic dietary index and gardening frequency. COVID-related measures were collected at 21-month follow-up. Differential changes and interactions were examined using repeated measures linear mixed models.<br><br>RESULTS: Adult F&amp;V intake increased significantly more in the intervention group than in the comparison group at nine months by 2.26 servings/day (95% CI: 0.45, 4.06). No other changes were associated with the intervention at nine or 21&#xa0;months. At 21&#xa0;months, in the subgroup with COVID concerns, the differential change in F&amp;V intake was 2.02 (95% CI: 0.21, 3.84) servings/day. In cross-sectional analyses, only healthy eating measures varied by levels of COVID concerns, stress and resilience.<br><br>CONCLUSIONS: The child focused school-based intervention had some impact on adult family members, particularly their F&amp;V intake, suggesting the reach of the intervention extended to students' families. The impact on adult F&amp;V intake persisted among those reporting COVID concerns. Findings have important implications for augmenting healthy eating interventions.}, }
@article {pmid39282444, year = {2024}, author = {Zych, MG and Contreras, M and Vashisth, M and Mammel, AE and Ha, G and Hatch, EM}, title = {RCC1 depletion drives protein transport defects and rupture in micronuclei.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39282444}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R35 GM124766/GM/NIGMS NIH HHS/United States ; T32 GM007270/GM/NIGMS NIH HHS/United States ; DP2 CA280624/CA/NCI NIH HHS/United States ; T32 CA009657/CA/NCI NIH HHS/United States ; }, abstract = {Micronuclei (MN) are a commonly used marker of chromosome instability that form when missegregated chromatin recruits its own nuclear envelope (NE) after mitosis. MN frequently rupture, which results in genome instability, upregulation of metastatic genes, and increased immune signaling. MN rupture is linked to NE defects, but the cause of these defects is poorly understood. Previous work from our lab found that chromosome identity correlates with rupture timing for small MN, i.e. MN containing a short chromosome, with more euchromatic chromosomes forming more stable MN with fewer nuclear lamina gaps. Here we demonstrate that histone methylation promotes rupture and nuclear lamina defects in small MN. This correlates with increased MN size, and we go on to find that all MN have a constitutive nuclear export defect that drives MN growth and nuclear lamina gap expansion, making the MN susceptible to rupture. We demonstrate that these export defects arise from decreased RCC1 levels in MN and that additional loss of RCC1 caused by low histone methylation in small euchromatic MN results in additional import defects that suppress nuclear lamina gaps and MN rupture. Through analysis of mutational signatures associated with early and late rupturing chromosomes in the Pan-Cancer Analysis of Whole Genomes (PCAWG) dataset, we identify an enrichment of APOBEC and DNA polymerase E hypermutation signatures in chromothripsis events on early and mid rupturing chromosomes, respectively, suggesting that MN rupture timing could determine the landscape of structural variation in chromothripsis. Our study defines a new model of MN rupture where increased MN growth, caused by defects in protein export, drives gaps in nuclear lamina organization that make the MN susceptible to membrane rupture with long-lasting effects on genome architecture.}, }
@article {pmid39282381, year = {2024}, author = {Shinde, P and Willemsen, L and Anderson, M and Aoki, M and Basu, S and Burel, JG and Cheng, P and Dastidar, SG and Dunleavy, A and Einav, T and Forschmiedt, J and Fourati, S and Garcia, J and Gibson, W and Greenbaum, JA and Guan, L and Guan, W and Gygi, JP and Ha, B and Hou, J and Hsiao, J and Huang, Y and Jansen, R and Kakoty, B and Kang, Z and Kobie, JJ and Kojima, M and Konstorum, A and Lee, J and Lewis, SA and Li, A and Lock, EF and Mahita, J and Mendes, M and Meng, H and Neher, A and Nili, S and Olsen, LR and Orfield, S and Overton, JA and Pai, N and Parker, C and Qian, B and Rasmussen, M and Reyna, J and Richardson, E and Safo, S and Sorenson, J and Srinivasan, A and Thrupp, N and Tippalagama, R and Trevizani, R and Ventz, S and Wang, J and Wu, CC and Ay, F and Grant, B and Kleinstein, SH and Peters, B}, title = {Putting computational models of immunity to the test - an invited challenge to predict B. pertussis vaccination outcomes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39282381}, issn = {2692-8205}, support = {U01 AI141995/AI/NIAID NIH HHS/United States ; U01 AI150753/AI/NIAID NIH HHS/United States ; U19 AI142742/AI/NIAID NIH HHS/United States ; }, abstract = {Systems vaccinology studies have been used to build computational models that predict individual vaccine responses and identify the factors contributing to differences in outcome. Comparing such models is challenging due to variability in study designs. To address this, we established a community resource to compare models predicting B. pertussis booster responses and generate experimental data for the explicit purpose of model evaluation. We here describe our second computational prediction challenge using this resource, where we benchmarked 49 algorithms from 53 scientists. We found that the most successful models stood out in their handling of nonlinearities, reducing large feature sets to representative subsets, and advanced data preprocessing. In contrast, we found that models adopted from literature that were developed to predict vaccine antibody responses in other settings performed poorly, reinforcing the need for purpose-built models. Overall, this demonstrates the value of purpose-generated datasets for rigorous and open model evaluations to identify features that improve the reliability and applicability of computational models in vaccine response prediction.}, }
@article {pmid39282263, year = {2024}, author = {Banjoko, AW and Ng'uni, T and Naidoo, N and Ramsuran, V and Hyrien, O and Ndhlovu, ZM}, title = {High Resolution Class I HLA -A, -B, and -C Diversity in Eastern and Southern African Populations.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39282263}, issn = {2692-8205}, support = {R01 AI181690/AI/NIAID NIH HHS/United States ; }, abstract = {Africa remains significantly underrepresented in high-resolution Human Leukocyte Antigen (HLA) data, despite being one of the most genetically diverse regions in the world. This critical gap in genetic information poses a substantial barrier to HLA-based research on the continent. In this study, Class I HLA data from Eastern and Southern African populations were analysed to assess genetic diversity across the region. We examined allele and haplotype frequency distributions, deviations from Hardy-Weinberg Equilibrium (HWE), linkage disequilibrium (LD), and conducted neutrality tests of homozygosity across various populations. Additionally, the African HLA data were compared to those of Caucasian and African American populations using the Jaccard index and multidimensional scaling (MDS) methods. The study revealed that South African populations exhibited 50.4% more genetic diversity within the Class I HLA region compared to other African populations. Zambia showed an estimated 36.5% genetic diversity, with Kenya, Rwanda and Uganda showing 35.7%, 34.2%, and 31.1%, respectively. Furthermore, an analysis of in-country diversity among different tribes indicated an average Class I HLA diversity of 25.7% in Kenya, 17% in Rwanda, 2.8% in South Africa, 13.6% in Uganda, and 6.5% in Zambia. The study also highlighted the genetic distinctness of Caucasian and African American populations compared to African populations. Notably, the differential frequencies of disease-promoting and disease-preventing HLA alleles across these populations emphasize the urgent need to generate high-quality HLA data for all regions of Africa and its major ethnic groups. Such efforts will be crucial in enhancing healthcare outcomes across the continent.}, }
@article {pmid39281752, year = {2024}, author = {Zanti, M and O'Mahony, DG and Parsons, MT and Dorling, L and Dennis, J and Boddicker, NJ and Chen, W and Hu, C and Naven, M and Yiangou, K and Ahearn, TU and Ambrosone, CB and Andrulis, IL and Antoniou, AC and Auer, PL and Baynes, C and Bodelon, C and Bogdanova, NV and Bojesen, SE and Bolla, MK and Brantley, KD and Camp, NJ and Campbell, A and Castelao, JE and Cessna, MH and Chang-Claude, J and Chen, F and Chenevix-Trench, G and ,  and Conroy, DM and Czene, K and De Nicolo, A and Domchek, SM and Dörk, T and Dunning, AM and Eliassen, AH and Evans, DG and Fasching, PA and Figueroa, JD and Flyger, H and Gago-Dominguez, M and García-Closas, M and Glendon, G and González-Neira, A and Grassmann, F and Hadjisavvas, A and Haiman, CA and Hamann, U and Hart, SN and Hartman, MBA and Ho, WK and Hodge, JM and Hoppe, R and Howell, SJ and ,  and Jakubowska, A and Khusnutdinova, EK and Ko, YD and Kraft, P and Kristensen, VN and Lacey, JV and Li, J and Lim, GH and Lindström, S and Lophatananon, A and Luccarini, C and Mannermaa, A and Martinez, ME and Mavroudis, D and Milne, RL and Muir, K and Nathanson, KL and Nuñez-Torres, R and Obi, N and Olson, JE and Palmer, JR and Panayiotidis, MI and Patel, AV and Pharoah, PDP and Polley, EC and Rashid, MU and Ruddy, KJ and Saloustros, E and Sawyer, EJ and Schmidt, MK and Southey, MC and Tan, VK and Teo, SH and Teras, LR and Torres, D and Trentham-Dietz, A and Truong, T and Vachon, CM and Wang, Q and Weitzel, JN and Yadav, S and Yao, S and Zirpoli, GR and Cline, MS and Devilee, P and Tavtigian, SV and Goldgar, DE and Couch, FJ and Easton, DF and Spurdle, AB and Michailidou, K}, title = {Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39281752}, support = {/WT_/Wellcome Trust/United Kingdom ; P50 CA116201/CA/NCI NIH HHS/United States ; R01 CA225662/CA/NCI NIH HHS/United States ; R35 CA253187/CA/NCI NIH HHS/United States ; }, abstract = {Clinical genetic testing identifies variants causal for hereditary cancer, information that is used for risk assessment and clinical management. Unfortunately, some variants identified are of uncertain clinical significance (VUS), complicating patient management. Case-control data is one evidence type used to classify VUS, and previous findings indicate that case-control likelihood ratios (LRs) outperform odds ratios for variant classification. As an initiative of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Analytical Working Group we analyzed germline sequencing data of BRCA1 and BRCA2 from 96,691 female breast cancer cases and 303,925 unaffected controls from three studies: the BRIDGES study of the Breast Cancer Association Consortium, the Cancer Risk Estimates Related to Susceptibility consortium, and the UK Biobank. We observed 11,227 BRCA1 and BRCA2 variants, with 6,921 being coding, covering 23.4% of BRCA1 and BRCA2 VUS in ClinVar and 19.2% of ClinVar curated (likely) benign or pathogenic variants. Case-control LR evidence was highly consistent with ClinVar assertions for (likely) benign or pathogenic variants; exhibiting 99.1% sensitivity and 95.4% specificity for BRCA1 and 92.2% sensitivity and 86.6% specificity for BRCA2. This approach provides case-control evidence for 785 unclassified variants, that can serve as a valuable element for clinical classification.}, }
@article {pmid39280607, year = {2024}, author = {Qin, G and Zhang, Y and Tyner, JW and Kemp, CJ and Shmulevich, I}, title = {Knowledge graphs facilitate prediction of drug response for acute myeloid leukemia.}, journal = {iScience}, volume = {27}, number = {9}, pages = {110755}, pmid = {39280607}, issn = {2589-0042}, support = {R01 CA270210/CA/NCI NIH HHS/United States ; }, abstract = {Acute myeloid leukemia (AML) is a highly aggressive and heterogeneous disease, underscoring the need for improved therapeutic options and methods to optimally predict responses. With the wealth of available data resources, including clinical features, multiomics analysis, and ex vivo drug screening from AML patients, development of drug response prediction models has become feasible. Knowledge graphs (KGs) embed the relationships between different entities or features, allowing for explanation of a wide breadth of drug sensitivity and resistance mechanisms. We designed AML drug response prediction models guided by KGs. Our models included engineered features, relative gene expression between marker genes for each drug and regulators (e.g., transcription factors). We identified relative gene expression of FGD4-MIR4519, NPC2-GATA2, and BCL2-NFKB2 as predictive features for venetoclax ex vivo drug response. The KG-guided models provided high accuracy in independent test sets, overcame potential platform batch effects, and provided candidate drug sensitivity biomarkers for further validation.}, }
@article {pmid39279497, year = {2024}, author = {Smoljo, T and Lalic, H and Dembitz, V and Tomic, B and Batinic, J and Vrhovac, R and Bedalov, A and Visnjic, D}, title = {Bone marrow stromal cells enhance differentiation of acute myeloid leukemia induced by pyrimidine synthesis inhibitors.}, journal = {American journal of physiology. Cell physiology}, volume = {327}, number = {5}, pages = {C1202-C1218}, pmid = {39279497}, issn = {1522-1563}, support = {GA KK01.1.1.01.0007//EC | European Regional Development Fund (ERDF)/ ; International Award for Research in Leukaemia to Vilma Dembitz//Lady Tata Memorial Trust (LTMT)/ ; DOK-2018-01-9599//Hrvatska Zaklada za Znanost (HRZZ)/ ; R01 GM117446/GM/NIGMS NIH HHS/United States ; R01GM117446//Foundation for the National Institutes of Health (FNIH)/ ; IP-2022-10-9146//Hrvatska Zaklada za Znanost (HRZZ)/ ; DOK-2020-01-2873//Hrvatska Zaklada za Znanost (HRZZ)/ ; }, mesh = {Humans ; *Leukemia, Myeloid, Acute/pathology/metabolism/drug therapy ; *Mesenchymal Stem Cells/drug effects/metabolism/pathology ; Animals ; *Cell Differentiation/drug effects ; Mice ; *Aminoimidazole Carboxamide/analogs &amp; derivatives/pharmacology ; *Pyrimidines/pharmacology ; *Ribonucleotides/pharmacology ; Dihydroorotate Dehydrogenase ; Cell Line, Tumor ; AMP-Activated Protein Kinases/metabolism ; Bone Marrow Cells/drug effects/metabolism/pathology ; Biphenyl Compounds ; Quinaldines ; }, abstract = {Acute myeloid leukemia (AML) is a heterogeneous group of hematological malignancies characterized by differentiation arrest, high relapse rates, and poor survival. The bone marrow (BM) microenvironment is recognized as a critical mediator of drug resistance and a primary site responsible for AML relapse. Our previous study reported that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr) induces AML cell differentiation by inhibiting pyrimidine synthesis and activating Checkpoint kinase 1. Although the protective effect of BM stroma on leukemia cells in response to cytotoxic drugs is well-documented, its effect on AML differentiation remains less explored. In this study, we investigated the impact of stromal cell lines and primary mesenchymal stromal cells (MSCs) on AML cell line differentiation triggered by AICAr and brequinar, a known dihydroorotate dehydrogenase (DHODH) inhibitor. Our findings indicate that the mouse MS-5 stromal cell line, known for its cytoprotective effects, does not inhibit AML cell differentiation induced by pyrimidine synthesis inhibitors. Interestingly, AICAr caused morphological changes and growth arrest in MS-5 stromal cells via an AMP-activated protein kinase (AMPK)-dependent pathway. Human stromal cell lines HS-5 and HS-27, as well as primary MSCs isolated from patient bone marrow, were superior in promoting AML differentiation compared with mouse cells in response to AICAr and brequinar, with the inhibitors not significantly affecting the stromal cells themselves. In conclusion, our study highlights the supportive role of human BM MSCs in enhancing the differentiation effects of pyrimidine synthesis inhibitors on AML cells, suggesting that AML treatment strategies focusing on differentiation rather than cell killing may be successful in clinical settings.NEW &amp; NOTEWORTHY This study is the first to demonstrate that human stromal cell lines and primary mesenchymal stromal cells from patients enhance the in vitro differentiation of acute myeloid leukemia (AML) cells induced by pyrimidine synthesis inhibitors, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr), and brequinar. Furthermore, this is the first report to show that AICAr affects mouse bone marrow stromal cells by activating AMP-activated protein kinase (AMPK) and that human stromal cells are superior to mouse cells for testing the effects of drugs on AML differentiation.}, }
@article {pmid39279226, year = {2024}, author = {Tandon, PS and Gabert, T and Kuhn, M and Tran, N and Ola, C and Sullivan, E and Zhou, C and Stein, M and Mendoza, JA and Sasser, T and Gonzalez, E}, title = {Modernizing behavioral parent training program for ADHD with mHealth strategies, telehealth groups, and health behavior curriculum: a randomized pilot trial.}, journal = {Journal of pediatric psychology}, volume = {49}, number = {9}, pages = {664-675}, pmid = {39279226}, issn = {1465-735X}, support = {R33 AT010041/AT/NCCIH NIH HHS/United States ; R33AT010041/NH/NIH HHS/United States ; }, mesh = {Humans ; *Attention Deficit Disorder with Hyperactivity/therapy ; Pilot Projects ; Child ; Male ; Female ; *Telemedicine ; *Parents/education ; *Health Behavior ; Feasibility Studies ; Curriculum ; Behavior Therapy/methods ; Adult ; }, abstract = {OBJECTIVE: Parent behavior management training (BMT) is an evidence-based yet underutilized tool to treat children with ADHD and address related health disparities. This pilot study investigated the acceptability and feasibility of a novel, health behavior-, and technology-adapted BMT (LEAP) vs. standard BMT.<br><br>METHODS: The weekly 9-session LEAP telemedicine group program is based on a standard BMT curriculum enhanced with strategies for supporting optimal child sleep, problematic media use (PMU), and physical activity, including wrist-worn activity trackers. Children ages 6-10&#x2009;years with ADHD and their caregivers were randomized to LEAP or standard BMT. Acceptability and feasibility were tracked. Caregivers completed standardized measures, and children wore hip-worn accelerometers for 1&#xa0;week at baseline, postintervention (10&#x2009;weeks), and follow-up (20&#x2009;weeks).<br><br>RESULTS: 84 parent/child dyads were randomized to LEAP or standard BMT, with high and comparable acceptability and feasibility. Both treatment groups demonstrated decreased ADHD symptoms and improved executive functions postintervention (p&#x2009;<&#x2009;.0001), maintained at follow-up. Average accelerometer-measured MVPA decreased and sleep duration remained unchanged, while PMU and bedtime resistance improved for both groups.<br><br>CONCLUSIONS: LEAP is highly feasible and acceptable, and yielded similar initial clinical and health behavior improvements to standard BMT. Innovative and targeted supports are needed to promote healthy behaviors in children with ADHD.}, }
@article {pmid39278553, year = {2024}, author = {Miranda, MA and Tsalatsanis, A and Trotter, JR and Arnold, DE and Squire, JD and Kidd, S and Parikh, S and Marsh, RA and Griffith, LM and Mallhi, K and Chellapandian, D and Lim, SS and Grunebaum, E and Sullivan, KE and Newburger, PE and Dinauer, MC and Cowan, MJ and Dvorak, CC and Haddad, E and Kohn, DB and Notarangelo, LD and Pai, SY and Puck, JM and Pulsipher, MA and Torgerson, TR and Malech, HL and Kang, EM and Morton, FB and Leiding, JW}, title = {High symptom burden in female X-linked chronic granulomatous disease carriers.}, journal = {Clinical immunology (Orlando, Fla.)}, volume = {268}, number = {}, pages = {110364}, doi = {10.1016/j.clim.2024.110364}, pmid = {39278553}, issn = {1521-7035}, }
@article {pmid39276915, year = {2024}, author = {Haab, B and Qian, L and Staal, B and Jain, M and Fahrmann, J and Worthington, C and Prosser, D and Velokokhatnaya, L and Lopez, C and Tang, R and Hurd, MW and Natarajan, G and Kumar, S and Smith, L and Hanash, S and Batra, SK and Maitra, A and Lokshin, A and Huang, Y and Brand, RE}, title = {A rigorous multi-laboratory study of known PDAC biomarkers identifies increased sensitivity and specificity over CA19-9 alone.}, journal = {Cancer letters}, volume = {604}, number = {}, pages = {217245}, doi = {10.1016/j.canlet.2024.217245}, pmid = {39276915}, issn = {1872-7980}, mesh = {Humans ; *Biomarkers, Tumor/blood ; *Carcinoma, Pancreatic Ductal/blood/diagnosis/pathology ; *Pancreatic Neoplasms/blood/diagnosis/pathology ; Case-Control Studies ; Female ; Male ; *CA-19-9 Antigen/blood ; Middle Aged ; Sensitivity and Specificity ; Aged ; Antigens, Tumor-Associated, Carbohydrate/blood ; }, abstract = {A blood test that enables surveillance for early-stage pancreatic ductal adenocarcinoma (PDAC) is an urgent need. Independent laboratories have reported PDAC biomarkers that could improve biomarker performance over CA19-9 alone, but the performance of the previously reported biomarkers in combination is not known. Therefore, we conducted a coordinated case/control study across multiple laboratories using common sets of blinded training and validation samples (132 and 295 plasma samples, respectively) from PDAC patients and non-PDAC control subjects representing conditions under which surveillance occurs. We analyzed the training set to identify candidate biomarker combination panels using biomarkers across laboratories, and we applied the fixed panels to the validation set. The panels identified in the training set, CA19-9 with CA199.STRA, LRG1, TIMP-1, TGM2, THSP2, ANG, and MUC16.STRA, achieved consistent performance in the validation set. The panel of CA19-9 with the glycan biomarker CA199.STRA improved sensitivity from 0.44 with 0.98 specificity for CA19-9 alone to 0.71 with 0.98 specificity (p < 0.001, 1000-fold bootstrap). Similarly, CA19-9 combined with the protein biomarker LRG1 and CA199.STRA improved specificity from 0.16 with 0.94 sensitivity for CA19-9 to 0.65 with 0.89 sensitivity (p < 0.001, 1000-fold bootstrap). We further validated significantly improved performance using biomarker panels that did not include CA19-9. This study establishes the effectiveness of a coordinated study of previously discovered biomarkers and identified panels of those biomarkers that significantly increased the sensitivity and specificity of early-stage PDAC detection in a rigorous validation trial.}, }
@article {pmid39276235, year = {2024}, author = {Miles, RC and Chou, SH and Lamb, LR and Narayan, A and Tran, NT and Lee, JM}, title = {Framework for Successful Integration of Health Services Research Into a Breast Imaging Career.}, journal = {Journal of breast imaging}, volume = {}, number = {}, pages = {}, doi = {10.1093/jbi/wbae042}, pmid = {39276235}, issn = {2631-6129}, abstract = {Health services research (HSR) is a multidisciplinary field of inquiry that examines how health care is structured, providing valuable data on health care outcomes and delivery. Over the past few decades, a shift in the U.S. health care system toward value-based care has placed a priority on health services topics. Health services research has been central to the evolution of breast imaging over this period, with increased emphasis placed on the following: (1) design of appropriate-use criteria for imaging services; (2) determination of cost-effectiveness of imaging protocols and screening regimens guiding policy; and (3) evaluation of policy related to reimbursement for diagnostic imaging and image-guided procedures. Examples of HSR topics that can be applied directly to breast imaging include evaluation of health care availability and accessibility, analysis of health care use patterns, exploration of patient preferences, assessment of technological innovation, development and implementation of clinical practice guidelines and screening strategies, and examination of health care organization and delivery models. Breast imaging radiologists who perform HSR are uniquely positioned to advocate for patients, to promote transformative health care interventions, and to influence policy changes and public health initiatives in breast imaging through analysis of health care data and translation of their research findings. In this Training and Professional Development article, we aim to provide practical approaches to explore interest in HSR and to describe a framework for successful integration of HSR into a breast imaging career.}, }
@article {pmid39271284, year = {2024}, author = {Grover, S and Court, L and Amoo-Mitchual, S and Longo, J and Rodin, D and Scott, AA and Lievens, Y and Yap, ML and Abdel-Wahab, M and Lee, P and Harsdorf, E and Khader, J and Jia, X and Dosanjh, M and Elzawawy, A and Ige, T and Pomper, M and Pistenmaa, D and Hardenbergh, P and Petereit, DG and Sargent, M and Cina, K and Li, B and Anacak, Y and Mayo, C and Prattipati, S and Lasebikan, N and Rendle, K and O'Brien, D and Wendling, E and Coleman, CN}, title = {Global Workforce and Access: Demand, Education, Quality.}, journal = {Seminars in radiation oncology}, volume = {34}, number = {4}, pages = {477-493}, doi = {10.1016/j.semradonc.2024.07.003}, pmid = {39271284}, issn = {1532-9461}, mesh = {Humans ; *Health Services Accessibility ; *Radiation Oncology ; *Neoplasms/radiotherapy ; Global Health ; Developing Countries ; Healthcare Disparities ; Health Services Needs and Demand ; }, abstract = {There has long existed a substantial disparity in access to radiotherapy globally. This issue has only been exacerbated as the growing disparity of cancer incidence between high-income countries (HIC) and low and middle-income countries (LMICs) widens, with a pronounced increase in cancer cases in LMICs. Even within HICs, iniquities within local communities may lead to a lack of access to care. Due to these trends, it is imperative to find solutions to narrow global disparities. This requires the engagement of a diverse cohort of stakeholders, including working professionals, non-governmental organizations, nonprofits, professional societies, academic and training institutions, and industry. This review brings together a diverse group of experts to highlight critical areas that could help reduce the current global disparities in radiation oncology. Advancements in technology and treatment, such as artificial intelligence, brachytherapy, hypofractionation, and digital networks, in combination with implementation science and novel funding mechanisms, offer means for increasing access to care and education globally. Common themes across sections reveal how utilizing these new innovations and strengthening collaborative efforts among stakeholders can help improve access to care globally while setting the framework for the next generation of innovations.}, }
@article {pmid39266311, year = {2024}, author = {Smibert, OC and Trubiano, JA and Kwong, JC and Markey, KA and Slavin, MA}, title = {Protocol for a clinically annotated biorepository of samples from Australian immune-compromised patients to investigate the host-microbiome interaction.}, journal = {BMJ open}, volume = {14}, number = {9}, pages = {e085504}, pmid = {39266311}, issn = {2044-6055}, mesh = {Humans ; Australia ; *Gastrointestinal Microbiome ; Host Microbial Interactions/immunology ; Biological Specimen Banks ; Prospective Studies ; Research Design ; Specimen Handling/methods ; }, abstract = {INTRODUCTION: The human gut microbiota has the potential to modulate the outcomes of several human diseases. This effect is likely to be mediated through interaction with the host immune system. This protocol details the establishment of a biorepository of clinically annotated samples, which we will use to explore correlations between the gut microbiota and the immune system of immune-compromised patients. We aim to identify microbiome-related risk factors for adverse outcomes.<br><br>METHODS AND ANALYSES: This is a protocol for the development of a biorepository of clinically annotated samples collected prospectively across three centres in Melbourne, Australia. Participants will be recruited across the following clinical streams: (1) acute leukaemia and allogeneic stem cell transplant; (2) end-stage liver disease and liver transplant; (3) patients receiving any cancer immunotherapies (eg, chimeric antigen receptor therapy); (4) deceased organ donors and (5) healthy adult controls. Participants will be asked to provide paired peripheral blood and microbiota samples (stool and saliva) at either (1) single time point for healthy controls and deceased organ donors or (2) longitudinally over multiple prespecified or event-driven time points for the remaining cohorts. Sampling of fluid from bronchoalveolar lavage and colonoscopy or biopsy of tissues undertaken during routine care will also be performed.<br><br>ETHICS AND DISSEMINATION: Ethical approval has been obtained from the relevant local ethics committee (The Royal Melbourne Hospital Human Research Ethics Committee). The results of this study will be disseminated by various scientific platforms including social media, international presentations and publication in peer-reviewed journals.<br><br>TRIAL REGISTRATION NUMBER: ACTRN12623001105639. Date registered 20 October 2023.}, }
@article {pmid39266299, year = {2024}, author = {Park, SH and Tsuzuki, S and Contino, KF and Ollodart, J and Eber, MR and Yu, Y and Steele, LR and Inaba, H and Kamata, Y and Kimura, T and Coleman, I and Nelson, PS and Muñoz-Islas, E and Jiménez-Andrade, JM and Martin, TJ and Mackenzie, KD and Stratton, JR and Hsu, FC and Peters, CM and Shiozawa, Y}, title = {Crosstalk between bone metastatic cancer cells and sensory nerves in bone metastatic progression.}, journal = {Life science alliance}, volume = {7}, number = {12}, pages = {}, pmid = {39266299}, issn = {2575-1077}, support = {R21 AR078366/AR/NIAMS NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; R01 CA234715/CA/NCI NIH HHS/United States ; P30 CA012197/CA/NCI NIH HHS/United States ; R01 CA238888/CA/NCI NIH HHS/United States ; R01 CA266452/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; *Bone Neoplasms/secondary/metabolism ; Humans ; Mice ; *Calcitonin Gene-Related Peptide/metabolism ; *Disease Progression ; *Sensory Receptor Cells/metabolism ; *Cell Proliferation ; Cell Line, Tumor ; Calcitonin Receptor-Like Protein/metabolism/genetics ; Female ; Male ; Signal Transduction ; }, abstract = {Although the role of peripheral nerves in cancer progression has been appreciated, little is known regarding cancer/sensory nerve crosstalk and its contribution to bone metastasis and associated pain. In this study, we revealed that the cancer/sensory nerve crosstalk plays a crucial role in bone metastatic progression. We found that (i) periosteal sensory nerves expressing calcitonin gene-related peptide (CGRP) are enriched in mice with bone metastasis; (ii) cancer patients with bone metastasis have elevated CGRP serum levels; (iii) bone metastatic patient tumor samples express elevated calcitonin receptor-like receptor (CRLR, a CGRP receptor component); (iv) higher CRLR levels in cancer patients are negatively correlated with recurrence-free survival; (v) CGRP induces cancer cell proliferation through the CRLR/p38/HSP27 pathway; and (vi) blocking sensory neuron-derived CGRP reduces cancer cell proliferation in vitro and bone metastatic progression in vivo. This suggests that CGRP-expressing sensory nerves are involved in bone metastatic progression and that the CGRP/CRLR axis may serve as a potential therapeutic target for bone metastasis.}, }
@article {pmid39265260, year = {2024}, author = {Bakaloudi, DR and Koehne, EL and Diamantopoulos, LN and Holt, SK and Sekar, RR and Ghali, F and Vakar-Lopez, F and Nyame, YA and Psutka, SP and Gore, JL and de la Calle, CM and Lin, DW and Schade, GR and Liao, JJ and Hsieh, AC and Yezefski, T and Hawley, JE and Yu, EY and Montgomery, RB and Grivas, P and Wright, JL}, title = {Small Cell Bladder Cancer: Treatment Patterns for Local Disease and Associated Outcomes. A Retrospective Cohort Study.}, journal = {Clinical genitourinary cancer}, volume = {22}, number = {6}, pages = {102208}, doi = {10.1016/j.clgc.2024.102208}, pmid = {39265260}, issn = {1938-0682}, mesh = {Humans ; *Urinary Bladder Neoplasms/therapy/pathology/mortality ; Retrospective Studies ; Male ; Female ; Aged ; *Cystectomy ; Treatment Outcome ; *Carcinoma, Small Cell/therapy/pathology/mortality ; *Chemoradiotherapy/methods ; Aged, 80 and over ; SEER Program ; Middle Aged ; Neoadjuvant Therapy ; Survival Analysis ; United States ; }, abstract = {BACKGROUND: Small cell bladder cancer (SCBC) is a rare histologic subtype with relative paucity of data regarding treatment response and outcomes. We reviewed 2 databases to compare outcomes in patients with localized SCBC treated with cystectomy versus concurrent chemoradiotherapy (CCRT). We hypothesized that survival would be similar with these therapy approaches.<br><br>METHODS: We retrospectively reviewed our institutional and SEER-Medicare databases to identify patients with SCBC. Overall survival (OS) was determined from the date of diagnosis to last follow-up/death. For those with nonmetastatic disease, a multivariate Cox analysis was used to compare locoregional therapy with neoadjuvant chemotherapy (NAC) + cystectomy versus CCRT.<br><br>RESULTS: We identified 53 patients in our institutional database and 1166 patients in SEER-Medicare with localized SCBC. Median OS (mOS) with NAC + cystectomy was 46 months (95% CI, 21-72) and 45 months (95% CI, 0-104) in the institutional and SEER-Medicare databases, respectively, whereas mOS with CCRT was 26 months (95% CI, 5-47) and 23 months (95% CI, 18-28) in the 2 series, respectively. In multivariate analysis, NAC followed by cystectomy was associated with an approximately 30% reduction in mortality compared to CCRT in both institutional and national databases but did not reach statistical significance (Institution HR 0.71, 95% CI, 0.22-2.4, P = .58; SEER HR 0.73, 95% CI, 0.49-1.08; P = .11).<br><br>CONCLUSIONS: SCBC is very aggressive with limited survival observed in our institutional and SEER-Medicare datasets regardless of locoregional therapy used. There is an unmet need to define the optimal locoregional therapy for nonmetastatic stage and identify novel therapeutic targets.}, }
@article {pmid39264595, year = {2024}, author = {Robbins, HA and Feng, X and Etzioni, R}, title = {Cancer Stage vs Mortality End Points in Randomized Clinical Trials of Cancer Screening.}, journal = {JAMA}, volume = {}, number = {}, pages = {}, doi = {10.1001/jama.2024.16365}, pmid = {39264595}, issn = {1538-3598}, support = {001/WHO_/World Health Organization/International ; }, }
@article {pmid39264541, year = {2024}, author = {Ratnayake, A and Hernandez, JH and Justman, J and Farley, JE and Hirsch-Moverman, Y and Ho, K and Mayer, S and Oluyomi, A and Sobieszczyk, ME and Swaminathan, S and Skalland, T and Tapsoba, JD and ,  and Kissinger, PJ}, title = {Vaccine Hesitancy at Nine Community Sites Across the United States, Early in COVID-19 Vaccine Rollout.}, journal = {Journal of racial and ethnic health disparities}, volume = {}, number = {}, pages = {}, pmid = {39264541}, issn = {2196-8837}, support = {UM1AI068619//Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ ; }, abstract = {BACKGROUND: Vaccine hesitancy has been a significant concern throughout the COVID-19 pandemic. Vaccine hesitancy can be attributed to lack of confidence in vaccines, complacency about the health threat, or lack of convenience of vaccination. To date, few studies have used methods designed to include populations underrepresented in research when identifying factors associated with vaccine hesitancy.<br><br>METHODS: Between January and July 2021, potential participants were recruited from community venues selected through time-location sampling in 15 defined communities in the United States. Study staff administered a questionnaire on demographics, COVID-19 behaviors and attitudes, and vaccination status or intention to consenting individuals. Vaccine hesitancy was analyzed among those age 18&#xa0;years and older from nine of the 15 sites and was defined as self-reported neutral, unlikely, or very unlikely vaccine intention. Logistic regression modeling, adjusted for site, identified factors associated with vaccine hesitancy.<br><br>RESULTS: Among 11,559 individuals, vaccine hesitancy by site ranged from 8.7 to 31.1%. Vaccine hesitancy was associated with being Black compared to White, being White compared to Asian, younger age, unstable housing, being unemployed, lower income, having a disability, providing care in home, not reporting inability to visit sick or elderly relatives during the pandemic, not reporting increased anxiety during the pandemic, and not spending more time with loved ones during the pandemic.<br><br>CONCLUSIONS: In these selected US communities, early in vaccine rollout, there were significant racial disparities in vaccine hesitancy. Additionally, individuals who were more marginalized due to their socioeconomic status were more likely to report vaccine hesitancy. Vaccine campaigns should make efforts to remove barriers to vaccination, by improving convenience.}, }
@article {pmid39261482, year = {2024}, author = {Zhang, B and Fong, Y and Fintzi, J and Chu, E and Janes, HE and Kenny, A and Carone, M and Benkeser, D and van der Laan, LWP and Deng, W and Zhou, H and Wang, X and Lu, Y and Yu, C and Borate, B and Chen, H and Reeder, I and Carpp, LN and Houchens, CR and Martins, K and Jayashankar, L and Huynh, C and Fichtenbaum, CJ and Kalams, S and Gay, CL and Andrasik, MP and Kublin, JG and Corey, L and Neuzil, KM and Priddy, F and Das, R and Girard, B and El Sahly, HM and Baden, LR and Jones, T and Donis, RO and Koup, RA and Gilbert, PB and Follmann, D and ,  and ,  and ,  and , }, title = {Omicron COVID-19 immune correlates analysis of a third dose of mRNA-1273 in the COVE trial.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {7954}, pmid = {39261482}, issn = {2041-1723}, support = {R37 AI054165/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *COVID-19/immunology/virology/prevention &amp; control ; *SARS-CoV-2/immunology ; *Antibodies, Neutralizing/immunology ; *Antibodies, Viral/immunology/blood ; *Spike Glycoprotein, Coronavirus/immunology ; *Immunization, Secondary ; *2019-nCoV Vaccine mRNA-1273/administration &amp; dosage/immunology ; COVID-19 Vaccines/immunology/administration &amp; dosage ; Female ; Male ; Adult ; Vaccine Efficacy ; }, abstract = {In the phase 3 Coronavirus Efficacy (COVE) trial (NCT04470427), post-dose two Ancestral Spike-specific binding (bAb) and neutralizing (nAb) antibodies were shown to be correlates of risk (CoR) and of protection against Ancestral-lineage COVID-19 in SARS-CoV-2 naive participants. In the SARS-CoV-2 Omicron era, Omicron subvariants with varying degrees of immune escape now dominate, seropositivity rates are high, and booster doses are administered, raising questions on whether and how these developments affect the bAb and nAb correlates. To address these questions, we assess post-boost BA.1 Spike-specific bAbs and nAbs as CoRs and as correlates of booster efficacy in COVE. For naive individuals, bAbs and nAbs inversely correlate with Omicron COVID-19: hazard ratios (HR) per 10-fold marker increase (95% confidence interval) are 0.16 (0.03, 0.79) and 0.31 (0.10, 0.96), respectively. In non-naive individuals the analogous results are similar: 0.15 (0.04, 0.63) and 0.28 (0.07, 1.08). For naive individuals, three vs two-dose booster efficacy correlates with predicted nAb titer at exposure, with estimates -8% (-126%, 48%), 50% (25%, 67%), and 74% (49%, 87%), at 56, 251, and 891 Arbitrary Units/ml. These results support the continued use of antibody as a surrogate endpoint.}, }
@article {pmid39260945, year = {2024}, author = {Barta, JA and Mazzone, PJ and Nair, VS}, title = {Multi-Cancer and Single-Cancer Early Detection Testing: Opportunities and Challenges.}, journal = {Chest}, volume = {166}, number = {3}, pages = {425-428}, doi = {10.1016/j.chest.2024.03.044}, pmid = {39260945}, issn = {1931-3543}, mesh = {Humans ; *Early Detection of Cancer/methods ; *Neoplasms/diagnosis ; Mass Screening/methods ; }, }
@article {pmid39260570, year = {2024}, author = {Kongtim, P and Vittayawacharin, P and Zou, J and Srour, S and Shaffer, B and Shapiro, RM and Varma, A and McGuirk, J and Dholaria, BR and McCurdy, SR and DeZern, AE and Bejanyan, N and Bashey, A and Furst, S and Castagna, L and Mariotti, J and Ruggeri, A and Bailen, R and Teshima, T and Xiao-Jun, H and Bonfim, C and Aung, F and Cao, K and Carpenter, PA and Hamadani, M and Askar, M and Fernandez-Vina, M and Girnita, A and Ciurea, SO}, title = {ASTCT Consensus Recommendations on Testing and Treatment of Patients with Donor-specific Anti-HLA Antibodies.}, journal = {Transplantation and cellular therapy}, volume = {30}, number = {12}, pages = {1139-1154}, doi = {10.1016/j.jtct.2024.09.005}, pmid = {39260570}, issn = {2666-6367}, mesh = {Humans ; *HLA Antigens/immunology ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Isoantibodies/immunology/blood ; Histocompatibility Testing/methods ; Graft Rejection/immunology/prevention &amp; control ; Tissue Donors ; Consensus ; }, abstract = {Donor-specific anti-HLA antibodies (DSA) are an important cause of engraftment failure and may negatively impact survival outcomes of patients receiving allogeneic hematopoietic stem cell transplantation (HSCT) using an HLA-mismatched allograft. The incidence of DSA varies across studies, depending on individual factors, detection or identification methods and thresholds considered clinically relevant. Although DSA testing by multiplex bead arrays remains semiquantitative, it has been widely adopted as a standard test in most transplant centers. Additional testing to determine risk of allograft rejection may include assays with HLA antigens in natural conformation, such as flow cytometric crossmatch, and/or antibody binding assays, such as C1q testing. Patients with low level of DSA (<2,000 mean fluorescence intensity; MFI) may not require treatment, while others with very high level of DSA (>20,000 MFI) may be at very high-risk for engraftment failure despite current therapies. By contrast, in patients with moderate or high level of DSA, desensitization therapy can successfully mitigate DSA levels and improve donor cell engraftment rate, with comparable outcomes to patients without DSA. Treatment is largely empirical and multimodal, involving the removal, neutralization, and blocking of antibodies, as well as inhibition of antibody production to prevent activation of the complement cascade. Desensitization protocols are based on accumulated multicenter experience, while prospective multicenter studies remain lacking. Most patients require a full intensity protocol that includes plasma exchange, while protocols relying only on rituximab and intravenous immunoglobulin may be sufficient for patients with lower DSA levels and negative C1q and/or flow cytometric crossmatch. Monitoring DSA levels before and after HSCT could guide preemptive treatment when high levels persist after stem cell infusion. This paper aims to standardize current evidence-based practice and formulate future directions to improve upon current knowledge and advance treatment for this relatively rare, but potentially serious complication in allogeneic HSCT recipients.}, }
@article {pmid39259414, year = {2024}, author = {Nuechterlein, N and Cimino, S and Shelbourn, A and Ha, V and Arora, S and Rajan, S and Shapiro, LG and Holland, EC and Aldape, K and McGranahan, T and Gilbert, MR and Cimino, PJ}, title = {HOXD12 defines an age-related aggressive subtype of oligodendroglioma.}, journal = {Acta neuropathologica}, volume = {148}, number = {1}, pages = {41}, pmid = {39259414}, issn = {1432-0533}, support = {DGE-1762114//National Science Foundation Graduate Research Fellowship Program/ ; Intramural Research Program/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Age Factors ; *Brain Neoplasms/genetics/pathology/metabolism ; DNA Methylation ; *Homeodomain Proteins/genetics/metabolism ; Mutation ; *Oligodendroglioma/genetics/pathology ; Transcription Factors/genetics/metabolism ; }, abstract = {Oligodendroglioma, IDH-mutant and 1p/19q-codeleted has highly variable outcomes that are strongly influenced by patient age. The distribution of oligodendroglioma age is non-Gaussian and reportedly bimodal, which motivated our investigation of age-associated molecular alterations that may drive poorer outcomes. We found that elevated HOXD12 expression was associated with both older patient age and shorter survival in the TCGA (FDR < 0.01, FDR = 1e-5) and the CGGA (p = 0.03, p < 1e-3). HOXD12 gene body hypermethylation was associated with older age, higher WHO grade, and shorter survival in the TCGA (p < 1e-6, p < 0.001, p < 1e-3) and with older age and higher WHO grade in Capper et al. (p < 0.002, p = 0.014). In the TCGA, HOXD12 gene body hypermethylation and elevated expression were independently prognostic of NOTCH1 and PIK3CA mutations, loss of 15q, MYC activation, and standard histopathological features. Single-nucleus RNA and ATAC sequencing data showed that HOXD12 activity was elevated in neoplastic tissue, particularly within cycling and OPC-like cells, and was associated with a stem-like phenotype. A pan-HOX DNA methylation analysis revealed an age and survival-associated HOX-high signature that was tightly associated with HOXD12 gene body methylation. Overall, HOXD12 expression and gene body hypermethylation were associated with an older, atypically aggressive subtype of oligodendroglioma.}, }
@article {pmid39259185, year = {2024}, author = {Kalia, SS and Boddicker, NJ and Yadav, S and Huang, H and Na, J and Hu, C and Ambrosone, CB and Yao, S and Haiman, CA and Chen, F and John, EM and Kurian, AW and Guo, B and Lindstrӧm, S and Auer, P and Lacey, JV and Neuhausen, SL and Martinez, ME and Sandler, DP and O'Brien, KM and Taylor, JA and Teras, LR and Hodge, JM and Lori, A and Bodelon, C and Trentham-Dietz, A and Burnside, ES and Vachon, CM and Winham, SJ and Goldgar, DE and Domchek, SM and Nathanson, KL and Weitzel, JN and Couch, FJ and Kraft, P}, title = {Development of a Breast Cancer Risk Prediction Model Integrating Monogenic, Polygenic, and Epidemiologic Risk.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {33}, number = {11}, pages = {1490-1499}, pmid = {39259185}, issn = {1538-7755}, support = {//Breast Cancer Research Foundation (BCRF)/ ; P50CA116201//National Institutes of Health (NIH)/ ; R01CA192393//National Institutes of Health (NIH)/ ; Z01ES044005//National Institutes of Health (NIH)/ ; P50 CA116201/CA/NCI NIH HHS/United States ; R35 CA253187/CA/NCI NIH HHS/United States ; Z01 ES044005/ImNIH/Intramural NIH HHS/United States ; //American Cancer Society (ACS)/ ; R01 CA192393/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Breast Neoplasms/genetics/epidemiology ; *Genetic Predisposition to Disease ; Middle Aged ; Case-Control Studies ; Risk Factors ; Risk Assessment/methods ; Multifactorial Inheritance ; Adult ; Aged ; Prospective Studies ; Polymorphism, Single Nucleotide ; }, abstract = {BACKGROUND: Breast cancer has been associated with monogenic, polygenic, and epidemiologic (clinical, reproductive, and lifestyle) risk factors, but studies evaluating the combined effects of these factors have been limited.<br><br>METHODS: We extended previous work in breast cancer risk modeling, incorporating pathogenic variants (PV) in six breast cancer predisposition genes and a 105-SNP polygenic risk score (PRS), to include an epidemiologic risk score (ERS) in a sample of non-Hispanic White women drawn from prospective cohorts and population-based case-control studies, with 23,518 cases and 22,832 controls, from the Cancer Risk Estimates Related to Susceptibility (CARRIERS) Consortium.<br><br>RESULTS: The model predicts 4.4-fold higher risk of breast cancer for postmenopausal women with no predisposition PV and median PRS, but with the highest versus lowest ERS. Overall, women with CHEK2 PVs had >20% lifetime risk of breast cancer. However, 15.6% of women with CHEK2 PVs and a family history of breast cancer, and 45.1% of women with CHEK2 PVs but without a family history of breast cancer, had low (<20%) predicted lifetime risk and thus were below the threshold for MRI screening. CHEK2 PV carriers at the 10th percentile of the joint distribution of ERS and PRS, without a family history of breast cancer, had a predicted lifetime risk similar to the general population.<br><br>CONCLUSIONS: These results illustrate that an ERS, alone and combined with the PRS, can contribute to clinically relevant risk stratification.<br><br>IMPACT: Integrating monogenic, polygenic, and epidemiologic risk factors in breast cancer risk prediction models may inform personalized screening and prevention efforts.}, }
@article {pmid39258792, year = {2024}, author = {Anderson, AC and Ho, J and Hall, ET and Hannan, R and Liao, JJ and Louie, AV and Ma, TM and Psutka, SP and Rengan, R and Siva, S and Swaminath, A and Tachiki, L and Tang, C and Teh, BS and Tsai, J and Tykodi, SS and Weg, E and Zaorsky, NG and Lo, SS}, title = {Focal therapy for oligometastatic and oligoprogressive renal cell carcinoma: a narrative review.}, journal = {Future oncology (London, England)}, volume = {20}, number = {33}, pages = {2573-2588}, pmid = {39258792}, issn = {1744-8301}, mesh = {Humans ; *Carcinoma, Renal Cell/therapy/secondary/pathology ; *Kidney Neoplasms/therapy/pathology ; Radiosurgery/methods ; Disease Progression ; Neoplasm Metastasis ; Treatment Outcome ; Combined Modality Therapy/methods ; Disease Management ; }, abstract = {Metastatic renal cell carcinoma (RCC) can present with oligometastatic disease and/or develop oligoprogression following systemic therapy. Cytoreductive and focal metastasis-directed therapy options include resection, stereotactic ablative radiation and thermal ablation. Aggressive focal therapy may allow delay in initiation of or modification to systemic therapy and improve clinical outcomes. In this narrative review we synthesize current practice guidelines and prospective data on focal therapy management options and highlight future research. Patient selection and the choice of focal treatment techniques are controversial due to limited and heterogeneous data and patients may benefit from multidisciplinary evaluation. Prospective comparative trials with clearly defined inclusion criteria and relevant end points are needed to clarify the risks and benefits of different approaches.}, }
@article {pmid39257755, year = {2024}, author = {Gray, CN and Ashokkumar, M and Janssens, DH and Kirchherr, J and Allard, B and Hsieh, E and Hafer, TL and Archin, NM and Browne, EP and Emerman, M}, title = {Integrator complex subunit 12 knockout overcomes a transcriptional block to HIV latency reversal.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39257755}, issn = {2692-8205}, support = {DP1 DA051110/DA/NIDA NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R61 DA047023/DA/NIDA NIH HHS/United States ; R01 AI143381/AI/NIAID NIH HHS/United States ; T32 AI083203/AI/NIAID NIH HHS/United States ; R56 AI170226/AI/NIAID NIH HHS/United States ; UM1 AI126619/AI/NIAID NIH HHS/United States ; }, abstract = {The latent HIV reservoir is a major barrier to HIV cure. Combining latency reversal agents (LRAs) with differing mechanisms of action such as AZD5582, a non-canonical NF-kB activator, and I-BET151, a bromodomain inhibitor is appealing towards inducing HIV-1 reactivation. However, even this LRA combination needs improvement as it is inefficient at activating proviruses in cells from people living with HIV (PLWH). We performed a CRISPR screen in conjunction with AZD5582 &amp; I-BET151 and identified a member of the Integrator complex as a target to improve this LRA combination, specifically Integrator complex subunit 12 (INTS12). Integrator functions as a genome-wide attenuator of transcription that acts on elongation through its RNA cleavage and phosphatase modules. Knockout of INTS12 improved latency reactivation at the transcriptional level and is more specific to the HIV-1 provirus than AZD5582 &amp; I-BET151 treatment alone. We found that INTS12 is present on chromatin at the promoter of HIV and therefore its effect on HIV may be direct. Additionally, we observed more RNAPII in the gene body of HIV only with the combination of INTS12 knockout with AZD5582 &amp; I-BET151, indicating that INTS12 induces a transcriptional elongation block to viral reactivation. Moreover, knockout of INTS12 increased HIV-1 reactivation in CD4 T cells from virally suppressed PLWH ex vivo. We also detected viral RNA in the supernatant from CD4 T cells of all three virally suppressed PLWH tested upon INTS12 knockout suggesting that INTS12 prevents full-length HIV RNA production in primary T cells.}, }
@article {pmid39257746, year = {2024}, author = {Owens, K and Rahman, A and Bozic, I}, title = {Spatiotemporal dynamics of tumor - CAR T-cell interaction following local administration in solid cancers.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39257746}, issn = {2692-8205}, support = {T32 AI118690/AI/NIAID NIH HHS/United States ; }, abstract = {The success of chimeric antigen receptor (CAR) T-cell therapy in treating hematologic malignancies has generated widespread interest in translating this technology to solid cancers. However, issues like tumor infiltration, the immunosuppressive tumor microenvironment, and tumor heterogeneity limit its efficacy in the solid tumor setting. Recent experimental and clinical studies propose local administration directly into the tumor or at the tumor site to increase CAR T-cell infiltration and improve treatment outcomes. Characteristics of the types of solid tumors that may be the most receptive to this treatment approach remain unclear. In this work, we develop a spatiotemporal model for CAR T-cell treatment of solid tumors, and use numerical simulations to compare the effect of introducing CAR T cells via intratumoral injection versus intracavitary administration in diverse cancer types. We demonstrate that the model can recapitulate tumor and CAR T-cell data from imaging studies of local administration of CAR T cells in mouse models. Our results suggest that locally administered CAR T cells will be most successful against slowly proliferating, highly diffusive tumors, which have the lowest average tumor cell density. These findings affirm the clinical observation that CAR T cells will not perform equally across different types of solid tumors, and suggest that measuring tumor density may be helpful when considering the feasibility of CAR T-cell therapy and planning dosages for a particular patient. We additionally find that local delivery of CAR T cells can result in deep tumor responses, provided that the initial CAR T-cell dose does not contain a significant fraction of exhausted cells.}, }
@article {pmid39255537, year = {2024}, author = {Triner, D and Graf, RP and Madison, RW and Gjoerup, O and Tukachinsky, H and Ross, JS and Quintanilha, JCF and Li, G and Cheng, HH and Pritchard, CC and Zurita, AJ and Qin, Q and Zhang, T and Agarwal, N and Reichert, ZR and Mateo, J and Cieslik, M and Morgan, TM}, title = {Durable benefit from poly(ADP-ribose) polymerase inhibitors in metastatic prostate cancer in routine practice: biomarker associations and implications for optimal clinical next-generation sequencing testing.}, journal = {ESMO open}, volume = {9}, number = {9}, pages = {103684}, pmid = {39255537}, issn = {2059-7029}, mesh = {Humans ; Male ; *Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use/pharmacology ; *Prostatic Neoplasms, Castration-Resistant/drug therapy/genetics/pathology ; Aged ; *High-Throughput Nucleotide Sequencing/methods ; Biomarkers, Tumor/genetics ; BRCA2 Protein/genetics ; Middle Aged ; Circulating Tumor DNA/genetics ; Liquid Biopsy/methods ; BRCA1 Protein/genetics ; Neoplasm Metastasis ; }, abstract = {BACKGROUND: Controlled trials have consistently demonstrated the efficacy of poly(ADP-ribose) polymerase inhibitors (PARPis) in patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA1 or BRCA2 alterations (BRCAalt). However, the reported efficacy of PARPi for alterations in other homologous recombination repair (HRR) genes is less consistent. We sought to evaluate the routine practice effectiveness of PARPi between and within these groups.<br><br>DESIGN: Patient-level data from a deidentified nationwide (USA-based) cancer clinico-genomic database between January 2011 and September 2023 were extracted. Patients with mCRPC and comprehensive genomic profiling by liquid biopsy [circulating tumor DNA (ctDNA)] or tissue (tumor) biopsy and who received single-agent PARPi were included and grouped by BRCAalt, ATMalt, other HRR, or no HRR. We further subcategorized BRCAalt into homozygous loss (BRCAloss) and all other deleterious BRCAalt (otherBRCAalt).<br><br>RESULTS: A total of 445 patients met inclusion criteria: 214 with tumor and 231 with ctDNA. BRCAalt had more favorable outcomes to PARPi compared with ATM, other HRR, and no HRR groups. Within the BRCAalt subgroup, compared with other BRCAalt, BRCAloss had a more favorable time to next treatment (median 9 versus 19.4 months, P&#xa0;= 0.005), time to treatment discontinuation (median 8 versus 14 months, P&#xa0;= 0.006), and routine practice overall survival (median 14.7 versus 19.4 months, P&#xa0;= 0.016). Tumor BRCAloss prevalence (3.1%) was similar to ctDNA prevalence in liquid biopsy specimens with high tumor fraction (>20%). BRCAloss was not detected in orthogonal germline testing.<br><br>CONCLUSIONS: PARPi routine practice effectiveness between groups mirrors prospective trials. Within the BRCAalt group, BRCAloss had the best outcomes. Unless the ctDNA tumor fraction is very high, somatic tissue testing (archival or metastatic) should be prioritized to identify patients who may benefit most from PARPi. When tissue testing is not clinically feasible, sufficient ctDNA tumor fraction levels for detection are enriched at clinical timepoints associated with tumor progression.}, }
@article {pmid39255440, year = {2024}, author = {Barata, P and Tangen, C and Plets, M and Thompson, IM and Narayan, V and George, DJ and Heng, DYC and Shuch, B and Stein, M and Gulati, S and Tretiakova, M and Tripathi, A and Bjarnason, GA and Humphrey, P and Adeniran, A and Vaishampayan, U and Alva, A and Zhang, T and Cole, S and Lara, PN and Lerner, SP and Balzer-Haas, N and Pal, SK}, title = {Final Overall Survival Analysis of S1500: A Randomized, Phase II Study Comparing Sunitinib With Cabozantinib, Crizotinib, and Savolitinib in Advanced Papillary Renal Cell Carcinoma.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {42}, number = {33}, pages = {3911-3916}, pmid = {39255440}, issn = {1527-7755}, support = {U10 CA180868/CA/NCI NIH HHS/United States ; U10 CA180821/CA/NCI NIH HHS/United States ; U10 CA180863/CA/NCI NIH HHS/United States ; U10 CA180820/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; U10 CA180819/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Sunitinib/therapeutic use ; *Pyridines/therapeutic use ; *Carcinoma, Renal Cell/drug therapy/mortality/pathology ; *Kidney Neoplasms/drug therapy/mortality/pathology ; *Anilides/therapeutic use ; Male ; Female ; Middle Aged ; Aged ; *Crizotinib/therapeutic use ; Adult ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Triazines/therapeutic use/adverse effects ; Progression-Free Survival ; Aged, 80 and over ; Pyrazines ; }, abstract = {Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Mesenchymal-epithelial transition (MET) signaling pathway plays a role in the pathogenesis of selected patients with papillary renal cell carcinoma (PRCC). In the phase II PAPMET trial (ClinicalTrials.gov identifier: NCT02761057), cabozantinib significantly prolonged progression-free survival and improved objective response rate compared with sunitinib in patients with advanced PRCC. Here, we present the final overall survival (OS) analysis. In this multicenter, randomized phase II, open-label trial, 147 patients with advanced PRCC who have received up to one previous therapy (excluding vascular endothelial growth factor-directed agents) were assigned to sunitinib, cabozantinib, crizotinib, or savolitinib. Ultimately, savolitinib and crizotinib arms were closed because of futility. With a median follow-up of 17.5 months, the median OS was 21.5 months (95% CI, 12.0 to 28.1) with cabozantinib and 17.3 months (95% CI, 12.8 to 21.8) with sunitinib (hazard ratio, 0.83; 95% CI, 0.51 to 1.36; P = .46). The OS landmark estimates for cabozantinib and sunitinib were 50% versus 39% at 24 months and 32% versus 28% at 36 months. In conclusion, we observed no significant difference in OS across treatment arms. Although cabozantinib represents a well-supported option for advanced PRCC, the lack of survival benefit underscores the need to develop novel therapies for this disease.}, }
@article {pmid39255368, year = {2024}, author = {Li, W and Li, R and Feng, Z and Ning, J and , }, title = {Dynamic and concordance-assisted learning for risk stratification with application to Alzheimer's disease.}, journal = {Biostatistics (Oxford, England)}, volume = {}, number = {}, pages = {}, doi = {10.1093/biostatistics/kxae036}, pmid = {39255368}, issn = {1468-4357}, support = {U24 CA230144/CA/NCI NIH HHS/United States ; R01CA269696/NH/NIH HHS/United States ; }, abstract = {Dynamic prediction models capable of retaining accuracy by evolving over time could play a significant role for monitoring disease progression in clinical practice. In biomedical studies with long-term follow up, participants are often monitored through periodic clinical visits with repeat measurements until an occurrence of the event of interest (e.g. disease onset) or the study end. Acknowledging the dynamic nature of disease risk and clinical information contained in the longitudinal markers, we propose an innovative concordance-assisted learning algorithm to derive a real-time risk stratification score. The proposed approach bypasses the need to fit regression models, such as joint models of the longitudinal markers and time-to-event outcome, and hence enjoys the desirable property of model robustness. Simulation studies confirmed that the proposed method has satisfactory performance in dynamically monitoring the risk of developing disease and differentiating high-risk and low-risk population over time. We apply the proposed method to the Alzheimer's Disease Neuroimaging Initiative data and develop a dynamic risk score of Alzheimer's Disease for patients with mild cognitive impairment using multiple longitudinal markers and baseline prognostic factors.}, }
@article {pmid39255259, year = {2024}, author = {Iwu, CD and Cox, SN and Sohlberg, SL and Kim, AE and Logue, J and Han, PD and Sibley, TR and Ilcisin, M and Fay, KA and Lee, J and McCulloch, DJ and Wang, Y and Boeckh, M and Englund, JA and Starita, LM and Hajat, A and Chu, HY}, title = {"I probably shouldn't go in today": Inequitable access to paid sick leave and its impacts on health behaviors during the emergence of COVID-19 in the Seattle area.}, journal = {PloS one}, volume = {19}, number = {9}, pages = {e0307734}, pmid = {39255259}, issn = {1932-6203}, support = {R01 AG060011/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *COVID-19/epidemiology ; Female ; Male ; Adult ; *Sick Leave/statistics &amp; numerical data/economics ; Middle Aged ; Washington/epidemiology ; Health Behavior ; SARS-CoV-2 ; Socioeconomic Factors ; Income ; Young Adult ; Surveys and Questionnaires ; Adolescent ; }, abstract = {This study examines inequities in access to paid sick leave (PSL) by race/ethnicity, income, and sex and the role of PSL access on leave-taking and care-seeking behaviors among Seattle-area workers in the months leading up to and during the emergence of COVID-19 in the region. Survey responses were collected online and in-person from individuals experiencing acute respiratory illness symptoms between November 2019 and March 2020 as part of a community-based respiratory viral surveillance study. Chi-square tests and log-binomial models were used to assess the association between PSL access and various socioeconomic indicators. A total of 66.6% (n = 2,276) respondents reported access to PSL. Proportionally, access to PSL was highest in respondents identifying as Asian (70.5%), followed by White (68.7%), Latine (58.4%), Multiracial (57.1%), Black (47.1%), and Other (43.1%). Access to PSL increased with household income. Eighty three percent of high-income respondents reported access compared to 52.9% of low-income households. Only 23.3% of the lowest-income households reported access to PSL. Fewer females (65.2%) than males (70.7%) reported access to PSL. Access to PSL is inequitably distributed across income, race/ethnicity, and sex. This study reinforces the vast body of knowledge on how socioeconomic inequalities increase individual and community-level vulnerability to the impacts of infectious disease outbreaks. It also supports the role of labor and economic policy in mitigating (or exacerbating) these impacts. Exemplified by the COVID-19 pandemic, universal access to PSL, especially for marginalized populations, benefits all.}, }
@article {pmid39253895, year = {2024}, author = {Naresh, KN}, title = {Understanding splenic B-cell lymphoma/leukaemia with prominent nucleoli: Diagnosis, underpinnings for disease classification and future directions.}, journal = {British journal of haematology}, volume = {}, number = {}, pages = {}, doi = {10.1111/bjh.19754}, pmid = {39253895}, issn = {1365-2141}, abstract = {The 5th edition of the WHO classification of haematolymphoid tumours (WHO-HAEM5) introduced a new category, splenic B-cell lymphoma/leukaemia with prominent nucleoli (SBLPN). The diagnostic entity B-cell prolymphocytic leukaemia (B-PLL) has been discontinued and the category of hairy cell leukaemia variant (HCLv) has been conceptually reframed. B-PLL and HCLv diagnoses were uncommon. Overlap existed between B-PLL and other indolent lymphomas like chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL). HCLv lacked consistent cytomorphological, immunophenotypic and genetic features. To address these issues, the WHO-HAEM5 classification has introduced SBLPN to serve as a temporary holding ground for entities that do not neatly fit into the existing classification. Cases previously classified as CD5-negative B-PLL and HCLv fall under the SBLPN category. Some splenic marginal zone lymphoma and splenic diffuse red pulp small B-cell lymphoma cases with higher number of medium or large nucleolated B cells would also be classified as SBLPN under the WHO-HAEM5. This review explores the rationale for discontinuing B-PLL and HCLv diagnoses. It then examines the concept of SBLPN, offers practical guidance for diagnosis and discusses future directions in classifying splenic B-cell lymphomas.}, }
@article {pmid39253833, year = {2024}, author = {Kaplan, RC and Chan, KCG}, title = {Unequal Management and Outcomes Among Asian American Patients With Coronary Heart Disease.}, journal = {Circulation. Cardiovascular quality and outcomes}, volume = {17}, number = {10}, pages = {e011440}, doi = {10.1161/CIRCOUTCOMES.124.011440}, pmid = {39253833}, issn = {1941-7705}, mesh = {Humans ; *Asian ; *Healthcare Disparities/ethnology ; United States/epidemiology ; *Coronary Disease/ethnology/therapy/diagnosis/mortality/epidemiology ; Treatment Outcome ; Male ; Female ; Aged ; Middle Aged ; Risk Assessment ; Race Factors ; Risk Factors ; }, }
@article {pmid39253641, year = {2024}, author = {Brusselmans, M and Carvalho, LM and Hong, SL and Gao, J and Matsen, FA and Rambaut, A and Lemey, P and Suchard, MA and Dudas, G and Baele, G}, title = {On the importance of assessing topological convergence in Bayesian phylogenetic inference.}, journal = {ArXiv}, volume = {}, number = {}, pages = {}, pmid = {39253641}, issn = {2331-8422}, support = {/WT_/Wellcome Trust/United Kingdom ; R01 AI153044/AI/NIAID NIH HHS/United States ; R01 AI162611/AI/NIAID NIH HHS/United States ; }, abstract = {Modern phylogenetics research is often performed within a Bayesian framework, using sampling algorithms such as Markov chain Monte Carlo (MCMC) to approximate the posterior distribution. These algorithms require careful evaluation of the quality of the generated samples. Within the field of phylogenetics, one frequently adopted diagnostic approach is to evaluate the effective sample size (ESS) and to investigate trace graphs of the sampled parameters. A major limitation of these approaches is that they are developed for continuous parameters and therefore incompatible with a crucial parameter in these inferences: the tree topology. Several recent advancements have aimed at extending these diagnostics to topological space. In this reflection paper, we present two case studies - one on Ebola virus and one on HIV - illustrating how these topological diagnostics can contain information not found in standard diagnostics, and how decisions regarding which of these diagnostics to compute can impact inferences regarding MCMC convergence and mixing. Our results show the importance of running multiple replicate analyses and of carefully assessing topological convergence using the output of these replicate analyses. To this end, we illustrate different ways of assessing and visualizing the topological convergence of these replicates. Given the major importance of detecting convergence and mixing issues in Bayesian phylogenetic analyses, the lack of a unified approach to this problem warrants further action, especially now that additional tools are becoming available to researchers.}, }
@article {pmid39253501, year = {2024}, author = {Nanduri, S and Black, A and Bedford, T and Huddleston, J}, title = {Dimensionality reduction distills complex evolutionary relationships in seasonal influenza and SARS-CoV-2.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39253501}, issn = {2692-8205}, support = {75N93021C00015/AI/NIAID NIH HHS/United States ; F31 AI140714/AI/NIAID NIH HHS/United States ; R35 GM119774/GM/NIGMS NIH HHS/United States ; }, abstract = {Public health researchers and practitioners commonly infer phylogenies from viral genome sequences to understand transmission dynamics and identify clusters of genetically-related samples. However, viruses that reassort or recombine violate phylogenetic assumptions and require more sophisticated methods. Even when phylogenies are appropriate, they can be unnecessary or difficult to interpret without specialty knowledge. For example, pairwise distances between sequences can be enough to identify clusters of related samples or assign new samples to existing phylogenetic clusters. In this work, we tested whether dimensionality reduction methods could capture known genetic groups within two human pathogenic viruses that cause substantial human morbidity and mortality and frequently reassort or recombine, respectively: seasonal influenza A/H3N2 and SARS-CoV-2. We applied principal component analysis (PCA), multidimensional scaling (MDS), t-distributed stochastic neighbor embedding (t-SNE), and uniform manifold approximation and projection (UMAP) to sequences with well-defined phylogenetic clades and either reassortment (H3N2) or recombination (SARS-CoV-2). For each low-dimensional embedding of sequences, we calculated the correlation between pairwise genetic and Euclidean distances in the embedding and applied a hierarchical clustering method to identify clusters in the embedding. We measured the accuracy of clusters compared to previously defined phylogenetic clades, reassortment clusters, or recombinant lineages. We found that MDS embeddings accurately represented pairwise genetic distances including the intermediate placement of recombinant SARS-CoV-2 lineages between parental lineages. Clusters from t-SNE embeddings accurately recapitulated known phylogenetic clades, H3N2 reassortment groups, and SARS-CoV-2 recombinant lineages. We show that simple statistical methods without a biological model can accurately represent known genetic relationships for relevant human pathogenic viruses. Our open source implementation of these methods for analysis of viral genome sequences can be easily applied when phylogenetic methods are either unnecessary or inappropriate.}, }
@article {pmid39251835, year = {2024}, author = {Vo, P and Srinivasan, R and Purev, E and McDuffee, E and Worthy, T and Shalabi, R and Wood, K and Wells, B and Reger, R and Stroncek, D and Geller, N and Aue, G and Tian, X and Childs, R}, title = {Durable remission of refractory and advanced stage mycosis fungoides/sezary syndrome utilizing an "outpatient" alemtuzumab, fludarabine-based reduced intensity allogeneic hematopoietic cell transplantation.}, journal = {Bone marrow transplantation}, volume = {59}, number = {12}, pages = {1777-1779}, pmid = {39251835}, issn = {1476-5365}, }
@article {pmid39251462, year = {2024}, author = {Ronsley, R and Bertrand, KC and Song, EZ and Timpanaro, A and Choe, M and Tlais, D and Vitanza, NA and Park, JR}, title = {CAR T cell therapy for pediatric central nervous system tumors: a review of the literature and current North American trials.}, journal = {Cancer metastasis reviews}, volume = {43}, number = {4}, pages = {1205-1216}, pmid = {39251462}, issn = {1573-7233}, mesh = {Humans ; Child ; *Immunotherapy, Adoptive/methods ; *Central Nervous System Neoplasms/therapy/immunology ; *Receptors, Chimeric Antigen/immunology ; Clinical Trials as Topic ; Animals ; T-Lymphocytes/immunology ; }, abstract = {Central nervous system (CNS) tumors are the leading cause of cancer-related death in children. Typical therapy for CNS tumors in children involves a combination of surgery, radiation, and chemotherapy. While upfront therapy is effective for many high-grade tumors, therapy at the time of relapse remains limited. Furthermore, for diffuse intrinsic pontine glioma (DIPG) and diffuse midline glioma (DMG), there are currently no curative therapies. Chimeric antigen receptor T (CAR T) cell therapy is a promising novel treatment avenue for these tumors. Here, we review the preclinical evidence for CAR T cell use in pediatric brain tumors, the preliminary clinical experience of CNS CAR T cell trials, toxicity associated with systemic and locoregional CAR T cell therapy for CNS tumors, challenges in disease response evaluation with CAR T cell therapy, and the knowledge gained from correlative biologic studies from these trials in the pediatric and young adult population.}, }
@article {pmid39248500, year = {2024}, author = {Srinivasan, S and Richardson, BA and Wallis, JM and Fiedler, TL and Strenk, SM and Hoffman, NG and Proll, S and Chirenje, ZM and Livant, EW and Fredricks, DN and Hillier, SL and Marrazzo, JM}, title = {Vaginal Bacteria and Proinflammatory Host Immune Mediators as Biomarkers of Human Immunodeficiency Virus Acquisition Risk Among African Women.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiae406}, pmid = {39248500}, issn = {1537-6613}, support = {UM1 AI068633/AI/NIAID NIH HHS/United States ; P30AI027757//University of Washington's Center for AIDS Research/ ; UM1 AI068615/AI/NIAID NIH HHS/United States ; /MH/NIMH NIH HHS/United States ; UM1 AI106707/AI/NIAID NIH HHS/United States ; UM1AI068633, UM1AI068615, UM1AI106707//National Institute of Allergy and Infectious Diseases/ ; /NH/NIH HHS/United States ; NCT00705679//VOICE study/ ; //National Institute of Child Health and Human Development/ ; }, abstract = {BACKGROUND: Few investigations have assessed contributions of both vaginal bacteria and proinflammatory immune mediators to human immunodeficiency virus (HIV) acquisition risk in a prospective cohort.<br><br>METHODS: We conducted a nested case-control study of African women who participated in a randomized placebo-controlled trial of daily oral versus vaginal tenofovir-based preexposure prophylaxis for HIV infection. Vaginal concentrations of 23 bacterial taxa and 16 immune mediators were measured. Relationships between individual bacterial concentrations or immune mediators and HIV risk were analyzed using generalized estimating equations in a multivariable model. Factor analysis assessed relationships between combinations of bacterial taxa, immune mediators, and HIV acquisition risk.<br><br>RESULTS: We identified 177 HIV pre-seroconversion visits from 150 women who acquired HIV and 531 visits from 436 women who remained HIV uninfected. Fourteen bacterial taxa and 6 proinflammatory cytokines and chemokines were individually associated with greater HIV risk after adjusting for confounders. Women with all 14 taxa versus <14 taxa (adjusted odds ratio [aOR], 4.45 [95% confidence interval {CI}, 2.20-8.98]; P < .001) or all 6 immune mediators versus <6 mediators (aOR, 1.77 [95% CI, 1.24-2.52]; P < .001) had greater risk for HIV acquisition. Factor analysis demonstrated that a bacterial factor comprised of 14 high-risk bacterial taxa (aOR, 1.57 [95% CI, 1.27-1.93]; P < 0.001) and the interferon gamma-induced protein 10 (highest quartile: aOR, 3.19 [95% CI, 1.32-7.72]; P = 0.002) contributed to the highest HIV risk.<br><br>CONCLUSIONS: Bacterial and host biomarkers for predicting HIV acquisition risk identify women at greatest risk for HIV infection and can focus prevention efforts.}, }
@article {pmid39245683, year = {2024}, author = {Stathis, CJ and Zhu, H and Carlin, K and Phan, TL and Toomey, D and Hill, JA and Zerr, DM}, title = {A systematic review and meta-analysis of HHV-6 and mortality after hematopoietic cell transplant.}, journal = {Bone marrow transplantation}, volume = {59}, number = {12}, pages = {1683-1693}, pmid = {39245683}, issn = {1476-5365}, mesh = {*Herpesvirus 6, Human ; *Hematopoietic Stem Cell Transplantation/adverse effects/mortality ; Humans ; *Roseolovirus Infections/mortality ; Male ; Female ; }, abstract = {Human herpesvirus-6B (HHV-6B) reactivation has been associated with non-relapse mortality (NRM) and overall mortality (OM) following allogeneic hematopoietic stem cell transplant (HCT). We performed a systematic review and meta-analysis to better quantify the association. Studies were included if they systematically tested a cohort of HCT recipients for HHV-6 infection or reactivation and described mortality for patients with and without HHV-6B. Random effects models were used to assess the pooled effect of HHV-6B positivity on each outcome of interest. Bayesian aggregation was additionally performed if models included 10 or fewer studies. Eight studies were included in the NRM analysis, which demonstrated a significant association between HHV-6 detection and NRM (pooled effect: 1.84; 95% CI: 1.29-2.62) without significant heterogeneity (I[2] = 0.0%, p = 0.55). A Bayesian aggregation of the raw data used to construct the NRM random effects model supported these findings (95% credible interval: 0.15-1.13). Twenty-five studies were included in OM analysis, which showed a significant positive association (pooled effect: 1.37; 95% CI: 1.07-1.76), though considerable heterogeneity was observed (I[2] = 36.7%, p < 0.05). HHV-6 detection is associated with NRM and OM following HCT. Randomized trials are warranted to evaluate if preventing or treating HHV-6B reactivation improves outcomes.}, }
@article {pmid39243788, year = {2024}, author = {Lama, JR and Duerr, A}, title = {Preventing sexually transmitted infections in the age of PrEP.}, journal = {The lancet. HIV}, volume = {11}, number = {10}, pages = {e651-e653}, doi = {10.1016/S2352-3018(24)00236-4}, pmid = {39243788}, issn = {2352-3018}, mesh = {Humans ; *Pre-Exposure Prophylaxis ; *Sexually Transmitted Diseases/prevention &amp; control/epidemiology ; *HIV Infections/prevention &amp; control/epidemiology ; Anti-HIV Agents/therapeutic use ; Male ; Female ; }, }
@article {pmid39243704, year = {2024}, author = {Puschel, K and Rioseco, A and Soto, M and Paz, S and Martinez, J and Soto, G and Faundez, M and Arenas, E and Vescovi, Z and Fuentes, I and Thompson, B and Emery, J}, title = {Implementation of cancer prevention practices in primary care: results of a cohort study in Chile 2018-2022.}, journal = {Public health}, volume = {236}, number = {}, pages = {168-174}, doi = {10.1016/j.puhe.2024.08.006}, pmid = {39243704}, issn = {1476-5616}, mesh = {Humans ; *Primary Health Care ; Chile/epidemiology ; Female ; Male ; Middle Aged ; Retrospective Studies ; Adult ; *Early Detection of Cancer/statistics &amp; numerical data ; Uterine Cervical Neoplasms/prevention &amp; control ; Papillomavirus Vaccines/administration &amp; dosage ; Aged ; Breast Neoplasms/prevention &amp; control ; Neoplasms/prevention &amp; control/epidemiology ; Cohort Studies ; Papillomavirus Infections/prevention &amp; control ; Young Adult ; }, abstract = {OBJECTIVES: The burden of cancer is increasing rapidly in Latin America. Primary care has an essential role in cancer prevention, but implementation levels of prevention practices are not well known. This study evaluated implementation levels and associated factors of cancer preventive practices in primary care over time.<br><br>STUDY DESIGN: The study incorporated a retrospective multicentre cohort study.<br><br>METHODS: A population of 59,949 patients registered at three primary care clinics was followed from January 2018 to December 2022 in Santiago, Chile. We studied human papillomavirus (HPV) and hepatitis B virus (HBV) immunisation, brief counselling for smoking cessation and alcohol consumption, and cervical and breast cancer screening practices. Standardised electronic medical records were utilised as the source of information. Social, clinical, and organisational factors associated with prevention practices were studied.<br><br>RESULTS: The cohort attrition level was 17.1%. Most of the population was of a low socioeconomic status, and 70% visited a primary health centre yearly. Implementation rates of immunisation practices were 90.84% for HPV and 80.94% for HBV in 2022. In contrast, brief counselling for smoking and alcohol consumption was below 20% during the study period. Cervical cancer screening decreased by 25.58% between 2018 and 2022, whereas breast cancer screening reached only 41.71% of the target population. Opportunistic medical visits were strongly associated with brief counselling and breast cancer screening.<br><br>CONCLUSION: Implementation practices for cancer prevention in a Chilean primary care cohort are high for immunisation and very low for brief counselling and screening practices. A comprehensive non-medical-based model is needed to improve cancer prevention in primary care.}, }
@article {pmid39241960, year = {2024}, author = {André, F and Cortés, J and Curigliano, G and Modi, S and Li, W and Park, YH and Chung, WP and Kim, SB and Yamashita, T and Pedrini, JL and Im, SA and Tseng, LM and Harbeck, N and Krop, I and Nakatani, S and Tecson, K and Ashfaque, S and Egorov, A and Hurvitz, SA}, title = {A pooled analysis of trastuzumab deruxtecan in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer with brain metastases.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {35}, number = {12}, pages = {1169-1180}, doi = {10.1016/j.annonc.2024.08.2347}, pmid = {39241960}, issn = {1569-8041}, mesh = {Humans ; Female ; *Breast Neoplasms/drug therapy/pathology/mortality ; *Brain Neoplasms/secondary/drug therapy ; *Trastuzumab/therapeutic use/administration &amp; dosage/adverse effects ; *Receptor, ErbB-2/metabolism ; Middle Aged ; Aged ; *Camptothecin/analogs &amp; derivatives/therapeutic use/administration &amp; dosage ; Adult ; Immunoconjugates/adverse effects/therapeutic use/administration &amp; dosage ; Antineoplastic Agents, Immunological/therapeutic use/adverse effects ; Progression-Free Survival ; }, abstract = {BACKGROUND: This exploratory pooled analysis investigated the efficacy and safety of trastuzumab deruxtecan (T-DXd) versus comparator treatment in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) with brain metastases (BMs) at baseline, categorized according to previous local treatment.<br><br>PATIENTS AND METHODS: T-DXd data were pooled from DESTINY-Breast01/-02/-03. Comparator data, from patients receiving physician's choice therapy and trastuzumab emtansine, were pooled from DESTINY-Breast02 and -03, respectively. Baseline BM status was assessed according to US Food and Drug Administration criteria. The endpoints included intracranial objective response rate (ORR; complete or partial response in the brain) per blinded independent central review (BICR) by RECIST version 1.1, time to intracranial response, intracranial duration of response (DoR), central nervous system progression-free survival (CNS-PFS) by BICR, overall survival (OS), and safety.<br><br>RESULTS: A total of 148 patients who received T-DXd and 83 patients who received comparator treatment had BMs at baseline. In those treated with T-DXd, the intracranial ORR of patients with treated/stable and untreated/active BMs was 45.2% and 45.5%, respectively. The median (range) time to intracranial response was 2.8 months (1.1-13.9 months) and 1.5 months (1.2-13.7 months) in patients with treated/stable and untreated/active BMs, respectively. For those with treated/stable BMs, the median intracranial DoR was 12.3 [95% confidence interval (CI) 9.1-17.9] months, and for those with untreated/active BMs, it was 17.5 months (95% CI 13.6-31.6 months). The median CNS-PFS and OS were 12.3 months (95% CI 11.1-13.8 months) and not reached (95% CI 22.1 months-not estimable) in those with treated/stable BMs, and 18.5 months (95% CI 13.6-23.3 months) and 30.2 months (95% CI 21.3 months-not estimable) in those with untreated/active BMs, respectively. Drug-related treatment-emergent adverse events grade &#x2265;3 were experienced by 43.2% of patients with BMs and 46.4% without BMs with T-DXd.<br><br>CONCLUSIONS: T-DXd demonstrated meaningful intracranial efficacy and clinical benefit in OS, with an acceptable and manageable safety profile in patients with HER2-positive mBC with treated/stable and untreated/active BMs.}, }
@article {pmid39241315, year = {2024}, author = {Bakaloudi, DR and Talukder, R and Makrakis, D and Diamantopoulos, L and Enright, T and Leary, JB and Patgunarajah, U and Thomas, VM and Swami, U and Agarwal, N and Jindal, T and Koshkin, VS and Brown, JR and Barata, P and Murgić, J and Miletić, M and Johnson, J and Zakharia, Y and Hui, G and Drakaki, A and Duran, I and Buznego, LA and Barrera, RM and Castañeda, DM and Rey-Cárdenas, M and Castellano, D and Nguyen, CB and Park, JJ and Alva, A and McKay, RR and Stewart, TF and Epstein, IB and Bellmunt, J and Wright, JL and Gupta, S and Grivas, P and Khaki, AR}, title = {Association of Tumor Mutational Burden and Microsatellite Instability With Response and Outcomes in Patients With Urothelial Carcinoma Treated With Immune Checkpoint Inhibitor.}, journal = {Clinical genitourinary cancer}, volume = {22}, number = {6}, pages = {102198}, doi = {10.1016/j.clgc.2024.102198}, pmid = {39241315}, issn = {1938-0682}, support = {P30 CA086862/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Microsatellite Instability ; *Immune Checkpoint Inhibitors/therapeutic use ; Male ; Female ; Aged ; Middle Aged ; *Mutation ; Aged, 80 and over ; Carcinoma, Transitional Cell/drug therapy/genetics/mortality ; Retrospective Studies ; Urologic Neoplasms/drug therapy/genetics/mortality/pathology ; Treatment Outcome ; Antibodies, Monoclonal, Humanized/therapeutic use ; Adult ; Biomarkers, Tumor/genetics ; Progression-Free Survival ; }, abstract = {BACKGROUND: Microsatellite Instability (MSI) and Tumor Mutational Burden (TMB) are associated with immune checkpoint inhibitor (ICI) efficacy. We examined the association between TMB and MSI status with survival in patients with urothelial carcinoma (UC) treated with ICI.<br><br>METHODS: Patients from 15 institutions were treated with ICI monotherapy. Primary endpoint was overall survival and secondary endpoints included observed response rate (ORR), and progression-free (PFS) calculated from ICI initiation. TMB was analyzed as dichotomous (&#x2265;10 vs. <10 mut/Mb) and continuous variable.<br><br>RESULTS: We identified 411 patients: 203 were treated with ICI 1L/upfront; 104 with 2 + L. For the 1L/upfront: median [m] OS was numerically longer in patients with TMB &#x2265;10 versus TMB <10: mOS 35 versus 26 months (HR = 0.6) and with MSI-H and MSI-S (mOS NR vs. 22 months), though neither association was statistically significant. A statistically significant association was found between TMB (continuous variable) and OS (HR = 0.96, P = .01). For 2 + L: mOS was numerically longer in patients with TMB &#x2265;10 versus TMB <10: (20 vs. 12 months; HR = 0.9); mOS was 12 and 17 months for patients with MSI-H and MSI-S, respectively. Eighty-nine patients received maintenance avelumab (mAV): mOS was longer in patients with TMB &#x2265;10 versus TMB <10: 61 versus 17 months; (HR = 0.2, P = .02) and with MSI-H and MSI-S (NR vs. 24 months).<br><br>CONCLUSIONS: Although not reaching statistical significance in several subsets, patients with high TMB and MSI-H had numerically longer OS with ICI, especially with mAV. Further validation is needed.}, }
@article {pmid39241195, year = {2024}, author = {Walter, RB and Potter, V and Craddock, C}, title = {Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia in Adults over 70 years old.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024024247}, pmid = {39241195}, issn = {1528-0020}, abstract = {The advent of reduced-intensity conditioning regimens, improvements in graft-versus-host disease prophylaxis, and better supportive care have permitted increasing use of allogeneic hematopoietic cell transplantation (allo-HCT) in adults age ≥70 with AML. However, while potentially curative, non-relapse mortality and relapse represent the main causes of treatment failure, highlighting the importance of refining both patient selection and transplant strategies. At the same time, continuously evolving non-transplant therapies and transplant technologies mandate prospective trials (re-)examining the role of allo-HCT and its optimal delivery.}, }
@article {pmid39241101, year = {2024}, author = {Abousamra, E and Figgins, M and Bedford, T}, title = {Fitness models provide accurate short-term forecasts of SARS-CoV-2 variant frequency.}, journal = {PLoS computational biology}, volume = {20}, number = {9}, pages = {e1012443}, pmid = {39241101}, issn = {1553-7358}, support = {R35 GM119774/GM/NIGMS NIH HHS/United States ; }, mesh = {*SARS-CoV-2/genetics ; Humans ; *COVID-19/epidemiology/virology ; *Forecasting/methods ; Computational Biology/methods ; Retrospective Studies ; }, abstract = {Genomic surveillance of pathogen evolution is essential for public health response, treatment strategies, and vaccine development. In the context of SARS-COV-2, multiple models have been developed including Multinomial Logistic Regression (MLR) describing variant frequency growth as well as Fixed Growth Advantage (FGA), Growth Advantage Random Walk (GARW) and Piantham parameterizations describing variant Rt. These models provide estimates of variant fitness and can be used to forecast changes in variant frequency. We introduce a framework for evaluating real-time forecasts of variant frequencies, and apply this framework to the evolution of SARS-CoV-2 during 2022 in which multiple new viral variants emerged and rapidly spread through the population. We compare models across representative countries with different intensities of genomic surveillance. Retrospective assessment of model accuracy highlights that most models of variant frequency perform well and are able to produce reasonable forecasts. We find that the simple MLR model provides ∼0.6% median absolute error and ∼6% mean absolute error when forecasting 30 days out for countries with robust genomic surveillance. We investigate impacts of sequence quantity and quality across countries on forecast accuracy and conduct systematic downsampling to identify that 1000 sequences per week is fully sufficient for accurate short-term forecasts. We conclude that fitness models represent a useful prognostic tool for short-term evolutionary forecasting.}, }
@article {pmid39241078, year = {2024}, author = {Nguyen, TNH and Horowitz, LF and Krilov, T and Lockhart, E and Kenerson, HL and Gujral, TS and Yeung, RS and Arroyo-Currás, N and Folch, A}, title = {Label-free, real-time monitoring of cytochrome C drug responses in microdissected tumor biopsies with a multi-well aptasensor platform.}, journal = {Science advances}, volume = {10}, number = {36}, pages = {eadn5875}, pmid = {39241078}, issn = {2375-2548}, mesh = {*Cytochromes c/metabolism ; Humans ; Animals ; Mice ; *Aptamers, Nucleotide ; Neoplasms/drug therapy/pathology/genetics/metabolism ; Biosensing Techniques/methods ; Biopsy ; Cell Line, Tumor ; Apoptosis/drug effects ; Antineoplastic Agents/pharmacology ; }, abstract = {Functional assays on intact tumor biopsies can complement genomics-based approaches for precision oncology, drug testing, and organs-on-chips cancer disease models by capturing key therapeutic response determinants, such as tissue architecture, tumor heterogeneity, and the tumor microenvironment. Most of these assays rely on fluorescent labeling, a semiquantitative method best suited for single-time-point assays or labor-intensive immunostaining analysis. Here, we report integrated aptamer electrochemical sensors for on-chip, real-time monitoring of cytochrome C, a cell death indicator, from intact microdissected tissues with high affinity and specificity. The platform features a multi-well sensor layout and a multiplexed electronic setup. The aptasensors measure increases in cytochrome C in the supernatant of mouse or human microdissected tumors after exposure to various drug treatments. Because of the sensor's high affinity, it primarily tracks rising concentrations of cytochrome C, capturing dynamic changes during apoptosis. This approach could help develop more advanced cancer disease models and apply to other complex in vitro disease models, such as organs-on-chips and organoids.}, }
@article {pmid39240995, year = {2024}, author = {Williamson, BD and Wu, L and Huang, Y and Hudson, A and Gilbert, PB}, title = {Predicting neutralization susceptibility to combination HIV-1 monoclonal broadly neutralizing antibody regimens.}, journal = {PloS one}, volume = {19}, number = {9}, pages = {e0310042}, pmid = {39240995}, issn = {1932-6203}, support = {UM1 AI068635/AI/NIAID NIH HHS/United States ; }, mesh = {*HIV-1/immunology/drug effects ; Humans ; *Antibodies, Neutralizing/immunology ; *HIV Antibodies/immunology ; *Antibodies, Monoclonal/immunology ; HIV Infections/immunology/drug therapy/virology ; Neutralization Tests/methods ; }, abstract = {Combination monoclonal broadly neutralizing antibodies (bnAbs) are currently being developed for preventing HIV-1 acquisition. Recent work has focused on predicting in vitro neutralization potency of both individual bnAbs and combination regimens against HIV-1 pseudoviruses using Env sequence features. To predict in vitro combination regimen neutralization potency against a given HIV-1 pseudovirus, previous approaches have applied mathematical models to combine individual-bnAb neutralization and have predicted this combined neutralization value; we call this the combine-then-predict (CP) approach. However, prediction performance for some individual bnAbs has exceeded that for the combination, leading to another possibility: combining the individual-bnAb predicted values and using these to predict combination regimen neutralization; we call this the predict-then-combine (PC) approach. We explore both approaches in both simulated data and data from the Los Alamos National Laboratory's Compile, Neutralize, and Tally NAb Panels repository. The CP approach is superior to the PC approach when the neutralization outcome of interest is binary (e.g., neutralization susceptibility, defined as inhibitory 80% concentration < 1 μg/mL). For continuous outcomes, the CP approach performs nearly as well as the PC approach when the individual-bnAb prediction algorithms have strong performance, and is superior to the PC approach when the individual-bnAb prediction algorithms have poor performance. This knowledge may be used when building prediction models for novel antibody combinations in the absence of in vitro neutralization data for the antibody combination; this, in turn, will aid in the evaluation and down-selection of these antibody combinations into prevention efficacy trials.}, }
@article {pmid39240590, year = {2024}, author = {Nyame, YA}, title = {Editor of the Month.}, journal = {Urology practice}, volume = {}, number = {}, pages = {101097UPJ0000000000000693}, doi = {10.1097/UPJ.0000000000000693}, pmid = {39240590}, issn = {2352-0787}, }
@article {pmid39240291, year = {2024}, author = {Donzella, SM and Deubler, E and Patel, AV and Phipps, AI and Zhong, C}, title = {Sleep and cancer mortality in the Cancer Prevention Study-II.}, journal = {Cancer causes &amp; control : CCC}, volume = {35}, number = {12}, pages = {1541-1555}, pmid = {39240291}, issn = {1573-7225}, mesh = {Humans ; Male ; Female ; *Neoplasms/mortality/epidemiology ; Middle Aged ; *Sleep/physiology ; Adult ; Aged ; Sleep Initiation and Maintenance Disorders/complications ; Risk Factors ; United States/epidemiology ; }, abstract = {PURPOSE: Sleep is a multi-dimensional human function that is associated with cancer outcomes. Previous work on sleep and cancer mortality have not investigated how this relationship varies by sex and cancer site. We investigated the association of sleep duration and perceived insomnia with site-specific and overall cancer mortality among participants in the Cancer Prevention Study-II.<br><br>METHODS: Sleep was collected at baseline in 1982 among 1.2 million cancer-free US adults. Cancer-specific mortality was determined through 2018. We used multivariable Cox proportional hazard models to calculate hazard ratios and 95% confidence intervals for overall and site-specific cancer mortality, stratified by sex.<br><br>RESULTS: Among 983,105 participants (56% female) followed for a median of 27.9 person-years, there were 146,911 primary cancer deaths. Results from the adjusted model showed short (6&#xa0;h/night) and long (8 h/night and 9-14 h/night) sleep duration, compared to 7 h/night, were associated with a modest 2%, 2%, and 5% higher risk of overall cancer mortality, respectively, and there was a significant non-linear trend (p-trend&#x2009;<&#x2009;0.01). This non-linear trend was statistically significant among male (p-trend&#x2009;<&#x2009;0.001) but not female (p-trend 0.71) participants. For male participants, short and long sleep were associated with higher risk of lung cancer mortality and long sleep was associated with higher risk of colorectal cancer mortality. Perceived insomnia was associated with a 3-7% lower risk of overall cancer mortality.<br><br>CONCLUSION: Sleep is important to consider in relation to sex- and site-specific cancer mortality. Future research should investigate other components of sleep in relation to cancer mortality.}, }
@article {pmid39240111, year = {2024}, author = {Agrawal, P and Knudsen, ML and MacCamy, A and Hurlburt, NK and Khechaduri, A and Salladay, KR and Kher, GM and Kallur Siddaramaiah, L and Stuart, AB and Bontjer, I and Shen, X and Montefiori, D and Gristick, HB and Bjorkman, PJ and Sanders, RW and Pancera, M and Stamatatos, L}, title = {Short CDRL1 in intermediate VRC01-like mAbs is not sufficient to overcome key glycan barriers on HIV-1 Env.}, journal = {Journal of virology}, volume = {98}, number = {10}, pages = {e0074424}, pmid = {39240111}, issn = {1098-5514}, support = {P01 AI100148/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P30 GM124169/GM/NIGMS NIH HHS/United States ; //P01 AI1382122/ ; //R01 AI104384/ ; P01 AI138212/AI/NIAID NIH HHS/United States ; P01 AI132122/AI/NIAID NIH HHS/United States ; S10 OD021832/OD/NIH HHS/United States ; R01 AI104384/AI/NIAID NIH HHS/United States ; }, mesh = {*HIV Antibodies/immunology ; *HIV-1/immunology ; Humans ; Animals ; *Antibodies, Neutralizing/immunology ; Mice ; *Polysaccharides/immunology ; *Broadly Neutralizing Antibodies/immunology ; *Antibodies, Monoclonal/immunology ; HIV Envelope Protein gp120/immunology/genetics ; Glycosylation ; AIDS Vaccines/immunology ; HIV Infections/immunology/virology/prevention &amp; control ; Receptors, Antigen, B-Cell/immunology ; Epitopes/immunology ; }, abstract = {UNLABELLED: VRC01-class broadly neutralizing antibodies (bnAbs) have been isolated from people with HIV-1, but they have not yet been elicited by vaccination. They are extensively somatically mutated and sometimes accumulate CDRL1 deletions. Such indels may allow VRC01-class antibodies to accommodate the glycans expressed on a conserved N276 N-linked glycosylation site in loop D of the gp120 subunit. These glycans constitute a major obstacle in the development of VRC01-class antibodies, as unmutated antibody forms are unable to accommodate them. Although immunizations of knock-in mice expressing human VRC01-class B-cell receptors (BCRs) with specifically designed Env-derived immunogens lead to the accumulation of somatic mutations in VRC01-class BCRs, CDRL1 deletions are rarely observed, and the elicited antibodies display narrow neutralizing activities. The lack of broad neutralizing potential could be due to the absence of deletions, the lack of appropriate somatic mutations, or both. To address this point, we modified our previously determined prime-boost immunization with a germline-targeting immunogen nanoparticle (426c.Mod.Core), followed by a heterologous core nanoparticle (HxB2.WT.Core), by adding a final boost with a cocktail of various stabilized soluble Env trimers. We isolated VRC01-like antibodies with extensive somatic mutations and, in one case, a seven-amino acid CDRL1 deletion. We generated chimeric antibodies that combine the vaccine-elicited somatic mutations with CDRL1 deletions present in human mature VRC01 bnAbs. We observed that CDRL1 indels did not improve the neutralizing antibody activities. Our study indicates that CDRL1 length by itself is not sufficient for the broadly neutralizing phenotype of this class of antibodies.<br><br>IMPORTANCE: HIV-1 broadly neutralizing antibodies will be a key component of an effective HIV-1 vaccine, as they prevent viral acquisition. Over the past decade, numerous broadly neutralizing antibodies (bnAbs) have been isolated from people with HIV. Despite an in-depth knowledge of their structures, epitopes, ontogenies, and, in a few rare cases, their maturation pathways during infection, bnAbs have, so far, not been elicited by vaccination. This necessitates the identification of key obstacles that prevent their elicitation by immunization and overcoming them. Here we examined whether CDRL1 shortening is a prerequisite for the broadly neutralizing potential of VRC01-class bnAbs, which bind within the CD4 receptor binding site of Env. Our findings indicate that CDRL1 shortening by itself is important but not sufficient for the acquisition of neutralization breadth, and suggest that particular combinations of amino acid mutations, not elicited so far by vaccination, are most likely required for the development of such a feature.}, }
@article {pmid39239793, year = {2024}, author = {Chen, Y and Zhao, L and Jung, SY and Pichardo, MS and Lopez-Pentecost, M and Rohan, TE and Saquib, N and Sun, Y and Tabung, FK and Zheng, T and Wactawski-Wende, J and Manson, JE and Neuhouser, ML and Zhang, X}, title = {Diabetes risk reduction diet and risk of liver cancer and chronic liver disease mortality: A prospective cohort study.}, journal = {Journal of internal medicine}, volume = {296}, number = {5}, pages = {410-421}, doi = {10.1111/joim.20007}, pmid = {39239793}, issn = {1365-2796}, support = {/HL/NHLBI NIH HHS/United States ; /NH/NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; R21 CA238651/CA/NCI NIH HHS/United States ; R21 CA252962/CA/NCI NIH HHS/United States ; R37 CA262299/CA/NCI NIH HHS/United States ; U01 CA259208/CA/NCI NIH HHS/United States ; U01 CA272452/CA/NCI NIH HHS/United States ; RSG-17-190-01-NEC//American Cancer Society Research Scholar Award/ ; PASD-221003396-01//American Cancer Society Interdisciplinary Team Award/ ; /HL/NHLBI NIH HHS/United States ; /NH/NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; R21 CA238651/CA/NCI NIH HHS/United States ; R21 CA252962/CA/NCI NIH HHS/United States ; R37 CA262299/CA/NCI NIH HHS/United States ; U01 CA259208/CA/NCI NIH HHS/United States ; U01 CA272452/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; Prospective Studies ; Middle Aged ; Aged ; *Liver Neoplasms/mortality/prevention &amp; control/epidemiology ; Risk Reduction Behavior ; Chronic Disease ; Risk Factors ; Liver Diseases/mortality ; Diet/adverse effects ; Incidence ; Postmenopause ; Proportional Hazards Models ; }, abstract = {BACKGROUND: We aimed to prospectively evaluate the association between a diabetes risk reduction diet (DRRD) score and the risk of liver cancer development and chronic liver disease-specific mortality.<br><br>METHODS: We included 98,786 postmenopausal women from the Women's Health Initiative-Observational Study and the usual diet arm of the Diet Modification trial. The DRRD score was derived from eight factors: high intakes of dietary fiber, coffee, nuts, polyunsaturated fatty acids, low intakes of red and processed meat, foods with high glycemic index, sugar-sweetened beverages (SSBs), and trans fat based on a validated Food-Frequency Questionnaire administered at baseline (1993-1998). Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for liver cancer incidence and chronic liver disease mortality were estimated using Cox proportional hazards regression models.<br><br>RESULTS AND CONCLUSION: After a median follow-up of 22.0 years, 216 incident liver cancer cases and 153 chronic liver disease deaths were confirmed. A higher DRRD score was significantly associated with a reduced risk of developing liver cancer (HRTertile 3 vs. Tertile 1&#xa0;=&#xa0;0.69; 95% CI: 0.49-0.97; Ptrend&#xa0;=&#xa0;0.03) and chronic liver disease mortality (HRT3 vs. T1&#xa0;=&#xa0;0.54; 95% CI: 0.35-0.82; Ptrend&#xa0;=&#xa0;0.003). We further found inverse associations with dietary fiber and coffee, and positive associations with dietary glycemic index, SSBs, and trans fat. A higher DRRD score was associated with reduced risk of developing liver cancer and chronic liver disease mortality among postmenopausal women.}, }
@article {pmid39238853, year = {2024}, author = {Leedy, DJ and Voit, JM and Rillamas-Sun, E and Kwan, ML and Shen, H and Li, S and Laurent, CA and Rana, JS and Lee, VS and Roh, JM and Huang, Y and Greenlee, H and Cheng, RK}, title = {Blood Pressure and Cardiovascular Risk in Women With Breast Cancer: The Pathways Heart Study.}, journal = {JACC. Advances}, volume = {3}, number = {9}, pages = {101207}, pmid = {39238853}, issn = {2772-963X}, abstract = {BACKGROUND: Hypertension is an important contributor to cardiovascular disease (CVD) in breast cancer (BC) survivors; however, research on blood pressure (BP) and CVD outcomes in BC survivors is limited.<br><br>OBJECTIVES: The purpose of this study was to better characterize the association between BP and CVD in a large, longitudinal cohort of BC patients.<br><br>METHODS: Women with invasive BC diagnosed from 2005 to 2013 at Kaiser Permanente Northern California were matched 1:5 to women without BC. Patient data were obtained from electronic health records. Multivariable Cox regression and penalized spline models were used to explore the linear and nonlinear relationship of systolic blood pressure (SBP) and diastolic blood pressure (DBP) on CVD outcomes.<br><br>RESULTS: BC cases (n&#xa0;=&#xa0;12,713) and controls (n&#xa0;=&#xa0;55,886) had median follow-up of 9.6&#xa0;years (IQR: 5.0-11.9 years). Women with BC had a mean age of 60.6&#xa0;years; 64.8% were non-Hispanic White. For ischemic heart disease (IHD), every 10&#xa0;mmHg increase in SBP and DBP was associated with 1.23 (95%&#xa0;CI: 1.14-1.33) and 1.10 (95%&#xa0;CI: 0.98-1.24) risk, respectively, in women with BC. For stroke, every 10&#xa0;mmHg increase in SBP and DBP was associated with a 1.45 (95%&#xa0;CI: 1.34-1.58) and 1.91 (95%&#xa0;CI: 1.68-2.18) risk, respectively. A U-shaped relationship was observed between heart failure/cardiomyopathy and BP. The associations between BP and risk of IHD, stroke, and any primary CVD were not statistically different comparing women with BC to controls, but risks varied by BC status for heart failure/cardiomyopathy (P for interaction&#xa0;=&#xa0;0.01).<br><br>CONCLUSIONS: Women with and without BC showed similar risks for IHD, stroke, and any primary CVD suggesting similar BP targets should be pursued regardless of BC survivorship status.}, }
@article {pmid39238483, year = {2024}, author = {Vitanza, NA and Choe, M and Brown, C and Beebe, A and Kong, A and Rogers, L and Jacob, S and Mano, E and Abuan, K and Mgebroff, S and Lindgren, C and Gustafson, JA and Wilson, AL and Noll, A and Ronsley, R and Crotty, EE and Leary, SES and Foster, JB and Pinto, N and Gust, J and Gardner, RA and Park, JR and Jensen, MC}, title = {Locoregional CAR T Cells for the Treatment of CNS Tumors in Children: Investigational Drug Service Pharmacy Activities.}, journal = {Journal of hematology oncology pharmacy}, volume = {14}, number = {4}, pages = {148-154}, pmid = {39238483}, issn = {2164-1153}, support = {U01 TR002487/TR/NCATS NIH HHS/United States ; }, abstract = {BACKGROUND: A major obstacle in translating the therapeutic potential of chimeric antigen receptor (CAR) T cells to children with central nervous system (CNS) tumors is the blood-brain barrier. To overcome this limitation, preclinical and clinical studies have supported the use of repeated, locoregional intracranial CAR T-cell delivery. However, there is limited literature available describing the process for the involvement of an investigational drug service (IDS) pharmacy, particularly in the setting of a children's hospital with outpatient dosing for CNS tumors.<br><br>OBJECTIVES: To describe Seattle Children's Hospital's experience in clinically producing CAR T cells and the implementation of IDS pharmacy practices used to deliver more than 300 intracranial CAR T-cell doses to children, as well as to share how we refined the processing techniques from CAR T-cell generation to the thawing of fractionated doses for intracranial delivery.<br><br>METHODS: Autologous CD4+ and CD8+ T cells were collected and transduced to express HER2, EGFR, or B7-H3-specific CAR T cells. Cryopreserved CAR T cells were thawed by the IDS pharmacy before intracranial delivery to patients with recurrent/refractory CNS tumors or with diffuse intrinsic pontine glioma/diffuse midline glioma.<br><br>RESULTS: The use of a thaw-and-dilute procedure for cryopreserved individual CAR T-cell doses provides reliable viability and is more efficient than typical thaw-and-wash protocols. Cell viability with the thaw-and-dilute protocol was approximately 75% and was always within 10% of the viability assessed at cryopreservation. Cell viability was preserved through 6 hours after thawing, which exceeded the 1-hour time frame from thawing to infusion.<br><br>CONCLUSION: As the field of adoptive immunotherapy grows and continues to bring hope to patients with fatal CNS malignancies, it is critical to focus on improving the preparatory steps for CAR T-cell delivery.}, }
@article {pmid39236759, year = {2024}, author = {Streiff, MB and Holmstrom, B and Angelini, D and Ashrani, A and Buckner, T and Diep, R and Fertrin, KY and Fogerty, AE and Crestani, NG and Gangaraju, R and Rojas-Hernandez, C and Goldhaber, SZ and Ibrahim, I and Kubal, T and Leavitt, AD and Lim, M and Mann, J and Mantha, S and Morton, C and Nester, A and O'Brien, A and Ortel, TL and Pine, A and Pishko, A and Ranade, M and Salmasi, A and Schaefer, J and Williams, E and Wool, G and Wun, T and Montgomery, S and Nguyen, J and Freedman-Cass, D and Sliker, B}, title = {Cancer-Associated Venous Thromboembolic Disease, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {7}, pages = {483-506}, doi = {10.6004/jnccn.2024.0046}, pmid = {39236759}, issn = {1540-1413}, mesh = {Humans ; *Venous Thromboembolism/etiology/diagnosis/therapy/prevention &amp; control ; *Neoplasms/complications/therapy/diagnosis ; Medical Oncology/standards/methods ; Anticoagulants/therapeutic use ; Disease Management ; }, abstract = {The NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease provide strategies for the prevention, diagnosis, and treatment of venous thromboembolism (VTE) in adult patients with cancer. VTE is a common and life-threatening condition in patients with cancer, and its management often requires multidisciplinary efforts. The NCCN panel is comprised of specialists spanning various fields, including cardiology, hematology, medical oncology, internal medicine, interventional radiology, and pharmacology. The content featured in this issue specifically addresses the evaluation and recommended treatment options outlined in the NCCN Guidelines for the diverse subtypes of cancer-associated VTE.}, }
@article {pmid39236750, year = {2024}, author = {Ness, RM and Llor, X and Abbass, MA and Bishu, S and Chen, CT and Cooper, G and Early, DS and Friedman, M and Fudman, D and Giardiello, FM and Glaser, K and Gurudu, S and Hall, M and Huang, LC and Issaka, R and Katona, B and Kidambi, T and Lazenby, AJ and Maratt, J and Markowitz, AJ and Marsano, J and May, FP and Mayer, RJ and Olortegui, K and Patel, S and Peter, S and Porter, LD and Shafi, M and Stanich, PP and Terdiman, J and Vu, P and Weiss, JM and Wood, E and Cassara, CJ and Sambandam, V}, title = {NCCN Guidelines® Insights: Colorectal Cancer Screening, Version 1.2024.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {7}, pages = {438-446}, doi = {10.6004/jnccn.2024.0047}, pmid = {39236750}, issn = {1540-1413}, support = {K08 CA241296/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Colorectal Neoplasms/diagnosis ; *Early Detection of Cancer/standards/methods ; Mass Screening/methods/standards ; }, abstract = {The NCCN Guidelines for Colorectal Cancer (CRC) Screening describe various colorectal screening modalities as well as recommended screening schedules for patients at average or increased risk of developing sporadic CRC. They are intended to aid physicians with clinical decision-making regarding CRC screening for patients without defined genetic syndromes. These NCCN Guidelines Insights focus on select recent updates to the NCCN Guidelines, including a section on primary and secondary CRC prevention, and provide context for the panel's recommendations regarding the age at which to initiate screening in average-risk individuals and those with increased risk based on personal history of childhood, adolescent, and young adult cancer.}, }
@article {pmid39236733, year = {2024}, author = {Isa, F and Gonzalez Ortiz, AM and Meyer, J and Hamilton, JD and Olenchock, BA and Brackin, T and Ganguly, S and Forleo-Neto, E and Faria, L and Heirman, I and Marovich, M and Hutter, J and Polakowski, L and Irvin, SC and Thakur, M and Hooper, AT and Baum, A and Petro, CD and Fakih, FA and McElrath, MJ and De Rosa, SC and Cohen, KW and Williams, LD and Hellman, CA and Odeh, AJ and Patel, AH and Tomaras, GD and Geba, GP and Kyratsous, CA and Musser, B and Yancopoulos, GD and Herman, GA and , }, title = {Effect of timing of casirivimab and imdevimab administration relative to mRNA-1273 COVID-19 vaccination on vaccine-induced SARS-CoV-2 neutralising antibody responses: a prospective, open-label, phase 2, randomised controlled trial.}, journal = {The Lancet. Infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1016/S1473-3099(24)00421-3}, pmid = {39236733}, issn = {1474-4457}, abstract = {BACKGROUND: Deeper insight is needed on how monoclonal antibodies (mAbs) affect vaccine-mediated immune responses when targeting the same protein. We describe the first prospective randomised trial designed to understand mAb-mediated alterations in vaccine-induced immune responses to SARS-CoV-2 spike protein epitopes.<br><br>METHODS: This randomised, open-label, parallel-group study assessed the potential interaction of a mAb combination, casirivimab and imdevimab, with a vaccine, Moderna's mRNA-1273, in healthy SARS-CoV-2 immunologically naive, seronegative adults at six centres in the USA. Participants were randomly assigned (per prespecified randomisation ratios within enrolment waves) according to a computer-generated randomisation scheme, stratified by age (<65 years and &#x2265;65 years), to various intravenous or subcutaneous doses of casirivimab and imdevimab before, after, or at the same time as mRNA-1273 or to mRNA-1273 only. The doses of casirivimab and imdevimab were chosen to mimic various time intervals between receipt of 1200 mg of the mAb and the first dose of a primary series with mRNA-1273. The primary endpoint was vaccine-induced 50% inhibitory dilution neutralising antibody titres to SARS-CoV-2 spike protein, 56 days after the first vaccination. Secondary endpoints included vaccine-induced total antibodies to SARS-CoV-2 antigens and incidence of treatment-emergent adverse events. Exploratory endpoints included blood-derived T-cell and B-cell responses. The per-protocol set was used for the analysis of the primary endpoint and included all randomly assigned participants who received both doses of the vaccine and completed the injection or infusion of casirivimab and imdevimab per protocol, had no evidence of SARS-CoV-2 infection in the past or in the 56 days after the first dose of vaccine, and did not receive any intervention outside of the study that could alter the immune response. Safety was assessed in the safety analysis set, which included all randomly assigned participants who had received one or more doses of mRNA-1273 or any study drug, and analysed based on treatment received. The study is registered with ClinicalTrials.gov, NCT04852978, and is complete.<br><br>FINDINGS: Between April 29, 2021, and Nov 21, 2022, 807 participants were assessed for eligibility and 295 were randomly assigned. 293 participants were included in the safety analysis set and 260 were included in the per-protocol set. All vaccinated participants developed neutralising antibodies to SARS-CoV-2, with median titres above the published protective threshold (100 IU/mL) against the SARS-CoV-2 D614G variant (considered a reference strain at the time the initial COVID-19 vaccines were developed). Titres were decreased up to 4-fold (median titres 280-450 IU/mL for casirivimab and imdevimab vs 1160 IU/mL for vaccine only on day 56) when casirivimab and imdevimab was given 85 days or less before vaccination (150-1200 mg intravenously) or co-administered subcutaneously (600 mg or 1200 mg) with vaccination. Minimal reduction in neutralisation titres was observed in the 48 mg and 12 mg intravenous groups, corresponding to receipt of casirivimab and imdevimab 113 days and 169 days, respectively, before vaccination, and when administering the vaccine 6 days before the mAb. Across all groups, mAbs had a minimal effect on vaccine-induced total antibodies and T-cell responses to the spike protein. Casirivimab and imdevimab plus mRNA-1273 was generally well tolerated; a slight increase in treatment-emergent adverse events was observed in the casirivimab and imdevimab plus vaccine groups versus the vaccine-only group.<br><br>INTERPRETATION: Casirivimab and imdevimab administration before or at the time of COVID-19 vaccination reduced the elicitation of SARS-CoV-2 neutralising antibodies, but minimal effect was observed when vaccination occurred before mAb administration. Although the clinical significance of this decrease in neutralisation is unclear, this evidence suggests that further investigation of potential interactions could be warranted before concurrent clinical use of mAbs and vaccines targeting the same viral proteins as their main modes of action for the prevention or treatment of infectious diseases.<br><br>FUNDING: Regeneron Pharmaceuticals and F Hoffmann-La Roche.}, }
@article {pmid39236556, year = {2024}, author = {Kenny, A and van Duijn, J and Dintwe, O and Heptinstall, J and Burnham, R and Sawant, S and Zhang, L and Mielke, D and Khuzwayo, S and Omar, FL and Stanfield-Oakley, S and Keyes, T and Dunn, B and Goodman, D and Fong, Y and Benkeser, D and Zou, R and Hural, J and Hyrien, O and Juraska, M and Luedtke, A and van der Laan, L and Giorgi, EE and Magaret, C and Carpp, LN and Pattacini, L and van de Kerkhof, T and Korber, B and Willems, W and Fisher, LH and Schuitemaker, H and Swann, E and Kublin, JG and Pau, MG and Buchbinder, S and Tomaka, F and Nijs, S and Lavreys, L and Gelderblom, HC and Corey, L and Mngadi, K and Gray, GE and Borducchi, E and Hendriks, J and Seaton, KE and Zolla-Pazner, S and Barouch, DH and Ferrari, G and De Rosa, SC and McElrath, MJ and Andersen-Nissen, E and Stieh, DJ and Tomaras, GD and Gilbert, PB and , }, title = {Immune correlates analysis of the Imbokodo (HVTN 705/HPX2008) efficacy trial of a mosaic HIV-1 vaccine regimen evaluated in Southern African people assigned female sex at birth: a two-phase case-control study.}, journal = {EBioMedicine}, volume = {108}, number = {}, pages = {105320}, pmid = {39236556}, issn = {2352-3964}, support = {R37 AI150590/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Female ; *AIDS Vaccines/immunology/administration &amp; dosage ; *HIV Infections/immunology/prevention &amp; control/virology ; *HIV-1/immunology ; Case-Control Studies ; Male ; Adult ; Vaccine Efficacy ; HIV Antibodies/blood/immunology ; Immunoglobulin G/blood/immunology ; env Gene Products, Human Immunodeficiency Virus/immunology ; Africa, Southern ; Young Adult ; Southern African People ; }, abstract = {BACKGROUND: The HVTN 705 Imbokodo trial of 2636 people without HIV and assigned female sex at birth, conducted in southern Africa, evaluated a heterologous HIV-1 vaccine regimen: mosaic adenovirus 26-based vaccine (Ad26.Mos4.HIV) at Months 0, 3, 6, 12 and alum-adjuvanted clade C gp140 at Months 6, 12. Per-protocol vaccine efficacy (VE) against HIV-1 diagnosis from seven to 24 months was 14.1% (95% CI: -22.0% to 39.5%). Immune correlates analysis was performed for markers selected based on prior evidence in efficacy trials and/or nonhuman primate models.<br><br>METHODS: Humoral and cellular immune response markers at Month 7 were evaluated as immune correlates of risk and of protection in a breakthrough case-control cohort (n&#xa0;=&#xa0;52 cases, 246 non-cases). Primary markers were IgG binding to vaccine-strain gp140, IgG3 binding to diverse Env antigens (IgG3 Env breadth), IgG3 binding to diverse V1V2 antigens (IgG3 V1V2 breadth), antibody-dependent phagocytosis against the vaccine-strain gp140, Env-specific CD4+ and CD8+ T-cell responses, and multi-epitope functions.<br><br>FINDINGS: No immune markers were statistically significant correlates of risk. IgG3 V1V2 breadth trended toward an inverse association: hazard ratio 0.70 (95% CI: 0.36 to 1.35; p&#xa0;=&#xa0;0.29) per 10-fold increase and 0.51 (95% CI: 0.21 to 1.24; p&#xa0;=&#xa0;0.14) in a Cox model with all primary markers. The VE estimate was 11.8% (95% CI:&#xa0;-17.9% to 34.0%) at all IgG3 V1V2 breadth values below 667 weighted geometric mean net MFI; just above this value, the VE estimate sharply increased to 62.6% (95% CI:&#xa0;-17.9% to 89.6%), and further increased to 80.9% (95% CI:&#xa0;-17.9% to 99.5%) at 1471 MFI, the 95th percentile of the marker distribution. Mediation analysis yielded a VE of 35.7% (95% CI: 15.0% to 51.3%) attributable to the vaccine's impact on this marker.<br><br>INTERPRETATION: The trend in association of greater IgG3 V1V2 antibody breadth with lower likelihood of HIV acquisition is consistent with the identification of antibodies against V1V2 as immune correlates in three other HIV vaccine efficacy trials and suggests that a greater emphasis should be placed on studying this region in the HIV-1 envelope as a vaccine immunogen.<br><br>FUNDING: National Institute of Allergy and Infectious Diseases and Janssen Vaccines &amp; Prevention BV.}, }
@article {pmid39235868, year = {2024}, author = {Piha-Paul, S and Olwill, SA and Hamilton, E and Tolcher, A and Pohlmann, P and Liu, SV and Wurzenberger, C and Hasenkamp, LC and Hansbauer, EM and Shroff, R and Hurvitz, S and Krishnamurthy, A and Patnaik, A and Hahn, N and Kumar, R and Duerr, M and Zettl, M and Aviano, K and Matis, L and Bruns, I and Ku, G}, title = {A First-in-Human Study of cinrebafusp alfa, a HER2/4-1BB Bispecific Molecule, in Patients with HER2-Positive Advanced Solid Malignancies.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-24-1552}, pmid = {39235868}, issn = {1557-3265}, abstract = {PURPOSE: 4-1BB (CD137) is a costimulatory immune receptor expressed on activated T cells, activated B cells, natural killer cells and tumor-infiltrating lymphocytes, making it a promising target for cancer immunotherapy. Cinrebafusp alfa, a monoclonal antibody-like bispecific protein targeting HER2 and 4-1BB, aims to localize 4-1BB activation to HER2-positive tumors. This study evaluated the safety, tolerability, and preliminary efficacy of cinrebafusp alfa in patients with previously treated HER2-positive malignancies.<br><br>EXPERIMENTAL DESIGN: This was a multi-center dose escalation study involving patients with HER2-positive malignancies who had received prior treatment. The study assessed the safety and efficacy of cinrebafusp alfa across various dose levels. Patients were assigned to different cohorts, and antitumor responses were evaluated. The study aimed to determine the maximum tolerated dose (MTD) and to observe any clinical activity at different dose levels.<br><br>RESULTS: Out of 40 evaluable patients in the 'active dose' efficacy cohorts, 5 showed an antitumor response, resulting in an overall response rate (ORR) of 12.5% and a disease control rate of 52.5%. Clinical activity was observed at the 8 mg/kg and 18 mg/kg dose levels, with confirmed objective response rates of 28.6% and 25.0%, respectively. Cinrebafusp alfa was safe and tolerable, with Grade &#x2264;2 infusion-related reactions being the most frequent treatment-related adverse event. MTD was not reached during the study.<br><br>CONCLUSION: Cinrebafusp alfa demonstrates promising activity in patients with HER2-positive malignancies who have progressed on prior HER2-targeting regimens. Its acceptable safety profile suggests it could be a treatment option for patients not responding to existing HER2-directed therapies.}, }
@article {pmid39235529, year = {2024}, author = {Hahn, WO and Parks, KR and Shen, M and Ozorowski, G and Janes, H and Ballweber-Fleming, L and Woodward Davis, AS and Duplessis, C and Tomai, M and Dey, AK and Sagawa, ZK and De Rosa, SC and Seese, A and Kallur Siddaramaiah, L and Stamatatos, L and Lee, WH and Sewall, LM and Karlinsey, D and Turner, HL and Rubin, V and Furth, S and MacPhee, K and Duff, M and Corey, L and Keefer, MC and Edupuganti, S and Frank, I and Maenza, J and Baden, LR and Hyrien, O and Sanders, RW and Moore, JP and Ward, AB and Tomaras, GD and Montefiori, DC and Rouphael, N and McElrath, MJ}, title = {Use of 3M-052-AF with Alum adjuvant in HIV trimer vaccine induces human autologous neutralizing antibodies.}, journal = {The Journal of experimental medicine}, volume = {221}, number = {10}, pages = {}, pmid = {39235529}, issn = {1540-9538}, support = {UM1 AI069534/AI/NIAID NIH HHS/United States ; OPP1107954//Gates Foundation/ ; UM1 AI069481/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; P01 AI110657/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Antibodies, Neutralizing/immunology ; *AIDS Vaccines/immunology/administration &amp; dosage ; *Alum Compounds/administration &amp; dosage ; Adult ; *Adjuvants, Immunologic/administration &amp; dosage ; *env Gene Products, Human Immunodeficiency Virus/immunology ; HIV Antibodies/immunology ; Female ; HIV-1/immunology ; Male ; HIV Infections/immunology/prevention &amp; control ; B-Lymphocytes/immunology ; Adjuvants, Vaccine ; Middle Aged ; Young Adult ; CD4-Positive T-Lymphocytes/immunology ; }, abstract = {Stabilized trimers preserving the native-like HIV envelope structure may be key components of a preventive HIV vaccine regimen to induce broadly neutralizing antibodies (bnAbs). We evaluated trimeric BG505 SOSIP.664 gp140 formulated with a novel TLR7/8 signaling adjuvant, 3M-052-AF/Alum, for safety, adjuvant dose-finding, and immunogenicity in a first-in-healthy adult (n = 17), randomized, and placebo-controlled trial (HVTN 137A). The vaccine regimen appeared safe. Robust, trimer-specific antibody, and B cell and CD4+ T cell responses emerged after vaccination. Five vaccinees developed serum autologous tier 2 nAbs (ID50 titer, 1:28-1:8647) after two to three doses targeting C3/V5 and/or V1/V2/V3 Env regions by electron microscopy and mutated pseudovirus-based neutralization analyses. Trimer-specific, B cell-derived monoclonal antibody activities confirmed these results and showed weak heterologous neutralization in the strongest responder. Our findings demonstrate the clinical utility of the 3M-052-AF/Alum adjuvant and support further improvements of trimer-based Env immunogens to focus responses on multiple broad nAb epitopes.}, }
@article {pmid39235112, year = {2025}, author = {Kwendakwema, CN and Sabo, MC and Roberts, ST and Masese, L and McClelland, RS and Shafi, J and Lehman, DA and Overbaugh, J and Graham, SM}, title = {Sexual Violence, Genital Cytokines, and Colposcopy Findings: A Cross-Sectional Study of Women Engaged in Sex Work in Mombasa, Kenya.}, journal = {Sexually transmitted diseases}, volume = {52}, number = {1}, pages = {29-36}, pmid = {39235112}, issn = {1537-4521}, mesh = {Humans ; Female ; Cross-Sectional Studies ; Kenya/epidemiology ; Adult ; *Cytokines/analysis/metabolism ; *Colposcopy ; *Sex Workers/statistics &amp; numerical data ; *Cervix Uteri/pathology ; *Sex Offenses ; HIV Infections ; Young Adult ; Sex Work ; Adolescent ; }, abstract = {BACKGROUND: Sexual violence (SV) increases human immunodeficiency virus (HIV) susceptibility in a sustained manner. This study evaluated genital cytokines and colposcopy findings in women reporting both recent and more remote SV.<br><br>METHODS: A cross-sectional study of HIV-1 negative Kenyan women who engage in sex work was performed. Cervicovaginal fluid was collected by menstrual cup and cytokines (IFN&#x3b3;, TNF&#x3b1;, IL-1&#x3b2;, IL-6, IL-10, MIP-1&#x3b1;, MIP-1&#x3b2;, and CXCL10) measured using chemiluminescence. Cervical injury was assessed by colposcopy. Associations between recent (&#x2264;30 days prior), more remote (>30 days prior), and no (reference category) SV exposure and cytokine concentrations were evaluated using linear regression.<br><br>RESULTS: Among 282 participants, 25 (8.9%) reported recent SV and 123 (43.6%) reported more remote SV. Only two cytokines (IL-10 and CXCL10) were associated with the 3-category SV variable in bivariable modeling at the prespecified cutoff (P < 0.2) and carried forward. In multivariable analyses, more remote SV (&#x3b2; = 0.72; 95% confidence interval [CI], 0.06-1.38; P = 0.03), but not recent SV (&#x3b2; = 0.20; 95% CI, -0.99 to 1.39; P = 0.74) was associated with cervicovaginal IL-10 compared with no SV. Recent (&#x3b2; = 0.36; 95% CI, -0.94 to 1.67; P = 0.58) and more remote (&#x3b2; = 0.51; 95% CI, -0.21 to 1.24; P = 0.16) SV were not associated with CXCL10 compared with no SV. Cervical epithelial friability (&#x3c7; 2 = 1.3, P = 0.51), erythema (&#x3c7; 2 = 2.9, P = 0.24), vascular disruption (&#x3c7; 2 = 1.4; P = 0.50), epithelial disruption (&#x3c7; 2 = 2.6, P = 0.27), or any colposcopy finding (&#x3c7; 2 = 1.2, P = 0.54) were not associated with SV category by &#x3c7; 2 test.<br><br>CONCLUSIONS: The mechanism linking SV to sustained increases in HIV susceptibility may not be related to persistent genital inflammation or injury.}, }
@article {pmid39234871, year = {2024}, author = {Mercadal, S and Ahn, KW and Allbee-Johnson, M and Ganguly, S and Geethakumari, PR and Hong, S and Malone, A and Murthy, H and Pawarode, A and Sica, AR and Solh, M and Ustun, C and Shadman, M and Sauter, CS and Hamadani, M and Herrera, AF and Lee, CJ}, title = {Outcomes of patients with primary central nervous system lymphoma following CD19-targeted chimeric antigen receptor T-cell therapy.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2024.285613}, pmid = {39234871}, issn = {1592-8721}, }
@article {pmid39234862, year = {2024}, author = {Phillips, T and Wang, M and Robak, T and Gallinson, D and Stevens, D and Patel, K and Ramadan, S and Wun, CC and Jurczak, W and Smith, SD}, title = {Safety and efficacy of acalabrutinib plus bendamustine and rituximab in patients with treatment-naive or relapsed / refractory mantle cell lymphoma: phase Ib trial.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2023.284896}, pmid = {39234862}, issn = {1592-8721}, abstract = {This multicenter, open-label, phase 1b study (ACE-LY-106) assessed the safety and efficacy of acalabrutinib, bendamustine, and rituximab (ABR) in treatment-naive (TN) and relapsed or refractory (R/R) mantle cell lymphoma (MCL). Patients received acalabrutinib from cycle 1 until disease progression or treatment discontinuation, bendamustine on days 1 and 2 of each cycle for up to 6 cycles, and rituximab on day 1 of each cycle for 6 cycles, continuing every other cycle from cycle 8 for 12 additional doses (TN cohort). Eighteen patients enrolled in the TN and 20 in the R/R cohort. Median duration of exposure to acalabrutinib was 34.0 and 14.6 months in the TN and R/R cohorts, respectively. No new safety risks were identified, and most adverse events (AEs) were grades 1 or 2. Thirteen patients from the TN cohort (72.2%) and 17 patients from the R/R cohort (85.0%) reported grade 3-4 AEs, most commonly neutropenia (TN: 38.9%, R/R: 50.0%). AEs leading to death were pneumonitis (n=1, TN cohort), COVID-19, and cerebrospinal meningitis (n=1 each, R/R cohort). Overall response was 94.4% and 85.0% in the TN and R/R cohorts, respectively; complete response rates were 77.8% and 70.0%, respectively. After a median follow-up of 47.6 months, median progression-free survival (PFS) and overall survival (OS) were not reached in the TN cohort. After a median follow-up of 20.4 months, median PFS was 28.6 months and OS was not reached in the R/R cohort. Results indicate that ABR was safe and efficacious, supporting further study in patients with TN MCL. ClinicalTrials.gov identifier: NCT02717624.}, }
@article {pmid39233917, year = {2024}, author = {Wesselink, E and Gauderman, W and Berndt, SI and Brenner, H and Buchanan, DD and Campbell, PT and Chan, AT and Chang-Claude, J and Cotterchoi, M and Gunter, MJ and Hoffmeister, M and Joshi, AD and Newton, CC and Pai, RK and Pellatt, AJ and Phipps, AI and Song, M and Um, CY and van Guelpen, B and White, E and Peters, U and van Duijnhoven, FJB}, title = {Calcium intake and genetic variants in the calcium sensing receptor in relation to colorectal cancer mortality: an international consortium study of 18,952 patients.}, journal = {BJC reports}, volume = {2}, number = {1}, pages = {63}, pmid = {39233917}, issn = {2731-9377}, support = {R01 CA059045/CA/NCI NIH HHS/United States ; U01 HG004438/HG/NHGRI NIH HHS/United States ; U01 HG004446/HG/NHGRI NIH HHS/United States ; U01 CA137088/CA/NCI NIH HHS/United States ; Z01 CP010200/ImNIH/Intramural NIH HHS/United States ; U01 CA164930/CA/NCI NIH HHS/United States ; R01 CA137178/CA/NCI NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; 001/WHO_/World Health Organization/International ; R01 CA248857/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA206279/CA/NCI NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, abstract = {BACKGROUND: Research on calcium intake as well as variants in the calcium sensor receptor (CaSR) gene and their interaction in relation to CRC survival is still limited.<br><br>METHODS: Data from 18,952 CRC patients, were included. Associations between primarily pre-diagnostic dietary (n&#x2009;=&#x2009;13.085), supplemental (n&#x2009;=&#x2009;11,837), total calcium intake (n&#x2009;=&#x2009;5970) as well as 325 single nucleotide polymorphisms (SNPs) of the CaSR gene (n&#x2009;=&#x2009;15,734) in relation to CRC-specific and all-cause mortality were assessed using Cox proportional hazard models. Also interactions between calcium intake and variants in the CaSR gene were assessed.<br><br>RESULTS: During a median follow-up of 4.8 years (IQR 2.4-8.4), 6801 deaths occurred, of which 4194 related to CRC. For all-cause mortality, no associations were observed for the highest compared to the lowest sex- and study-specific quartile of dietary (HR 1.00, 95%CI 0.92-1.09), supplemental (HR 0.97, 95%CI 0.89-1.06) and total calcium intake (HR 0.99, 95%CI 0.88-1.11). No associations with CRC-specific mortality were observed either. Interactions were observed between supplemental calcium intake and several SNPs of the CaSR gene.<br><br>CONCLUSION: Calcium intake was not associated with all-cause or CRC-specific mortality in CRC patients. The association between supplemental calcium intake and all-cause and CRC-specific mortality may be modified by genetic variants in the CaSR gene.}, }
@article {pmid39233850, year = {2024}, author = {Roos, CR and Bricker, J and Kiluk, B and Trull, TJ and Bowen, S and Witkiewitz, K and Kober, H}, title = {A smartphone app-based mindfulness intervention to enhance recovery from substance use disorders: Protocol for a pilot feasibility randomized controlled trial.}, journal = {Contemporary clinical trials communications}, volume = {41}, number = {}, pages = {101338}, pmid = {39233850}, issn = {2451-8654}, abstract = {BACKGROUND: Poor long-term recovery outcomes after treatment (e.g., readmission to inpatient treatment) are common among individuals with substance use disorders (SUDs). In-person mindfulness-based treatments (MBTs) are efficacious for SUDs and may improve recovery outcomes. However, existing MBTs for SUD have limited public health reach, and thus scalable delivery methods are needed. A digitally-delivered MBT for SUDs may hold promise.<br><br>METHODS: We recently developed Mindful Journey, a smartphone app-based adjunctive MBT for improving long-term recovery outcomes. In this paper, we present details on the app and describe the protocol for a single-site pilot feasibility randomized controlled trial of Mindful Journey. In this trial, individuals (n&#xa0;=&#xa0;34) in an early phase of outpatient treatment for SUDs will be randomized to either treatment-as-usual (TAU) plus Mindful Journey, or TAU only. The trial will focus on testing the feasibility (e.g., engagement) and acceptability of the app (e.g., perceived usability and helpfulness for recovery), as well as feasibility of study procedures (e.g., assessment completion). The trial will incorporate ecological momentary assessment before and after treatment to assess mechanisms in real-time, including mindfulness, craving, difficulties with negative emotion regulation, and savoring. To examine the sensitivity to change of outcomes (substance use, substance-related problems, and psychological distress) and mechanism variables (noted above), we will test within-treatment-condition changes over time.<br><br>DISCUSSION: The proposed pilot trial will provide important preliminary data on whether Mindful Journey is feasible and acceptable among individuals with SUDs.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT05109507.}, }
@article {pmid39233462, year = {2024}, author = {Reiner, AS and Knight, JA and John, EM and Lynch, CF and Malone, KE and Liang, X and Woods, M and Root, JC and Bernstein, JL}, title = {Reply to "Critical analysis of the study from Reiner et al. on agreement of medical record abstraction and self-report of breast cancer treatment".}, journal = {Cancer}, volume = {130}, number = {23}, pages = {4151-4152}, doi = {10.1002/cncr.35549}, pmid = {39233462}, issn = {1097-0142}, support = {CA097397/NH/NIH HHS/United States ; CA083178/NH/NIH HHS/United States ; P30 CA086862/CA/NCI NIH HHS/United States ; CA008748/NH/NIH HHS/United States ; CA129639/NH/NIH HHS/United States ; CA114236/NH/NIH HHS/United States ; CA008748/NH/NIH HHS/United States ; CA083178/NH/NIH HHS/United States ; CA097397/NH/NIH HHS/United States ; CA114236/NH/NIH HHS/United States ; CA129639/NH/NIH HHS/United States ; }, }
@article {pmid39232161, year = {2024}, author = {Zheng, XF and Sarkar, A and Lotana, H and Syed, A and Nguyen, H and Ivey, RG and Kennedy, JJ and Whiteaker, JR and Tomasik, B and Huang, K and Li, F and D'Andrea, AD and Paulovich, AG and Shah, K and Spektor, A and Chowdhury, D}, title = {CDK5-cyclin B1 regulates mitotic fidelity.}, journal = {Nature}, volume = {633}, number = {8031}, pages = {932-940}, pmid = {39232161}, issn = {1476-4687}, mesh = {Humans ; Coenzymes/metabolism ; *Cyclin B1/metabolism ; *Cyclin-Dependent Kinase 5/antagonists &amp; inhibitors/deficiency/genetics/metabolism ; HeLa Cells ; *Mitosis ; Models, Molecular ; *Multiprotein Complexes/metabolism ; Mutation ; Phosphoproteins/metabolism ; Protein Binding ; Proteome/metabolism ; Reproducibility of Results ; }, abstract = {CDK1 has been known to be the sole cyclin-dependent kinase (CDK) partner of cyclin B1 to drive mitotic progression[1]. Here we demonstrate that CDK5 is active during mitosis and is necessary for maintaining mitotic fidelity. CDK5 is an atypical CDK owing to its high expression in post-mitotic neurons and activation by non-cyclin proteins p35 and p39[2]. Here, using independent chemical genetic approaches, we specifically abrogated CDK5 activity during mitosis, and observed mitotic defects, nuclear atypia and substantial alterations in the mitotic phosphoproteome. Notably, cyclin B1 is a mitotic co-factor of CDK5. Computational modelling, comparison with experimentally derived structures of CDK-cyclin complexes and validation with mutational analysis indicate that CDK5-cyclin B1 can form a functional complex. Disruption of the CDK5-cyclin B1 complex phenocopies CDK5 abrogation in mitosis. Together, our results demonstrate that cyclin B1 partners with both CDK5 and CDK1, and CDK5-cyclin B1 functions as a canonical CDK-cyclin complex to ensure mitotic fidelity.}, }
@article {pmid39230981, year = {2024}, author = {Collett, JA and Flannery, AH and Liu, LJ and Takeuchi, T and Basile, DP and Neyra, JA}, title = {IL-17A Levels and Progression of Kidney Disease Following Hospitalization with and without Acute Kidney Injury.}, journal = {Kidney360}, volume = {5}, number = {11}, pages = {1623-1632}, pmid = {39230981}, issn = {2641-7650}, support = {R01DK063114/DK/NIDDK NIH HHS/United States ; U54DK137307/DK/NIDDK NIH HHS/United States ; K23DK128562/DK/NIDDK NIH HHS/United States ; R01DK063114/DK/NIDDK NIH HHS/United States ; U54DK137307/DK/NIDDK NIH HHS/United States ; K23DK128562/DK/NIDDK NIH HHS/United States ; R01DK063114/DK/NIDDK NIH HHS/United States ; U54DK137307/DK/NIDDK NIH HHS/United States ; K23DK128562/DK/NIDDK NIH HHS/United States ; }, }
@article {pmid39229223, year = {2024}, author = {Tisoncik-Go, J and Lewis, TB and Whitmore, LS and Voss, K and Niemeyer, S and Dai, J and Kim, P and Hubbell, K and Iwayama, N and Ahrens, C and Wangari, S and Murnane, R and Edlefsen, PT and Guerriero, KA and Gale, M and Fuller, DH and O'Connor, MA}, title = {Chronic innate immune impairment and ZIKV persistence in the gastrointestinal tract during SIV infection in pigtail macaques.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39229223}, issn = {2692-8205}, support = {P51 OD010425/OD/NIH HHS/United States ; U19 AI113173/AI/NIAID NIH HHS/United States ; U42 OD011123/OD/NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; R01 AI145296/AI/NIAID NIH HHS/United States ; HHSN272201800003C/AI/NIAID NIH HHS/United States ; K01 MH123258/MH/NIMH NIH HHS/United States ; UL1 TR000423/TR/NCATS NIH HHS/United States ; }, abstract = {Mosquito borne flaviviruses, including dengue (DENV) and Zika (ZIKV) viruses, have caused global epidemics in areas with high HIV prevalence due to the expanded geographic range of arthropod vectors. Despite the occurrence of large flavivirus outbreaks in countries with high HIV prevalence, there is little knowledge regarding the effects of flavivirus infection in people living with HIV (PLWH). Here, we use a pigtail macaque model of HIV/AIDS to investigate the impact of simian immunodeficiency virus (SIV)-induced immunosuppression on ZIKV replication and pathogenesis. Early acute SIV infection induced expansion of peripheral ZIKV cellular targets and increased innate immune activation and peripheral blood mononuclear cells (PBMC) from SIV infected macaques were less permissive to ZIKV infection in vitro. In SIV-ZIKV co-infected animals, we found increased persistence of ZIKV in the periphery and tissues corresponding to alterations in innate cellular (monocytes, neutrophils) recruitment to the blood and tissues, decreased anti-ZIKV immunity, and chronic peripheral inflammatory and innate immune gene expression. Collectively, these findings suggest that untreated SIV infection may impair cellular innate responses and create an environment of chronic immune activation that promotes prolonged ZIKV viremia and persistence in the gastrointestinal tract. These results suggest that PLWH or other immunocompromised individuals could be at a higher risk for chronic ZIKV replication, which in turn could increase the timeframe of ZIKV transmission. Thus, PLWH are important populations to target during the deployment of vaccine and treatment strategies against ZIKV.}, }
@article {pmid39229127, year = {2024}, author = {Kulsuptrakul, J and Emerman, M and Mitchell, PS}, title = {CARD8 inflammasome activation during HIV-1 cell-to-cell transmission.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39229127}, issn = {2692-8205}, support = {DP1 DA051110/DA/NIDA NIH HHS/United States ; DP2 AI154432/AI/NIAID NIH HHS/United States ; T32 GM007270/GM/NIGMS NIH HHS/United States ; }, abstract = {Our previous work demonstrated that CARD8 detects HIV-1 infection by sensing the enzymatic activity of the HIV protease, resulting in CARD8-dependent inflammasome activation (Kulsuptrakul et al., 2023). CARD8 recognition of HIV-1 protease activity is conferred by a HIV protease substrate mimic within the CARD8 N-terminus, which when cleaved by HIV protease triggers CARD8 inflammasome activation. Here, we sought to understand CARD8 responses to HIV-1 when the virus is transmitted through cell-to-cell infection from infected cells to target cells via a viral synapse. We observed that cell-to-cell transmission of HIV-1 induces CARD8 inflammasome activation in immortalized cells and primary human monocyte-derived macrophages in a manner that is dependent on viral protease activity and largely independent of the NLRP3 inflammasome. Additionally, to further evaluate the viral determinants of CARD8 sensing, we tested a panel of HIV protease inhibitor resistant clones to establish how variation in HIV protease affects CARD8 activation. We identified mutant HIV-1 proteases that differentially cleave and activate CARD8 compared to wildtype HIV-1, thus indicating that natural variation in HIV protease affects not only the cleavage of the viral Gag-Pol polyprotein but also likely impacts innate sensing and inflammation.}, }
@article {pmid39229066, year = {2024}, author = {Binkowski, B and Klamer, Z and Gao, C and Staal, B and Repesh, A and Tran, HL and Brass, DM and Bartlett, P and Gallinger, S and Blomqvist, M and Morrow, JB and Allen, P and Shi, C and Singhi, A and Brand, R and Huang, Y and Hostetter, G and Haab, BB}, title = {Multiplexed Glycan Immunofluorescence Identification of Pancreatic Cancer Cell Subpopulations in Both Tumor and Blood Samples.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39229066}, issn = {2692-8205}, support = {U01 CA152653/CA/NCI NIH HHS/United States ; U01 CA200466/CA/NCI NIH HHS/United States ; U01 CA226158/CA/NCI NIH HHS/United States ; }, abstract = {Pancreatic ductal adenocarcinoma (PDAC) tumor heterogeneity impedes the development of biomarker assays suitable for early disease detection that would improve patient outcomes. The CA19-9 glycan is currently used as a standalone biomarker for PDAC. Furthermore, previous studies have shown that cancer cells may display aberrant membrane-associated glycans. We therefore hypothesized that PDAC cancer cell subpopulations could be distinguished by aberrant glycan signatures. We used multiplexed glycan immunofluorescence combined with pathologist annotation and automated image processing to distinguish between PDAC cancer cell subpopulations within tumor tissue. Using a training-set/test-set approach, we found that PDAC cancer cells may be identified by signatures comprising 4 aberrant glycans (VVL, CA19-9, sTRA, and GM2) and that there are three glycan-defined PDAC tumor types: sTRA type, CA19-9 type, and intermixed. To determine whether the aberrant glycan signatures could be detected in blood samples, we developed hybrid glycan sandwich assays for membrane-associated glycans. In both patient-matched tumor and blood samples, the proportion of aberrant glycans detected was consistent. Furthermore, our multiplexed glycan immunofluorescent approach proved to be more sensitive and more specific than CA19-9 alone. Our results provide proof of concept for a novel methodology to improve early PDAC detection and patient outcomes.}, }
@article {pmid39229031, year = {2024}, author = {Bhattacharya, T and Alleman, EM and Noyola, AC and Emerman, M and Malik, HS}, title = {A conserved opal termination codon optimizes a temperature-dependent tradeoff between protein production and processing in alphaviruses.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39229031}, issn = {2692-8205}, support = {U54 AI170792/AI/NIAID NIH HHS/United States ; }, abstract = {Alphaviruses are enveloped, single-stranded, positive-sense RNA viruses that often require transmission between arthropod and vertebrate hosts for their sustained propagation. Most alphaviruses encode an opal (UGA) termination codon in nonstructural protein 3 (nsP3) upstream of the viral polymerase, nsP4. The selective constraints underlying the conservation of the opal codon are poorly understood. Using primate and mosquito cells, we explored the role and selective pressure on the nsP3 opal codon through extensive mutational analysis in the prototype alphavirus, Sindbis virus (SINV). We found that the opal codon is highly favored over all other codons in primate cells under native 37°C growth conditions. However, this preference is diminished in mosquito and primate cells grown at a lower temperature. Thus, the primary determinant driving the selection of the opal stop codon is not host genetics but the passaging temperature. We show that the opal codon is preferred over amber and ochre termination codons because it results in the highest translational readthrough and polymerase production. However, substituting the opal codon with sense codons leads to excessive full-length polyprotein (P1234) production, which disrupts optimal nsP polyprotein processing, delays the switch from minus-strand to positive-strand RNA production, and significantly reduces SINV fitness at 37°C; this fitness defect is relieved at lower temperatures. A naturally occurring suppressor mutation unexpectedly compensates for a delayed transition from minus to genomic RNA production by also delaying the subsequent transition between genomic and sub-genomic RNA production. Our study reveals that the opal stop codon is the best solution for alphavirus replication at 37°C, producing enough nsP4 protein to maximize replication without disrupting nsP processing and RNA replication transitions needed for optimal fitness. Our study uncovers the intricate strategy dual-host alphaviruses use at a single codon to optimize fitness.}, }
@article {pmid39228737, year = {2024}, author = {Weinstock, JS and Chaudhry, SA and Ioannou, M and Viskadourou, M and Reventun, P and Jakubek, YA and Liggett, LA and Laurie, C and Broome, JG and Khan, A and Taylor, KD and Guo, X and Peyser, PA and Boerwinkle, E and Chami, N and Kenny, EE and Loos, RJ and Psaty, BM and Russell, TP and Brody, JA and Yun, JH and Cho, MH and Vasan, RS and Kardia, SL and Smith, JA and Raffield, LM and Bidulescu, A and O'Brien, E and de Andrade, M and Rotter, JI and Rich, SS and Tracy, RP and Chen, YI and Gu, CC and Hsiung, CA and Kooperberg, C and Haring, B and Nassir, R and Mathias, R and Reiner, A and Sankaran, V and Lowenstein, CJ and Blackwell, TW and Abecasis, GR and Smith, AV and Kang, HM and Natarajan, P and Jaiswal, S and Bick, A and Post, WS and Scheet, P and Auer, P and Karantanos, T and Battle, A and Arvanitis, M}, title = {The Genetic Determinants and Genomic Consequences of Non-Leukemogenic Somatic Point Mutations.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39228737}, support = {R01 HL120393/HL/NHLBI NIH HHS/United States ; K08 HL166690/HL/NHLBI NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; R35 GM139580/GM/NIGMS NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; }, abstract = {Clonal hematopoiesis (CH) is defined by the expansion of a lineage of genetically identical cells in blood. Genetic lesions that confer a fitness advantage, such as point mutations or mosaic chromosomal alterations (mCAs) in genes associated with hematologic malignancy, are frequent mediators of CH. However, recent analyses of both single cell-derived colonies of hematopoietic cells and population sequencing cohorts have revealed CH frequently occurs in the absence of known driver genetic lesions. To characterize CH without known driver genetic lesions, we used 51,399 deeply sequenced whole genomes from the NHLBI TOPMed sequencing initiative to perform simultaneous germline and somatic mutation analyses among individuals without leukemogenic point mutations (LPM), which we term CH-LPMneg. We quantified CH by estimating the total mutation burden. Because estimating somatic mutation burden without a paired-tissue sample is challenging, we developed a novel statistical method, the Genomic and Epigenomic informed Mutation (GEM) rate, that uses external genomic and epigenomic data sources to distinguish artifactual signals from true somatic mutations. We performed a genome-wide association study of GEM to discover the germline determinants of CH-LPMneg. After fine-mapping and variant-to-gene analyses, we identified seven genes associated with CH-LPMneg (TCL1A, TERT, SMC4, NRIP1, PRDM16, MSRA, SCARB1), and one locus associated with a sex-associated mutation pathway (SRGAP2C). We performed a secondary analysis excluding individuals with mCAs, finding that the genetic architecture was largely unaffected by their inclusion. Functional analyses of SMC4 and NRIP1 implicated altered HSC self-renewal and proliferation as the primary mediator of mutation burden in blood. We then performed comprehensive multi-tissue transcriptomic analyses, finding that the expression levels of 404 genes are associated with GEM. Finally, we performed phenotypic association meta-analyses across four cohorts, finding that GEM is associated with increased white blood cell count and increased risk for incident peripheral artery disease, but is not significantly associated with incident stroke or coronary disease events. Overall, we develop GEM for quantifying mutation burden from WGS without a paired-tissue sample and use GEM to discover the genetic, genomic, and phenotypic correlates of CH-LPMneg.}, }
@article {pmid39227162, year = {2024}, author = {Tordoff, DM and Minalga, B and Catháin, N&#xd3; and Fernandez, A and Gross, B and Glick, SN and , }, title = {Comparing Two-Step Approaches to Measuring Gender Identity: The Reliability and Applications of Asking About Sex Assigned at Birth versus Transgender Self-Identification.}, journal = {American journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/aje/kwae341}, pmid = {39227162}, issn = {1476-6256}, support = {F31 AI152542/AI/NIAID NIH HHS/United States ; }, abstract = {Inclusive measures of gender are critical for health equity research. This study compared the reliability and applications of two different approaches for measuring gender in response to emerging community concerns regarding the potential harms of asking about sex assigned at birth (SAAB) within transgender and gender diverse (TGD) populations. Using data from a 2021 survey of LGBTQ+ people in Washington state, we compared approaches for measuring gender via a two-step question that collected data on: (1) current gender and SAAB versus (2) current gender and transgender self-identification. Among 2,275 LGBTQ+ participants aged 9-81, 63% were cisgender, 35% TGD, and 2% were not categorized. There was near perfect agreement between the two methods in their ability to identify TGD participants (percent agreement=99.7%, unweighted Cohen's Kappa=0.99). Among gender diverse participants, stratification by SAAB revealed differences in sexual health outcomes, while stratification by transgender self-identification revealed differences in access to gender-affirming care and lifetime experiences of discrimination. Ascertaining SAAB may be most useful for identifying sexual health disparities while transgender self-identification may better illuminate healthcare needs and social determinants of health among TGD people. Researchers and public health practitioners should critically consider the acceptability and relevance of SAAB questions to their research goals.}, }
@article {pmid39226919, year = {2024}, author = {Lin, W and Zou, J and Di, C and Rock, CL and Natarajan, L}, title = {Multilevel Longitudinal Functional Principal Component Model.}, journal = {Statistics in medicine}, volume = {43}, number = {25}, pages = {4781-4795}, doi = {10.1002/sim.10207}, pmid = {39226919}, issn = {1097-0258}, support = {R01DK114945/DK/NIDDK NIH HHS/United States ; PO1AG052352/AG/NIA NIH HHS/United States ; R01HL130483//National Heart, Lung and Blood Institute/ ; 2120019//National Science Foundation/ ; 2100237//National Science Foundation/ ; U54CA155435-01/CA/NCI NIH HHS/United States ; R01 HL130483/HL/NHLBI NIH HHS/United States ; PO1AG052352/AG/NIA NIH HHS/United States ; U54CA155435-01/CA/NCI NIH HHS/United States ; R01DK114945/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; Longitudinal Studies ; *Principal Component Analysis ; *Computer Simulation ; *Obesity ; Accelerometry ; Body Mass Index ; Models, Statistical ; Female ; Exercise/physiology ; Multilevel Analysis ; Male ; }, abstract = {Sensor devices, such as accelerometers, are widely used for measuring physical activity (PA). These devices provide outputs at fine granularity (e.g., 10-100 Hz or minute-level), which while providing rich data on activity patterns, also pose computational challenges with multilevel densely sampled data, resulting in PA records that are measured continuously across multiple days and visits. On the other hand, a scalar health outcome (e.g., BMI) is usually observed only at the individual or visit level. This leads to a discrepancy in numbers of nested levels between the predictors (PA) and outcomes, raising analytic challenges. To address this issue, we proposed a multilevel longitudinal functional principal component analysis (mLFPCA) model to directly model multilevel functional PA inputs in a longitudinal study, and then implemented a longitudinal functional principal component regression (FPCR) to explore the association between PA and obesity-related health outcomes. Additionally, we conducted a comprehensive simulation study to examine the impact of imbalanced multilevel data on both mLFPCA and FPCR performance and offer guidelines for selecting optimal methods.}, }
@article {pmid39226462, year = {2024}, author = {Huffman, JE and Nicholas, J and Hahn, J and Heath, AS and Raffield, LM and Yanek, LR and Brody, JA and Thibord, F and Almasy, L and Bartz, TM and Bielak, LF and Bowler, RP and Carrasquilla, GD and Chasman, DI and Chen, MH and Emmert, DB and Ghanbari, M and Haessler, J and Hottenga, JJ and Kleber, ME and Le, NQ and Lee, J and Lewis, JP and Li-Gao, R and Luan, J and Malmberg, A and Mangino, M and Marioni, RE and Martinez-Perez, A and Pankratz, N and Polasek, O and Richmond, A and Rodriguez, BAT and Rotter, JI and Steri, M and Suchon, P and Trompet, S and Weiss, S and Zare, M and Auer, P and Cho, MH and Christofidou, P and Davies, G and de Geus, E and Deleuze, JF and Delgado, GE and Ekunwe, L and Faraday, N and Gögele, M and Greinacher, A and Gao, H and Howard, T and Joshi, PK and Kilpeläinen, TO and Lahti, J and Linneberg, A and Naitza, S and Noordam, R and Paüls-Vergés, F and Rich, SS and Rosendaal, FR and Rudan, I and Ryan, KA and Souto, JC and van Rooij, FJA and Wang, H and Zhao, W and Becker, LC and Beswick, A and Brown, MR and Cade, BE and Campbell, H and Cho, K and Crapo, JD and Curran, JE and de Maat, MPM and Doyle, M and Elliott, P and Floyd, JS and Fuchsberger, C and Grarup, N and Guo, X and Harris, SE and Hou, L and Kolcic, I and Kooperberg, C and Menni, C and Nauck, M and O'Connell, JR and Orrù, V and Psaty, BM and Räikkönen, K and Smith, JA and Soria, JM and Stott, DJ and van Hylckama Vlieg, A and Watkins, H and Willemsen, G and Wilson, PWF and Ben-Shlomo, Y and Blangero, J and Boomsma, D and Cox, SR and Dehghan, A and Eriksson, JG and Fiorillo, E and Fornage, M and Hansen, T and Hayward, C and Ikram, MA and Jukema, JW and Kardia, SLR and Lange, LA and März, W and Mathias, RA and Mitchell, BD and Mook-Kanamori, DO and Morange, PE and Pedersen, O and Pramstaller, PP and Redline, S and Reiner, A and Ridker, PM and Silverman, EK and Spector, TD and Völker, U and Wareham, NJ and Wilson, JF and Yao, J and Trégouët, DA and Johnson, AD and Wolberg, AS and de Vries, PS and Sabater-Lleal, M and Morrison, AC and Smith, NL}, title = {Whole-genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles.}, journal = {Blood}, volume = {144}, number = {21}, pages = {2248-2265}, pmid = {39226462}, issn = {1528-0020}, support = {R01 HL139553/HL/NHLBI NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; R01 HL134894/HL/NHLBI NIH HHS/United States ; I01 BX004821/BX/BLRD VA/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; R01 HL141291/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Fibrinogen/genetics/metabolism ; *Genome-Wide Association Study ; Liver/metabolism ; Polymorphism, Single Nucleotide ; Whole Genome Sequencing ; Female ; Male ; Gene Frequency ; }, abstract = {Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole-genome sequencing (WGS) data provide better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program (n = 32 572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 131 340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, 4 are driven by common variants of small effect with reported minor allele frequency (MAF) at least 10 percentage points higher in African populations. Three signals (SERPINA1, ZFP36L2, and TLR10) contain predicted deleterious missense variants. Two loci, SOCS3 and HPN, each harbor 2 conditionally distinct, noncoding variants. The gene region encoding the fibrinogen protein chain subunits (FGG;FGB;FGA) contains 7 distinct signals, including 1 novel signal driven by rs28577061, a variant common in African ancestry populations but extremely rare in Europeans (MAFAFR = 0.180; MAFEUR = 0.008). Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation.}, }
@article {pmid39226323, year = {2024}, author = {Wang, K and Jordan, T and Dowdell, K and Herbert, R and Moore, IN and Koelle, DM and Cohen, JI}, title = {A nonhuman primate model for genital herpes simplex virus 2 infection that results in vaginal vesicular lesions, virus shedding, and seroconversion.}, journal = {PLoS pathogens}, volume = {20}, number = {9}, pages = {e1012477}, pmid = {39226323}, issn = {1553-7374}, mesh = {Animals ; *Herpes Genitalis/immunology/virology ; Female ; *Herpesvirus 2, Human/immunology ; *Virus Shedding/immunology ; *Disease Models, Animal ; *Seroconversion ; Antibodies, Viral/immunology ; Vagina/virology/immunology/pathology ; Macaca mulatta ; }, abstract = {The most commonly used animal models for evaluating the efficacy of HSV-2 candidate vaccines are mice and guinea pigs. While numerous HSV-2 vaccine candidates have been tested in these animals and were effective in reducing disease and mortality, these results did not predict the effectiveness of the vaccines in human trials. Infection of rhesus macaques rarely results in lesions or HSV-2 specific antibody responses. In seeking an animal model that better recapitulates human disease and that might be more predictive of the efficacy of prophylactic vaccines than mice and guinea pigs, we evaluated Cebus apella (C. apella), a New World primate, in an HSV-2 genital infection model. Infectious HSV-2 was cultured from vaginal swabs from all 4 animals for 9-14 days after intravaginal inoculation of HSV-2 seronegative monkeys. Two of 4 monkeys had vesicular lesions in the vagina or vulva. No neurological symptoms were noted. Recurrent lesions and HSV-2 DNA shedding after acute disease resolved was infrequent. UV irradiation of the genital area did not induce recurrent genital lesions or virus shedding. All 4 monkeys developed HSV-2 neutralizing antibodies as well as virus-specific CD4 and CD8 T cell responses. Reinfection of animals 15 to 19 months after primary infection did not result in lesions; animals had reduced virus shedding and a shorter duration of shedding compared with that during primary infection, suggesting that primary infection induced protective immunity. Primary fibroblasts from C. apella monkeys supported the growth of HSV-2 in vitro; in contrast, HSV-2 did not replicate above the titer of the input inoculum in fibroblasts from rhesus macaques. These observations suggest that the C. apella monkey has potential to serve as a model for evaluating the efficacy of prophylactic vaccines, antivirals, or monoclonal antibodies to HSV-2.}, }
@article {pmid39225478, year = {2024}, author = {Janes, H and Fisher, LH and Kee, JJ and Parameswaran, L and Goepfert, PA and Falsey, AR and Ludwig, J and Magaret, CA and Gilbert, PB and Kublin, JG and Rouphael, N and Sobieszczyk, ME and El Sahly, HM and Baden, LR and Grinsztejn, B and Walsh, SR and Gray, GE and Kotloff, KL and Gay, CL and Greninger, AL and Tapia, MD and Hammershaimb, EA and Priddy, FH and Green, JA and Struyf, F and Dunkle, L and Neuzil, KM and Corey, L and Huang, Y}, title = {Association Between SARS-CoV-2 Viral Load and COVID-19 Vaccination in 4 Phase 3 Trials.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiae400}, pmid = {39225478}, issn = {1537-6613}, support = {UM1 AI069470/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; //Biomedical Advanced Research/ ; //United States Government/ ; UM1 AI148574/AI/NIAID NIH HHS/United States ; UM1 AI148689/AI/NIAID NIH HHS/United States ; UM1 AI148450/AI/NIAID NIH HHS/United States ; //and Development Authority/ ; U01 AI069470/AI/NIAID NIH HHS/United States ; }, abstract = {Coronavirus disease 2019 (COVID-19) vaccines reduce severe disease and mortality and may lessen transmission, measured by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load (VL). Evaluating vaccine associations in VL at COVID-19 diagnosis in 4 phase 3 randomized, placebo-controlled vaccine trials, July 2020 to July 2021, VL reductions were 2.78 log10 copies/mL (95% confidence interval [CI], 1.38-4.18; n = 60 placebo, 11 vaccine) and 2.12 log10 copies/mL (95% CI, 1.44-2.80; n = 594 placebo, 36 vaccine) for NVX-CoV2373 and mRNA-1273, respectively. Associations were not significant for AZD1222 (0.59 log10 copies/mL; 95% CI, -.19 to 1.36; n = 90 placebo, 78 vaccine) or Ad26.COV2.S (0.23 log10 copies/mL; 95% CI, -.01 to .47; n = 916 placebo, 424 vaccine). Thus, vaccines potentially decreased transmission when ancestral SARS-CoV-2 predominated. Clinical Trials Registration. NCT04470427, NCT04505722, NCT04516746, NCT04611802.}, }
@article {pmid39225130, year = {2024}, author = {Wang, Y and Scurll, J and Rascón, IA and Cui, C and Ni, Y and Shi, AM and Gangadharannambiar, P and Wang, Y and Akamatsu, S and Beltran, H and Cox, M and Crea, F and Daugaard, M and Dong, X and Haffner, M and He, H and Jachetti, E and Kyprianou, N and Li, B and Ong, CE and Rickman, DS and Sen, T and Zhu, HH and Zoubeidi, A and Gleave, ME}, title = {The third symposium on treatment-induced neuroendocrine prostate cancer: insights and future directions.}, journal = {Epigenomics}, volume = {16}, number = {17}, pages = {1129-1132}, doi = {10.1080/17501911.2024.2391729}, pmid = {39225130}, issn = {1750-192X}, support = {PCS-195086//Institute of Cancer Research/ ; //Pharma Planter Inc./ ; //Vancouver Prostate Centre/ ; //PCF Canada/ ; //Mr. Jmaes Killam/ ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms/therapy/genetics/pathology ; Carcinoma, Neuroendocrine/genetics/therapy/pathology ; Receptors, Androgen/metabolism/genetics ; Tumor Microenvironment ; Epigenesis, Genetic ; Neuroendocrine Tumors/therapy/genetics ; }, abstract = {Neuroendocrine prostate cancer (NEPC) is a rare and aggressive subtype of prostate cancer (PCa), emerging from advanced treatments and characterized by loss of androgen receptor (AR) signaling and neuroendocrine features, leading to rapid progression and treatment resistance. The third symposium on treatment-induced NEPC, held from 21 to 23 June 2024, at Harrison Hot Springs Resort, BC, Canada, united leading global researchers and clinicians. Sponsored by the Vancouver Prostate Centre (VPC), Canadian Institute of Health Research, Prostate Cancer Foundation Canada and Pharma Planter Inc, the event focused on the latest NEPC research and innovative treatment strategies. Co-chaired by Drs. Yuzhuo Wang and Martin Gleave, the symposium featured sessions on NEPC's historical context, molecular pathways, epigenetic regulation and the role of the tumor microenvironment and metabolism in its progression. Keynotes from experts like Dr. Himisha Beltran and Dr. Martin Gleave highlighted the complexity of NEPC. The Emerging Talent session showcased new research, pointing to the future of NEPC treatment. The symposium concluded with a consensus on the need for early detection, targeted therapies and personalized medicine to effectively combat NEPC, emphasizing the importance of global collaboration in advancing NEPC understanding and treatment.}, }
@article {pmid39224838, year = {2024}, author = {Zhao, Y and Jia, Q and Goodrich, J and Darst, B and Conti, DV}, title = {An extension of latent unknown clustering integrating multi-omics data (LUCID) incorporating incomplete omics data.}, journal = {Bioinformatics advances}, volume = {4}, number = {1}, pages = {vbae123}, pmid = {39224838}, issn = {2635-0041}, abstract = {MOTIVATION: Latent unknown clustering integrating multi-omics data is a novel statistical model designed for multi-omics data analysis. It integrates omics data with exposures and an outcome through a latent cluster, elucidating how exposures influence processes reflected in multi-omics measurements, ultimately affecting an outcome. A significant challenge in multi-omics analysis is the issue of list-wise missingness. To address this, we extend the model to incorporate list-wise missingness within an integrated imputation framework, which can also handle sporadic missingness when necessary.<br><br>RESULTS: Simulation studies demonstrate that our integrated imputation approach produces consistent and less biased estimates, closely reflecting true underlying values. We applied this model to data from the ISGlobal/ATHLETE "Exposome Data Challenge Event" to explore the association between maternal exposure to hexachlorobenzene and childhood body mass index by integrating incomplete proteomics data from 1301 children. The model successfully estimated proteomics profiles for two clusters representing higher and lower body mass index, characterizing the potential profiles linking prenatal hexachlorobenzene levels and childhood body mass index.<br><br>The proposed methods have been implemented in the R package LUCIDus. The source code is available at https://github.com/USCbiostats/LUCIDus.}, }
@article {pmid39224504, year = {2024}, author = {Fiorenza, S and Lim, SYT and Laszlo, GS and Kimble, EL and Phi, TD and Lunn-Halbert, MC and Kirchmeier, DR and Huo, J and Kiem, HP and Turtle, CJ and Walter, RB}, title = {Targeting the membrane-proximal C2-set domain of CD33 for improved CAR T cell therapy.}, journal = {Molecular therapy. Oncology}, volume = {32}, number = {3}, pages = {200854}, pmid = {39224504}, issn = {2950-3299}, abstract = {Current CD33-targeted immunotherapies typically recognize the membrane-distal V-set domain of CD33. Here, we show that decreasing the distance between T cell and leukemia cell membrane increases the efficacy of CD33 chimeric antigen receptor (CAR) T cells. We therefore generated and optimized second-generation CAR constructs containing single-chain variable fragments from antibodies raised against the membrane-proximal C2-set domain, which bind CD33 regardless of whether the V-set domain is present (CD33[PAN] antibodies). CD33[PAN] CAR T cells resulted in efficient tumor clearance and improved survival of immunodeficient mice bearing human AML cell xenografts and, in an AML model with limited CD33 expression, forced escape of CD33[neg] leukemia. Compared to CD33[V-set] CAR T cells, CD33[PAN] CAR T cells showed greater in vitro and in vivo efficacy against several human AML cell lines with differing levels of CD33 without increased expression of exhaustion markers. CD33[PAN] moieties were detected at a higher frequency on human leukemic stem cells, and CD33[PAN] CAR T cells had greater in vitro efficacy against primary human AML cells. Together, our studies demonstrate improved efficacy with CAR T cells binding CD33 close to the cell membrane, providing the rationale to investigate CD33[PAN] CAR T cells further toward possible clinical application.}, }
@article {pmid39223980, year = {2024}, author = {Zheng, Y and Wagner, PD and Singal, AG and Hanash, SM and Srivastava, S and Huang, Y and Zhao, YQ and Chari, ST and Marquez, G and Etizioni, R and Marsh, TL and Feng, Z}, title = {Designing Rigorous and Efficient Clinical Utility Studies for Early Detection Biomarkers.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {33}, number = {9}, pages = {1150-1157}, pmid = {39223980}, issn = {1538-7755}, support = {U01 CA200468/CA/NCI NIH HHS/United States ; R01 CA222900/CA/NCI NIH HHS/United States ; U24 CA086368/CA/NCI NIH HHS/United States ; U01 CA271887/CA/NCI NIH HHS/United States ; U01 DK126365/DK/NIDDK NIH HHS/United States ; U01 CA213285/CA/NCI NIH HHS/United States ; U01 CA194733/CA/NCI NIH HHS/United States ; U01 CA230694/CA/NCI NIH HHS/United States ; R01 CA236558/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Biomarkers, Tumor/blood/analysis ; *Early Detection of Cancer/methods ; *Research Design ; *Neoplasms/diagnosis ; }, abstract = {Before implementing a biomarker in routine clinical care, it must demonstrate clinical utility by leading to clinical actions that positively affect patient-relevant outcomes. Randomly controlled early detection utility trials, especially those targeting mortality endpoint, are challenging due to their high costs and prolonged duration. Special design considerations are required to determine the clinical utility of early detection assays. This commentary reports on discussions among the National Cancer Institute's Early Detection Research Network investigators, outlining the recommended process for carrying out single-organ biomarker-driven clinical utility studies. We present the early detection utility studies in the context of phased biomarker development. We describe aspects of the studies related to the features of biomarker tests, the clinical context of endpoints, the performance criteria for later phase evaluation, and study size. We discuss novel adaptive design approaches for improving the efficiency and practicality of clinical utility trials. We recommend using multiple strategies, including adopting real-world evidence, emulated trials, and mathematical modeling to circumvent the challenges in conducting early detection utility trials.}, }
@article {pmid39222529, year = {2024}, author = {Naresh, KN}, title = {Classification of Haematolymphoid Neoplasms: A work in progress towards more precise disease definitions in the era of precision oncology.}, journal = {The National medical journal of India}, volume = {37}, number = {2}, pages = {61-63}, doi = {10.25259/NMJI_918_2024}, pmid = {39222529}, issn = {2583-150X}, mesh = {Humans ; *Precision Medicine ; Hematologic Neoplasms/classification/diagnosis/therapy ; Medical Oncology/standards/trends ; }, }
@article {pmid39221247, year = {2024}, author = {Arias-Badia, M and Pai, CS and Chen, P and Chang, A and Lwin, YM and Srinath, A and Gotts, JE and Glantz, SA and Fong, L}, title = {E-cigarette exposure disrupts antitumor immunity and promotes metastasis.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1444020}, pmid = {39221247}, issn = {1664-3224}, mesh = {Animals ; *Electronic Nicotine Delivery Systems ; Mice ; *Nicotine ; Neoplasm Metastasis ; Mice, Inbred C57BL ; Cell Line, Tumor ; CTLA-4 Antigen/immunology ; Female ; Cell Movement/drug effects ; Programmed Cell Death 1 Receptor ; }, abstract = {Electronic cigarettes (e-cigarettes) are thought to pose low risk of cancer because the components of e-cigarette liquid are not carcinogens. We analyzed the effects of the two major components, PG/VG and nicotine, on tumor development in preclinical models. We found that PG/VG promoted tumor cell migration in migration assays and contributed to more aggressive, metastatic, and immunosuppressive tumors in vivo, aggravated by the presence of nicotine. Whole body exposure of mice to PG/VG and nicotine rendered animals more susceptible to developing tumors with high frequencies of infiltrating proinflammatory macrophages expressing IL-6 and TNFα. Moreover, tumor-infiltrating and circulating T cells in e-cigarette exposed mice showed increased levels of immune checkpoints including CTLA4 and PD-1. Treatment with anti-CTLA4 antibody was able to abrogate metastasis with no detrimental effects on its ability to induce tumor regression in exposed mice. These findings suggest that the major components used in e-cigarette fluid can impact tumor development through induced immunosuppression.}, }
@article {pmid39221180, year = {2024}, author = {Rader, NA and Lee, KS and Loes, AN and Miller-Stump, OA and Cooper, M and Wong, TY and Boehm, DT and Barbier, M and Bevere, JR and Heath Damron, F}, title = {Influenza virus strains expressing SARS-CoV-2 receptor binding domain protein confer immunity in K18-hACE2 mice.}, journal = {Vaccine: X}, volume = {20}, number = {}, pages = {100543}, pmid = {39221180}, issn = {2590-1362}, support = {R01 AI153250/AI/NIAID NIH HHS/United States ; }, abstract = {Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease (COVID-19), rapidly spread across the globe in 2019. With the emergence of the Omicron variant, COVID-19 shifted into an endemic phase. Given the anticipated rise in cases during the fall and winter seasons, the strategy of implementing seasonal booster vaccines for COVID-19 is becoming increasingly valuable to protect public health. This practice already exists for seasonal influenza vaccines to combat annual influenza seasons. Our goal was to investigate an easily modifiable vaccine platform for seasonal use against SARS-CoV-2. In this study, we evaluated the genetically modified influenza virus ΔNA(RBD) as an intranasal vaccine candidate for COVID-19. This modified virus was engineered to replace the coding sequence for the neuraminidase (NA) protein with a membrane-anchored form of the receptor binding domain (RBD) protein of SARS-CoV-2. We designed experiments to assess the protection of ΔNA(RBD) in K18-hACE2 mice using lethal (Delta) and non-lethal (Omicron) challenge models. Controls of COVID-19 mRNA vaccine and our lab's previously described intranasal virus like particle vaccine were used as comparisons. Immunization with ΔNA(RBD) expressing ancestral RBD elicited high anti-RBD IgG levels in the serum of mice, high anti-RBD IgA in lung tissue, and improved survival after Delta variant challenge. Modifying ΔNA(RBD) to express Omicron variant RBD shifted variant-specific antibody responses and limited viral burden in the lungs of mice after Omicron variant challenge. Overall, this data suggests that ΔNA(RBD) could be an effective intranasal vaccine platform that generates mucosal and systemic immunity towards SARS-CoV-2.}, }
@article {pmid39219850, year = {2024}, author = {Alvarez, L and April-Sanders, A and Duran Luciano, P and Lee, UJ and Swett, K and Herrera, C and Collado, D and Kaplan, R and Gonzalez Ii, F and Daviglus, M and Garcia-Bedoya, O and Elfassy, T and Schneiderman, N and Perreira, K and Talavera, GA and Corsino, L and Rodriguez, CJ}, title = {Hypertension Prevalence among Hispanics/Latinos of Dominican Background: A Transnational Comparison of HCHS/SOL and ENPREFAR-HAS-17.}, journal = {Global heart}, volume = {19}, number = {1}, pages = {71}, pmid = {39219850}, issn = {2211-8179}, mesh = {Humans ; Male ; Female ; *Hypertension/epidemiology/ethnology ; Prevalence ; *Hispanic or Latino/statistics &amp; numerical data ; Adult ; Dominican Republic/ethnology/epidemiology ; Middle Aged ; United States/epidemiology ; Risk Factors ; Cross-Sectional Studies ; }, abstract = {BACKGROUND: Hispanics/Latinos of Dominican background living in United States (US) have the highest hypertension prevalence compared with other Hispanic/Latino persons.<br><br>OBJECTIVE: To understand cardiovascular health among Dominicans, we evaluated hypertension prevalence and risk factors among Dominicans from the US and Dominican Republic (DR) using data from Hispanic Community Health Study/ Study of Latinos [HCHS/SOL] and the Prevalencia de Hipertension Arterial y Factores de Riesgo Cardiovasculares en la Rep&#xfa;blica Dominicana al 2017 (ENPREFAR-HAS 17) study.<br><br>METHODS: Hypertension was defined as blood pressure &#x2265;140/90 mmHg, self-reported hypertension, or antihypertensive use. Exposures included sociodemographic/socioeconomic, clinical, and lifestyle/behavioral characteristics. Weighted generalized linear models were used to estimate associations between study characteristics and hypertension prevalence (PR = prevalence ratio), age-and-sex adjusted. HCHS/SOL (n = 1,473, US Dominicans; mean age 41 years, 60.4% female) was analyzed with survey procedures, while ENPREFAR-HAS 17 (n = 2,015 DR Dominicans; mean age 40 years, 50.3% female) was analyzed with statistical analyses for simple random sampling.<br><br>RESULTS: Hypertension prevalence was 30.5% and 26.9% for DR and US Dominicans, respectively. Hypertension control was low in both cohorts (36.0% DR, 35.0% US). Alcohol use among DR Dominicans was inversely associated with hypertension prevalence (PRDR = 0.8) with no association among US Dominicans. In both settings, diabetes (PRDR = 1.4; PRUS = 1.4) and obesity (PRDR = 1.8; PRUS = 2.0) were associated with greater hypertension prevalence in Hispanics/Latinos of Dominican background. Physical activity was lower among US Dominicans (PR = 0.80) but higher among DR Dominicans (PR = 1.16); all p < 0.05.<br><br>CONCLUSIONS: Variations in social, lifestyle/behavioral, and clinical characteristics associated with hypertension among Dominicans in the US and DR were identified, suggesting that social context and cultural factors matter among immigrant populations.}, }
@article {pmid39219510, year = {2023}, author = {Thomas, LD and Batarseh, E and Hamdan, L and Haddadin, Z and Dulek, D and Kalams, S and Stewart, LS and Stahl, AL and Rahman, H and Amarin, JZ and Hayek, H and Ison, M and Overton, ET and Pergam, SA and Spieker, AJ and Halasa, NB and , }, title = {Comparison of Two High-Dose Versus Two Standard-Dose Influenza Vaccines in Adult Allogeneic Hematopoietic Cell Transplant Recipients.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {77}, number = {12}, pages = {1723-1732}, pmid = {39219510}, issn = {1537-6591}, support = {//NIH/ ; U01 AI132004/AI/NIAID NIH HHS/United States ; UL1 TR002243/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Influenza Vaccines/administration &amp; dosage/immunology ; *Hematopoietic Stem Cell Transplantation ; Male ; Middle Aged ; Female ; Adult ; *Influenza, Human/prevention &amp; control/immunology ; Double-Blind Method ; *Antibodies, Viral/blood ; Young Adult ; Aged ; Transplant Recipients ; Influenza A Virus, H3N2 Subtype/immunology ; Hemagglutination Inhibition Tests ; Influenza A Virus, H1N1 Subtype/immunology ; Transplantation, Homologous ; Vaccination/methods ; Influenza B virus/immunology ; Immunogenicity, Vaccine ; }, abstract = {BACKGROUND: Adult hematopoietic cell transplant (HCT) recipients are at high risk for influenza-related morbidity and mortality and have suboptimal influenza vaccine immune responses compared to healthy adults, particularly within 2 years of transplant.<br><br>METHODS: This phase II, double-blind, multicenter randomized controlled trial compared 2 doses of high-dose trivalent (HD-TIV) to 2 doses of standard-dose quadrivalent (SD-QIV) influenza vaccine administered 1 month apart in adults 3-23 months post-allogeneic HCT. Hemagglutinin antibody inhibition (HAI) titers were measured at baseline, 4 weeks following each vaccine dose, and approximately 7 months post-second vaccination. Injection-site and systemic reactions were assessed for 7 days post-vaccination. The primary immunogenicity comparison was geometric mean HAI titer (GMT) at visit 3 (4 weeks after the second dose); we used linear mixed models to estimate adjusted GMT ratios (aGMRs) comparing HD-TIV/SD-QIV for each antigen.<br><br>RESULTS: We randomized 124 adults; 64 received SD-QIV and 60 received HD-TIV. Following the second vaccination, HD-TIV was associated with higher GMTs compared to SD-QIV for A/H3N2 (aGMR = 2.09; 95% confidence interval [CI]: [1.19, 3.68]) and B/Victoria (aGMR = 1.61; 95% CI: [1.00, 2.58]). The increase was not statistically significant for A/H1N1 (aGMR = 1.16; 95% CI: [0.67, 2.02]). There was a trend to more injection-site reactions for HD-TIV after the second vaccination compared to SD-QIV (50% vs 33%; adjusted odds ratio [aOR] = 4.53; 95% CI: [0.71, 28.9]), whereas systemic reactions were similar between groups with both injections.<br><br>CONCLUSIONS: Adult allogeneic HCT recipients who received 2 doses of HD-TIV produced higher HAI antibody responses for A/H3N2 and B/Victoria compared with 2 doses of SD-QIV, with comparable injection-site or systemic reactions.}, }
@article {pmid39219377, year = {2024}, author = {Petersen, E and Cavanaugh, D and Psutka, SP}, title = {Current developments in prehabilitation in urologic oncology.}, journal = {Current opinion in urology}, volume = {34}, number = {6}, pages = {477-483}, doi = {10.1097/MOU.0000000000001224}, pmid = {39219377}, issn = {1473-6586}, mesh = {Humans ; *Preoperative Exercise ; Urologic Neoplasms/surgery/rehabilitation ; Quality of Life ; Recovery of Function ; Urogenital Neoplasms/surgery/rehabilitation ; }, abstract = {PURPOSE OF REVIEW: Prehabilitation describes interventions that are undertaken prior to a major surgical or medical intervention with the objective of improving functional capability with the goal of improving candidacy for therapy, bolstering one's ability to withstand treatment-associated toxicity, functional decline, and facilitating accelerated recovery. The objective of this review is to detail the key tenets of prehabilitation, synthesize contemporary advances in prehabilitation science within Urologic Oncology , and discuss key methodologic trial design considerations salient to future prehabilitation investigations.<br><br>RECENT FINDINGS: Contemporary prehabilitation clinical trials have primarily evaluated unimodal interventions aiming to improve functional capacity across the domains of physical exercise, nutrition, and cognition with heightened interest in evaluating multimodal interventions addressing two or more domains. Recent investigations have have demonstrated variable improvements in strength, balance, physical function, and quality of life with preoperative exercise. Although presurgical immunonutrition showed promise in other fields, initial results in uro-oncology have not demonstrated reductions in complications nor improvements in early survival. Emerging data supports the potential of multimodal prehabilitation programs to offer more comprehensive benefits, improving functional outcomes, reducing length of stay, and supporting improved recovery.<br><br>SUMMARY: To date, early prehabilitation studies in patients undergoing surgery for genitourinary malignancies have demonstrated variable ability to facilitate gains in functional capacity and perioperative outcomes. Key issues have arisen including the need to ensure that interventions are pragmatic, scalable, feasible, and acceptable in these populations that often also have a high prevalence of coincident multimorbidity, frailty, and mental health concerns that can increase risk of adverse outcomes after surgery. The integration of personalized prehabilitation strategies as extensions of perioperative enhanced recovery after surgery protocols, supportive care and survivorship paradigms offers of promise to further engage patients in their care, enhance patient resilience and outcomes, while reducing treatment burden in urologic oncology.}, }
@article {pmid39218742, year = {2024}, author = {Contieri, R and Soloway, MS and Gontero, P and Herr, H and Kassouf, W and Mertens, LS and Moschini, M and O'Donnell, M and Palou, J and Psutka, SP and Rouprêt, M and Teoh, JYC and Kamat, AM}, title = {Deintensification of Treatment for Low-grade Bladder Tumors: A Collaborative Review by the International Bladder Cancer Group (IBCG).}, journal = {European urology oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.euo.2024.08.001}, pmid = {39218742}, issn = {2588-9311}, support = {P30 CA086862/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVE: Management of low-grade (LG) urothelium-confined (Ta stage) non-muscle-invasive bladder cancer (NMIBC) poses a distinct therapeutic challenge. Transurethral resection of bladder tumor (TURBT), the standard treatment, frequently has to be repeated because of high tumor recurrence rates. This places a considerable strain on both patients and health care infrastructure, underscoring the need for alternative management approaches. Herein, the IBCG (International Bladder Cancer Group), conducted a review to explore the efficacy and safety of deintensified treatment strategies for recurrent LG Ta NMIBC.<br><br>METHODS: We conducted a collaborative review of relevant literature in the PubMed/MEDLINE and Cochrane CENTRAL databases. Our focus was on high-quality evidence, including randomized controlled trials, systematic reviews, and meta-analyses. We also reviewed guidelines published by prominent urological associations.<br><br>KEY FINDINGS AND LIMITATIONS: Active surveillance, chemoablation, and office fulguration are valid treatment options for recurrent LG Ta NMIBC. These deintensified approaches offer several advantages over TURBT: lower complication rates, less morbidity, lower health care costs, and better quality of life for patients. Importantly, these benefits are achieved without compromising oncological safety.<br><br>Our review demonstrates that less intensive treatment strategies for recurrent LG Ta NMIBC are both feasible and valuable. The IBCG recommends use of these approaches for carefully selected patients to help lower health care costs and enhance patients' quality of life.<br><br>PATIENT SUMMARY: We reviewed studies on less invasive management options for low-grade noninvasive bladder cancer, including active surveillance, chemical ablation, and heat treatment. Recent results confirm that these less intense treatment options can reduce the treatment burden and costs for patients and preserve their quality of life without negatively affecting cancer control outcomes.}, }
@article {pmid39218309, year = {2024}, author = {Aziz, AB and Sugimoto, JD and Hong, SL and You, YA and Bravo, L and Roa, C and Borja-Tabora, C and Montellano, MEB and Carlos, J and de Los Reyes, MRA and Alberto, ER and Salvani-Bautista, M and Kim, HY and Njau, I and Clemens, R and Marks, F and Tadesse, BT}, title = {Indirect effectiveness of a novel SARS-COV-2 vaccine (SCB-2019) in unvaccinated household contacts in the Philippines: A cluster randomised analysis.}, journal = {The Journal of infection}, volume = {89}, number = {4}, pages = {106260}, doi = {10.1016/j.jinf.2024.106260}, pmid = {39218309}, issn = {1532-2742}, mesh = {Humans ; Philippines/epidemiology ; *COVID-19/prevention &amp; control/epidemiology ; *COVID-19 Vaccines/administration &amp; dosage/immunology ; *SARS-CoV-2/immunology ; Male ; Female ; Adult ; Middle Aged ; *Family Characteristics ; Antibodies, Viral/blood ; Young Adult ; Adolescent ; Double-Blind Method ; Prospective Studies ; Child ; Child, Preschool ; Cluster Analysis ; Aged ; Vaccine Efficacy ; Vaccines, Subunit ; }, abstract = {BACKGROUND: Though observational evidence supports indirect effects of SARS-CoV-2 vaccines, randomised experiments are lacking. To address this gap, the double-blinded, prospective follow-up of the household contacts (HHCs) of Philippine participants of the individually-randomised, placebo-controlled trial of the adjuvanted-subunit protein COVID-19 vaccine, SCB-2019, (EudraCT, 2020-004272-17; ClinicalTrials.gov, NCT04672395) was analyzed in a cluster-randomised fashion.<br><br>METHODS: Over an eight-week period, HHCs were followed by rRT-PCR and paired rapid antibody tests (RATs) to detect symptomatic (SCI, primary) and all (ACI, secondary) SARS-CoV-2 infection. A standard analysis estimated the indirect effectiveness of SCB-2019 for each endpoint, excluding HHC RAT-positive at enrollment. A secondary analysis employed enzyme-linked immunosorbent assay (ELISA) results to correct for suspected bias.<br><br>FINDINGS: SCB-2019 (N&#xa0;=&#xa0;3470) and placebo (N&#xa0;=&#xa0;3225) exposed HHCs contributed to at least one analysis. The standard analysis estimated that SCB-2019 reduced the risk of SCI by 83% (95% confidence/credible interval [CI: 32% to 96%), with no effect against ACI. The bias-corrected relative risk reduction was 97% (95% CI: 74% to 100%) for SCI and 79% (95% CI: 14% to 96%) for ACI, with an estimated one SARS-CoV-2 infection prevented per 4.8 households where one member received SCB-2019.<br><br>INTERPRETATION: SCB-2019 demonstrated bias-corrected indirect effectiveness against SARS-CoV-2 infection among HHC, even at a modest coverage level in the household (approximately 25%). Further research into the indirect effects of SARS-CoV-2 vaccines is needed to optimize the impact of limited doses in low and middle-income settings.}, }
@article {pmid39217999, year = {2024}, author = {Kahn, J and Brazauskas, R and Bo-Subait, S and Buchbinder, D and Hamilton, BK and Schoemans, H and Abraham, AA and Agrawal, V and Auletta, JJ and Badawy, SM and Beitinjaneh, A and Bhatt, NS and Broglie, L and Diaz Perez, MA and Farhadfar, N and Freytes, CO and Gale, RP and Ganguly, S and Hayashi, RJ and Hematti, P and Hildebrandt, GC and Inamoto, Y and Kamble, RT and Koo, J and Lazarus, HM and Mayo, SJ and Mehta, PA and Myers, KC and Nishihori, T and Prestidge, T and Rotz, SJ and Savani, BN and Schears, RM and Sharma, A and Stenger, E and Ustun, C and Williams, KM and Vrooman, LM and Satwani, P and Phelan, R}, title = {Late effects after allogeneic haematopoietic cell transplantation in children and adolescents with non-malignant disorders: a retrospective cohort study.}, journal = {The Lancet. Child &amp; adolescent health}, volume = {8}, number = {10}, pages = {740-750}, pmid = {39217999}, issn = {2352-4650}, support = {27305C0011/ES/NIEHS NIH HHS/United States ; 27307C0011/ES/NIEHS NIH HHS/United States ; 27398C0011/ES/NIEHS NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Child ; Retrospective Studies ; Adolescent ; Female ; Male ; Child, Preschool ; Risk Factors ; Incidence ; Infant ; Young Adult ; Transplantation, Homologous/adverse effects ; }, abstract = {BACKGROUND: Continued advances in haematopoietic cell transplantation (HCT) for children with non-malignant diseases (NMDs) have led to a growing population of survivors in whom late occurring toxic effects remain a challenge. We investigated the incidence of and risk factors for post-transplant toxicities in a contemporary cohort of children and adolescents undergoing HCT for NMDs.<br><br>METHODS: In this retrospective cohort study, we extracted data from the Center for International Blood and Marrow Transplantation Research (CIBMTR) database to analyse timing and incidence of effects and risk factors associated with late effects of HCT for treatment of NMDs at age 21 years or younger. Late effects of interest were avascular necrosis, cataracts, congestive heart failure, myocardial infarction, diabetes, gonadal dysfunction, growth hormone deficiency, hypothyroidism, renal failure requiring dialysis, and neurological events (stroke and seizure). Cumulative incidence of each late effect was calculated at 5 years and 7 years after HCT. Risk factors were evaluated in Cox proportional hazards regression analyses. Main exposures were primary NMD, age, sex, ethnicity and race, insurance, donor and graft type, myoablative conditioning, total-body irradiation exposure, graft-versus-host disease (GVHD), and transplant year. Primary outcomes were rates, cumulative incidence probability (95% CI), and risk-factors for organ-specific late effects.<br><br>FINDINGS: Between Jan 1, 2000, and Dec 31, 2017, 7785 patients aged 21 years or younger underwent HCT. 1995 patients were ineligible or did not consent to be included. 5790 patients from 171 centres were included in the analysis. 3505 (60&#xb7;5%) of 5790 patients were male and 2285 (39&#xb7;5%) were female. 2106 (36&#xb7;4%) patients were White, 771 (13&#xb7;3%) were Hispanic, and 773 (12&#xb7;7%) were Black. 1790 (30&#xb7;9%) patients were non-USA residents. Median age at HCT was 5&#xb7;5 years (range 0&#xb7;0-21&#xb7;0). 1127 (19%) of 5790 patients had one late effect, and 381 (7%) had at least two. At 7 years post-HCT, the cumulative incidence probability was 1&#xb7;9 (95% CI 1&#xb7;5-2&#xb7;3) for cataracts, 4&#xb7;9 (4&#xb7;3-5&#xb7;6) for diabetes, 2&#xb7;6 (2&#xb7;1-3&#xb7;1) for gonadal dysfunction, 3&#xb7;2 (2&#xb7;7-3&#xb7;8) for hypothyroidism, 5&#xb7;0 (4&#xb7;4-5&#xb7;7) for growth disturbance, 8&#xb7;1 (7&#xb7;4-8&#xb7;9) for renal failure, 1&#xb7;6 (1&#xb7;3-2&#xb7;0) for avascular necrosis, 0&#xb7;6 (0&#xb7;4-0&#xb7;8) for congestive heart failure, 0&#xb7;2 (0&#xb7;1-0&#xb7;3) for myocardial infarction, and 9&#xb7;4 (8&#xb7;6-10&#xb7;2) for neurological effects. Age 10 years or older at HCT, unrelated donor source, total-body irradiation, and GVHD were identified as risk factors for long-term effects.<br><br>INTERPRETATION: The findings highlight the need for, and access to, multidisciplinary and lifelong follow-up for children undergoing HCT for NMDs. As more children undergo treatment with cellular therapies for non-malignant conditions, further analyses of post-transplant data could increasingly guide treatment decisions and subsequent long-term surveillance.<br><br>FUNDING: National Cancer Institute, National Heart, Lung and Blood Institute, National Institute of Allergy and Infectious Diseases, Health Resources and Services Administration, and Office of Naval Research.}, }
@article {pmid39213169, year = {2024}, author = {Andrews, KR and Besser, TE and Stalder, T and Top, EM and Baker, KN and Fagnan, MW and New, DD and Schneider, GM and Gal, A and Andrews-Dickert, R and Hunter, SS and Beckmen, KB and Christensen, L and Justice-Allen, A and Konetchy, D and Lehman, CP and Manlove, K and Miyasaki, H and Nordeen, T and Roug, A and Cassirer, EF}, title = {Comparative genomic analysis identifies potential adaptive variation in Mycoplasma ovipneumoniae.}, journal = {Microbial genomics}, volume = {10}, number = {8}, pages = {}, pmid = {39213169}, issn = {2057-5858}, mesh = {Animals ; *Mycoplasma ovipneumoniae/genetics ; *Goats/microbiology ; *Phylogeny ; Sheep/microbiology ; *Genome, Bacterial ; Genomics ; Reindeer/microbiology ; China ; Sheep Diseases/microbiology ; Adaptation, Physiological/genetics ; Australia ; Pneumonia, Mycoplasma/microbiology/veterinary ; }, abstract = {Mycoplasma ovipneumoniae is associated with respiratory disease in wild and domestic Caprinae globally, with wide variation in disease outcomes within and between host species. To gain insight into phylogenetic structure and mechanisms of pathogenicity for this bacterial species, we compared M. ovipneumoniae genomes for 99 samples from 6 countries (Australia, Bosnia and Herzegovina, Brazil, China, France and USA) and 4 host species (domestic sheep, domestic goats, bighorn sheep and caribou). Core genome sequences of M. ovipneumoniae assemblies from domestic sheep and goats fell into two well-supported phylogenetic clades that are divergent enough to be considered different bacterial species, consistent with each of these two clades having an evolutionary origin in separate host species. Genome assemblies from bighorn sheep and caribou also fell within these two clades, indicating multiple spillover events, most commonly from domestic sheep. Pangenome analysis indicated a high percentage (91.4 %) of accessory genes (i.e. genes found only in a subset of assemblies) compared to core genes (i.e. genes found in all assemblies), potentially indicating a propensity for this pathogen to adapt to within-host conditions. In addition, many genes related to carbon metabolism, which is a virulence factor for Mycoplasmas, showed evidence for homologous recombination, a potential signature of adaptation. The presence or absence of annotated genes was very similar between sheep and goat clades, with only two annotated genes significantly clade-associated. However, three M. ovipneumoniae genome assemblies from asymptomatic caribou in Alaska formed a highly divergent subclade within the sheep clade that lacked 23 annotated genes compared to other assemblies, and many of these genes had functions related to carbon metabolism. Overall, our results suggest that adaptation of M. ovipneumoniae has involved evolution of carbon metabolism pathways and virulence mechanisms related to those pathways. The genes involved in these pathways, along with other genes identified as potentially involved in virulence in this study, are potential targets for future investigation into a possible genomic basis for the high variation observed in disease outcomes within and between wild and domestic host species.}, }
@article {pmid39209823, year = {2024}, author = {Baden, LR and El Sahly, HM and Essink, B and Follmann, D and Hachigian, G and Strout, C and Overcash, JS and Doblecki-Lewis, S and Whitaker, JA and Anderson, EJ and Neuzil, K and Corey, L and Priddy, F and Tomassini, JE and Brown, M and Girard, B and Stolman, D and Urdaneta, V and Wang, X and Deng, W and Zhou, H and Dixit, A and Das, R and Miller, JM and , }, title = {Long-term safety and effectiveness of mRNA-1273 vaccine in adults: COVE trial open-label and booster phases.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {7469}, pmid = {39209823}, issn = {2041-1723}, support = {UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI148684/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI068619/AI/NIAID NIH HHS/United States ; UM1 AI068636/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *2019-nCoV Vaccine mRNA-1273/immunology ; *COVID-19/prevention &amp; control/immunology ; *Immunization, Secondary ; Adult ; Male ; Female ; *SARS-CoV-2/immunology ; Middle Aged ; *COVID-19 Vaccines/immunology/adverse effects/administration &amp; dosage ; Vaccine Efficacy ; Antibodies, Viral/immunology/blood ; Immunogenicity, Vaccine ; Aged ; Young Adult ; Vaccination ; Adolescent ; }, abstract = {Primary vaccination with mRNA-1273 (100-µg) was safe and efficacious at preventing coronavirus disease 2019 (COVID-19) in the previously reported, blinded Part A of the phase 3 Coronavirus Efficacy (COVE; NCT04470427) trial in adults (≥18 years) across 99 U.S. sites. The open-label (Parts B and C) primary objectives were evaluation of long-term safety and effectiveness of primary vaccination plus a 50-µg booster dose; immunogenicity was a secondary objective. Of 29,035 open-label participants, 19,609 received boosters (mRNA-1273 [n = 9647]; placebo-mRNA-1273 [n = 9952]; placebo [n = 10] groups). Booster safety was consistent with that reported for primary vaccination. Incidences of COVID-19 and severe COVID-19 were higher during the Omicron BA.1 than Delta variant waves and boosting versus non-boosting was associated with a significant, 47.0% (95% CI : 39.0-53.9%) reduction of Omicron BA.1 incidence (24.6 [23.4 - 25.8] vs 46.4 [40.6 - 52.7]/1000 person-months). In an exploratory Cox regression model adjusted for time-varying covariates, a longer median interval between primary vaccination and boosting (mRNA-1273 [13 months] vs placebo-mRNA-1273 [8 months]) was associated with significantly lower, COVID-19 risk (24.0% [16.0% - 32.0%]) during Omicron BA.1 predominance. Boosting elicited greater immune responses against SARS-CoV-2 than primary vaccination, irrespective of prior SARS-CoV-2 infection. Primary vaccination and boosting with mRNA-1273 demonstrated acceptable safety, effectiveness and immunogenicity against COVID-19, including emergent variants.}, }
@article {pmid39211945, year = {2024}, author = {Huang, IJ and Baek, GT and Siu, C and Shadman, M}, title = {Pharmacological management of chronic lymphocytic leukemia: current and emerging therapies.}, journal = {Expert opinion on pharmacotherapy}, volume = {25}, number = {13}, pages = {1759-1783}, doi = {10.1080/14656566.2024.2398603}, pmid = {39211945}, issn = {1744-7666}, mesh = {*Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Humans ; *Antineoplastic Agents/therapeutic use ; Molecular Targeted Therapy ; Survival Rate ; Immunotherapy/methods ; Disease Progression ; Patient Selection ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; }, abstract = {INTRODUCTION: Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), characterized by its monoclonal lymphoproliferative nature, is an indolent but incurable malignancy. The treatment landscape of CLL/SLL has drastically transformed in the last decade since the introduction of targeted therapy and immune-effector T-cell therapy. The paradigm shift from chemoimmunotherapy to targeted and cellular therapies was largely driven by improved efficacy and safety. With the success of targeted therapies, novel agents and combinations are rapidly emerging on the horizon.<br><br>AREAS COVERED: In this review, we will summarize clinical evidence supporting current and emerging therapies with emphasis on investigational therapies and novel combinations of commercial agents. Clinical trials were identified via clinicaltrials.gov, and a PubMed literature search was last performed in June 2024.<br><br>EXPERT OPINION: With the availability of more effective and better-tolerated treatments for CLL/SLL, the role of early intervention should be further investigated due to its potential to alter disease course, delay progression, and improve overall survival rates. With many highly effective agents and combinations expected to become commercially available, attention to safety profiles and careful selection of patients for each treatment will be critical, with consideration of comorbidities, logistical issues, and financial burden of treatment.}, }
@article {pmid39210036, year = {2024}, author = {Othus, M and Baccon, D and Ali, N and Rodríguez-Arbolí, E and Orvain, C and Milano, F and Sandmaier, BM and Davis, C and Basom, RS and Walter, RB}, title = {Relationship between morphologic remission with or without hematologic recovery and outcome after allogeneic hematopoietic cell transplantation in adult acute myeloid leukemia.}, journal = {Bone marrow transplantation}, volume = {59}, number = {12}, pages = {1667-1675}, pmid = {39210036}, issn = {1476-5365}, support = {P01-CA078902//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P01-CA018029//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P30-CA015704//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/methods ; *Leukemia, Myeloid, Acute/therapy/mortality ; Adult ; Middle Aged ; Male ; Female ; *Remission Induction ; Aged ; Transplantation, Homologous/methods ; Adolescent ; Young Adult ; Allografts ; Treatment Outcome ; Disease-Free Survival ; }, abstract = {Outcomes of adults with AML after allografting vary widely. While numerous covariates have been associated with relapse, non-relapse mortality (NRM), and/or shorter survival, the impact of incomplete blood count recovery before transplantation has remained unclear. To address this uncertainty, we examined all adults with AML or MDS/AML who received an allograft in first or second remission between 2006 and 2023 at a single institution. Of 1264 patients, 891 (70%) met criteria for CR, whereas 291 (23%), 24 (2%), and 58 (5%) were classified as CRh, CRi, and morphologic leukemia-free state (MLFS), respectively. CR, CRh, CRi, and MLFS patients differed significantly regarding demographics, disease biology, pre-transplant measurable residual disease, and types of transplants. After multivariable adjustment, outcomes for CRh and CRi patients were not significantly different from each other or from those of CR patients. In contrast, outcomes of MLFS patients were substantially worse than those of CR and CRh patients, with significantly higher risk of NRM and relapse, and significantly shorter relapse-free and overall survival. Similar results were obtained in several distinct subsets. Together, our analysis provides empiric evidence for the importance of distinguishing MLFS from CR and CRh patients for optimized risk assessment and, possibly, individualized treatment decision making.}, }
@article {pmid39210026, year = {2024}, author = {Repetto, L and Chen, J and Yang, Z and Zhai, R and Timmers, PRHJ and Feng, X and Li, T and Yao, Y and Maslov, D and Timoshchuk, A and Tu, F and Twait, EL and May-Wilson, S and Muckian, MD and Prins, BP and Png, G and Kooperberg, C and Johansson, &#xc5; and Hillary, RF and Wheeler, E and Pan, L and He, Y and Klasson, S and Ahmad, S and Peters, JE and Gilly, A and Karaleftheri, M and Tsafantakis, E and Haessler, J and Gyllensten, U and Harris, SE and Wareham, NJ and Göteson, A and Lagging, C and Ikram, MA and van Duijn, CM and Jern, C and Landén, M and Langenberg, C and Deary, IJ and Marioni, RE and Enroth, S and Reiner, AP and Dedoussis, G and Zeggini, E and Sharapov, S and Aulchenko, YS and Butterworth, AS and Mälarstig, A and Wilson, JF and Navarro, P and Shen, X}, title = {The genetic landscape of neuro-related proteins in human plasma.}, journal = {Nature human behaviour}, volume = {8}, number = {11}, pages = {2222-2234}, pmid = {39210026}, issn = {2397-3374}, support = {12171495//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2021A1515010866//Natural Science Foundation of Guangdong Province (Guangdong Natural Science Foundation)/ ; 2022-01309//Vetenskapsr&#xe5;det (Swedish Research Council)/ ; }, mesh = {Humans ; *Genome-Wide Association Study ; *Quantitative Trait Loci ; Nerve Tissue Proteins/genetics/blood ; Mental Disorders/genetics/blood ; }, abstract = {Understanding the genetic basis of neuro-related proteins is essential for dissecting the molecular basis of human behavioural traits and the disease aetiology of neuropsychiatric disorders. Here the SCALLOP Consortium conducted a genome-wide association meta-analysis of over 12,000 individuals for 184 neuro-related proteins in human plasma. The analysis identified 125 cis-regulatory protein quantitative trait loci (cis-pQTL) and 164 trans-pQTL. The mapped pQTL capture on average 50% of each protein's heritability. At the cis-pQTL, multiple proteins shared a genetic basis with human behavioural traits such as alcohol and food intake, smoking and educational attainment, as well as neurological conditions and psychiatric disorders such as pain, neuroticism and schizophrenia. Integrating with established drug information, the causal inference analysis validated 52 out of 66 matched combinations of protein targets and diseases or side effects with available drugs while suggesting hundreds of repurposing and new therapeutic targets.}, }
@article {pmid39209385, year = {2024}, author = {Deschamps, MM and Bat-Erdene, M and Duerr, A and Pape, JW}, title = {GHESKIO's model of patient care during civil unrest in Haiti.}, journal = {The lancet. HIV}, volume = {11}, number = {9}, pages = {e572-e573}, doi = {10.1016/S2352-3018(24)00208-X}, pmid = {39209385}, issn = {2352-3018}, mesh = {Humans ; Haiti/epidemiology ; *HIV Infections/epidemiology/prevention &amp; control ; Patient Care ; Delivery of Health Care ; }, }
@article {pmid39208801, year = {2024}, author = {Long, D and Chan, M and Han, M and Kamdar, Z and Ma, RK and Tsai, PY and Francisco, AB and Barrow, J and Shackelford, DB and Yarchoan, M and McBride, MJ and Orre, LM and Vacanti, NM and Gujral, TS and Sethupathy, P}, title = {Proteo-metabolomics and patient tumor slice experiments point to amino acid centrality for rewired mitochondria in fibrolamellar carcinoma.}, journal = {Cell reports. Medicine}, volume = {5}, number = {9}, pages = {101699}, pmid = {39208801}, issn = {2666-3791}, mesh = {Humans ; *Mitochondria/metabolism ; *Carcinoma, Hepatocellular/metabolism/genetics/pathology ; *Metabolomics/methods ; *Amino Acids/metabolism ; Liver Neoplasms/metabolism/genetics/pathology ; Voltage-Dependent Anion Channels/metabolism/genetics ; Proteomics/methods ; Female ; }, abstract = {Fibrolamellar carcinoma (FLC) is a rare, lethal, early-onset liver cancer with a critical need for new therapeutics. The primary driver in FLC is the fusion oncoprotein, DNAJ-PKAc, which remains challenging to target therapeutically. It is critical, therefore, to expand understanding of the FLC molecular landscape to identify druggable pathways/targets. Here, we perform the most comprehensive integrative proteo-metabolomic analysis of FLC. We also conduct nutrient manipulation, respirometry analyses, as well as key loss-of-function assays in FLC tumor tissue slices from patients. We propose a model of cellular energetics in FLC pointing to proline anabolism being mediated by ornithine aminotransferase hyperactivity and ornithine transcarbamylase hypoactivity with serine and glutamine catabolism fueling the process. We highlight FLC's potential dependency on voltage-dependent anion channel (VDAC), a mitochondrial gatekeeper for anions including pyruvate. The metabolic rewiring in FLC that we propose in our model, with an emphasis on mitochondria, can be exploited for therapeutic vulnerabilities.}, }
@article {pmid39208097, year = {2024}, author = {Martin, S and Scorzoni, S and Cordone, S and Mazzagatti, A and Beznoussenko, GV and Gunn, AL and Di Bona, M and Eliezer, Y and Leor, G and Ben-Yishay, T and Loffreda, A and Cancila, V and Rainone, MC and Ippolito, MR and Martis, V and Bedin, F and Garrè, M and Vaites, LP and Vasapolli, P and Polo, S and Parazzoli, D and Tripodo, C and Mironov, AA and Cuomo, A and Ben-David, U and Bakhoum, SF and Hatch, EM and Ly, P and Santaguida, S}, title = {A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements.}, journal = {Science (New York, N.Y.)}, volume = {385}, number = {6712}, pages = {eadj7446}, doi = {10.1126/science.adj7446}, pmid = {39208097}, issn = {1095-9203}, support = {DP5 OD026395/OD/NIH HHS/United States ; R01 CA280572/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Sequestosome-1 Protein/metabolism/genetics ; *Chromosomal Instability ; *Chromothripsis ; *Autophagy ; *Micronuclei, Chromosome-Defective ; *Colorectal Neoplasms/genetics/pathology/metabolism ; Cell Line, Tumor ; DNA Damage ; Endosomal Sorting Complexes Required for Transport/metabolism/genetics ; Mitochondria/metabolism/genetics ; Nuclear Envelope/metabolism ; }, abstract = {Chromosomal instability (CIN) generates micronuclei-aberrant extranuclear structures that catalyze the acquisition of complex chromosomal rearrangements present in cancer. Micronuclei are characterized by persistent DNA damage and catastrophic nuclear envelope collapse, which exposes DNA to the cytoplasm. We found that the autophagic receptor p62/SQSTM1 modulates micronuclear stability, influencing chromosome fragmentation and rearrangements. Mechanistically, proximity of micronuclei to mitochondria led to oxidation-driven homo-oligomerization of p62, limiting endosomal sorting complex required for transport (ESCRT)-dependent micronuclear envelope repair by triggering autophagic degradation. We also found that p62 levels correlate with increased chromothripsis across human cancer cell lines and with increased CIN in colorectal tumors. Thus, p62 acts as a regulator of micronuclei and may serve as a prognostic marker for tumors with high CIN.}, }
@article {pmid39207900, year = {2024}, author = {Elum, JE and Szelenyi, ER and Juarez, B and Murry, AD and Loginov, G and Zamorano, CA and Gao, P and Wu, G and Ng-Evans, S and Yee, JX and Xu, X and Golden, SA and Zweifel, LS}, title = {Distinct dynamics and intrinsic properties in ventral tegmental area populations mediate reward association and motivation.}, journal = {Cell reports}, volume = {43}, number = {9}, pages = {114668}, pmid = {39207900}, issn = {2211-1247}, support = {K99 DA054265/DA/NIDA NIH HHS/United States ; R01 MH104450/MH/NIMH NIH HHS/United States ; P30 DA048736/DA/NIDA NIH HHS/United States ; R01 DA059374/DA/NIDA NIH HHS/United States ; R00 DA045662/DA/NIDA NIH HHS/United States ; F31 DA053724/DA/NIDA NIH HHS/United States ; R01 DA044315/DA/NIDA NIH HHS/United States ; R00 DA054265/DA/NIDA NIH HHS/United States ; }, mesh = {*Ventral Tegmental Area/physiology ; Animals ; *Reward ; *Motivation/physiology ; Mice ; *Dopaminergic Neurons/physiology/metabolism ; Male ; *Nucleus Accumbens/physiology ; GABAergic Neurons/metabolism/physiology ; Mice, Inbred C57BL ; }, abstract = {Ventral tegmental area (VTA) dopamine neurons regulate reward-related associative learning and reward-driven motivated behaviors, but how these processes are coordinated by distinct VTA neuronal subpopulations remains unresolved. Here, we compare the contribution of two primarily dopaminergic and largely non-overlapping VTA subpopulations, all VTA dopamine neurons and VTA GABAergic neurons of the mouse midbrain, to these processes. We find that the dopamine subpopulation that projects to the nucleus accumbens (NAc) core preferentially encodes reward-predictive cues and prediction errors. In contrast, the subpopulation that projects to the NAc shell preferentially encodes goal-directed actions and relative reward anticipation. VTA GABA neuron activity strongly contrasts VTA dopamine population activity and preferentially encodes reward outcome and retrieval. Electrophysiology, targeted optogenetics, and whole-brain input mapping reveal multiple convergent sources that contribute to the heterogeneity among VTA dopamine subpopulations that likely underlies their distinct encoding of reward-related associations and motivation that defines their functions in these contexts.}, }
@article {pmid39207259, year = {2024}, author = {Serrano-Villar, S and Gala, A and Bacchetti, P and Hoh, R and di Germanio, C and Cohn, LB and Henrich, TJ and Hunt, PW and Laird, GM and Pillai, SK and Deeks, SG and Peluso, MJ}, title = {Galectin-9 Levels as a Potential Predictor of Intact HIV Reservoir Decay.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiae426}, pmid = {39207259}, issn = {1537-6613}, support = {UM1 AI164560/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: During antiretroviral therapy (ART), the HIV reservoir exhibits variability as cells with intact genomes decay faster than those with defective genomes, especially in the first years of therapy. The host factors influencing this decay are yet to be characterized.<br><br>METHODS: &#xfeff;Observational study in 74 PWH on ART, of whom 70 (94.6%) were male. We used the intact proviral DNA assay to measure intact proviruses and Luminex immunoassay to measure 32 inflammatory cytokines in plasma. Linear spline models, with a knot at seven years, evaluated the impact of baseline cytokine levels and their trajectories on intact HIV kinetics over these years.<br><br>RESULTS: Baseline Gal-9 was the most predictive marker for intact HIV kinetics, with lower Gal-9 predicting faster decay over the subsequent seven years. For each 10-fold decrease in Gal-9 at baseline, there was a mean 45% (95%CI 14%-84%) greater decay of intact HIV genomes per year. Conversely, higher baseline ITAC, IL-17, and MIP-1&#x3b1; predicted faster intact HIV decreases. Longitudinal changes in MIP-3&#x3b1; and IL-6 levels strongly associated with intact HIV kinetics, with a 10-fold increase in MIP-3&#x3b1; and a 10-fold decrease in IL-6 associated with a a 9.5% and 10% faster decay of intact HIV genomes per year, respectively.<br><br>CONCLUSION: The pronounced association between baseline Gal-9 levels and subsequent intact HIV decay suggests that strategies reducing Gal-9 levels could accelerate reservoir decay. Additionally, the correlations of MIP-3&#x3b1; and IL-6 with HIV kinetics indicate a broader cytokine-mediated regulatory network, hinting at multi-targeted interventions that could modulate HIV reservoir dynamics.}, }
@article {pmid39206927, year = {2024}, author = {Neary, J and Chebet, D and Benki-Nugent, S and Moraa, H and Richardson, BA and Njuguna, I and Langat, A and Ngugi, E and Lehman, DA and Slyker, J and Wamalwa, D and John-Stewart, G}, title = {Association between HIV and cytomegalovirus and neurocognitive outcomes among children with HIV.}, journal = {AIDS (London, England)}, volume = {38}, number = {14}, pages = {1972-1977}, pmid = {39206927}, issn = {1473-5571}, support = {R01 HD094718/HD/NICHD NIH HHS/United States ; R01 AI076105/AI/NIAID NIH HHS/United States ; F31 HD106261/HD/NICHD NIH HHS/United States ; K01 NS080637/NS/NINDS NIH HHS/United States ; K24 HD054314/HD/NICHD NIH HHS/United States ; R01 HD023412/HD/NICHD NIH HHS/United States ; K43 TW011422/TW/FIC NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; TL1 TR002318/TR/NCATS NIH HHS/United States ; K01 AI087369/AI/NIAID NIH HHS/United States ; UL1 TR002319/TR/NCATS NIH HHS/United States ; KL2 TR002317/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Viral Load ; Male ; Female ; *Cytomegalovirus Infections/complications/psychology ; *HIV Infections/drug therapy/psychology/complications ; Child ; Child, Preschool ; Infant ; Kenya ; DNA, Viral/blood ; Cohort Studies ; Cytomegalovirus ; Anti-Retroviral Agents/therapeutic use ; Viremia ; }, abstract = {OBJECTIVES: Children with HIV may experience adverse neurocognitive outcomes despite antiretroviral therapy (ART). Cytomegalovirus (CMV) is common in children with HIV. Among children on ART, we examined the influences of early HIV viral load and CMV DNA on neurocognition.<br><br>DESIGN: We determined the association between pre-ART viral load, cumulative viral load, and CMV viremia and neurocognition using data from a cohort study.<br><br>METHODS: Children who initiated ART before 12&#x200a;months of age were enrolled from 2007 to 2010 in Nairobi, Kenya. Blood was collected at enrollment and every 6&#x200a;months thereafter. Four neurocognitive assessments with 12 domains were conducted when children were a median age of 7&#x200a;years. Primary outcomes included cognitive ability, executive function, attention, and motor z scores. Generalized linear models were used to determine associations between HIV viral load (pre-ART and cumulative; N &#x200a;=&#x200a;38) and peak CMV DNA (by 24&#x200a;months of age; N &#x200a;=&#x200a;20) and neurocognitive outcomes.<br><br>RESULTS: In adjusted models, higher peak CMV viremia by 24&#x200a;months of age was associated with lower cognitive ability and motor z scores. Higher pre-ART HIV viral load was associated with lower executive function z scores. Among secondary outcomes, higher pre-ART viral load was associated with lower mean nonverbal and metacognition z scores.<br><br>CONCLUSION: Higher pre-ART viral load and CMV DNA in infancy were associated with lower executive function, nonverbal and metacognition scores and cognitive ability and motor scores in childhood, respectively. These findings suggest long-term benefits of early HIV viral suppression and CMV control on neurocognition.}, }
@article {pmid39197073, year = {2024}, author = {Chakraborty, R and Zanwar, S and Hegenbart, U and Bhutani, D and Gertz, MA and Dispenzieri, A and Kumar, SK and D'Souza, A and Patwari, A and Cowan, AJ and Chen, G and Milani, P and Palladini, G and Sanchorawala, V and Bodanapu, G and Schönland, S and Lentzsch, S and Muchtar, E}, title = {Prognostic impact of cytogenetic abnormalities by FISH in AL amyloidosis with daratumumab-based frontline therapy.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024025899}, pmid = {39197073}, issn = {1528-0020}, abstract = {We performed an international retrospective cohort study to investigate the prognostic impact of cytogenetic abnormalities by FISH in 283 patients with AL amyloidosis treated with frontline daratumumab-bortezomib-cyclophosphamide-dexamethasone (Dara-VCD) or Dara-VD. The cytogenetic subgroups of interest were t(11;14), gain/amp(1q) [hereafter, +1q], hyperdiploidy, deletion(13q), del(17p), and myeloma high-risk (HR) translocations (t[4;14], t[14;16], or t[14;20]). The endpoints of interest were rate of hematologic complete response (heme CR), very good partial response or better (≥VGPR), and hematologic event-free survival (Heme EFS). The incidence of abnormalities was following: t(11;14)-53.4%; deletion (13q)-28.9%; +1q-22.3%; hyperdiploidy-19.4%; HR translocations-6.6%; and deletion(17p)-4.5%. The heme-CR rate by cytogenetic subgroups were: t(11;14) vs no t(11;14)-45.2% vs 41.8% (p=0.597); del(13q) vs no del(13q)-46.8% vs 42.8% (p=0.594); +1q vs no +1q-30.2% vs 47.9% (p=0.022); hyperdiploidy vs no hyperdiploidy-39.5% vs 44.9% (p=0.541); HR translocations vs none: 45.5% vs 43.1% (p=0.877); and del(17p) vs no del(17p)-50.0% vs 42.9% respectively (p=0.658). Similarly, +1q was the only subgroup with a significantly lower ≥VGPR rate (64.2% vs 79.0%; p=0.033). At a median follow-up of 19.8 months, the median heme-EFS was 49.6 months (95% CI, 24.7-not reached [NR]), and the 2-year OS was 80.98% (95% CI, 75.6-85.4). The presence of+1q was significantly associated with worse heme-EFS on multivariate analysis (HR 2.06, 95% CI, 1.14-3.71; p=0.017). Notably, there was no adverse prognostic impact of t(11;14) on heme EFS or OS. In conclusion, +1q is associated with worse outcome in the daratumumab-era. Clinical trials testing novel immunotherapies frontline should be enriched in +1q to further improve outcomes in this subgroup.}, }
@article {pmid39196656, year = {2024}, author = {Drowne, T and Armgardt, E and Svoboda, A}, title = {Real-world experience of abemaciclib for adjuvant and metastatic breast cancer.}, journal = {Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners}, volume = {}, number = {}, pages = {10781552241279189}, doi = {10.1177/10781552241279189}, pmid = {39196656}, issn = {1477-092X}, abstract = {OBJECTIVE: Hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer is the most common subtype. Abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6, was approved to reduce risk of recurrence in high-risk, HR+, HER2-, early breast cancer based on the monarchE trial. The most common adverse events reported in monarchE were diarrhea, neutropenia, and fatigue. Real-world tolerability data and incidence of adverse events with abemaciclib in the adjuvant setting versus the metastatic setting is lacking.<br><br>DATA SOURCES: This is a retrospective analysis of HR+, HER2- breast cancer patients on abemaciclib from March 2018 to September 2021 at Robert H. Lurie Comprehensive Cancer Center in Chicago, Illinois. Incidence, grade of adverse events, dose reductions, and discontinuations were evaluated in patients taking abemaciclib in the adjuvant setting and the metastatic setting.<br><br>DATA SUMMARY: Of the 30 patients included in this analysis, 100% experienced an adverse event of any grade. During treatment, 12.5% treated in the adjuvant setting and 35.7% in the metastatic setting experienced grade &#x2265;3 adverse events. Adverse events leading to discontinuation of abemaciclib occurred in 18.8% of patients in the adjuvant setting and 57.1% in the metastatic setting.<br><br>CONCLUSIONS: This data suggests abemaciclib is better tolerated in high-risk, HR+, HER2-, node-positive, early breast cancer treated in the adjuvant setting compared to the metastatic setting. Management of adverse events is crucial to help patients stay on therapy to improve clinical outcomes. Real-world tolerability of abemaciclib in both the adjuvant and metastatic settings is of importance.}, }
@article {pmid39195559, year = {2024}, author = {Navarro, SL and Williamson, BD and Huang, Y and Nagana Gowda, GA and Raftery, D and Tinker, LF and Zheng, C and Beresford, SAA and Purcell, H and Djukovic, D and Gu, H and Strickler, HD and Tabung, FK and Prentice, RL and Neuhouser, ML and Lampe, JW}, title = {Metabolite Predictors of Breast and Colorectal Cancer Risk in the Women's Health Initiative.}, journal = {Metabolites}, volume = {14}, number = {8}, pages = {}, pmid = {39195559}, issn = {2218-1989}, support = {75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; R01 CA277133/CA/NCI NIH HHS/United States ; S10 OD021562/CD/ODCDC CDC HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; R01 CA119171/CA/NCI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; P30 DK035816/DK/NIDDK NIH HHS/United States ; 75N92021D00001 75N92021D00002 75N92021D00003 75N92021D00004 75N92021D00005//NHLBI, NIH, USDHHS/ ; 75N92021D00004/WH/WHI NIH HHS/United States ; S10 OD021562/OD/NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {Metabolomics has been used extensively to capture the exposome. We investigated whether prospectively measured metabolites provided predictive power beyond well-established risk factors among 758 women with adjudicated cancers [n = 577 breast (BC) and n = 181 colorectal (CRC)] and n = 758 controls with available specimens (collected mean 7.2 years prior to diagnosis) in the Women's Health Initiative Bone Mineral Density subcohort. Fasting samples were analyzed by LC-MS/MS and lipidomics in serum, plus GC-MS and NMR in 24 h urine. For feature selection, we applied LASSO regression and Super Learner algorithms. Prediction models were subsequently derived using logistic regression and Super Learner procedures, with performance assessed using cross-validation (CV). For BC, metabolites did not increase predictive performance over established risk factors (CV-AUCs~0.57). For CRC, prediction increased with the addition of metabolites (median CV-AUC across platforms increased from ~0.54 to ~0.60). Metabolites related to energy metabolism: adenosine, 2-hydroxyglutarate, N-acetyl-glycine, taurine, threonine, LPC (FA20:3), acetate, and glycerate; protein metabolism: histidine, leucic acid, isoleucine, N-acetyl-glutamate, allantoin, N-acetyl-neuraminate, hydroxyproline, and uracil; and dietary/microbial metabolites: myo-inositol, trimethylamine-N-oxide, and 7-methylguanine, consistently contributed to CRC prediction. Energy metabolism may play a key role in the development of CRC and may be evident prior to disease development.}, }
@article {pmid39192316, year = {2024}, author = {Fahrmann, JF and Ghasemi, SM and Han, CY and Wu, R and Dennison, JB and Vykoukal, J and Celestino, J and Lu, K and Lu, Z and Drescher, C and Do, KA and Hanash, S and Bast, RC and Irajizad, E}, title = {A metabolite-based liquid biopsy for detection of ovarian cancer.}, journal = {Biomarker research}, volume = {12}, number = {1}, pages = {91}, pmid = {39192316}, issn = {2050-7771}, abstract = {Serial CA125 and second line transvaginal ultrasound (TVS) screening in the UKCTOCS indicated a shift towards detection of earlier stage ovarian cancer (OvCa), but did not yield a significant mortality reduction. There remains a need to establish additional biomarkers that can complement CA125 for even earlier and at a larger proportion of new cases. Using a cohort of plasma samples from 219 OvCa cases (59 stage I/II and 160 stage III/IV) and 409 female controls and a novel Sensitivity Maximization At A Given Specificity (SMAGS) method, we developed a blood-based metabolite-based test consisting of 7 metabolites together with CA125 for detection of OvCa. At a 98.5% specificity cutpoint, the metabolite test achieved sensitivity of 86.2% for detection of early-stage OvCa and was able to capture 64% of the cases with low CA125 levels (< 35 units/mL). In an independent test consisting of 65 early-stage OvCa cases and 141 female controls, the metabolite panel achieved sensitivity of 73.8% at a 91.4% specificity and captured 13 (44.8%) out of 29 early-stage cases with CA125 levels < 35 units/mL. The metabolite test has utility for ovarian cancer screening, capable of improving upon CA125 for detection of early-stage disease.}, }
@article {pmid39191946, year = {2024}, author = {Javed, Z and Shin, DH and Pan, W and White, SR and Elhaw, AT and Kim, YS and Kamlapurkar, S and Cheng, YY and Benson, JC and Abdelnaby, AE and Phaëton, R and Wang, HG and Yang, S and Sullivan, MLG and St Croix, CM and Watkins, SC and Mullett, SJ and Gelhaus, SL and Lee, N and Coffman, LG and Aird, KM and Trebak, M and Mythreye, K and Walter, V and Hempel, N}, title = {Drp1 splice variants regulate ovarian cancer mitochondrial dynamics and tumor progression.}, journal = {EMBO reports}, volume = {25}, number = {10}, pages = {4281-4310}, pmid = {39191946}, issn = {1469-3178}, support = {R01CA242021//HHS | NIH | National Cancer Institute (NCI)/ ; S10RR025488//HHS | NIH | National Center for Research Resources (NCRR)/ ; 2T32HL110849-11A1//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01 CA230628/CA/NCI NIH HHS/United States ; P50 CA272218/CA/NCI NIH HHS/United States ; P30 CA047904/CA/NCI NIH HHS/United States ; P50CA272218//HHS | NIH | National Cancer Institute (NCI)/ ; W81XWH-22-10252//U.S. Department of Defense (DOD)/ ; S10 OD023402/OD/NIH HHS/United States ; S10RR019003//HHS | NIH | National Center for Research Resources (NCRR)/ ; S10OD023402//HHS | NIH | NIH Office of the Director (OD)/ ; W81XWH-16-1-0117//U.S. Department of Defense (DOD)/ ; P30CA047904//HHS | NIH | National Cancer Institute (NCI)/ ; R35HL150778//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R35 HL150778/HL/NHLBI NIH HHS/United States ; R01CA230628//HHS | NIH | National Cancer Institute (NCI)/ ; S10RR016236//HHS | NIH | National Center for Research Resources (NCRR)/ ; S10 RR019003/RR/NCRR NIH HHS/United States ; R01 CA242021/CA/NCI NIH HHS/United States ; T32 HL110849/HL/NHLBI NIH HHS/United States ; S10 RR025488/RR/NCRR NIH HHS/United States ; }, mesh = {Humans ; *Dynamins/genetics/metabolism ; *Mitochondrial Dynamics/genetics ; *Ovarian Neoplasms/genetics/pathology/metabolism ; Female ; *Alternative Splicing ; *Microtubule-Associated Proteins/genetics/metabolism ; Cell Line, Tumor ; *Mitochondrial Proteins/genetics/metabolism ; *GTP Phosphohydrolases/genetics/metabolism ; *Mitochondria/metabolism/genetics ; Animals ; Disease Progression ; Exons/genetics ; Mice ; Gene Expression Regulation, Neoplastic ; Protein Isoforms/genetics/metabolism ; Microtubules/metabolism ; Apoptosis/genetics ; }, abstract = {Aberrant mitochondrial fission/fusion dynamics are frequently associated with pathologies, including cancer. We show that alternative splice variants of the fission protein Drp1 (DNM1L) contribute to the complexity of mitochondrial fission/fusion regulation in tumor cells. High tumor expression of the Drp1 alternative splice variant lacking exon 16 relative to other transcripts is associated with poor outcome in ovarian cancer patients. Lack of exon 16 results in Drp1 localization to microtubules and decreased association with mitochondrial fission sites, culminating in fused mitochondrial networks, enhanced respiration, changes in metabolism, and enhanced pro-tumorigenic phenotypes in vitro and in vivo. These effects are inhibited by siRNAs designed to specifically target the endogenously expressed transcript lacking exon 16. Moreover, lack of exon 16 abrogates mitochondrial fission in response to pro-apoptotic stimuli and leads to decreased sensitivity to chemotherapeutics. These data emphasize the pathophysiological importance of Drp1 alternative splicing, highlight the divergent functions and consequences of changing the relative expression of Drp1 splice variants in tumor cells, and strongly warrant consideration of alternative splicing in future studies focused on Drp1.}, }
@article {pmid39191731, year = {2024}, author = {Banerjee, R and Biru, Y and Cole, CE and Faiman, B and Midha, S and Ailawadhi, S}, title = {Disparities in relapsed or refractory multiple myeloma: recommendations from an interprofessional consensus panel.}, journal = {Blood cancer journal}, volume = {14}, number = {1}, pages = {149}, pmid = {39191731}, issn = {2044-5385}, mesh = {*Multiple Myeloma/therapy/drug therapy/epidemiology/diagnosis ; Humans ; *Healthcare Disparities ; Consensus ; United States/epidemiology ; }, abstract = {Many studies have documented racial, socioeconomic, geographic, and other disparities for United States (US) patients with multiple myeloma pertaining to diagnosis and frontline management. In contrast, very little is known about disparities in the management of relapsed/refractory multiple myeloma (RRMM) despite a plethora of novel treatment options. In this review, we discuss the manifestations of disparities in RRMM and strategies to mitigate their impact. Immunomodulatory drugs can create disparities on many axes, for example inappropriately low dosing due to Duffy-null status as well as time toxicity and financial toxicity from logistical hurdles for socioeconomically vulnerable patients. Access to myeloma expertise at high-volume centers is a critical consideration given the disconnect between how drugs like carfilzomib and dexamethasone are prescribed in trials versus optimized in real-world practice to lower toxicities. Disparities in chimeric antigen receptor T-cell therapy and bispecific antibody therapy span across racial, ethnic, and socioeconomic lines in large part due to their limited availability outside of high-volume centers. Another insidious source of disparities is supportive care in RRMM, ranging from inadequate pain control in Black patients to limited primary care provider access in rural settings. We discuss the rationales and evidence base for several solutions aimed at mitigating these disparities: for example, (1) bidirectional co-management with community-based oncologists, (2) screening for risk factors based on social determinants of health, (3) strategies to build patient trust with regard to clinical trials, and (4) longitudinal access to a primary care provider. As the treatment landscape for RRMM continues to expand, these types of efforts by the field will help ensure that this landscape is equally accessible and traversable for all US patients.}, }
@article {pmid39191530, year = {2024}, author = {Borazanci, EH and Bahary, N and Chung, V and Huyck, TK and Kio, EA and Chiorean, EG and Skeel, RT and Alese, OB and Cardin, DB and Fountzilas, C and Hanna, WT and Leal, AD and Lee, V and Noonan, AM and Philip, PA and Wainberg, ZA and Pashova, H and Mann, G and Oberstein, PE}, title = {Relacorilant plus nab-paclitaxel for the treatment of metastatic pancreatic ductal adenocarcinoma: results from the open-label RELIANT study.}, journal = {The oncologist}, volume = {29}, number = {11}, pages = {957-965}, pmid = {39191530}, issn = {1549-490X}, support = {//Corcept Therapeutics/ ; }, mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; *Albumins/administration &amp; dosage/therapeutic use/adverse effects/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use/pharmacology/adverse effects ; *Carcinoma, Pancreatic Ductal/drug therapy/pathology ; Neoplasm Metastasis ; *Paclitaxel/administration &amp; dosage/adverse effects ; *Pancreatic Neoplasms/drug therapy/pathology ; *Isoquinolines/administration &amp; dosage/adverse effects ; *Pyrazoles/administration &amp; dosage/adverse effects ; *Pyridines/administration &amp; dosage/adverse effects ; }, abstract = {BACKGROUND: Modulation of glucocorticoid receptor (GR) activity in tumor cells enhances chemotherapy efficacy. We evaluated the selective GR modulator relacorilant plus nab-paclitaxel in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who had received at least 2 prior therapy lines.<br><br>PATIENTS AND METHODS: In this open-label, single-arm, phase III study, patients received once-daily oral relacorilant (100 mg, titrated to 150 mg in 25 mg increments/cycle) and nab-paclitaxel (80 mg/m2) on days 1, 8, and 15 of 28-day cycles. The primary efficacy endpoint was objective response rate (ORR) by blinded independent central review. Progression-free survival (PFS), overall survival (OS), target gene modulation, and safety were also assessed.<br><br>RESULTS: Of 43 patients enrolled, 31 were evaluable for ORR (12 did not reach first postbaseline radiographic assessment). An interim analysis to assess whether ORR was &#x2265;10% showed no confirmed responses and the study was discontinued. Two (6.5%) patients attained unconfirmed partial responses and 15 (48.4%) had stable disease. Fourteen of 31 (45.2%) patients had reductions in target lesion size, despite prior nab-paclitaxel exposure in 12 of the 14. Median PFS and OS were 2.4 months (95% CI, 1.4-4.2) and 3.9 months (95% CI, 2.8-4.9), respectively. The most common adverse events were fatigue and nausea. RNA analysis confirmed that relacorilant plus nab-paclitaxel suppressed 8 cortisol target genes of interest.<br><br>CONCLUSION: Relacorilant plus nab-paclitaxel showed modest antitumor activity in heavily pretreated patients with mPDAC, with no new safety signals. Studies of this combination in other indications with a high unmet medical need are ongoing.}, }
@article {pmid39191488, year = {2024}, author = {Driessen, A and Unger, S and Nguyen, AP and Ries, RE and Meshinchi, S and Kreutmair, S and Alberti, C and Sumazin, P and Aplenc, R and Redell, MS and Becher, B and Rodríguez Martínez, M}, title = {Identification of single-cell blasts in pediatric acute myeloid leukemia using an autoencoder.}, journal = {Life science alliance}, volume = {7}, number = {11}, pages = {}, pmid = {39191488}, issn = {2575-1077}, support = {U10 CA180886/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; U24 CA196173/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Leukemia, Myeloid, Acute/pathology/immunology/genetics ; Child ; *Single-Cell Analysis/methods ; *Immunophenotyping ; Female ; Male ; Child, Preschool ; Adolescent ; Myeloid-Lymphoid Leukemia Protein/genetics/metabolism ; Flow Cytometry/methods ; Infant ; Histone-Lysine N-Methyltransferase/genetics/metabolism ; Computational Biology/methods ; Prognosis ; }, abstract = {Pediatric acute myeloid leukemia (AML) is an aggressive blood cancer with a poor prognosis and high relapse rate. Current challenges in the identification of immunotherapy targets arise from patient-specific blast immunophenotypes and their change during disease progression. To overcome this, we present a new computational research tool to rapidly identify malignant cells. We generated single-cell flow cytometry profiles of 21 pediatric AML patients with matched samples at diagnosis, remission, and relapse. We coupled a classifier to an autoencoder for anomaly detection and classified malignant blasts with 90% accuracy. Moreover, our method assigns a developmental stage to blasts at the single-cell level, improving current classification approaches based on differentiation of the dominant phenotype. We observed major immunophenotype and developmental stage alterations between diagnosis and relapse. Patients with KMT2A rearrangement had more profound changes in their blast immunophenotypes at relapse compared to patients with other molecular features. Our method provides new insights into the immunophenotypic composition of AML blasts in an unbiased fashion and can help to define immunotherapy targets that might improve personalized AML treatment.}, }
@article {pmid39190070, year = {2024}, author = {Purice, MD and Severs, LJ and Singhvi, A}, title = {Glia in Invertebrate Models: Insights from Caenorhabditis elegans.}, journal = {Advances in neurobiology}, volume = {39}, number = {}, pages = {19-49}, pmid = {39190070}, issn = {2190-5215}, mesh = {Animals ; *Caenorhabditis elegans ; *Neuroglia/metabolism ; Models, Animal ; }, abstract = {Glial cells modulate brain development, function, and health across all bilaterian animals, and studies in the past two decades have made rapid strides to uncover the underlying molecular mechanisms of glial functions. The nervous system of the invertebrate genetic model Caenorhabditis elegans (C. elegans) has small cell numbers with invariant lineages, mapped connectome, easy genetic manipulation, and a short lifespan, and the animal is also optically transparent. These characteristics are revealing C. elegans to be a powerful experimental platform for studying glial biology. This chapter discusses studies in C. elegans that add to our understanding of how glia modulate adult neural functions, and thereby animal behaviors, as well as emerging evidence of their roles as autonomous sensory cells. The rapid molecular and cellular advancements in understanding C. elegans glia in recent years underscore the utility of this model in studies of glial biology. We conclude with a perspective on future research avenues for C. elegans glia that may readily contribute molecular mechanistic insights into glial functions in the nervous system.}, }
@article {pmid39189966, year = {2024}, author = {Zhang, Y and Lindström, S and Kraft, P and Liu, Y}, title = {Genetic Risk, Health-Associated Lifestyle, and Risk of Early-onset Total Cancer and Breast Cancer.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djae208}, pmid = {39189966}, issn = {1460-2105}, abstract = {BACKGROUND: Early-onset cancer (diagnosed under age 50) generally manifests as an aggressive disease phenotype. The association between healthy lifestyle and early-onset cancer and whether it varies by common genetic variants remains unclear.<br><br>METHODS: We analyzed a prospective cohort of 66,308 participants who were under age 50 and free of cancer at baseline in the UK Biobank. Using Cox regression, we estimated Hazard ratios (HRs) and 95% confidence intervals (CIs) for early-onset total and breast cancer based on sex-specific composite total cancer polygenic risk scores (PRSs), a breast cancer-specific PRS, and sex-specific health-associated lifestyle scores (HLSs).<br><br>RESULTS: In multivariable-adjusted analyses with 2-year latency, higher genetic risk (highest vs lowest tertile of PRS) was associated with significantly increased risks of early-onset total cancer in females (HR, 95% CI: 1.83, 1.49-2.26) and males (2.03, 1.51-2.73) as well as early-onset breast cancer in females (3.06, 2.20-4.26). An unfavorable lifestyle (highest vs lowest category of HLS) was associated with higher risk of total cancer and breast cancer in females across genetic risk categories; the association with total cancer and breast cancer was stronger in the highest genetic risk category than the lowest: HRs (95% CIs) were 1.55 (1.12, 2.14) and 1.69 (1.11, 2.57) in the highest genetic risk category and 1.03 (0.64, 1.67) and 0.81 (0.36, 1.85) in the lowest.<br><br>CONCLUSIONS: Genetic and lifestyle factors were independently associated with early-onset total and breast cancer risk. Individuals with a high genetic risk may benefit more from adopting a healthy lifestyle in preventing early-onset cancer.}, }
@article {pmid39189932, year = {2024}, author = {Epperla, N and Zayac, AS and Landsburg, DJ and Bock, AM and Nowakowski, GS and Ayers, EC and Girton, M and Hu, M and Beckman, A and Li, S and Medeiros, LJ and Chang, JE and Kurt, H and Sandoval-Sus, J and Ansari-Lari, MA and Kothari, SK and Kress, A and Xu, ML and Torka, P and Sundaram, S and Smith, SD and Naresh, KN and Karimi, Y and Bond, DA and Evens, AM and Naik, SG and Kamdar, M and Haverkos, BM and Karmali, R and Farooq, U and Vose, JM and Rubinstein, P and Chaudhry, A and Olszewski, AJ}, title = {High-grade B-cell lymphoma, not otherwise specified: CNS involvement and outcomes in a multi-institutional series.}, journal = {Blood advances}, volume = {8}, number = {20}, pages = {5355-5364}, pmid = {39189932}, issn = {2473-9537}, support = {P30 CA086862/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; Male ; Middle Aged ; Adult ; *Central Nervous System Neoplasms/therapy/diagnosis/mortality ; Aged ; Retrospective Studies ; *Lymphoma, B-Cell/therapy/mortality/pathology ; Neoplasm Grading ; Aged, 80 and over ; Young Adult ; Prognosis ; Treatment Outcome ; }, abstract = {Little is known about the central nervous system (CNS) risk in high-grade B-cell lymphoma, not otherwise specified (HGBL NOS). Hence, we sought to describe the rates of baseline CNS involvement, risk of CNS recurrence after primary therapy, and management strategies in HGBL NOS. In this multicenter retrospective study, we included 160 adults with newly diagnosed HGBL NOS treated between 2016 and 2021 at 20 US institutions. Eleven patients (7%) had baseline CNS involvement at diagnosis (leptomeningeal = 6, parenchymal = 4, and both = 1). Baseline CNS involvement was significantly associated only with MYC rearrangement (OR = 3.5) and testicular (in men) or female pelvic (in women) involvement (OR = 8.1). There was no significant difference in survival outcomes between patients with HGBL NOS with (median PFS = 4 years) or without (median PFS = 2.4 years) baseline CNS involvement (P = 0.45). The cumulative incidence of CNS recurrence at 3 years was 11%. Patients with baseline CNS involvement were at the highest risk (48.5% vs 8% for those without baseline CNS involvement) and were excluded from the risk factors analysis for CNS recurrence. The risk for CNS recurrence was significantly associated with blood or bone marrow involvement, CD5 expression, non-germinal center B-cell subtype, and "dual-expresser lymphoma" phenotype, however, high CNS IPI was not. The prognosis of relapsed HGBL NOS was poor, regardless of whether recurrence was systemic or limited to the CNS, and with currently available salvage strategies, including autologous transplantation and chimeric antigen receptor T-cell modalities, almost all patients with CNS recurrence ultimately succumbed to their disease.}, }
@article {pmid39189646, year = {2024}, author = {Lin, L and Huang, Y and McIntyre, J and Chang, CH and Colmenares, S and Lee, YCG}, title = {Prevalent Fast Evolution of Genes Involved in Heterochromatin Functions.}, journal = {Molecular biology and evolution}, volume = {41}, number = {9}, pages = {}, pmid = {39189646}, issn = {1537-1719}, support = {R35 GM139653/GM/NIGMS NIH HHS/United States ; //NIH/ ; //NIH R35-GM14292/ ; //Cancer Research Foundation/ ; //NIH R35GM139653/ ; }, mesh = {*Heterochromatin/genetics ; Animals ; *Evolution, Molecular ; DNA Transposable Elements ; Drosophila/genetics ; Selection, Genetic ; Drosophila melanogaster/genetics ; Gene Dosage ; }, abstract = {Heterochromatin is a gene-poor and repeat-rich genomic compartment universally found in eukaryotes. Despite its low transcriptional activity, heterochromatin plays important roles in maintaining genome stability, organizing chromosomes, and suppressing transposable elements. Given the importance of these functions, it is expected that genes involved in heterochromatin regulation would be highly conserved. Yet, a handful of these genes were found to evolve rapidly. To investigate whether these previous findings are anecdotal or general to genes modulating heterochromatin, we compile an exhaustive list of 106 candidate genes involved in heterochromatin functions and investigate their evolution over short and long evolutionary time scales in Drosophila. Our analyses find that these genes exhibit significantly more frequent evolutionary changes, both in the forms of amino acid substitutions and gene copy number change, when compared to genes involved in Polycomb-based repressive chromatin. While positive selection drives amino acid changes within both structured domains with diverse functions and intrinsically disordered regions, purifying selection may have maintained the proportions of intrinsically disordered regions of these proteins. Together with the observed negative associations between the evolutionary rate of these genes and the genomic abundance of transposable elements, we propose an evolutionary model where the fast evolution of genes involved in heterochromatin functions is an inevitable outcome of the unique functional roles of heterochromatin, while the rapid evolution of transposable elements may be an effect rather than cause. Our study provides an important global view of the evolution of genes involved in this critical cellular domain and provides insights into the factors driving the distinctive evolution of heterochromatin.}, }
@article {pmid39187601, year = {2024}, author = {Marcoux, CM and Alousi, AM and Im, J and Hill, LC and Smallbone, P and Popat, U and Hosing, C and Kebriaei, P and Olson, A and Mehta, R and Chen, G and Qazilbash, M and Shpall, E and Champlin, RC and Saliba, RM}, title = {Gastrointestinal involvement refines prognosis in minnesota standard risk acute graft-vs.-host disease.}, journal = {Bone marrow transplantation}, volume = {59}, number = {11}, pages = {1594-1600}, pmid = {39187601}, issn = {1476-5365}, mesh = {Humans ; *Graft vs Host Disease/mortality ; Male ; Female ; Middle Aged ; Adult ; Retrospective Studies ; Minnesota ; Acute Disease ; Aged ; Gastrointestinal Diseases/etiology ; Adolescent ; Prognosis ; Risk Factors ; Young Adult ; Hematopoietic Stem Cell Transplantation ; }, abstract = {Minnesota acute graft versus host disease (AGVHD) risk score is a validated tool to stratify newly-diagnosed patients into standard-risk (SR) and high-risk (HR) groups with ~85% having SR AGVHD. We aimed to identify factors for further risk-stratification within Minnesota SR patients. A single-center, retrospective analysis of consecutive patients between 1/2010 and 12/2014 was performed. Patients who developed AGVHD within 100 days and treated with systemic corticosteroids were included (N = 416), 356 (86%) of which were Minnesota SR and 60 (14%) had HR AGVHD. Isolated upper gastrointestinal (GI) AGVHD patients had significantly better day 28 and 56 CR/PR rates (90% vs. 72%, p = 0.004) and (83% vs 66%, p = 0.01), respectively, and lower 1-year non-relapse mortality (NRM; 10% vs. 22%; HR 0.4, p = 0.03). Lower GI AGVHD had less favorable outcomes with 1-year NRM of 40% (HR 2.1, p = 0.001), although CR/PR rates were not statistically different. In multivariate analysis, lower GI involvement (HR 2.6, p < 0.001), age ≥ 50 (HR 2.9, p < 0.001) and HCT-CI > 3 (HR 2.1, p = 0.002) predicted for 1-year NRM. Heterogeneity within Minnesota SR patients requires consideration in clinical trials, as distinct outcomes are observed in those with isolated upper GI and lower GI AGVHD, highlighting the importance of stratification in clinical trial design.}, }
@article {pmid39186707, year = {2024}, author = {Petrylak, DP and Tagawa, ST and Jain, RK and Bupathi, M and Balar, A and Kalebasty, AR and George, S and Palmbos, P and Nordquist, L and Davis, N and Ramamurthy, C and Sternberg, CN and Loriot, Y and Agarwal, N and Park, C and Tonelli, J and Vance, M and Zhou, H and Grivas, P}, title = {TROPHY-U-01 Cohort 2: A Phase II Study of Sacituzumab Govitecan in Cisplatin-Ineligible Patients With Metastatic Urothelial Cancer Progressing After Previous Checkpoint Inhibitor Therapy.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {42}, number = {29}, pages = {3410-3420}, pmid = {39186707}, issn = {1527-7755}, mesh = {Humans ; Male ; Aged ; Female ; *Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects/administration &amp; dosage ; Middle Aged ; *Cisplatin/administration &amp; dosage/adverse effects ; *Immunoconjugates/therapeutic use/adverse effects/administration &amp; dosage ; *Camptothecin/analogs &amp; derivatives/therapeutic use/adverse effects/administration &amp; dosage ; Aged, 80 and over ; Immune Checkpoint Inhibitors/adverse effects/therapeutic use ; Urologic Neoplasms/drug therapy/pathology ; Disease Progression ; Carcinoma, Transitional Cell/drug therapy/secondary ; Cohort Studies ; Progression-Free Survival ; Neoplasm Metastasis ; }, abstract = {PURPOSE: Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate with an SN-38 payload, approved for patients with locally advanced (LA) or metastatic urothelial cancer (mUC) who progressed after platinum (PT)-based chemotherapy and a checkpoint inhibitor (CPI). Here, we report results from Cohort 2 of TROPHY-U-01 trial, evaluating the efficacy and safety of SG in patients with mUC.<br><br>METHODS: TROPHY-U-01 (ClinicalTrials.gov identifier: NCT03547973) is a multicohort, open-label phase II study. Cohort 2 includes patients with LA or mUC who have had progression or recurrence after a CPI and were cisplatin-ineligible at study initiation. Patients received SG 10 mg/kg on days 1 and 8 of 21-day cycles. The primary end point was objective response rate (ORR) per central review; secondary end points were clinical benefit rate (CBR), duration of response (DOR), and progression-free survival (PFS) per central review and safety.<br><br>RESULTS: Cohort 2 included 38 patients (61% male; median age 72.5 years; 66% visceral metastases [29% liver]; 50% received previous PT-based chemotherapy as previous [neo]adjuvant therapy]). At a median follow-up of 9.3 months, ORR was 32% (95% CI, 17.5 to 48.7), CBR 42% (95% CI, 26.3 to 59.2), median DOR 5.6 months (95% CI, 2.8 to 13.3), median PFS 5.6 months (95% CI, 4.1 to 8.3), and median overall survival 13.5 months (95% CI, 7.6 to 15.6). Grade &#x2265;3 treatment-emergent adverse events occurred in 87% of patients, most commonly neutropenia (34%), anemia (24%), leukopenia (19%), fatigue (18%), and diarrhea (16%).<br><br>CONCLUSION: SG monotherapy demonstrated a relatively high ORR with rapid responses; this was feasible with a manageable toxicity profile in cisplatin-ineligible patients who had progression after CPI therapy. Limitations include a moderate sample size and lack of random assignment. These results warrant further evaluation of SG alone and in combinations in patients with LA/mUC.}, }
@article {pmid39186304, year = {2024}, author = {Stout, NK and Miglioretti, DL and Su, YR and Lee, CI and Abraham, L and Alagoz, O and de Koning, HJ and Hampton, JM and Henderson, L and Lowry, KP and Mandelblatt, JS and Onega, T and Schechter, CB and Sprague, BL and Stein, S and Trentham-Dietz, A and van Ravesteyn, NT and Wernli, KJ and Kerlikowske, K and Tosteson, ANA}, title = {Breast Cancer Screening Using Mammography, Digital Breast Tomosynthesis, and Magnetic Resonance Imaging by Breast Density.}, journal = {JAMA internal medicine}, volume = {184}, number = {10}, pages = {1222-1231}, pmid = {39186304}, issn = {2168-6114}, support = {R01 CA248068/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Breast Neoplasms/diagnostic imaging ; *Mammography/methods ; Middle Aged ; *Early Detection of Cancer/methods ; *Magnetic Resonance Imaging/methods ; *Breast Density ; Aged ; Adult ; Breast/diagnostic imaging/pathology ; United States/epidemiology ; Mass Screening/methods ; }, abstract = {IMPORTANCE: Information on long-term benefits and harms of screening with digital breast tomosynthesis (DBT) with or without supplemental breast magnetic resonance imaging (MRI) is needed for clinical and policy discussions, particularly for patients with dense breasts.<br><br>OBJECTIVE: To project long-term population-based outcomes for breast cancer mammography screening strategies (DBT or digital mammography) with or without supplemental MRI by breast density.<br><br>Collaborative modeling using 3 Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer simulation models informed by US Breast Cancer Surveillance Consortium data. Simulated women born in 1980 with average breast cancer risk were included. Modeling analyses were conducted from January 2020 to December 2023.<br><br>INTERVENTION: Annual or biennial mammography screening with or without supplemental MRI by breast density starting at ages 40, 45, or 50 years through age 74 years.<br><br>MAIN OUTCOMES AND MEASURES: Lifetime breast cancer deaths averted, false-positive recall and false-positive biopsy recommendations per 1000 simulated women followed-up from age 40 years to death summarized as means and ranges across models.<br><br>RESULTS: Biennial DBT screening for all simulated women started at age 50 vs 40 years averted 7.4 vs 8.5 breast cancer deaths, respectively, and led to 884 vs 1392 false-positive recalls and 151 vs 221 false-positive biopsy recommendations, respectively. Biennial digital mammography had similar deaths averted and slightly more false-positive test results than DBT screening. Adding MRI for women with extremely dense breasts to biennial DBT screening for women aged 50 to 74 years increased deaths averted (7.6 vs 7.4), false-positive recalls (919 vs 884), and false-positive biopsy recommendations (180 vs 151). Extending supplemental MRI to women with heterogeneously or extremely dense breasts further increased deaths averted (8.0 vs 7.4), false-positive recalls (1088 vs 884), and false-positive biopsy recommendations (343 vs 151). The same strategy for women aged 40 to 74 years averted 9.5 deaths but led to 1850 false-positive recalls and 628 false-positive biopsy recommendations. Annual screening modestly increased estimated deaths averted but markedly increased estimated false-positive results.<br><br>CONCLUSIONS AND RELEVANCE: In this model-based comparative effectiveness analysis, supplemental MRI for women with dense breasts added to DBT screening led to greater benefits and increased harms. The balance of this trade-off for supplemental MRI use was more favorable when MRI was targeted to women with extremely dense breasts who comprise approximately 10% of the population.}, }
@article {pmid39186243, year = {2024}, author = {Torabi, A and Love, J and Hyun, T and Pham, A and Gauthier, J and Hirayama, A and Wu, D and Naresh, K}, title = {Complete loss of lineage defining antigens in two cases of B-cell malignancies following CAR-T therapy.}, journal = {Journal of hematopathology}, volume = {}, number = {}, pages = {}, pmid = {39186243}, issn = {1865-5785}, abstract = {Targeted immunotherapy is a promising approach in treating high-risk and refractory/relapsed lymphoid malignancies. Although this strategy has shown a significant success in treating non-Hodgkin B-cell lymphomas and plasma cell myeloma, relapse with loss of targeted antigen can occur. Rarely, complete loss of multiple lineage specific markers can happen. We are describing 2 cases of B-cell neoplasms along with contributing immunohistochemistry, cytogenetic, and molecular results. Post-targeted CAR-T therapy, both cases, one aggressive B-cell lymphoma and the other plasma cell myeloma, lost B-cell, and plasma cell antigens, respectively. Complete loss of lineage specific markers post-targeted therapy is a rare event that makes the diagnosis of the relapsed neoplasm challenging. In this article, we also reviewed the literature and highlighted possible mechanisms of antigen loss following targeted therapy.}, }
@article {pmid39185682, year = {2024}, author = {Maqsood, R and Holland, LA and Wu, LI and Begnel, ER and Adhiambo, J and Owiti, P and Chohan, BH and Gantt, S and Kinuthia, J and Wamalwa, D and Ojee, E and Richardson, BA and Slyker, J and Lehman, DA and Lim, ES}, title = {Gut virome and microbiome dynamics before and after SARS-CoV-2 infection in women living with HIV and their infants.}, journal = {Gut microbes}, volume = {16}, number = {1}, pages = {2394248}, pmid = {39185682}, issn = {1949-0984}, support = {R01 HD092311/HD/NICHD NIH HHS/United States ; }, mesh = {Humans ; Female ; *COVID-19/microbiology/virology ; *HIV Infections/microbiology/virology ; *Virome ; *Gastrointestinal Microbiome ; *SARS-CoV-2/genetics/isolation &amp; purification ; Adult ; Infant, Newborn ; *Feces/microbiology/virology ; Infant ; Bacteria/classification/isolation &amp; purification/genetics ; Longitudinal Studies ; }, abstract = {Microbiome perturbations can have long-term effects on health. The dynamics of the gut microbiome and virome in women living with HIV (WLHIV) and their newborn infants is poorly understood. Here, we performed metagenomic sequencing analyses on longitudinal stool samples including 23 mothers (13 WLHIV, 10 HIV-negative) and 12 infants that experienced SARS-CoV-2 infection with mild disease, as well as 40 mothers (18 WLHIV, 22 HIV-negative) and 60 infants that remained SARS-CoV-2 seronegative throughout the study follow-up. Regardless of HIV or SARS-CoV-2 status, maternal bacterial and viral profiles were distinct from infants. Using linear mixed effects models, we showed that the microbiome alpha diversity trajectory was not significantly different between SARS-CoV-2 seropositive and seronegative women. However, seropositive women's positive trajectory while uninfected was abruptly reversed after SARS-CoV-2 infection (p = 0.015). Gut virome signatures of women were not associated with SARS-CoV-2. Alterations in infant microbiome and virome diversities were generally not impacted by SARS-CoV-2 but were rather driven by development. We did not find statistically significant interactions between HIV and SARS-CoV-2 on the gut microbiome and virome. Overall, our study provides insights into the complex interplay between maternal and infant bacterial microbiome, virome, and the influence of SARS-CoV-2 and HIV status.}, }
@article {pmid39184837, year = {2024}, author = {Westling, T and Luedtke, A and Gilbert, PB and Carone, M}, title = {Inference for treatment-specific survival curves using machine learning.}, journal = {Journal of the American Statistical Association}, volume = {119}, number = {546}, pages = {1541-1553}, pmid = {39184837}, issn = {0162-1459}, support = {DP2 LM013340/LM/NLM NIH HHS/United States ; R01 HL137808/HL/NHLBI NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; }, abstract = {In the absence of data from a randomized trial, researchers may aim to use observational data to draw causal inference about the effect of a treatment on a time-to-event outcome. In this context, interest often focuses on the treatment-specific survival curves, that is, the survival curves were the population under study to be assigned to receive the treatment or not. Under certain conditions, including that all confounders of the treatment-outcome relationship are observed, the treatment-specific survival curve can be identified with a covariate-adjusted survival curve. In this article, we propose a novel cross-fitted doubly-robust estimator that incorporates data-adaptive (e.g. machine learning) estimators of the conditional survival functions. We establish conditions on the nuisance estimators under which our estimator is consistent and asymptotically linear, both pointwise and uniformly in time. We also propose a novel ensemble learner for combining multiple candidate estimators of the conditional survival estimators. Notably, our methods and results accommodate events occurring in discrete or continuous time, or an arbitrary mix of the two. We investigate the practical performance of our methods using numerical studies and an application to the effect of a surgical treatment to prevent metastases of parotid carcinoma on mortality.}, }
@article {pmid39182827, year = {2024}, author = {Banerjee, SC and Malling, CD and Schofield, EA and Carter-Bawa, L and Bylund, CL and Hamann, HA and Parker, PA and Shen, MJ and Studts, JL and Williamson, TJ and Ostroff, JS}, title = {Empathic communication skills training to reduce lung cancer stigma: Study protocol of a cluster randomized control trial.}, journal = {Contemporary clinical trials}, volume = {145}, number = {}, pages = {107669}, pmid = {39182827}, issn = {1559-2030}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; R01 CA255522/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Lung Neoplasms/psychology/therapy ; *Social Stigma ; *Communication ; *Empathy ; Physician-Patient Relations ; Female ; }, abstract = {BACKGROUND: Prior research demonstrates that nearly all (95 %) people with lung cancer (PwLC) report stigma, and approximately half (48 %) PwLC experience stigma during clinical encounters with oncology care providers (OCPs). When stigma is experienced in a medical context, it can have undesirable consequences including patients' delaying and underreporting of symptoms, misreporting of smoking behavior, and avoiding help-seeking such as psychosocial support and cessation counseling. Multi-level interventions are needed to prevent and mitigate lung cancer stigma. One promising intervention for reducing patient perception and experience of stigma is to train OCPs in responding empathically to patient emotions and promoting empathic communication within clinical encounters.<br><br>METHODS: This paper describes the study protocol for a cluster randomized trial comparing Usual Care (waitlist control group) with Empathic Communication Skills (ECS) training (intervention group). For this study, we will recruit 16 community oncology practice sites, 9-11 OCPs per site, and 6 PwLCs per OCP.<br><br>RESULTS: The goal of this trial is to investigate the effect of the ECS training on (a) OCP primary outcomes (communication and empathic skill uptake) and secondary outcomes (ECS training appraisal - relevance, novelty, clarity; self-efficacy, attitude towards communication with patients); and (b) patient-reported primary outcomes (lung cancer stigma), and secondary outcomes (perceived clinician empathy, satisfaction with OCP communication, psychological distress, social isolation, and appraisal of care).<br><br>CONCLUSION: Findings from this trial will advance understanding of the effectiveness of the ECS training intervention and inform future provider-level training interventions that may reduce lung cancer stigma and improve cancer care delivery.<br><br>CLINICALTRIALS: govIdentifier: NCT05456841.}, }
@article {pmid39182315, year = {2024}, author = {Vielot, NA and Kelly, NK and Ludema, C and Rosenberg, M and Brown, ER and Janes, HE and Kublin, JG and Stephenson, KE and Marcelin, JR and Pettifor, A}, title = {Patterns and predictors of COVID-19 vaccination among young adults at 44 US sites: Secondary analysis of a randomized, controlled, open-label trial, March - December 2021.}, journal = {Vaccine}, volume = {42}, number = {23}, pages = {126237}, pmid = {39182315}, issn = {1873-2518}, support = {T32 AI070114/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; *COVID-19/prevention &amp; control/epidemiology ; Young Adult ; Adult ; United States ; *COVID-19 Vaccines/administration &amp; dosage/immunology ; *Vaccination/statistics &amp; numerical data ; Adolescent ; *SARS-CoV-2/immunology ; 2019-nCoV Vaccine mRNA-1273/immunology ; }, abstract = {BACKGROUND: The introduction of vaccines during the COVID-19 pandemic provided an opportunity to slow transmission of SARS-CoV-2, but initial uptake of COVID-19 vaccination was slow. We analyzed data from a randomized clinical trial of the mRNA-1273 vaccine (NCT04811664) to describe the patterns of uptake of COVID-19 vaccines among young adults.<br><br>METHODS: The CoVPN 3006 trial randomized adults ages 18-29 from 44 sites in the United States to receive 1) immediate mRNA-1273 vaccination from the study site, or 2) standard of care, including the option to seek vaccination at any time in the future. Randomization occurred between March and November 2021, and an observational arm of adults who declined vaccination was enrolled beginning June 2021. Among participants in the standard of care (SoC) or Vaccine Declined arms, we estimated demographic, behavioral, and health history correlates of vaccination, and the four-month cumulative incidence of COVID-19 vaccination using inverse probability weighted Kaplan-Meier estimators.<br><br>RESULTS: Among 728 SoC and 470 Vaccine Declined participants, 79% and 16% received COVID-19 vaccination, respectively. SoC and Vaccine Declined participants were more likely to seek and receive vaccination if they reported COVID-19 preventive behaviors, including wearing masks, physically distancing, and avoiding large gatherings. We identified strong predictors of vaccination in the Vaccine Declined arm, including attending class in person (adjusted risk ratio [aRR]: 0.47, 95% confidence interval [CI] 0.21, 1.03), having a COVID-19 relevant medical condition (aRR: 1.95, 95% CI: 0.89, 4.26), and avoiding large gatherings (aRR: 2.24, 95% CI: 1.18, 4.25), though low vaccination rates in this arm led to imprecise estimates.<br><br>CONCLUSIONS: Individuals who initially decline vaccination can be convinced to vaccinate, particularly if they are already practicing other forms of COVID-19 prevention. Continued outreach and education from the scientific community can combat low vaccine confidence.}, }
@article {pmid39181323, year = {2024}, author = {Blouin, AG and Nelson, W and Geraghty, D and Askar, M and Ye, F}, title = {Performance Characteristics of Next-Generation Sequencing-Based Engraftment Monitoring and Microchimerism Detection in Allogeneic Hematopoietic Cell Transplantation: A Practical Approach for Clinical Assay Validation.}, journal = {The Journal of molecular diagnostics : JMD}, volume = {26}, number = {11}, pages = {995-1006}, pmid = {39181323}, issn = {1943-7811}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {*Hematopoietic Stem Cell Transplantation ; Humans ; *High-Throughput Nucleotide Sequencing/methods ; *Chimerism ; Reproducibility of Results ; *Transplantation, Homologous ; Sensitivity and Specificity ; Transplantation Chimera/genetics ; Polymorphism, Single Nucleotide ; Microsatellite Repeats/genetics ; }, abstract = {Chimerism analysis by next-generation sequencing (NGS) is an emerging method for engraftment monitoring after allogeneic hematopoietic cell transplantation. A high-sensitivity method is required for the detection of microchimerism (<1% chimerism), which may have clinical utility in early relapse detection, allograft monitoring in organ transplantation, and other allogeneic cellular therapies (such as microtransplantations). As more clinical laboratories adopt this method, a thorough assessment of performance is needed. This study evaluated one such NGS-based assay that uses both single-nucleotide polymorphisms and insertions/deletions as genetic markers. An assessment of accuracy, linearity, sensitivity, and reproducibility was performed. Analytical sensitivity was 0.2% donor for single donor and 0.5% donors for double donors. The assay showed a high degree of reproducibility over a full range of chimerism. Comparison to short-tandem-repeat (STR) PCR showed high concordance; yet <5% chimerism was consistently detected by NGS, but not by STR-PCR. Comparison to real-time quantitative PCR showed high concordance, but with lower correlation in the midrange (40% to 60% chimerism). Overall, the assay showed consistent performance with high sensitivity and accuracy compared with STR-PCR and real-time quantitative PCR across a full range of chimerism in the setting of single-donor and multidonor transplantations. In addition, criteria for quality metrics were established for sequencing performance and data analysis and considerations made for clinical laboratory validation of NGS-based chimerism assay and analysis software.}, }
@article {pmid39179671, year = {2024}, author = {Cuglievan, B and Kantarjian, H and Rubnitz, JE and Cooper, TM and Zwaan, CM and Pollard, JA and DiNardo, CD and Kadia, TM and Guest, E and Short, NJ and McCall, D and Daver, N and Nunez, C and Haddad, FG and Garcia, M and Bhalla, KN and Maiti, A and Catueno, S and Fiskus, W and Carter, BZ and Gibson, A and Roth, M and Khazal, S and Tewari, P and Abbas, HA and Bourgeois, W and Andreeff, M and Shukla, NN and Truong, DD and Connors, J and Ludwig, JA and Stutterheim, J and Salzer, E and Juul-Dam, KL and Sasaki, K and Mahadeo, KM and Tasian, SK and Borthakur, G and Dickson, S and Jain, N and Jabbour, E and Meshinchi, S and Garcia-Manero, G and Ravandi, F and Stein, EM and Kolb, EA and Issa, GC}, title = {Menin inhibitors in pediatric acute leukemia: a comprehensive review and recommendations to accelerate progress in collaboration with adult leukemia and the international community.}, journal = {Leukemia}, volume = {38}, number = {10}, pages = {2073-2084}, pmid = {39179671}, issn = {1476-5551}, mesh = {Humans ; *Proto-Oncogene Proteins/genetics/metabolism ; Child ; *Nucleophosmin ; Adult ; Leukemia/drug therapy/genetics ; Leukemia, Myeloid, Acute/drug therapy/genetics ; }, abstract = {Aberrant expression of HOX and MEIS1 family genes, as seen in KMT2A-rearranged, NUP98-rearranged, or NPM1-mutated leukemias leads to arrested differentiation and leukemia development. HOX family genes are essential gatekeepers of physiologic hematopoiesis, and their expression is regulated by the interaction between KMT2A and menin. Menin inhibitors block this interaction, downregulate the abnormal expression of MEIS1 and other transcription factors and thereby release the differentiation block. Menin inhibitors show significant clinical efficacy against KMT2A-rearranged and NPM1-mutated acute leukemias, with promising potential to address unmet needs in various pediatric leukemia subtypes. In this collaborative initiative, pediatric and adult hematologists/oncologists, and stem cell transplant physicians have united their expertise to explore the potential of menin inhibitors in pediatric leukemia treatment internationally. Our efforts aim to provide a comprehensive clinical overview of menin inhibitors, integrating preclinical evidence and insights from ongoing global clinical trials. Additionally, we propose future international, inclusive, and efficient clinical trial designs, integrating pediatric populations in adult trials, to ensure broad access to this promising therapy for all children and adolescents with menin-dependent leukemias.}, }
@article {pmid39179107, year = {2024}, author = {Rosen, EA and Krantz, EM and McCulloch, DJ and Wilson, MH and Tverdek, F and Kassamali Escobar, Z and Drucker, D and Sanchez, E and Ueda Oshima, M and Mielcarek, M and Gauthier, J and Pergam, SA and Hill, JA and Liu, C}, title = {COVID-19 Outcomes Among Hematopoietic Cell Transplant and Chimeric Antigen Receptor T-Cell Recipients in the Era of SARS-CoV-2 Omicron Variants and COVID-19 Therapeutics.}, journal = {Transplantation and cellular therapy}, volume = {30}, number = {11}, pages = {1108.e1-1108.e11}, pmid = {39179107}, issn = {2666-6367}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; T32 AI118690/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *COVID-19 ; Male ; Retrospective Studies ; Female ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Middle Aged ; *SARS-CoV-2 ; *Antiviral Agents/therapeutic use ; Adult ; Aged ; Ritonavir/therapeutic use ; Treatment Outcome ; Receptors, Chimeric Antigen ; COVID-19 Drug Treatment ; Alanine/analogs &amp; derivatives/therapeutic use ; Adenosine Monophosphate/analogs &amp; derivatives/therapeutic use ; Immunotherapy, Adoptive ; Hospitalization ; Drug Combinations ; }, abstract = {Recipients of cellular therapies, including hematopoietic cell transplant (HCT) and chimeric antigen receptor T-cell (CART) therapy, are at risk for poor outcomes from coronavirus disease 2019 (COVID-19). There are limited data describing outcomes among patients in the pre- and early post-cellular therapy period during the Omicron era when multiple antiviral therapeutics were widely available. The objective of this study is to describe COVID-19 treatment and outcomes in patients diagnosed with COVID-19 during the pre- or early post-cellular therapy period. This is a single-center retrospective cohort study of adult HCT and CART recipients diagnosed with COVID-19 in the pre- and early post-cellular therapy period who tested positive for COVID-19 at our cancer center between January 1, 2022 and March 1, 2023. Primary outcomes were 30-day COVID-19-related hospitalization and death. A secondary outcome was development of persistent COVID-19, defined by a positive SARS-CoV-2 polymerase chain reaction (PCR) 31 to 90 days after COVID-19 diagnosis. Among 65 patients included, 52 (80%) received at least one COVID-19 therapeutic. The most common treatment after initial COVID-19 diagnosis was nirmatrelvir/ritonavir (29%), followed by monoclonal antibody therapy (26%) and remdesivir (11%). Of the 64 patients with at least 30 days of follow-up, 8 (12%) had at least one COVID-19-related hospitalization and one patient died, though cause of death was not due to COVID-19. Of the 8 patients hospitalized for COVID-19, one had severe disease and 7 had mild or moderate infection. Persistent COVID-19 was observed in 13/65 (20%) patients, with 4 patients requiring additional antiviral therapy. Three pre-cellular therapy patients had delays in receiving cellular therapy due to persistent COVID-19. During the Omicron era, rates of 30-day COVID-19-related hospitalization and death were relatively low in this cohort of pre- and early post-HCT and CART recipients, the majority of whom received treatment with at least one antiviral agent. Persistent COVID-19 occurred in 1 in 5 patients in the peri-cellular therapy period and led to cellular therapy treatment delays in several patients, highlighting the need for new COVID-19 treatment strategies.}, }
@article {pmid39178368, year = {2024}, author = {Graham, LS and Henderson, NC and Kellezi, O and Hwang, C and Barata, PC and Bilen, MA and Kilari, D and Pierro, M and Thapa, B and Tripathi, A and Mo, G and Labriola, M and Park, JJ and Rothstein, S and Garje, R and Koshkin, VS and Patel, VG and Dorff, T and Armstrong, AJ and McKay, RR and Alva, A and Schweizer, MT}, title = {DNA-Damaging Therapies in Patients With Prostate Cancer and Pathogenic Alterations in Homologous Recombination Repair Genes.}, journal = {JCO precision oncology}, volume = {8}, number = {}, pages = {e2400014}, pmid = {39178368}, issn = {2473-4284}, support = {K12 CA086913/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; Retrospective Studies ; Aged ; Middle Aged ; *Prostatic Neoplasms/drug therapy/genetics ; *Recombinational DNA Repair/genetics ; *Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; Mutation ; DNA Damage ; Aged, 80 and over ; }, abstract = {PURPOSE: Outcomes data for DNA-damaging therapeutics for men with prostate cancer (PC) and non-BRCA1/2 homologous recombination repair (HRR) mutations are limited. We evaluated outcomes by HRR alteration in men with PC treated with poly(ADP-ribose)polymerase inhibitors (PARPi) and/or platinum chemotherapy.<br><br>METHODS: Retrospective data from the PROMISE consortium were used. Clinical outcomes differences were assessed between patients with BRCA1/2 mutations (cohort A) and those with HRR mutations without direct BRCA complex interaction (cohort B: ATM, CDK12, CHEK1, CHEK2, and FANCL). Outcomes in patients with HRR mutations with direct BRCA complex interaction were also explored (cohort C: RAD51B/C/D, RAD54L2, BARD1, GEN1, PALB2, FANCA, and BRIP1).<br><br>RESULTS: One hundred and forty-six patients received PARPi (cohort A: 94, cohort B: 45, cohort C: 7) and 104 received platinum chemotherapy (cohort A: 48, cohort B: 44, cohort C: 10). PSA50 response rate to PARPi was higher in cohort A (61%) than cohort B (5%), P < .001. Median clinical/radiographic progression-free survival (crPFS) with PARPi in cohort A was significantly longer than in cohort B: 15.9 versus 8.7 months, P = .005. PSA50 response rate to platinum therapy was higher in cohort A (62%) than in cohort B (32%), P = .024, although crPFS was not significantly different. PSA50 response rate to PARPi and platinum was 40% and 32%, respectively, in cohort C. In multivariable analysis, cohort A had significantly improved overall survival and crPFS compared with cohort B with PARPi but not platinum chemotherapy.<br><br>CONCLUSION: Patients with BRCA1/2-mutated PC had significantly improved outcomes to PARPi but not platinum chemotherapy compared with those with HRR mutations without direct BRCA complex interaction.}, }
@article {pmid39177120, year = {2024}, author = {Higano, CS and Cheng, H}, title = {Editorial Comment.}, journal = {The Journal of urology}, volume = {212}, number = {6}, pages = {841-842}, doi = {10.1097/JU.0000000000004212}, pmid = {39177120}, issn = {1527-3792}, }
@article {pmid39175935, year = {2024}, author = {Wolock, CJ and Gilbert, PB and Simon, N and Carone, M}, title = {A framework for leveraging machine learning tools to estimate personalized survival curves.}, journal = {Journal of computational and graphical statistics : a joint publication of American Statistical Association, Institute of Mathematical Statistics, Interface Foundation of North America}, volume = {33}, number = {3}, pages = {1098-1108}, pmid = {39175935}, issn = {1061-8600}, support = {R01 HL137808/HL/NHLBI NIH HHS/United States ; R37 AI029168/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; }, abstract = {The conditional survival function of a time-to-event outcome subject to censoring and truncation is a common target of estimation in survival analysis. This parameter may be of scientific interest and also often appears as a nuisance in nonparametric and semiparametric problems. In addition to classical parametric and semiparametric methods (e.g., based on the Cox proportional hazards model), flexible machine learning approaches have been developed to estimate the conditional survival function. However, many of these methods are either implicitly or explicitly targeted toward risk stratification rather than overall survival function estimation. Others apply only to discrete-time settings or require inverse probability of censoring weights, which can be as difficult to estimate as the outcome survival function itself. Here, we employ a decomposition of the conditional survival function in terms of observable regression models in which censoring and truncation play no role. This allows application of an array of flexible regression and classification methods rather than only approaches that explicitly handle the complexities inherent to survival data. We outline estimation procedures based on this decomposition, empirically assess their performance, and demonstrate their use on data from an HIV vaccine trial. Supplementary materials for this article are available online.}, }
@article {pmid39173097, year = {2024}, author = {Varco-Merth, B and Chaunzwa, M and Duell, DM and Marenco, A and Goodwin, W and Dannay, R and Nekorchuk, M and Shao, D and Busman-Sahay, K and Fennessey, CM and Silipino, L and Hull, M and Bosche, WJ and Fast, R and Oswald, K and Shoemaker, R and Bochart, R and MacAllister, R and Labriola, CS and Smedley, JV and Axthelm, MK and Davenport, MP and Edlefsen, PT and Estes, JD and Keele, BF and Lifson, JD and Lewin, SR and Picker, LJ and Okoye, AA}, title = {Impact of alemtuzumab-mediated lymphocyte depletion on SIV reservoir establishment and persistence.}, journal = {PLoS pathogens}, volume = {20}, number = {8}, pages = {e1012496}, pmid = {39173097}, issn = {1553-7374}, support = {P51 OD011092/OD/NIH HHS/United States ; 75N91019D00024/CA/NCI NIH HHS/United States ; HHSN261201500003C/CA/NCI NIH HHS/United States ; UM1 AI164560/AI/NIAID NIH HHS/United States ; UM1 AI126611/AI/NIAID NIH HHS/United States ; HHSN261201500003I/CA/NCI NIH HHS/United States ; UM1 AI124377/AI/NIAID NIH HHS/United States ; HHSN261200800001E/CA/NCI NIH HHS/United States ; HHSN261200800001C/CA/NCI NIH HHS/United States ; S10 OD025002/OD/NIH HHS/United States ; }, mesh = {Animals ; *Simian Immunodeficiency Virus/drug effects/immunology ; *Simian Acquired Immunodeficiency Syndrome/drug therapy/immunology/virology ; *Alemtuzumab/pharmacology ; *Macaca mulatta ; *Lymphocyte Depletion/methods ; *Viral Load/drug effects ; CD4-Positive T-Lymphocytes/immunology/virology/drug effects ; }, abstract = {Persistence of the rebound-competent viral reservoir (RCVR) within the CD4+ T cell compartment of people living with HIV remains a major barrier to HIV cure. Here, we determined the effects of the pan-lymphocyte-depleting monoclonal antibody (mAb) alemtuzumab on the RCVR in SIVmac239-infected rhesus macaques (RM) receiving antiretroviral therapy (ART). Alemtuzumab administered during chronic ART or at the time of ART initiation induced >95% depletion of circulating CD4+ T cells in peripheral blood and substantial CD4+ T cell depletion in lymph nodes. However, treatment was followed by proliferation and reconstitution of CD4+ T cells in blood, and despite ongoing ART, levels of cell-associated SIV DNA in blood and lymphoid tissues were not substantially different between alemtuzumab-treated and control RM after immune cell reconstitution, irrespective of the time of alemtuzumab treatment. Upon ART cessation, 19 of 22 alemtuzumab-treated RM and 13 of 13 controls rebounded with no difference in the time to rebound between treatment groups. Time to rebound and reactivation rate was associated with plasma viral loads (pVLs) at time of ART initiation, suggesting lymphocyte depletion had no durable impact on the RCVR. However, 3 alemtuzumab-treated RM that had lowest levels of pre-ART viremia, failed to rebound after ART withdrawal, in contrast to controls with similar levels of SIV replication. These observations suggest that alemtuzumab therapy has little to no ability to reduce well-established RCVRs but may facilitate RCVR destabilization when pre-ART virus levels are particularly low.}, }
@article {pmid39173088, year = {2024}, author = {Chlebowski, RT and Aragaki, AK and Pan, K and Haque, R and Rohan, TE and Song, M and Wactawski-Wende, J and Lane, DS and Harris, HR and Strickler, H and Kauntiz, AM and Runowicz, CD}, title = {Menopausal Hormone Therapy and Ovarian and Endometrial Cancers: Long-Term Follow-Up of the Women's Health Initiative Randomized Trials.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {42}, number = {30}, pages = {3537-3549}, doi = {10.1200/JCO.23.01918}, pmid = {39173088}, issn = {1527-7755}, mesh = {Humans ; Female ; *Endometrial Neoplasms/mortality/epidemiology ; Middle Aged ; *Ovarian Neoplasms/epidemiology/mortality ; Aged ; *Estrogens, Conjugated (USP)/adverse effects/administration &amp; dosage/therapeutic use ; *Medroxyprogesterone Acetate/adverse effects/administration &amp; dosage/therapeutic use ; *Estrogen Replacement Therapy/adverse effects ; Follow-Up Studies ; Incidence ; Women's Health ; Postmenopause ; }, abstract = {PURPOSE: Menopausal hormone therapy's influence on ovarian and endometrial cancers remains unsettled. Therefore, we assessed the long-term influence of conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) and CEE-alone on ovarian and endometrial cancer incidence and mortality in the Women's Health Initiative randomized, placebo-controlled clinical trials.<br><br>MATERIALS AND METHODS: Postmenopausal women, age 50-79 years, were entered on two randomized clinical trials evaluating different menopausal hormone therapy regimens. In 16,608 women with a uterus, 8,506 were randomly assigned to once daily 0.625 mg of CEE plus 2.5 mg once daily of MPA and 8,102 placebo. In 10,739 women with previous hysterectomy, 5,310 were randomly assigned to once daily 0.625 mg of CEE-alone and 5,429 placebo. Intervention was stopped for cause before planned 8.5-year intervention after 5.6 years (CEE plus MPA) and after 7.2 years (CEE-alone). Outcomes include incidence and mortality from ovarian and endometrial cancers and deaths after these cancers.<br><br>RESULTS: After 20-year follow-up, CEE-alone, versus placebo, significantly increased ovarian cancer incidence (35 cases [0.041%] v 17 [0.020%]; hazard ratio [HR], 2.04 [95% CI, 1.14 to 3.65]; P = .014) and ovarian cancer mortality (P = .006). By contrast, CEE plus MPA, versus placebo, did not increase ovarian cancer incidence (75 cases [0.051%] v 63 [0.045%]; HR, 1.14 [95% CI, 0.82 to 1.59]; P = .44) or ovarian cancer mortality but did significantly lower endometrial cancer incidence (106 cases [0.073%] v 140 [0.10%]; HR, 0.72 [95% CI, 0.56 to 0.92]; P = .01).<br><br>CONCLUSION: In randomized clinical trials, CEE-alone increased ovarian cancer incidence and ovarian cancer mortality, while CEE plus MPA did not. By contrast, CEE plus MPA significantly reduced endometrial cancer incidence.}, }
@article {pmid39172451, year = {2024}, author = {Onyeaka, HK and Chido-Amajuoyi, OG and Sokale, I and Ajayi, KV and Evins, AE and Amonoo, HL and Shete, S}, title = {Disparities in Exposure to Tobacco on Television or Streaming Platforms.}, journal = {JAMA network open}, volume = {7}, number = {8}, pages = {e2427781}, pmid = {39172451}, issn = {2574-3805}, mesh = {Humans ; Female ; Male ; *Television/statistics &amp; numerical data ; Cross-Sectional Studies ; Adult ; Middle Aged ; *Advertising/statistics &amp; numerical data ; United States/epidemiology ; Tobacco Products/statistics &amp; numerical data ; Adolescent ; Young Adult ; Marketing ; Aged ; Tobacco Industry ; }, abstract = {IMPORTANCE: With the rise in popularity of streaming platforms concerns about exposure to tobacco advertising and promotion have emerged. While tobacco marketing and promotion through traditional television (TV) media channels has been extensively studied, less is known about exposure to tobacco through TV or streaming platforms and its associated factors.<br><br>OBJECTIVE: To examine the prevalence and factors associated with exposure to tobacco products advertised, marketed, or promoted on TV or streaming platforms among US adults.<br><br>This cross-sectional study used data from the National Cancer Institute's Health Information National Trends Survey (HINTS 6), conducted from March 7 to November 8, 2022. The nationally representative survey included noninstitutionalized civilian US adults.<br><br>MAIN OUTCOMES AND MEASURES: The primary outcome was self-reported exposure to tobacco advertisements, marketing, or promotion on TV or streaming platforms in the past 3 months. Factors associated with exposure were explored using multivariable survey logistic regression.<br><br>RESULTS: The study included 5775 participants (3415 females [weighted percentage, 50.5%], 970 Hispanic individuals [weighted percentage, 16.9%], 872 non-Hispanic Black or African American individuals [11.1%], 3144 non-White individuals [61.5%], and 632 individuals who currently smoke [12.0%]). The estimated exposure to tobacco advertisements, marketing, or promotion on television or streaming platforms was 12.4% (95% CI, 10.8%-14.2%). Multivariable logistic regression analysis revealed that exposure odds were higher among those who had a level of education of high school or less (adjusted odds ratio [aOR], 1.60; 95% CI, 1.08-2.37), individuals who currently smoke (aOR, 1.85; 95% CI, 1.06-3.25), non-Hispanic Black or African American respondents (aOR, 2.20; 95% CI, 1.40-3.45) and Hispanic respondents (aOR, 1.58; 95% CI, 1.04-2.42).<br><br>CONCLUSIONS AND RELEVANCE: In this study of the prevalence of exposure to tobacco advertisements on TV or streaming platforms among US adults, disparities in exposure by race or ethnicity, education level, and smoking status were identified. These findings underscore the need for targeted public health interventions and regulation to address these disparities and reduce the impact of tobacco advertisements on vulnerable populations.}, }
@article {pmid39169220, year = {2024}, author = {Wang, JZ and Patil, V and Landry, AP and Gui, C and Ajisebutu, A and Liu, J and Saarela, O and Pugh, SL and Won, M and Patel, Z and Yakubov, R and Kaloti, R and Wilson, C and Cohen-Gadol, A and Zaazoue, MA and Tabatabai, G and Tatagiba, M and Behling, F and Almiron Bonnin, DA and Holland, EC and Kruser, TJ and Barnholtz-Sloan, JS and Sloan, AE and Horbinski, C and Chotai, S and Chambless, LB and Gao, A and Rebchuk, AD and Makarenko, S and Yip, S and Sahm, F and Maas, SLN and Tsang, DS and ,  and Rogers, CL and Aldape, K and Nassiri, F and Zadeh, G}, title = {Molecular classification to refine surgical and radiotherapeutic decision-making in meningioma.}, journal = {Nature medicine}, volume = {30}, number = {11}, pages = {3173-3183}, pmid = {39169220}, issn = {1546-170X}, support = {U10 CA180868/CA/NCI NIH HHS/United States ; HHSN261201500003C/CA/NCI NIH HHS/United States ; U10 CA180822/CA/NCI NIH HHS/United States ; U24 CA196067/CA/NCI NIH HHS/United States ; HHSN261201500003I/CA/NCI NIH HHS/United States ; }, mesh = {*Meningioma/genetics/radiotherapy/pathology/therapy ; Humans ; *Meningeal Neoplasms/radiotherapy/genetics/pathology/therapy ; Female ; Male ; Middle Aged ; Aged ; Retrospective Studies ; Clinical Decision-Making ; Adult ; Progression-Free Survival ; Biomarkers, Tumor/genetics ; Treatment Outcome ; Decision Making ; }, abstract = {Treatment of the tumor and dural margin with surgery and sometimes radiation are cornerstones of therapy for meningioma. Molecular classifications have provided insights into the biology of disease; however, response to treatment remains heterogeneous. In this study, we used retrospective data on 2,824 meningiomas, including molecular data on 1,686 tumors and 100 prospective meningiomas, from the RTOG-0539 phase 2 trial to define molecular biomarkers of treatment response. Using propensity score matching, we found that gross tumor resection was associated with longer progression-free survival (PFS) across all molecular groups and longer overall survival in proliferative meningiomas. Dural margin treatment (Simpson grade 1/2) prolonged PFS compared to no treatment (Simpson grade 3). Molecular group classification predicted response to radiotherapy, including in the RTOG-0539 cohort. We subsequently developed a molecular model to predict response to radiotherapy that discriminates outcome better than standard-of-care classification. This study highlights the potential for molecular profiling to refine surgical and radiotherapy decision-making.}, }
@article {pmid39169114, year = {2024}, author = {Rodríguez-Arbolí, E and Othus, M and Freeman, SD and Buccisano, F and Ngai, LL and Thomas, I and Palmieri, R and Cloos, J and Johnson, S and Meddi, E and Russell, NH and Venditti, A and Gradowska, P and Ossenkoppele, GJ and Löwenberg, B and Walter, RB}, title = {Optimal prognostic threshold for measurable residual disease positivity by multiparameter flow cytometry in acute myeloid leukemia (AML).}, journal = {Leukemia}, volume = {38}, number = {10}, pages = {2266-2269}, pmid = {39169114}, issn = {1476-5551}, support = {P30-CA015704//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P01-CA018029//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P01-CA078902//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P01 CA078902/CA/NCI NIH HHS/United States ; P01 CA018029/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Neoplasm, Residual/diagnosis ; *Leukemia, Myeloid, Acute/pathology/diagnosis/mortality ; *Flow Cytometry/methods ; Prognosis ; Middle Aged ; Male ; Female ; Aged ; Adult ; }, }
@article {pmid39167805, year = {2024}, author = {Carpenter, PA and Gooley, TA and Boiko, J and Lee, CJ and Burroughs, LM and Mehta, R and Salit, RB and Bhatt, NS and Krakow, E and Dahlberg, AE and Yeh, AC and Summers, CN and Ueda Oshima, M and Petersdorf, EW and Vo, P and Connelly-Smith, L and Lee, SJ}, title = {Decreasing chronic graft-versus-host disease rates in all populations.}, journal = {Blood advances}, volume = {8}, number = {22}, pages = {5829-5837}, pmid = {39167805}, issn = {2473-9537}, support = {KL2 TR002317/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Graft vs Host Disease/etiology/prevention &amp; control/epidemiology ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Female ; Male ; Adult ; Child ; Adolescent ; Chronic Disease ; Middle Aged ; Child, Preschool ; Young Adult ; Aged ; Infant ; }, abstract = {Since 2005, there has been a steady decline in chronic graft-versus-host disease (cGVHD) at the Fred Hutchinson Cancer Center. To better understand this phenomenon, we studied the risk of cGVHD requiring systemic immunosuppression (cGVHD-IS) as a function of hematopoietic cell transplantation (HCT) date in 3066 survivors from 2005 through 2019. Cox regression models were fit to assess associations of HCT date (as a continuous linear variable) with cause-specific hazards of cGVHD using unadjusted and adjusted models. Median follow-up for study subjects was 7.0 years (range, 1.0-17.2). Two-year probabilities of cGVHD-IS declined among all survivors from 45% to 52% (2005-2007) to ∼40% (2008-2012) and then further to ∼26% by 2017. A decline was also observed when the analysis was restricted to 502 pediatric survivors, with cGVHD-IS probabilities <10% since 2013. Among 305 adult and pediatric survivors who underwent transplantation for nonmalignant diseases, cGVHD rates showed greater fluctuation but remained <20% after 2016. Each 5-year increase in HCT date was associated with a 27% decrease in the cause-specific hazard of cGVHD (unadjusted hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.68-0.78; P < .0001); the HR was 0.81 (95% CI, 0.75-0.87; P < .0001) even after adjusting for various factors (age, donor/stem-cell source, race, sex, conditioning intensity, GVHD prophylaxis, among others) that could lead to cGVHD reduction. The decline in cGVHD was not fully explained by demographic shifts and greater use of HCT approaches that are generally associated with lower cGVHD rates. This observation underscores that single-cohort cGVHD prevention studies should use contemporaneous and not historical controls for comparison.}, }
@article {pmid39167766, year = {2024}, author = {Hamilton, BK and Pandya, BJ and Ivanescu, C and Elsouda, D and Hamadani, M and Chen, YB and Levis, MJ and Ueda Oshima, M and Litzow, MR and Soiffer, RJ and Ustun, C and Perl, AE and Singh, AK and Geller, N and Hasabou, N and Rosales, M and Cella, D and Corredoira, L and Pestana, C and Horowitz, MM and Logan, B}, title = {Health-related quality of life with gilteritinib vs placebo posttransplant for FLT3-ITD+ acute myeloid leukemia.}, journal = {Blood advances}, volume = {8}, number = {19}, pages = {5091-5099}, pmid = {39167766}, issn = {2473-9537}, support = {U24 CA076518/CA/NCI NIH HHS/United States ; U10 HL069294/HL/NHLBI NIH HHS/United States ; U24 HL138660/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Quality of Life ; *Leukemia, Myeloid, Acute/drug therapy/therapy ; *fms-Like Tyrosine Kinase 3/genetics ; Middle Aged ; *Pyrazines/therapeutic use ; Female ; Male ; *Aniline Compounds/therapeutic use ; *Hematopoietic Stem Cell Transplantation/methods ; Adult ; Aged ; }, abstract = {The Blood and Marrow Transplant (BMT) Clinical Trials Network conducted a phase 3 randomized trial comparing gilteritinib with placebo after allogeneic hematopoietic cell transplantation (HCT) for FLT3-ITD+ acute myeloid leukemia (AML). The primary analysis demonstrated no statistically significant difference in relapse-free survival (RFS); however, patients with FLT3-ITD measurable residual disease (MRD) peri-HCT had significantly longer RFS with gilteritinib. This analysis investigates the effect of post-HCT gilteritinib vs placebo on health-related quality of life (HRQOL). HRQOL was measured with Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), FACT-Leukemia (FACT-Leu), and EuroQOL-5 Dimensions (EQ-5D-5L) at post-HCT randomization; day 29; months 3, 6, 12, 18, 24; and/or end of therapy. HRQOL and clinically meaningful differences were summarized using descriptive statistics and compared using mixed model repeated measures to evaluate longitudinal change from baseline and stratified Cox model to evaluate time to improvement. HRQOL completion rate was acceptable (>70%) across all time points and measures. There were no differences in HRQOL scores at any time point between cohorts. Clinically meaningful and time to improvement in HRQOL were similar in both arms. Despite higher treatment-emergent adverse effects with gilteritinib, response to the question of being "bothered by side effects of treatment" did not differ between groups. Subgroup analysis of MRD-positive and negative patients demonstrated no differences in HRQOL between arms. For patients with FLT3-ITD+ AML undergoing HCT, gilteritinib maintenance was not associated with any difference in HRQOL or patient-reported impact of side effects. This trial was registered at www.ClinicalTrials.gov as #NCT02997202.}, }
@article {pmid39167765, year = {2024}, author = {Mehta, RS and Ramdial, J and Kebriaei, P and Champlin, RE and Popat, U and Rezvani, K and Shpall, EJ}, title = {Haploidentical vs HLA-matched sibling donor HCT with PTCy prophylaxis: HLA factors and donor age considerations.}, journal = {Blood advances}, volume = {8}, number = {20}, pages = {5306-5314}, pmid = {39167765}, issn = {2473-9537}, support = {U24 CA076518/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/methods ; Middle Aged ; Female ; Adult ; *Siblings ; Male ; *Tissue Donors ; Age Factors ; *Cyclophosphamide/therapeutic use ; HLA Antigens/immunology ; Graft vs Host Disease/prevention &amp; control/etiology ; Histocompatibility Testing ; Aged ; Transplantation, Haploidentical/methods ; Adolescent ; Young Adult ; Transplantation Conditioning/methods ; }, abstract = {HLA-matched sibling donors (MSDs) are preferred for hematopoietic cell transplantation (HCT). However, the use of alternative donors, especially haploidentical, is increasing, as is our understanding of the impact of HLA factors such as B-leader and DRB1-matching on its outcomes. Yet, data comparing these donor types, particularly considering these HLA factors, is lacking. Herein, we compared haploidentical-HCT (n = 1052) with MSD-HCT (n = 400), both with posttransplant cyclophosphamide (PTCy)-based graft-versus-host disease prophylaxis. In multivariate analysis, haploidentical group had similar overall survival (OS; hazard ratio (HR), 0.94; 95% confidence interval [CI], 0.78-1.14; P = .54), nonrelapse mortality (HR, 0.98; 95% CI, 0.72-1.32; P = .87), and relapse (HR, 0.87; 95% CI, 0.70-1.08; P = .20) as the MSD group. Younger donor age was a significant predictor of improved OS. Next, we directly compared the outcomes of "younger" haploidentical (donor age <35 years, n = 347) vs an "older" MSD (donor age ≥50 years, n = 143) in older recipients (patient age ≥50 years). Patients with younger haploidentical B-leader-matched donors had significantly superior OS (HR, 0.65; 95% CI, 0.48-0.90; P = .009) than the older MSD group. Additionally, patients with younger DRB1-mismatched haploidentical donors (HR, 0.63; 95% CI, 0.46-0.87; P = .004) had significantly lower risk of relapse than older MSDs. Our study suggests that haploidentical-HCT may offer comparable outcomes to MSD-PTCy HCT. Moreover, among older patients, a younger haploidentical B-leader-matched donor might be preferable to an older MSD. These findings need validation in larger data sets.}, }
@article {pmid39164488, year = {2024}, author = {Hamazaki, N and Yang, W and Kubo, CA and Qiu, C and Martin, BK and Garge, RK and Regalado, SG and Nichols, EK and Pendyala, S and Bradley, N and Fowler, DM and Lee, C and Daza, RM and Srivatsan, S and Shendure, J}, title = {Retinoic acid induces human gastruloids with posterior embryo-like structures.}, journal = {Nature cell biology}, volume = {26}, number = {10}, pages = {1790-1803}, pmid = {39164488}, issn = {1476-4679}, support = {R01 HG010632/HG/NHGRI NIH HHS/United States ; UM1 HG011586/HG/NHGRI NIH HHS/United States ; UM1HG011586//U.S. Department of Health &amp; Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; }, mesh = {Humans ; *Tretinoin/pharmacology/metabolism ; Animals ; *Neural Crest/metabolism/drug effects/embryology ; Mice ; *T-Box Domain Proteins/metabolism/genetics ; *Somites/metabolism/embryology/drug effects ; *PAX3 Transcription Factor/metabolism/genetics ; Gene Expression Regulation, Developmental/drug effects ; Gastrula/metabolism/drug effects ; Embryonic Development/drug effects ; Macaca fascicularis/embryology ; Neural Tube/metabolism/embryology/drug effects ; Embryo, Mammalian/metabolism/drug effects ; Wnt Signaling Pathway/drug effects ; Mesoderm/metabolism/drug effects/embryology ; Signal Transduction/drug effects ; }, abstract = {Gastruloids are a powerful in vitro model of early human development. However, although elongated and composed of all three germ layers, human gastruloids do not morphologically resemble post-implantation human embryos. Here we show that an early pulse of retinoic acid (RA), together with later Matrigel, robustly induces human gastruloids with posterior embryo-like morphological structures, including a neural tube flanked by segmented somites and diverse cell types, including neural crest, neural progenitors, renal progenitors and myocytes. Through in silico staging based on single-cell RNA sequencing, we find that human RA-gastruloids progress further than other human or mouse embryo models, aligning to E9.5 mouse and CS11 cynomolgus monkey embryos. We leverage chemical and genetic perturbations of RA-gastruloids to confirm that WNT and BMP signalling regulate somite formation and neural tube length in the human context, while transcription factors TBX6 and PAX3 underpin presomitic mesoderm and neural crest, respectively. Looking forward, RA-gastruloids are a robust, scalable model for decoding early human embryogenesis.}, }
@article {pmid39164407, year = {2024}, author = {Gambacorti-Passerini, C and Brümmendorf, TH and Abruzzese, E and Kelly, KR and Oehler, VG and García-Gutiérrez, V and Hjorth-Hansen, H and Ernst, T and Leip, E and Purcell, S and Luscan, G and Viqueira, A and Giles, FJ and Hochhaus, A}, title = {Efficacy and safety of bosutinib in previously treated patients with chronic myeloid leukemia: final results from the BYOND trial.}, journal = {Leukemia}, volume = {38}, number = {10}, pages = {2162-2170}, pmid = {39164407}, issn = {1476-5551}, mesh = {Humans ; *Aniline Compounds/therapeutic use/adverse effects/administration &amp; dosage ; *Nitriles/adverse effects/therapeutic use/administration &amp; dosage ; *Quinolines/therapeutic use/adverse effects/administration &amp; dosage ; *Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy/mortality ; Middle Aged ; Female ; Male ; Aged ; Adult ; *Protein Kinase Inhibitors/therapeutic use/adverse effects ; Aged, 80 and over ; Treatment Outcome ; Young Adult ; Follow-Up Studies ; Drug Resistance, Neoplasm/drug effects ; }, abstract = {This final analysis from the phase 4 BYOND trial reports outcomes with bosutinib in patients with previously treated chronic myeloid leukemia (CML); 163 patients with CML resistant/intolerant to previous tyrosine kinase inhibitors received bosutinib (starting dose: 500 mg QD). At study completion (median follow-up, 47.8 months), 48.1% (n = 75/156) of patients with Philadelphia chromosome-positive chronic phase CML were still receiving treatment. Among evaluable patients, 71.8% (95% CI, 63.9-78.9) and 59.7% (95% CI, 51.4-67.7) attained or maintained major molecular response (MMR) and molecular response (MR)[4], respectively, at any time on treatment. The majority of patients achieved a deeper molecular response relative to baseline while on bosutinib. Kaplan-Meier probabilities (95% CI) of maintaining MMR and MR[4] at 36 months were 87.2% (78.0-92.7) and 80.7% (69.4-88.1), respectively. At 48 months, the Kaplan-Meier overall survival rate was 88.3% (95% CI, 81.8-92.6); there were 17 deaths, including 2 that were considered CML related. Long-term adverse events (AEs) were consistent with the known safety profile of bosutinib, and no new safety issues were identified. The management of AEs through dose reduction maintained efficacy while improving tolerability. These results support the use of bosutinib in patients with previously treated CML.ClinicalTrials.gov, NCT02228382.}, }
@article {pmid39163750, year = {2024}, author = {Suzuki, Y and Chen, L and Matsuo, K and Ferris, JS and Elkin, EB and Melamed, A and Kong, CY and Bickell, N and Myers, ER and Havrilesky, LJ and Xu, X and Blank, SV and Hazelton, WD and Hershman, DL and Wright, JD}, title = {Weight-loss therapy in patients with obesity with endometrial intraepithelial neoplasia and uterine cancer.}, journal = {Gynecologic oncology}, volume = {190}, number = {}, pages = {78-83}, pmid = {39163750}, issn = {1095-6859}, support = {U01 CA265739/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; Middle Aged ; *Obesity/complications/epidemiology/therapy ; Adult ; *Uterine Neoplasms/therapy/epidemiology ; Aged ; *Endometrial Neoplasms/therapy ; Young Adult ; Adolescent ; Weight Loss ; Carcinoma in Situ/therapy ; }, abstract = {OBJECTIVE: Although obesity is an important risk factor for endometrial intraepithelial neoplasia (EIN) and uterine cancer, little is known about the trends in use of weight-loss therapy for patients with obesity with EIN and uterine cancer. We examined the use of weight-loss therapy among patients with obesity with EIN and uterine cancer.<br><br>METHODS: The Merative MarketScan Database was used to identify patients aged 18-70&#xa0;years who were obese and diagnosed with EIN or uterine cancer. The primary treatment for EIN or uterine cancer was categorized as either primary hysterectomy or hormonal therapy. Nutrition counseling, bariatric surgeries, and weight-management medications were identified as weight-loss therapy. We analyzed trends in the use of any weight-loss therapies with Cochran-Armitage tests. A multivariable logistic regression model was developed to examine factors associated with weight-loss therapy use.<br><br>RESULTS: Overall, 15,374 patients were identified, including 5561 (36.2%) patients with EIN and obesity, and 9813 (63.8%) patients with uterine cancer and obesity. Weight-loss therapy was utilized within 1&#xa0;year after diagnosis in 480 (8.6%) patients with EIN and in 802 (8.2%) patients with uterine cancer. Use of any weight-loss therapy after diagnosis of EIN increased from 4.1% in 2009 to 12.6% in 2020 (P&#xa0;<&#xa0;.001), and the use of any weight-loss therapy after diagnosis of uterine cancer increased from 4.9% in 2009 to 11.4% in 2020 (P&#xa0;<&#xa0;.001). In a multivariable regression model, younger age and patients with high comorbidity score were associated with a higher likelihood of using any weight-loss therapy.<br><br>CONCLUSIONS: Use of weight-loss therapy has increased, however there is still a significant underuse of this adjunctive therapy in patients with obesity with EIN or uterine cancer.}, }
@article {pmid39163616, year = {2024}, author = {Sharifi, H and Bertini, CD and Alkhunaizi, M and Hernandez, M and Musa, Z and Borges, C and Turk, I and Bashoura, L and Dickey, BF and Cheng, GS and Yanik, G and Galban, CJ and Guo, HH and Godoy, MCB and Reinhardt, JM and Hoffman, EA and Castro, M and Rondon, G and Alousi, AM and Champlin, RE and Shpall, EJ and Lu, Y and Peterson, S and Datta, K and Nicolls, MR and Hsu, J and Sheshadri, A}, title = {CT strain metrics allow for earlier diagnosis of bronchiolitis obliterans syndrome after hematopoietic cell transplant.}, journal = {Blood advances}, volume = {8}, number = {19}, pages = {5156-5165}, pmid = {39163616}, issn = {2473-9537}, support = {R01 HL161037/HL/NHLBI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 HL162661/HL/NHLBI NIH HHS/United States ; R01 HL157414/HL/NHLBI NIH HHS/United States ; K23 AI117024/AI/NIAID NIH HHS/United States ; }, mesh = {*Bronchiolitis Obliterans/etiology/diagnosis ; Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Male ; Female ; Middle Aged ; *Tomography, X-Ray Computed ; Adult ; Respiratory Function Tests ; Early Diagnosis ; Aged ; Bronchiolitis Obliterans Syndrome ; }, abstract = {Bronchiolitis obliterans syndrome (BOS) after hematopoietic cell transplantation (HCT) is associated with substantial morbidity and mortality. Quantitative computed tomography (qCT) can help diagnose advanced BOS meeting National Institutes of Health (NIH) criteria (NIH-BOS) but has not been used to diagnose early, often asymptomatic BOS (early BOS), limiting the potential for early intervention and improved outcomes. Using pulmonary function tests (PFTs) to define NIH-BOS, early BOS, and mixed BOS (NIH-BOS with restrictive lung disease) in patients from 2 large cancer centers, we applied qCT to identify early BOS and distinguish between types of BOS. Patients with transient impairment or healthy lungs were included for comparison. PFTs were done at month 0, 6, and 12. Analysis was performed with association statistics, principal component analysis, conditional inference trees (CITs), and machine learning (ML) classifier models. Our cohort included 84 allogeneic HCT recipients, 66 with BOS (NIH-defined, early, or mixed) and 18 without BOS. All qCT metrics had moderate correlation with forced expiratory volume in 1 second, and each qCT metric differentiated BOS from those without BOS (non-BOS; P < .0001). CITs distinguished 94% of participants with BOS vs non-BOS, 85% of early BOS vs non-BOS, 92% of early BOS vs NIH-BOS. ML models diagnosed BOS with area under the curve (AUC) of 0.84 (95% confidence interval [CI], 0.74-0.94) and early BOS with AUC of 0.84 (95% CI, 0.69-0.97). qCT metrics can identify individuals with early BOS, paving the way for closer monitoring and earlier treatment in this vulnerable population.}, }
@article {pmid39163531, year = {2024}, author = {Hatashima, A and Shadman, M}, title = {BTK inhibitors: moving the needle on the treatment of chronic lymphocytic leukemia.}, journal = {Expert review of hematology}, volume = {17}, number = {10}, pages = {687-703}, doi = {10.1080/17474086.2024.2391097}, pmid = {39163531}, issn = {1747-4094}, mesh = {Humans ; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; *Agammaglobulinaemia Tyrosine Kinase/antagonists &amp; inhibitors ; *Protein Kinase Inhibitors/therapeutic use/adverse effects ; *Piperidines/therapeutic use ; *Adenine/analogs &amp; derivatives/therapeutic use ; *Pyrazoles/therapeutic use/adverse effects ; *Pyrimidines/therapeutic use ; Mutation ; Treatment Outcome ; Antineoplastic Agents/therapeutic use/adverse effects ; Benzamides ; Pyrazines ; }, abstract = {INTRODUCTION: Bruton's tyrosine kinaseinhibitors (BTKis) changed the trajectory of upfront and relapsed/refractory chronic lymphocytic leukemia (CLL) treatment. However, BTKis are plagued by a spectrum of toxicities. Zanubrutinib was developed to circumvent challenges with prolonged tolerability by increasing BTK selectivity and maximizing efficacy through pharmacokinetic/pharmacodynamic optimization. However, with the availability of ibrutinib, acalabrutinib, and zanubrutinib, limited data exists to guide sequencing of BTKi therapy in the relapsed/refractory setting.<br><br>AREAS COVERED: We review the first head-to-head trial (ALPINE) of zanubrutinib versus ibrutinib for the treatment of relapsed/refractory CLL and compare zanubrutinib's clinical efficacy and toxicities, including in patients with del(17p) and/or TP53 mutations to ibrutinib and acalabrutinib.<br><br>EXPERT OPINION: Zanubrutinibrepresents one of the new standards of care for relapsed/refractory CLL based on superior progression-free survival and response rates over ibrutinib. Whilezanubrutinib is associated with fewer cardiac toxicities, similar rates of neutropenia and hypertension are noted. Ongoing studies are pushing the envelope, utilizing targeted drug combinations and minimal residual disease markers as well as receptor tyrosine kinase-like orphan receptor 1 inhibitors, chimeric antigen receptor T-cells, and novel BTK degraders. However, zanubrutinibrepresents a strong contender in the arsenal of treatment options for relapsed/refractory CLL.}, }
@article {pmid39161959, year = {2024}, author = {Riley, AK and Grant, M and Snell, A and Cromwell, E and Vichas, A and Moorthi, S and Rominger, C and Modukuri, SP and Urisman, A and Castel, P and Wan, L and Berger, AH}, title = {The deubiquitinase USP9X regulates RIT1 protein abundance and oncogenic phenotypes.}, journal = {iScience}, volume = {27}, number = {8}, pages = {110499}, pmid = {39161959}, issn = {2589-0042}, support = {F31 CA271637/CA/NCI NIH HHS/United States ; R01 CA279171/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R00 CA197762/CA/NCI NIH HHS/United States ; R01 CA262556/CA/NCI NIH HHS/United States ; R37 CA252050/CA/NCI NIH HHS/United States ; R01 CA255398/CA/NCI NIH HHS/United States ; }, abstract = {RIT1 is a rare and understudied oncogene in lung cancer. Despite structural similarity to other RAS GTPase proteins such as KRAS, oncogenic RIT1 activity does not appear to be tightly regulated by nucleotide exchange or hydrolysis. Instead, there is a growing understanding that the protein abundance of RIT1 is important for its regulation and function. We previously identified the deubiquitinase USP9X as a RIT1 dependency in RIT1-mutant cells. Here, we demonstrate that both wild-type and mutant forms of RIT1 are substrates of USP9X. Depletion of USP9X leads to decreased RIT1 protein stability and abundance and resensitizes cells to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in vitro and in vivo. Our work expands upon the current understanding of RIT1 protein regulation and presents USP9X as a key regulator of RIT1-driven oncogenic phenotypes.}, }
@article {pmid39159422, year = {2024}, author = {García-Albéniz, X and Hsu, J and Etzioni, R and Chan, JM and Shi, J and Dickerman, B and Hernán, MA}, title = {Prostate-Specific Antigen Screening and Prostate Cancer Mortality: An Emulation of Target Trials in US Medicare.}, journal = {JCO clinical cancer informatics}, volume = {8}, number = {}, pages = {e2400094}, pmid = {39159422}, issn = {2473-4276}, support = {P01 CA134294/CA/NCI NIH HHS/United States ; R00 CA248335/CA/NCI NIH HHS/United States ; R01 CA164023/CA/NCI NIH HHS/United States ; R01 HS023128/HS/AHRQ HHS/United States ; }, mesh = {Humans ; Male ; Aged ; *Prostate-Specific Antigen/blood ; United States/epidemiology ; *Prostatic Neoplasms/mortality/diagnosis ; *Medicare ; Aged, 80 and over ; *Early Detection of Cancer/methods ; Mass Screening/methods ; Incidence ; }, abstract = {PURPOSE: No consensus about the effectiveness of prostate-specific antigen (PSA) screening exists among clinical guidelines, especially for the elderly. Randomized trials of PSA screening have yielded different results, partly because of variations in adherence, and it is unlikely that new trials will be conducted. Our objective was to estimate the effect of annual PSA screening on prostate cancer (PC) mortality in Medicare beneficiaries age 67-84 years.<br><br>METHODS: This is a large-scale, population-based, observational study of two screening strategies: annual PSA screening and no screening. We used data from 537,599 US Medicare (2001-2008) beneficiaries age 67-84 years who had a good life expectancy, no previous PC, and no PSA test in the 2 years before baseline. We estimated the 8-year PC mortality and incidence, treatments for PC, and treatment complications of PSA screening.<br><br>RESULTS: In men age 67-74 years, the estimated difference in 8-year risk of PC death between PSA screening and no screening was -2.3 (95% CI, -4.1 to -1.1) deaths per 1,000 men (a negative risk difference favors screening). Treatment complications were more frequent under PSA screening than under no screening. In men age 75-84 years, risk difference estimates were closer to zero.<br><br>CONCLUSION: Our estimates suggest that under conventional statistical criteria, annual PSA screening for 8 years is highly compatible with reductions of PC mortality from four to one fewer PC deaths per 1,000 screened men age 67-74 years. As with any study using real-world data, the estimates could be affected by residual confounding.}, }
@article {pmid39158801, year = {2024}, author = {Husnik, MJ and Heffron, R and Hughes, JP and Richardson, B and van der Straten, A and Palanee-Phillips, T and Soto-Torres, L and Singh, D and Mirembe, BG and Livant, E and Gaffoor, Z and Mansoor, LE and Siva, SS and Dadabhai, S and Kiweewa, FM and Baeten, JM and , }, title = {Efficacy of the Dapivirine Vaginal Ring Accounting for Imperfect Adherence.}, journal = {AIDS and behavior}, volume = {28}, number = {11}, pages = {3873-3882}, pmid = {39158801}, issn = {1573-3254}, support = {UM1AI106707//Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases/ ; UM1 AI068633/AI/NIAID NIH HHS/United States ; UM1AI068633//Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases/ ; UM1 AI068615/AI/NIAID NIH HHS/United States ; UM1 AI106707/AI/NIAID NIH HHS/United States ; UM1 AI069518/AI/NIAID NIH HHS/United States ; UM1AI068615//Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases/ ; }, mesh = {Humans ; Female ; *HIV Infections/prevention &amp; control/drug therapy ; *Pyrimidines/administration &amp; dosage ; *Contraceptive Devices, Female/statistics &amp; numerical data ; *Anti-HIV Agents/administration &amp; dosage/therapeutic use ; *HIV-1/drug effects ; Adult ; Medication Adherence/statistics &amp; numerical data ; Pre-Exposure Prophylaxis ; Treatment Outcome ; Intention to Treat Analysis ; }, abstract = {Product adherence is critical to obtaining objective estimates of efficacy of pre-exposure prophylactic interventions against HIV-1 infection. With imperfect adherence, intention-to-treat analyses assess the collective effects of complete, sub-optimal and non-adherence, providing a biased and attenuated estimate of the average causal effect of an intervention. Using data from the MTN-020/ASPIRE phase III trial evaluating HIV-1 efficacy of the dapivirine vaginal ring, we conducted per-protocol, and adherence-adjusted causal inference analyses using principal stratification and marginal structural models. We constructed two adherence cut offs of ≥ 0.9 mg (low cutoff) and > 4.0 mg (high cutoff) that represent drug released from the ring over a 28-day period. The HIV-1 efficacy estimate (95% CI) was 30.8% (3.6%, 50.3%) (P = 0.03) from the per-protocol analysis, and 53.6% (16.5%, 74.3%) (P = 0.01) among the highest predicted adherers from principal stratification analyses using the low cutoff. Marginal structural models produced efficacy estimates (95% CIs) ranging from 48.8 (21.8, 66.4) (P = 0.0019) to 56.5% (32.8%, 71.9%) (P = 0.0002). Application of adherence-adjusted causal inference methods are useful in interpreting HIV-1 efficacy in secondary analyses of PrEP clinical trials.}, }
@article {pmid39158464, year = {2024}, author = {Mukand, NH and Chirikova, E and Lichtensztajn, D and Negoita, S and Aboushwareb, T and Bennett, J and Brooks, JD and Leppert, JT and Chung, BI and Li, C and Schwartz, SM and Gershman, ST and Insaf, T and Morawski, BM and Stroup, A and Wu, XC and Doherty, JA and Petkov, VI and Zambon, JP and Gomez, SL and Cheng, I}, title = {Assessing sociodemographic and regional disparities in Oncotype DX Genomic Prostate Score uptake.}, journal = {Cancer}, volume = {130}, number = {24}, pages = {4298-4305}, doi = {10.1002/cncr.35511}, pmid = {39158464}, issn = {1097-0142}, support = {HHSN261201800032I/CA/NCI NIH HHS/United States ; 5NU58DP006344//Centers for Disease Control and Prevention's National Program of Cancer Registries/ ; HHSN261201800015I/CA/NCI NIH HHS/United States ; HHSN261201800009I/CA/NCI NIH HHS/United States ; T32AG049663//National Institute on Aging of the National Institutes of Health/ ; T32MD015070/MD/NIMHD NIH HHS/United States ; HHSN261201800032I/CA/NCI NIH HHS/United States ; HHSN261201800015I/CA/NCI NIH HHS/United States ; HHSN261201800009I/CA/NCI NIH HHS/United States ; T32MD015070/MD/NIMHD NIH HHS/United States ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms/genetics/diagnosis/pathology/epidemiology ; Aged ; Middle Aged ; SEER Program ; Neoplasm Grading ; Healthcare Disparities/statistics &amp; numerical data ; Socioeconomic Factors ; Genomics/methods ; United States/epidemiology ; Sociodemographic Factors ; Social Class ; }, abstract = {BACKGROUND: The Oncotype DX Genomic Prostate Score (ODX-GPS) is a gene expression assay that predicts disease aggressiveness. The objective of this study was to identify sociodemographic and regional factors associated with ODX-GPS uptake.<br><br>METHODS: Data from Surveillance Epidemiology and End Results registries on men with localized prostate cancer with a Gleason score of 3&#xa0;+&#xa0;3 or 3&#xa0;+&#xa0;4, PSA &#x2264;20 ng/mL, and stage T1c to T2c disease from 2013 through 2017 were linked with ODX-GPS data. Census-tract level neighborhood socioeconomic status (nSES) quintiles were constructed using a composite socioeconomic score. Multivariable logistic regression was used to estimate the associations of ODX-GPS uptake with age at diagnosis, race and ethnicity, nSES, geographic region, insurance type, and marital status, accounting for National Comprehensive Cancer Network risk group, year of diagnosis, and clustering by census tract.<br><br>RESULTS: Among 111,434 eligible men, 5.5% had ODX-GPS test uptake. Of these, 78.3% were non-Hispanic White, 9.6% were Black, 6.7% were Hispanic, and 3.6% were Asian American. Black men had the lowest odds of ODX-GPS uptake (odds ratio, 0.70; 95% confidence interval [CI], 0.63-0.76). Those in the highest versus lowest quintile of nSES were 1.64 times more likely (95% CI, 1.38-2.94) to have ODX-GPS uptake. The odds of ODX-GPS uptake were statistically significantly higher among men residing in the Northeast, West, and Midwest compared to the South.<br><br>CONCLUSIONS: Disparities in ODX-GPS uptake by race, ethnicity, nSES, and geographical region were identified. Concerted efforts should be made to ensure that this clinical test is equitably available.}, }
@article {pmid39158404, year = {2024}, author = {Liss, MA and Zeltser, N and Zheng, Y and Lopez, C and Liu, M and Patel, Y and Yamaguchi, TN and Eng, SE and Tian, M and Semmes, OJ and Lin, DW and Brooks, JD and Wei, JT and Klein, EA and Tewari, AK and Mosquera, JM and Khani, F and Robinson, BD and Aasad, M and Troyer, DA and Kagan, J and Sanda, MG and Thompson, IM and Boutros, PC and Leach, RJ}, title = {Upgrading of Grade Group 1 Prostate Cancer at Prostatectomy: Germline Risk Factors in a Prospective Cohort.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {33}, number = {11}, pages = {1500-1511}, pmid = {39158404}, issn = {1538-7755}, support = {W81XWH-22-1-0247//U.S. Department of Defense (DOD)/ ; T32HG002536//National Human Genome Research Institute (NHGRI)/ ; U2C CA271894/CA/NCI NIH HHS/United States ; P30 CA016042/CA/NCI NIH HHS/United States ; W81XWH-15-1-0441//U.S. Department of Defense (DOD)/ ; P30CA016042//National Cancer Institute (NCI)/ ; U01 CA214194/CA/NCI NIH HHS/United States ; T32 HG002536/HG/NHGRI NIH HHS/United States ; U01 CA086402/CA/NCI NIH HHS/United States ; R01CA270108//National Cancer Institute (NCI)/ ; U01CA086402//National Cancer Institute (NCI)/ ; U24CA086368//National Cancer Institute (NCI)/ ; U24 CA086368/CA/NCI NIH HHS/United States ; U01CA113913//National Cancer Institute (NCI)/ ; U01 CA113913/CA/NCI NIH HHS/United States ; R01 CA270108/CA/NCI NIH HHS/United States ; P50CA211024//National Cancer Institute (NCI)/ ; U2CCA271894//National Cancer Institute (NCI)/ ; P50 CA211024/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms/genetics/surgery/pathology ; *Prostatectomy/methods ; Prospective Studies ; *Neoplasm Grading ; Middle Aged ; Risk Factors ; Aged ; Germ-Line Mutation ; }, abstract = {BACKGROUND: Localized prostate tumors show significant spatial heterogeneity, with regions of high-grade disease adjacent to lower grade disease. Consequently, prostate cancer biopsies are prone to sampling bias, potentially leading to underestimation of tumor grade. To study the clinical, epidemiologic, and molecular hallmarks of this phenomenon, we conducted a prospective study of grade upgrading: differences in detected prostate cancer grade between biopsy and surgery.<br><br>METHODS: We established a prospective, multi-institutional cohort of men with grade group 1 (GG1) prostate cancer on biopsy who underwent radical prostatectomy. Upgrading was defined as detection of GG2+ in the resected tumor. Germline DNA from 192 subjects was subjected to whole-genome sequencing to quantify ancestry, pathogenic variants in DNA damage response genes, and polygenic risk.<br><br>RESULTS: Of 285 men, 67% upgraded at surgery. PSA density and percent of cancer in pre-prostatectomy positive biopsy cores were significantly associated with upgrading. No assessed genetic risk factor was predictive of upgrading, including polygenic risk scores for prostate cancer diagnosis.<br><br>CONCLUSIONS: In a cohort of patients with low-grade prostate cancer, a majority upgraded at radical prostatectomy. PSA density and percent of cancer in pre-prostatectomy positive biopsy cores portended the presence of higher-grade disease, while germline genetics was not informative in this setting. Patients with low-risk prostate cancer, but elevated PSA density or percent cancer in positive biopsy cores, may benefit from repeat biopsy, additional imaging or other approaches to complement active surveillance.<br><br>IMPACT: Further risk stratification of patients with low-risk prostate cancer may provide useful context for active surveillance decision-making.}, }
@article {pmid39158354, year = {2024}, author = {Triplette, M and Giustini, N and Anderson, N and Go, T and Scout, NFN and Heffner, JL}, title = {A Multistakeholder Qualitative Study to Inform Sexual Orientation and Gender Identity Data Collection in the Cancer Care Setting.}, journal = {LGBT health}, volume = {}, number = {}, pages = {}, doi = {10.1089/lgbt.2024.0065}, pmid = {39158354}, issn = {2325-8306}, abstract = {Purpose: Sexual and gender minoritized (SGM) populations face health disparities along the cancer care continuum, although attempts to define these disparities are limited by a lack of comprehensive sexual orientation and gender identity (SOGI) data collection. The objective of this study was to interview a diverse group of stakeholders to understand attitudes, barriers, and facilitators to inform data collection approaches in a cancer care setting. Methods: This was a qualitative study conducted from March to July 2023 with paired surveys of stakeholders including patients, caregivers, providers, and cancer registry staff. Twenty participants across these categories, including half who identified as SGM, completed surveys and interviews. Qualitative data were reduced to themes with exemplar quotations using rapid qualitative analysis methods and compared to survey data. Results: Themes revealed general support for SOGI data collection as part of holistic cancer care, and all participants acknowledged that specific SOGI-related information, particularly correct pronoun usage, was essential to inform patient-centered care. Themes revealed tensions around optimal SOGI data collection methods, mixed opinions on the relevance of sexual orientation, experiences of discrimination and discomfort related to SOGI, and limited acknowledgment of population benefits of SOGI data collection. Conclusion: Themes demonstrated overall support for SOGI data collection but also revealed several barriers, such as a lack of recognition of population benefits and experiences of discrimination and discomfort, that will need to be addressed to comprehensively collect these data. Based on diverse preferences and limitations of all methods of collection, a multimodal approach may be needed to optimize completion.}, }
@article {pmid39158218, year = {2024}, author = {Garderet, L and Gras, L and Koster, L and Baaij, L and Hamad, N and Dsouza, A and Estrada-Merly, N and Hari, P and Saber, W and Cowan, AJ and Iida, M and Okamoto, S and Takamatsu, H and Mizuno, S and Kawamura, K and Kodera, Y and Ko, BS and Liam, C and Ho, KW and Goh, AS and Tan, SK and Elhaddad, AM and Bazarbachi, A and Chaudhry, QUN and Alfar, R and Bekadja, MA and Benakli, M and Ortiz, CAF and Riva, E and Galeano, S and Bass, F and Mian, HS and McCurdy, A and Wang, FR and Meng, L and Neumann, D and Koh, M and Snowden, JA and Schönland, S and McLornan, DP and Hayden, PJ and Sureda, A and Greinix, HT and Aljurf, M and Atsuta, Y and Niederwieser, D}, title = {Global characteristics and outcomes of autologous hematopoietic stem cell transplantation for newly diagnosed multiple myeloma: A study of the worldwide network for blood and marrow transplantation (WBMT).}, journal = {American journal of hematology}, volume = {99}, number = {11}, pages = {2084-2095}, doi = {10.1002/ajh.27451}, pmid = {39158218}, issn = {1096-8652}, mesh = {Humans ; *Multiple Myeloma/therapy/mortality ; Middle Aged ; *Hematopoietic Stem Cell Transplantation ; Male ; Female ; Aged ; Adult ; *Transplantation, Autologous ; Registries ; Treatment Outcome ; Lenalidomide/therapeutic use/administration &amp; dosage ; Survival Rate ; }, abstract = {Autologous hematopoietic cell transplantation (AHCT) is a commonly used treatment in multiple myeloma (MM). However, real-world global demographic and outcome data are scarce. We collected data on baseline characteristics and outcomes from 61 725 patients with newly diagnosed MM who underwent upfront AHCT between 2013 and 2017 from nine national/international registries. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), relapse incidence (RI) and non-relapse mortality (NRM). Median OS amounted to 90.2 months (95% CI 88.2-93.6) and median PFS 36.5 months (95% CI 36.1-37.0). At 24 months, cumulative RI was 33% (95% CI 32.5%-33.4%) and NRM was 2.5% (95% CI 2.3%-2.6%). In the multivariate analysis, superior outcomes were associated with younger age, IgG subtype, complete hematological response at auto-HCT, Karnofsky score of 100%, international staging scoring (ISS) stage 1, HCT-comorbidity index (CI) 0, standard cytogenetic risk, auto-HCT in recent years, and use of lenalidomide maintenance. There were differences in the baseline characteristics and outcomes between registries. While the NRM was 1%-3% at 12 months worldwide, the OS at 36 months was 69%-84%, RI at 12 months was 12%-24% and PFS at 36 months was 43%-63%. The variability in these outcomes is attributable to differences in patient and disease characteristics as well as the use of maintenance and macroeconomic factors. In conclusion, worldwide data indicate that AHCT in MM is a safe and effective therapy with an NRM of 1%-3% with considerable regional differences in OS, PFS, RI, and patient characteristics. Maintenance treatment post-AHCT had a beneficial effect on OS.}, }
@article {pmid39157608, year = {2024}, author = {Gajzer, DC and Chen, X and Sabath, DE and Poh, C and Naresh, KN}, title = {Does a subset of mature T-cell leukemias with features akin to T-cell prolymphocytic leukemia but lacking rearrangement of the TCL1 represent peripheral T-cell lymphoma, NOS in a leukemic phase?.}, journal = {EJHaem}, volume = {5}, number = {4}, pages = {900-904}, pmid = {39157608}, issn = {2688-6146}, abstract = {In the current WHO classification, a T-cell prolymphocytic leukemia (T-PLL) diagnosis requires lymphocytosis of >5 × 109/L, evidence of monoclonality, and TCL1A or MTCP1 rearrangement. However, the 2019 consensus document suggested that in the absence of rearrangement of TCL1-family, the presence of abnormalities involving chromosome 11 (11q22.3; ATM), chromosome 8 (idic(8)(p11), t(8;8), trisomy 8q), 5, 12, 13, 22, or a complex karyotype, as well as involvement specific sites (e.g., splenomegaly, effusions) would suffice for a diagnosis of T-PLL. We present a patient diagnosed with T-PLL with MTCP1 rearrangement who was successfully treated with alemtuzumab followed by consolidative allogeneic unrelated donor stem cell transplantation. Eight years later, the patient presented with inguinal lymphadenopathy with features more akin to peripheral T-cell lymphoma, NOS (PTCL, NOS) of the GATA3 subtype, and there was no evidence of peripheral blood involvement. However, the lymphoma cells were clonally related to those at presentation. Currently, literature on T-PLL-like cases lacking the rearrangement of TCL1A is limited, and the possibility of whether a proportion of such cases could represent PTCL, NOS (with leukemic involvement) needs consideration.}, }
@article {pmid39157604, year = {2024}, author = {Kannan, A and Zhuo, Y and Banerjee, R}, title = {Dramatically elevated plasma vascular endothelial growth factor levels from influenza A infection in polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome: A case report.}, journal = {EJHaem}, volume = {5}, number = {4}, pages = {842-844}, pmid = {39157604}, issn = {2688-6146}, abstract = {We present a patient with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome who had a dramatic and sustained elevation in plasma vascular endothelial growth factor (VEGF) levels from 182 to 740 pg/mL while on lenalidomide-dexamethasone therapy. Given his biochemical evidence of progression, second-line daratumumab was added. In hindsight, a concurrent influenza A infection was the likely driver of his VEGF elevation rather than his underlying POEMS syndrome. Given the importance of longitudinal VEGF monitoring and the infectious risks of plasma cell therapies, our case highlights the need for caution with POEMS response assessments in the setting of a respiratory viral infection.}, }
@article {pmid39155578, year = {2024}, author = {Boothby, A and Hegerova, L and Fletcher, SN and Shadman, M and Johnsen, JM}, title = {Successful treatment of acquired von Willebrand syndrome secondary to low-grade CLL with rituximab and venetoclax.}, journal = {Leukemia &amp; lymphoma}, volume = {65}, number = {13}, pages = {2068-2070}, doi = {10.1080/10428194.2024.2392813}, pmid = {39155578}, issn = {1029-2403}, }
@article {pmid39154703, year = {2024}, author = {Gu, T and Vasilatos, SN and Yin, J and Qin, Y and Zhang, L and Davidson, NE and Huang, Y}, title = {Restoration of TFPI2 by LSD1 inhibition suppresses tumor progression and potentiates antitumor immunity in breast cancer.}, journal = {Cancer letters}, volume = {600}, number = {}, pages = {217182}, pmid = {39154703}, issn = {1872-7980}, support = {P30 CA086862/CA/NCI NIH HHS/United States ; R01 CA236271/CA/NCI NIH HHS/United States ; R01 CA260357/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; *Histone Demethylases/metabolism/genetics ; Female ; Mice ; Humans ; *Triple Negative Breast Neoplasms/pathology/immunology/genetics/metabolism ; *Disease Progression ; *Glycoproteins/genetics/metabolism ; Mice, Knockout ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; BRCA1 Protein/genetics ; }, abstract = {Histone lysine-specific demethylase 1 (LSD1) is frequently overexpressed in triple negative breast cancer (TNBC), which is associated with worse clinical outcome in TNBC patients. However, the underlying mechanisms by which LSD1 promotes TNBC progression remain to be identified. We recently established a genetically engineered murine model by crossing mammary gland conditional LSD1 knockout mice with Brca1-deficient mice to explore the role of LSD1 in TNBC pathogenesis. Cre-mediated Brca1 loss led to higher incidence of tumor formation in mouse mammary glands, which was hindered by concurrent depletion of LSD1, indicating a critical role of LSD1 in promoting Brca1-deficient tumors. We also demonstrated that the silencing of a tumor suppressor gene, Tissue Factor Pathway Inhibitor 2 (TFPI2), is functionally associated with LSD1-mediated TNBC progression. Mouse Brca1-deficient tumors exhibited elevated LSD1 expression and decreased TFPI2 level compared to normal mammary tissues. Analysis of TCGA database revealed that TFPI2 expression is significantly lower in aggressive ER-negative or basal-like BC. Restoration of TFPI2 through LSD1 inhibition increased H3K4me2 enrichment at the TFPI2 promoter, suppressed tumor progression, and enhanced antitumor efficacy of chemotherapeutic agent. Induction of TFPI2 by LSD1 ablation downregulates activity of matrix metalloproteinases (MMPs) that in turn increases the level of cytotoxic T lymphocyte attracting chemokines in tumor environment, leading to enhanced tumor infiltration of CD8[+] T cells. Moreover, induction of TFPI2 potentiates antitumor effect of LSD1 inhibitor and immune checkpoint blockade in poorly immunogenic TNBC. Together, our study identifies previously unrecognized roles of TFPI2 in LSD1-mediated TNBC progression, therapeutic response, and immunogenic effects.}, }
@article {pmid39154228, year = {2024}, author = {Snyder, C and Smith, KC and Leisenring, WM and Stratton, KL and Boyd, CM and Choi, Y and Dean, LT and Hudson, MM and Chow, EJ and Oeffinger, KC and Park, ER and McDonald, AJ and Armstrong, GT and Nathan, PC}, title = {Continuity and coordination of care for childhood cancer survivors with multiple chronic conditions: Results from the Childhood Cancer Survivor Study.}, journal = {Cancer}, volume = {130}, number = {24}, pages = {4347-4359}, pmid = {39154228}, issn = {1097-0142}, support = {CA21765/CA/NCI NIH HHS/United States ; P30 CA006973/CA/NCI NIH HHS/United States ; P30CA006973/CA/NCI NIH HHS/United States ; K24 AG056578/AG/NIA NIH HHS/United States ; P30 CA021765/CA/NCI NIH HHS/United States ; CA55727/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; K24AG056578/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Cancer Survivors/statistics &amp; numerical data ; *Continuity of Patient Care/organization &amp; administration ; Female ; Male ; Child ; Adult ; Adolescent ; Young Adult ; Multiple Chronic Conditions/epidemiology/therapy ; Neoplasms/therapy ; Child, Preschool ; Surveys and Questionnaires ; Middle Aged ; Infant ; }, abstract = {INTRODUCTION: Continuity and coordination-of-care for childhood cancer survivors with multiple chronic conditions are understudied but critical for appropriate follow-up care.<br><br>METHODS: From April through June 2022, 800 Childhood Cancer Survivor Study participants with two or more chronic conditions (one or more severe/life-threatening/disabling) were emailed the "Patient Perceived Continuity-of-Care from Multiple Clinicians" survey. The survey asked about survivors' main (takes care of most health care) and coordinating (ensures follow-up) provider, produced three care-coordination summary scores (main provider, across multiple providers, patient-provider partnership), and included six discontinuity indicators (e.g., having to organize own care). Discontinuity (yes/no) was defined as poor care on one or more discontinuity item. Chi-square tests assessed associations between discontinuity and sociodemographics. Modified Poisson regression models estimated prevalence ratios (PRs) for discontinuity risk associated with the specialty and number of years seeing the main and coordinating provider, and PRs associated with better scores on the three care-coordination summary measures. Inverse probability weights adjusted for survey non-participation.<br><br>RESULTS: A total of 377 (47%) survivors responded (mean age 48 years, 68% female, 89% non-Hispanic White, 78% privately insured, 74% &#x2265;college graduate); 147/373 (39%) reported discontinuity. Younger survivors were more likely to report discontinuity (chi-square p&#xa0;=&#xa0;.02). Seeing the main provider &#x2264;3 years was associated with more prevalent discontinuity (PR; 95%CI) (1.17; 1.02-1.34 vs&#xa0;&#x2265;&#xa0;10 years). Cancer specialist main providers were associated with less prevalent discontinuity (0.81; 0.66-0.99 vs. primary care). Better scores on all three care-coordination summary measures were associated with less prevalent discontinuity: main provider (0.73; 0.64-0.83), across multiple providers (0.81; 0.78-0.83), patient-provider partnership (0.85; 0.80-0.89).<br><br>CONCLUSIONS: Care discontinuity among childhood cancer survivors is prevalent and requires intervention.}, }
@article {pmid39151729, year = {2024}, author = {Sajulga, RW and Bolon, YT and Maiers, MJ and Petersdorf, EW}, title = {A Tool for the Assessment of HLA-DQ Heterodimer Variation in Hematopoietic Cell Transplantation.}, journal = {Transplantation and cellular therapy}, volume = {30}, number = {11}, pages = {1084.e1-1084.e15}, pmid = {39151729}, issn = {2666-6367}, support = {R01 CA231838/CA/NCI NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; U01 AI069197/AI/NIAID NIH HHS/United States ; 27307C0011/ES/NIEHS NIH HHS/United States ; R01 CA100019/CA/NCI NIH HHS/United States ; 27398C0011/ES/NIEHS NIH HHS/United States ; R01 CA218285/CA/NCI NIH HHS/United States ; 27305C0011/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation ; HLA-DQ Antigens/genetics ; Histocompatibility Testing/methods ; Haplotypes ; Alleles ; HLA-DQ alpha-Chains/genetics ; HLA-DQ beta-Chains/genetics ; }, abstract = {When optimizing transplants, clinical decision-makers consider HLA-A, -B, -C, -DRB1 (8 matched alleles out of 8), and sometimes HLA-DQB1 (10 out of 10) matching between the patient and donor. HLA-DQ is a heterodimer formed by the β chain product of HLA-DQB1 and an α chain product of HLA-DQA1. In addition to molecules defined by the parentally inherited cis haplotypes, α-β trans-dimerization is possible between certain alleles, leading to unique molecules and a potential source of mismatched molecules. Recently, researchers uncovered that clinical outcome after HLA-DQB1-mismatched unrelated donor HCT depends on the total number of HLA-DQ molecule mismatches and the specific α-β heterodimer mismatch. Our objective in this study is to develop an automated tool for analyzing HLA-DQ heterodimer data and validating it through numerous datasets and analyses. By doing so, we provide an HLA-DQ heterodimer tool for DQα-DQβ trans-heterodimer evaluation, HLA-DQ imputation, and HLA-DQ-featured source selection to the transplant field. In our study, we leverage 352,148 high-confidence, statistically phased (via a modified expectation-maximization algorithm) HLA-DRB1∼DQA1∼DQB1 haplotypes, 1,052 pedigree-phased HLA-DQA1∼DQB1 haplotypes, and 13,663 historical transplants to characterize HLA-DQ heterodimers data. Using our developed QLASSy (HLA-DQA1 and HLA-DQB1 Heterodimers Assessment) tool, we first assessed the data quality of HLA-DQ heterodimers in our data for trans-dimers, missing HLA-DQA1 typing, and unexpected HLA-DQA1 and HLA-DQB1 combinations. Since trans-dimers enable up to four unique HLA-DQ molecules in individuals, we provide in-silico validations for 99.7% of 275 unique trans-dimers generated by 176,074 U.S. donors with HLA-DQA1 and HLA-DQB1 data. Many individuals lack HLA-DQA1 typing, so we developed and validated high-confidence HLA-DQ annotation imputation via HLA-DRB1 with >99% correct predictions in 23,698 individuals. A select few individuals displayed unexpected HLA-DQ combinations. We revisited the typing of 61 donors with unexpected HLA-DQ combinations based on their HLA-DQA1 and HLA-DQB1 typing and corrected 22 out of 61 (36%) cases of donors through data review or retyping and used imputation to resolve unexpected combinations. After verifying the data quality of our datasets, we analyzed our datasets further: we explored the frequencies of observed HLA-DQ combinations to compare HLA-DQ across populations (for instance, we found more high-risk molecules in Asian/Pacific Islander and Black/African American populations), demonstrated the effect of HLA-DQA1 and HLA-DQB1 mismatching on HLA-DQ molecular mismatches, and highlighted where donor selections could be improved at the time of search for historical transplants with this new HLA-DQ information (where 51.9% of G2-mismatched transplants had lower-risk, G2-matched alternatives). We encapsulated our findings into a tool that imputes missing HLA-DQA1 as needed, annotates HLA-DQ (mis)matches, and highlights other important HLA-DQ data to consider for the present and future. Altogether, these valuable datasets, analyses, and a culminating tool serve as actionable resources to enhance donor selection and improve patient outcomes.}, }
@article {pmid39151454, year = {2024}, author = {Benson, AB and Venook, AP and Adam, M and Chang, G and Chen, YJ and Ciombor, KK and Cohen, SA and Cooper, HS and Deming, D and Garrido-Laguna, I and Grem, JL and Haste, P and Hecht, JR and Hoffe, S and Hunt, S and Hussan, H and Johung, KL and Joseph, N and Kirilcuk, N and Krishnamurthi, S and Malla, M and Maratt, JK and Messersmith, WA and Meyerhardt, J and Miller, ED and Mulcahy, MF and Nurkin, S and Parikh, A and Patel, H and Pedersen, K and Saltz, L and Schneider, C and Shibata, D and Shogan, B and Skibber, JM and Sofocleous, CT and Tavakkoli, A and Willett, CG and Wu, C and Jones, F and Gurski, L}, title = {NCCN Guidelines® Insights: Rectal Cancer, Version 3.2024.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {6}, pages = {366-375}, doi = {10.6004/jnccn.2024.0041}, pmid = {39151454}, issn = {1540-1413}, mesh = {Humans ; *Rectal Neoplasms/therapy/diagnosis/pathology ; Neoadjuvant Therapy/methods/standards ; Combined Modality Therapy/methods ; Neoplasm Staging ; Medical Oncology/standards/methods ; }, abstract = {The determination of an optimal treatment plan for an individual patient with rectal cancer is a complex process. In addition to decisions relating to the intent of rectal cancer surgery (ie, curative or palliative), consideration must also be given to the likely functional results of treatment, including the probability of maintaining or restoring normal bowel function/anal continence and preserving genitourinary functions. Particularly for patients with distal rectal cancer, finding a balance between curative-intent therapy while having minimal impact on quality of life can be challenging. Furthermore, the risk of pelvic recurrence is higher in patients with rectal cancer compared with those with colon cancer, and locally recurrent rectal cancer is associated with a poor prognosis. Careful patient selection and the use of sequenced multimodality therapy following a multidisciplinary approach is recommended. These NCCN Guidelines Insights detail recent updates to the NCCN Guidelines for Rectal Cancer, including the addition of endoscopic submucosal dissection as an option for early-stage rectal cancer, updates to the total neoadjuvant therapy approach based on the results of recent clinical trials, and the addition of a "watch-and-wait" nonoperative management approach for clinical complete responders to neoadjuvant therapy.}, }
@article {pmid39151112, year = {2024}, author = {Bhatt, VR and Shostrom, VK and Choe, HK and Hamilton, BK and Gundabolu, K and Maness, LJ and Kumar, V and Mahato, RI and Smith, LM and Nishihori, T and Lee, SJ}, title = {A Multicenter Phase II Trial of Ruxolitinib for Treatment of Corticosteroid Refractory Sclerotic Chronic Graft-Versus-Host Disease.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {42}, number = {33}, pages = {3977-3985}, pmid = {39151112}, issn = {1527-7755}, support = {P30 CA036727/CA/NCI NIH HHS/United States ; U54 GM115458/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Graft vs Host Disease/drug therapy ; *Pyrimidines/therapeutic use ; *Nitriles/therapeutic use ; *Pyrazoles/therapeutic use ; Male ; Middle Aged ; Female ; Adult ; Aged ; Chronic Disease ; Adrenal Cortex Hormones/therapeutic use ; Sclerosis/chemically induced ; Young Adult ; }, abstract = {PURPOSE: Sclerotic chronic graft-versus-host disease (cGVHD) represents a highly morbid and refractory form of cGVHD, and novel therapies for sclerotic cGVHD are critically needed. This study aimed to determine the efficacy of ruxolitinib in patients with corticosteroid refractory sclerotic cGVHD.<br><br>PATIENTS AND METHODS: In a single-arm multicenter phase II trial (N = 47), adults with sclerotic cGVHD refractory to corticosteroids and &#x2265;one additional line of systemic therapy for cGVHD received ruxolitinib for &#x2265;six months (ClinicalTrials.gov identifier: NCT03616184). The primary end point was complete or partial response (PR) in skin and/or joint defined according to the 2014 National Institute of Health cGVHD Consensus Criteria.<br><br>RESULTS: Following the use of ruxolitinib for a median of 11 months, PR in skin and/or joints was noted in 49% (95% CI, 34 to 64) at 6 months, with 45% having joint and fascia response and 19% having skin response. The duration of skin/joint response was 77% (95% CI, 48 to 91) at 12 months. Overall cGVHD PR was noted in 47% (95% CI, 32 to 61). Improvement in Lee Symptom Scale summary and skin subscale scores was noted in 38% of patients. With a cumulative incidence of treatment failure of 20.8% (95% CI, 10.0 to 34.1), nonrelapse mortality (NRM) of 2.2% (95% CI, 0.17 to 10.3), and no recurrent malignancy, failure-free survival (FFS) was 77.1% (95% CI, 61.3 to 87.0) at 12 months. Ruxolitinib was overall well tolerated with no new safety signals.<br><br>CONCLUSION: The use of ruxolitinib was associated with relatively high rates of skin/joint responses and overall cGVHD responses, improvement in patient-reported outcomes, low NRM, and high FFS in patients with refractory sclerotic cGVHD. Ruxolitinib offers an effective treatment option for refractory sclerotic cGVHD.}, }
@article {pmid39151108, year = {2024}, author = {Cigliola, A and Basnet, A and Jacob, JM and Mercinelli, C and Tateo, V and Patanè, DA and Bratslavsky, G and Cheng, L and Grivas, P and Kamat, AM and Spiess, PE and Pavlick, DC and Lin, DI and Ross, JS and Necchi, A}, title = {Urachal and Nonurachal Adenocarcinomas of the Urinary Bladder: A Comprehensive Genomic Profiling Study.}, journal = {JCO precision oncology}, volume = {8}, number = {}, pages = {e2400200}, doi = {10.1200/PO.24.00200}, pmid = {39151108}, issn = {2473-4284}, mesh = {Humans ; *Urinary Bladder Neoplasms/genetics/pathology ; *Adenocarcinoma/genetics/pathology ; Female ; Male ; Middle Aged ; Aged ; Adult ; Genomics ; Aged, 80 and over ; Gene Expression Profiling ; }, abstract = {PURPOSE: Although both urachal (U) and nonurachal (NU) bladder adenocarcinomas (adenoCas) share several histologic similarities, they differ in location and sometimes in therapeutic options. We analyzed the differences in genomic alterations (GAs) between these tumor entities, with the aim of identifying potential therapeutic targets for clinical trials.<br><br>MATERIALS AND METHODS: Overall, 133 U and 328 NU adenoCas were analyzed. Hybrid capture-based comprehensive genomic profiling (CGP) was performed to evaluate all classes of GA. Germline status of GA was predicted using a validated somatic-germline computational method. CGP was performed using the FoundationOne and FoundationOne CDx assays (Foundation Medicine, Inc).<br><br>RESULTS: The most frequent GA in both U and NU cohorts included TP53 (86.5% v 81.1%) and KRAS (34.6% v 27.7%). GAs characteristic of colorectal adenoCa, such as SMAD4 (P = .069) and GNAS (P = .071), were more common in U versus NU. Conversely, TERT (P < .01) and RB1 (P = .071) were more prevalent in NU adenoCa. Notably, both U and NU adenoCas exhibited possibly targetable GA in PIK3CA (7.5% v 7.9%) and ERBB2 (6.8% v 7.6%). Biomarkers associated with potential benefit from anti-PD-1/L1 were infrequent. Median tumor mutational burden was 2.6 and 3.5 mutations per megabase for U and NU, respectively, and PD-L1 expression >1% was rare. Genomic ancestry and genomic signature distribution were similar in both tumor types. GAs were most commonly of somatic nature. Limitations include lack of clinical data, tumor heterogeneity, and retrospective nature.<br><br>CONCLUSION: U and NU adenoCAs revealed differences in GA, with PIK3CA and ERBB2 being identified as putative therapeutic targets. Biomarkers of response to anti-PD-(L)1 were uncommon. Results highlight the potential of CGP to personalize treatment options of bladder adenoCa and inform clinical trial designs.}, }
@article {pmid39150991, year = {2024}, author = {Belleville, AE and Thomas, JD and Tonnies, J and Gabel, AM and Borrero Rossi, A and Singh, P and Queitsch, C and Bradley, RK}, title = {An autoregulatory poison exon in Smndc1 is conserved across kingdoms and influences organism growth.}, journal = {PLoS genetics}, volume = {20}, number = {8}, pages = {e1011363}, pmid = {39150991}, issn = {1553-7404}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R01 HL128239/HL/NHLBI NIH HHS/United States ; R01 HL151651/HL/NHLBI NIH HHS/United States ; R01 CA251138/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Alternative Splicing/genetics ; *Arabidopsis/genetics/growth &amp; development ; Codon, Nonsense/genetics ; Conserved Sequence ; *Exons/genetics ; *Nonsense Mediated mRNA Decay/genetics ; RNA, Messenger/genetics/metabolism ; }, abstract = {Many of the most highly conserved elements in the human genome are "poison exons," alternatively spliced exons that contain premature termination codons and permit post-transcriptional regulation of mRNA abundance through induction of nonsense-mediated mRNA decay (NMD). Poison exons are widely assumed to be highly conserved due to their presumed importance for organismal fitness, but this functional importance has never been tested in the context of a whole organism. Here, we report that a poison exon in Smndc1 is conserved across mammals and plants and plays a molecular autoregulatory function in both kingdoms. We generated mouse and A. thaliana models lacking this poison exon to find its loss leads to deregulation of SMNDC1 protein levels, pervasive alterations in mRNA processing, and organismal size restriction. Together, these models demonstrate the importance of poison exons for both molecular and organismal phenotypes that likely explain their extraordinary conservation.}, }
@article {pmid39150988, year = {2024}, author = {Byrne, CM and Márquez, AC and Cai, B and Coombs, D and Gantt, S}, title = {Spatial kinetics and immune control of murine cytomegalovirus infection in the salivary glands.}, journal = {PLoS computational biology}, volume = {20}, number = {8}, pages = {e1011940}, pmid = {39150988}, issn = {1553-7358}, mesh = {Animals ; *Salivary Glands/virology/immunology ; Mice ; *Muromegalovirus/immunology/physiology ; Virus Replication/physiology ; Kinetics ; Herpesviridae Infections/immunology/virology ; Cytomegalovirus Infections/immunology/virology/transmission ; Computational Biology ; }, abstract = {Human cytomegalovirus (HCMV) is the most common congenital infection. Several HCMV vaccines are in development, but none have yet been approved. An understanding of the kinetics of CMV replication and transmission may inform the rational design of vaccines to prevent this infection. The salivary glands (SG) are an important site of sustained CMV replication following primary infection and during viral reactivation from latency. As such, the strength of the immune response in the SG likely influences viral dissemination within and between hosts. To study the relationship between the immune response and viral replication in the SG, and viral dissemination from the SG to other tissues, mice were infected with low doses of murine CMV (MCMV). Following intra-SG inoculation, we characterized the viral and immunological dynamics in the SG, blood, and spleen, and identified organ-specific immune correlates of protection. Using these data, we constructed compartmental mathematical models of MCMV infection. Model fitting to data and analysis indicate the importance of cellular immune responses in different organs and point to a threshold of infection within the SG necessary for the establishment and spread of infection.}, }
@article {pmid39150951, year = {2024}, author = {Donzella, SM and Masters, M and Phipps, AI and Patel, AV and Zhong, C}, title = {Validity of self-reported sleep duration in the Cancer Prevention Study- 3.}, journal = {PloS one}, volume = {19}, number = {8}, pages = {e0307409}, pmid = {39150951}, issn = {1932-6203}, mesh = {Female ; Humans ; Male ; *Neoplasms/prevention &amp; control ; Reproducibility of Results ; *Self Report/statistics &amp; numerical data ; *Sleep Duration ; Time Factors ; }, abstract = {PURPOSE: We examined the one-year test re-test reliability and validity criterion of survey-assessed sleep duration collected from two separate questions.<br><br>METHODS: The Activity Validation Sub Study included 751 participants of the Cancer Prevention Study-3 study to further investigate rest/activity cycles. Sleep duration was collected using three methods: survey, Daysimeter device, and sleep diary. Survey-assessed sleep duration was collected using 2 different questions, each with different response options (categorical and continuous). Selected participants (n = 170) were asked to wear a Daysimeter device for seven consecutive days for two non-consecutive quarters. Participants were excluded from the current study due to incomplete/implausible survey or device data or reported working night shift. We calculated reliability of pre- and post-survey sleep duration for both survey question using Spearman correlation. We used the method of triads to estimate the validity coefficient (VC) between the three sleep duration measurements in the present study and the "true" latent sleep duration measure, and bootstrapping methods to calculate the 95% confidence intervals (95%CI).<br><br>RESULTS: Of 119 participants included in the study (52.10% male), test-retest correlation showed strong and moderate correlations for sleep duration collected continuously and categorically, respectively. The VC for survey-assessed continuous sleep duration was 0.82 (95%CI 0.71, 0.90) for weekday and 0.68 (95%CI 0.46, 0.83) for weekend. Performance of the VC was slightly weaker for survey-assessed categorical sleep duration (weekday VC = 0.57 95%CI 0.42, 0.71; weekend VC = 0.47 95%CI 0.29, 0.62).<br><br>CONCLUSION: The two survey-assessed sleep duration questions used in the AVSS and CPS-3 cohorts are valid approximations of sleep duration.}, }
@article {pmid39150133, year = {2024}, author = {Corey, L}, title = {Reflections on Progress in Genital Herpes Therapy and Prevention 1997 to 2024.}, journal = {Sexually transmitted diseases}, volume = {51}, number = {9}, pages = {614-615}, doi = {10.1097/OLQ.0000000000002030}, pmid = {39150133}, issn = {1537-4521}, mesh = {Humans ; *Herpes Genitalis/drug therapy/prevention &amp; control ; *Antiviral Agents/therapeutic use ; Female ; Male ; }, }
@article {pmid39149908, year = {2024}, author = {Vermulst, M and Paskvan, SL and Chung, CS and Franke, K and Clegg, N and Minot, S and Madeoy, J and Long, AS and Gout, JF and Bielas, JH}, title = {MADDD-seq, a novel massively parallel sequencing tool for simultaneous detection of DNA damage and mutations.}, journal = {Nucleic acids research}, volume = {52}, number = {16}, pages = {e76}, pmid = {39149908}, issn = {1362-4962}, support = {R01 CA204894/CA/NCI NIH HHS/United States ; R01CA204894/CA/NCI NIH HHS/United States ; //University of Southern California/ ; R01 AG054641/AG/NIA NIH HHS/United States ; R01ES026222/ES/NIEHS NIH HHS/United States ; U01 ES029516/ES/NIEHS NIH HHS/United States ; R01 ES026222/ES/NIEHS NIH HHS/United States ; R01AG054641/AG/NIA NIH HHS/United States ; }, mesh = {*High-Throughput Nucleotide Sequencing/methods ; *DNA Damage ; *Mutation ; *Saccharomyces cerevisiae/genetics ; *DNA Repair/genetics ; Sequence Analysis, DNA/methods ; DNA Adducts ; Mutagenesis ; }, abstract = {Our genome is exposed to a wide variety of DNA-damaging agents. If left unrepaired, this damage can be converted into mutations that promote carcinogenesis or the development of genetically inherited diseases. As a result, researchers and clinicians require tools that can detect DNA damage and mutations with exceptional sensitivity. In this study, we describe a massively parallel sequencing tool termed Mutation And DNA Damage Detection-seq (MADDD-seq) that is capable of detecting O6-methyl guanine lesions and mutations simultaneously, with a single assay. To illustrate the dual capabilities of MADDD-seq, we treated WT and DNA repair deficient yeast cells with the DNA-damaging agent MNNG and tracked DNA lesions and mutations over a 24-h time period. This approach allowed us to identify thousands of DNA adducts and mutations in a single sequencing run and gain deep insight into the kinetics of DNA repair and mutagenesis.}, }
@article {pmid39149486, year = {2024}, author = {Stanton, S and Schmitz, F and Copeland, W and DellAringa, J and Newhall, K and Disis, M}, title = {Populations of triple negative and hormone receptor positive HER2 negative breast tumors share immune gene profiles.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39149486}, issn = {2693-5015}, support = {KL2 TR000421/TR/NCATS NIH HHS/United States ; }, abstract = {In breast cancer, triple negative (TN) breast cancer has most responses to immune checkpoint inhibitor (ICI) therapy. Lymphocyte infiltrate does not impact prognosis in Hormone receptor positive HER2 negative (HR + HER2-) breast tumors and few HR + HER2- tumors respond to ICI. We contrasted immune-associated gene expression between 119 TN and 475 HR + HER2- breast tumors from The Cancer Genome Atlas (TCGA) and confirmed our findings in 299 TN and 1369 HR + HER2- breast tumors in the METABRIC database. TN and HR+ HER2- tumors grouped into immune-high or -low tumors, both subtypes were represented in the immune-high group. The largest difference between the immune-high TN and HR + HER2- tumors was TN tumors had more abundant Th1 and Th2 CD4[+] T cells while HR + HER2- tumors had more abundant fibroblasts (log2FC > 0.3; p < 10×10[-10]). This suggests an immune-high signature is not dictated by breast cancer subtype, but fibroblast subsets associated with worse outcome were higher in the immune-high HR + HER2- tumors.}, }
@article {pmid39149278, year = {2024}, author = {Langley, CA and Dietzen, PA and Emerman, M and Tenthorey, JL and Malik, HS}, title = {Antiviral Mx proteins have an ancient origin and widespread distribution among eukaryotes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39149278}, issn = {2692-8205}, support = {T32 GM007270/GM/NIGMS NIH HHS/United States ; U54 AI170792/AI/NIAID NIH HHS/United States ; }, abstract = {First identified in mammals, Mx proteins are potent antivirals against a broad swathe of viruses. Mx proteins arose within the Dynamin superfamily of proteins (DSP), mediating critical cellular processes, such as endocytosis and mitochondrial, plastid, and peroxisomal dynamics. And yet, the evolutionary origins of Mx proteins are poorly understood. Using a series of phylogenomic analyses with stepwise increments in taxonomic coverage, we show that Mx proteins predate the interferon signaling system in vertebrates. Our analyses find an ancient monophyletic DSP lineage in eukaryotes that groups vertebrate and invertebrate Mx proteins with previously undescribed fungal MxF proteins, the relatively uncharacterized plant and algal Dynamin 4A/4C proteins, and representatives from several early-branching eukaryotic lineages. Thus, Mx-like proteins date back close to the origin of Eukarya. Our phylogenetic analyses also reveal that host-encoded and NCLDV (nucleocytoplasmic large DNA viruses)-encoded DSPs are interspersed in four distinct DSP lineages, indicating recurrent viral theft of host DSPs. Our analyses thus reveal an ancient history of viral and antiviral functions encoded by the Dynamin superfamily in eukaryotes.}, }
@article {pmid39149271, year = {2024}, author = {Liao, H and Kottapalli, S and Huang, Y and Chaw, M and Gehring, J and Waltner, O and Phung-Rojas, M and Daza, RM and Matsen, FA and Trapnell, C and Shendure, J and Srivatsan, S}, title = {Optics-free reconstruction of 2D images via DNA barcode proximity graphs.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39149271}, issn = {2692-8205}, support = {R01 AI146028/AI/NIAID NIH HHS/United States ; R01 HG010632/HG/NHGRI NIH HHS/United States ; }, abstract = {Spatial genomic technologies include imaging- and sequencing-based methods (1-3). An emerging subcategory of sequencing-based methods relies on a surface coated with coordinate-associated DNA barcodes, which are leveraged to tag endogenous nucleic acids or cells in an overlaid tissue section (4-7). However, the physical registration of DNA barcodes to spatial coordinates is challenging, necessitating either high density printing of coordinate-specific oligonucleotides or in situ sequencing/probing of randomly deposited, oligonucleotide-bearing beads. As a consequence, the surface areas available to sequencing-based spatial genomic methods are constrained by the time, labor, cost, and instrumentation required to either print, synthesize or decode a coordinate-tagged surface. To address this challenge, we developed SCOPE (Spatial reConstruction via Oligonucleotide Proximity Encoding), an optics-free, DNA microscopy (8) inspired method. With SCOPE, the relative positions of randomly deposited beads on a 2D surface are inferred from the ex situ sequencing of chimeric molecules formed from diffusing "sender" and tethered "receiver" oligonucleotides. As a first proof-of-concept, we apply SCOPE to reconstruct an asymmetric "swoosh" shape resembling the Nike logo (16.75 × 9.25 mm). Next, we use a microarray printer to encode a "color" version of the Snellen eye chart for visual acuity (17.18 × 40.97 mm), and apply SCOPE to achieve optics-free reconstruction of individual letters. Although these are early demonstrations of the concept and much work remains to be done, we envision that the optics-free, sequencing-based quantitation of the molecular proximities of DNA barcodes will enable spatial genomics in constant experimental time, across fields of view and at resolutions that are determined by sequencing depth, bead size, and diffusion kinetics, rather than the limitations of optical instruments or microarray printers.}, }
@article {pmid39149252, year = {2024}, author = {Sui, Z and Li, Z and Sun, W}, title = {Exploit Spatially Resolved Transcriptomic Data to Infer Cellular Features from Pathology Imaging Data.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39149252}, issn = {2692-8205}, support = {R01 GM105785/GM/NIGMS NIH HHS/United States ; }, abstract = {Digital pathology is a rapidly advancing field where deep learning methods can be employed to extract meaningful imaging features. However, the efficacy of training deep learning models is often hindered by the scarcity of annotated pathology images, particularly images with detailed annotations for small image patches or tiles. To overcome this challenge, we propose an innovative approach that leverages paired spatially resolved transcriptomic data to annotate pathology images. We demonstrate the feasibility of this approach and introduce a novel transfer-learning neural network model, STpath (Spatial Transcriptomics and pathology images), designed to predict cell type proportions or classify tumor microenvironments. Our findings reveal that the features from pre-trained deep learning models are associated with cell type identities in pathology image patches. Evaluating STpath using three distinct breast cancer datasets, we observe its promising performance despite the limited training data. STpath excels in samples with variable cell type proportions and high-resolution pathology images. As the influx of spatially resolved transcriptomic data continues, we anticipate ongoing updates to STpath, evolving it into an invaluable AI tool for assisting pathologists in various diagnostic tasks.}, }
@article {pmid39147634, year = {2024}, author = {Chahine, SY and Alkhatib, KY and Arakelyan, G and Buxton, C and Giannarini, G and Hamilton, RJ and Holt, SK and Bernhard, JC and Jiang, DM and Lin, D and Liu, JJ and Manley, B and Master, VA and Matveev, V and Necchi, A and Packiam, VT and Patel, SH and Peak, T and Peyton, CC and Pierorazio, PM and Prakash, G and Salari, K and Sexton, WJ and Singla, N and Spiess, PE and Psutka, SP}, title = {Testicular Germ Cell Tumors with Venous Tumor Thrombus: Prevalence, Presentation, and Management.}, journal = {European urology focus}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.euf.2024.07.017}, pmid = {39147634}, issn = {2405-4569}, abstract = {BACKGROUND AND OBJECTIVE: There are limited data on the prevalence and management of testicular germ cell tumor (TGCT) cases presenting with venous tumor thrombus (VTT). Our objectives were to describe the prevalence of TGCT with VTT, to identify a multicenter retrospective cohort, and to ascertain expert opinion regarding optimal management of this entity.<br><br>METHODS: Using the IBM Marketscan database, we identified men with testicular cancer who underwent retroperitoneal lymph node dissection (RPLND) with concurrent VTT or inferior vena cava (IVC) tumor thrombectomy to estimate the prevalence of VTT in TGCT. To identify a multicenter retrospective cohort of patients, we surveyed surgeons and described the presentation, management, and outcomes for the cohort.<br><br>KEY FINDINGS AND LIMITATIONS: The prevalence of TGCT with VTT in the IBM Marketscan database was 0.3% (n&#xa0;=&#xa0;7/2517) when using stringent criteria and 3.1% (n&#xa0;=&#xa0;79/2517) when using broad criteria. In response to our survey, 16 surgeons from ten centers contributed data for 34 patients. Most patients (n&#xa0;=&#xa0;29, 85%) presented with nonseminomatous germ cell tumor. Surgical management was used for 93.9% (n&#xa0;=&#xa0;31), including postchemotherapy tumor thrombectomy with primary cavorrhaphy in 63%. The Marketscan analysis was limited to insured individuals and did not include clinicopathological details, and use of billing codes may have included patients with stromal tumors. In addition, lack of responses to the anonymous survey limited data capture, and the RedCap survey did not address symptoms specific to IVC obstruction or allow central review of the imaging leading to VTT diagnosis.<br><br>VTT among males with TGCT is rare and requires complex multidisciplinary management, including venous tumor thrombectomy at the time of postchemotherapy RPLND.<br><br>PATIENT SUMMARY: Using a medical database, we estimated that the frequency of testicular cancer cases in which the tumor extends into a blood vessel (called venous tumor thrombus, VTT) is just 0.3-3.1%. We carried out a survey of surgeons with experience of this condition. Our results indicate that although testicular cancers respond well to chemotherapy, VTT is less responsive and complex surgery is necessary for this rare condition.}, }
@article {pmid39146495, year = {2024}, author = {Jones, SMW and Ohlsen, TJD and Karvonen, KA and Sorror, M}, title = {Addressing financial hardship in malignant hematology and hematopoietic cell transplant: a team approach.}, journal = {Blood advances}, volume = {8}, number = {19}, pages = {5146-5155}, pmid = {39146495}, issn = {2473-9537}, mesh = {Humans ; Cost of Illness ; Financial Stress ; *Hematologic Neoplasms/therapy/economics ; *Hematopoietic Stem Cell Transplantation/economics ; Patient Care Team ; Quality of Life ; }, abstract = {Financial hardship is a common experience for patients and their families after the diagnosis of a hematologic malignancy and is associated with worse outcomes. Health care costs, increased costs of living, income poverty, and inadequate wealth contribute to financial hardship after the diagnosis and treatment of a hematologic malignancy and/or hematopoietic cell transplant. Given the multidimensional nature of financial hardship, a multidisciplinary team-based approach is needed to address this public health hazard. Hematologists and oncologists may mitigate the impact of financial hardship by matching treatment options with patient goals of care and reducing symptom burden disruptive to employment. Social workers and financial navigators can assist with screening and resource deployment. Policymakers and researchers can identify structural and policy changes to prevent financial hardship. By alleviating this major health care burden from patients, care teams may improve survival and quality of life for patients with hematologic malignancies.}, }
@article {pmid39146390, year = {2024}, author = {Yuan, AE and Shou, W}, title = {A rigorous and versatile statistical test for correlations between stationary time series.}, journal = {PLoS biology}, volume = {22}, number = {8}, pages = {e3002758}, pmid = {39146390}, issn = {1545-7885}, support = {R01 GM124128/GM/NIGMS NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; }, mesh = {Time Factors ; Animals ; *Computer Simulation ; Models, Statistical ; Statistics, Nonparametric ; Data Interpretation, Statistical ; }, abstract = {In disciplines from biology to climate science, a routine task is to compute a correlation between a pair of time series and determine whether the correlation is statistically significant (i.e., unlikely under the null hypothesis that the time series are independent). This problem is challenging because time series typically exhibit autocorrelation and thus cannot be properly analyzed with the standard iid-oriented statistical tests. Although there are well-known parametric tests for time series, these are designed for linear correlation statistics and thus not suitable for the increasingly popular nonlinear correlation statistics. There are also nonparametric tests that can be used with any correlation statistic, but for these, the conditions that guarantee correct false positive rates are either restrictive or unclear. Here, we describe the truncated time-shift (TTS) test, a nonparametric procedure to test for dependence between 2 time series. We prove that this test correctly controls the false positive rate as long as one of the time series is stationary, a minimally restrictive requirement among current tests. The TTS test is versatile because it can be used with any correlation statistic. Using synthetic data, we demonstrate that this test performs correctly even while other tests suffer high false positive rates. In simulation examples, simple guidelines for parameter choices allow high statistical power to be achieved with sufficient data. We apply the test to datasets from climatology, animal behavior, and microbiome science, verifying previously discovered dependence relationships and detecting additional relationships.}, }
@article {pmid39145953, year = {2024}, author = {O'Regan, RM and Zhang, Y and Fleming, GF and Francis, PA and Kammler, R and Viale, G and Dell'Orto, P and Lang, I and Bellet, M and Bonnefoi, HR and Tondini, C and Villa, F and Bernardo, A and Ciruelos, EM and Neven, P and Karlsson, P and Müller, B and Jochum, W and Zaman, K and Martino, S and Geyer, CE and Jerzak, KJ and Davidson, NE and Coleman, RE and Ingle, JN and van Mackelenbergh, MT and Loi, S and Colleoni, M and Schnabel, CA and Treuner, K and Regan, MM}, title = {Breast Cancer Index in Premenopausal Women With Early-Stage Hormone Receptor-Positive Breast Cancer.}, journal = {JAMA oncology}, volume = {10}, number = {10}, pages = {1379-1389}, pmid = {39145953}, issn = {2374-2445}, mesh = {Humans ; Female ; *Breast Neoplasms/drug therapy/pathology/genetics ; *Premenopause ; Adult ; Prospective Studies ; *Tamoxifen/therapeutic use ; *Biomarkers, Tumor/genetics/metabolism ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; *Antineoplastic Agents, Hormonal/therapeutic use ; Middle Aged ; Retrospective Studies ; Receptors, Interleukin-17 ; Receptors, Estrogen/metabolism ; Chemotherapy, Adjuvant ; Homeodomain Proteins/genetics ; Receptors, Progesterone/metabolism ; Androstadienes/therapeutic use/administration &amp; dosage ; Neoplasm Staging ; Treatment Outcome ; Predictive Value of Tests ; Aromatase Inhibitors/therapeutic use ; }, abstract = {IMPORTANCE: Adjuvant ovarian function suppression (OFS) with oral endocrine therapy improves outcomes for premenopausal patients with hormone receptor-positive (HR+) breast cancer but adds adverse effects. A genomic biomarker for selecting patients most likely to benefit from OFS-based treatment is lacking.<br><br>OBJECTIVE: To assess the predictive and prognostic performance of the Breast Cancer Index (BCI) for OFS benefit in premenopausal women with HR+ breast cancer.<br><br>This prospective-retrospective translational study used all available tumor tissue samples from female patients from the Suppression of Ovarian Function Trial (SOFT). These individuals were randomized to receive 5 years of adjuvant tamoxifen alone, tamoxifen plus OFS, or exemestane plus OFS. BCI testing was performed blinded to clinical data and outcome. The a priori hypothesis was that BCI HOXB13/IL17BR ratio (BCI[H/I])-high tumors would benefit more from OFS and high BCI portended poorer prognosis in this population. Settings spanned multiple centers internationally. Participants included premenopausal female patients with HR+ early breast cancer with specimens in the International Breast Cancer Study Group tumor repository available for RNA extraction. Data were collected from December 2003 to April 2021 and were analyzed from May 2022 to October 2022.<br><br>MAIN OUTCOMES AND MEASURES: Primary end points were breast cancer-free interval (BCFI) for the predictive analysis and distant recurrence-free interval (DRFI) for the prognostic analyses.<br><br>RESULTS: Tumor specimens were available for 1718 of the 3047 female patients in the SOFT intention-to-treat population. The 1687 patients (98.2%) who had specimens that yielded sufficient RNA for BCI testing represented the parent trial population. The median (IQR) follow-up time was 12 (10.5-13.4) years, and 512 patients (30.3%) were younger than 40 years. Tumors were BCI(H/I)-low for 972 patients (57.6%) and BCI(H/I)-high for 715 patients (42.4%). Patients with tumors classified as BCI(H/I)-low exhibited a 12-year absolute benefit in BCFI of 11.6% from exemestane plus OFS (hazard ratio [HR], 0.48 [95% CI, 0.33-0.71]) and an absolute benefit of 7.3% from tamoxifen plus OFS (HR, 0.69 [95% CI, 0.48-0.97]) relative to tamoxifen alone. In contrast, patients with BCI(H/I)-high tumors did not benefit from either exemestane plus OFS (absolute benefit, -0.4%; HR, 1.03 [95% CI, 0.70-1.53]; P for interaction&#x2009;=&#x2009;.006) or tamoxifen plus OFS (absolute benefit, -1.2%; HR, 1.05 [95% CI, 0.72-1.54]; P for interaction&#x2009;=&#x2009;.11) compared with tamoxifen alone. BCI continuous index was significantly prognostic in the N0 subgroup for DRFI (n&#x2009;=&#x2009;1110; P&#x2009;=&#x2009;.004), with 12-year DRFI of 95.9%, 90.8%, and 86.3% in BCI low-risk, intermediate-risk, and high-risk N0 cancers, respectively.<br><br>CONCLUSIONS AND RELEVANCE: In this prospective-retrospective translational study of patients enrolled in SOFT, BCI was confirmed as prognostic in premenopausal women with HR+ breast cancer. The benefit from OFS-containing adjuvant endocrine therapy was greater for patients with BCI(H/I)-low tumors than BCI(H/I)-high tumors. BCI(H/I)-low status may identify premenopausal patients who are likely to benefit from this more intensive endocrine therapy.}, }
@article {pmid39143224, year = {2024}, author = {Pölönen, P and Di Giacomo, D and Seffernick, AE and Elsayed, A and Kimura, S and Benini, F and Montefiori, LE and Wood, BL and Xu, J and Chen, C and Cheng, Z and Newman, H and Myers, J and Iacobucci, I and Li, E and Sussman, J and Hedges, D and Hui, Y and Diorio, C and Uppuluri, L and Frank, D and Fan, Y and Chang, Y and Meshinchi, S and Ries, R and Shraim, R and Li, A and Bernt, KM and Devidas, M and Winter, SS and Dunsmore, KP and Inaba, H and Carroll, WL and Ramirez, NC and Phillips, AH and Kriwacki, RW and Yang, JJ and Vincent, TL and Zhao, Y and Ghate, PS and Wang, J and Reilly, C and Zhou, X and Sanders, MA and Takita, J and Kato, M and Takasugi, N and Chang, BH and Press, RD and Loh, M and Rampersaud, E and Raetz, E and Hunger, SP and Tan, K and Chang, TC and Wu, G and Pounds, SB and Mullighan, CG and Teachey, DT}, title = {The genomic basis of childhood T-lineage acute lymphoblastic leukaemia.}, journal = {Nature}, volume = {632}, number = {8027}, pages = {1082-1091}, pmid = {39143224}, issn = {1476-4687}, support = {U24 CA196173/CA/NCI NIH HHS/United States ; T32 CA236748/CA/NCI NIH HHS/United States ; K12 CA076931/CA/NCI NIH HHS/United States ; P30 CA021765/CA/NCI NIH HHS/United States ; F32 CA254140/CA/NCI NIH HHS/United States ; T32 CA009615/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; U10 CA180886/CA/NCI NIH HHS/United States ; R35 CA197695/CA/NCI NIH HHS/United States ; R01 GM115634/GM/NIGMS NIH HHS/United States ; U54 CA243124/CA/NCI NIH HHS/United States ; K99 CA279756/CA/NCI NIH HHS/United States ; R01 CA193776/CA/NCI NIH HHS/United States ; R01 CA264837/CA/NCI NIH HHS/United States ; R03 CA256550/CA/NCI NIH HHS/United States ; U24 CA114766/CA/NCI NIH HHS/United States ; }, mesh = {Child ; Female ; Humans ; Male ; Chromatin/genetics/metabolism ; Enhancer Elements, Genetic/genetics ; Epigenomics ; Gene Expression Regulation, Leukemic ; *Genome, Human/genetics ; *Genomics ; *Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics/pathology ; Single-Cell Analysis ; Transcriptome/genetics ; T-Lymphocytes/cytology/pathology ; }, abstract = {T-lineage acute lymphoblastic leukaemia (T-ALL) is a high-risk tumour[1] that has eluded comprehensive genomic characterization, which is partly due to the high frequency of noncoding genomic alterations that result in oncogene deregulation[2,3]. Here we report an integrated analysis of genome and transcriptome sequencing of tumour and remission samples from more than 1,300 uniformly treated children with T-ALL, coupled with epigenomic and single-cell analyses of malignant and normal T cell precursors. This approach identified 15 subtypes with distinct genomic drivers, gene expression patterns, developmental states and outcomes. Analyses of chromatin topology revealed multiple mechanisms of enhancer deregulation that involve enhancers and genes in a subtype-specific manner, thereby demonstrating widespread involvement of the noncoding genome. We show that the immunophenotypically described, high-risk entity of early T cell precursor ALL is superseded by a broader category of 'early T cell precursor-like' leukaemia. This category has a variable immunophenotype and diverse genomic alterations of a core set of genes that encode regulators of hematopoietic stem cell development. Using multivariable outcome models, we show that genetic subtypes, driver and concomitant genetic alterations independently predict treatment failure and survival. These findings provide a roadmap for the classification, risk stratification and mechanistic understanding of this disease.}, }
@article {pmid39142704, year = {2024}, author = {Wright, NC and Follis, S and Larson, JC and Crandall, CJ and Stefanick, ML and Ing, SW and Cauley, JA}, title = {Fractures by race and ethnicity in a diverse sample of postmenopausal women: a current evaluation among Hispanic and Asian origin groups.}, journal = {Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research}, volume = {39}, number = {9}, pages = {1296-1305}, pmid = {39142704}, issn = {1523-4681}, support = {1R01AR080868-01A1/AR/NIAMS NIH HHS/United States ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; R01 AR080868/AR/NIAMS NIH HHS/United States ; /NH/NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; }, mesh = {Aged ; Female ; Humans ; Middle Aged ; *Asian ; *Fractures, Bone/ethnology/epidemiology ; *Hispanic or Latino ; Incidence ; *Postmenopause/ethnology ; White ; }, abstract = {Using 1998-2022 Women's Health Initiative (WHI) data, our study provides contemporary fracture data by race and ethnicity, specifically focusing on Hispanic and Asian women. Fractures of interest included any clinical, hip, and major osteoporotic fractures (MOFs). We utilized the updated race and ethnicity information collected in 2003, which included seven Asian and five Hispanic origin groups. We computed crude and age-standardized fracture incidence rates per 10 000 woman-years across race and ethnic categories and by Asian and Hispanic origin. We used Cox proportional hazards model, adjusting for age and WHI clinical trial arm, to evaluate the risk of fracture (1) by race compared to White women, (2) Asian origin compared to White women, (3) Hispanic compared to non-Hispanic women, and (4) Asian and Hispanic origins compared the most prevalent origin group. Over a median (interquartile range) follow-up of 19.4 (9.2-24.2) years, 44.2% of the 160 824 women experienced any clinical fracture, including 36 278 MOFs and 8962 hip fractures. Compared to White women, Black, Pacific Islander, Asian, and multiracial women had significantly lower risk of any clinical and MOFs, while only Black and Asian women had significantly lower hip fracture risk. Within Asian women, Filipina women had 24% lower risk of any clinical fracture compared to Japanese women. Hispanic women had significantly lower risk of any clinical, hip, and MOF fractures compared to non-Hispanic women, with no differences in fracture risk observed within Hispanic origin groups. In this diverse sample of postmenopausal women, we confirmed racial and ethnic differences in fracture rates and risk, with novel findings among within Asian and Hispanic subgroups. These data can aid in future longitudinal studies evaluate contributors to racial and ethnic differences in fractures.}, }
@article {pmid39142660, year = {2024}, author = {Huang, Y and Follmann, D}, title = {Exposure proximal immune correlates analysis.}, journal = {Biostatistics (Oxford, England)}, volume = {}, number = {}, pages = {}, doi = {10.1093/biostatistics/kxae031}, pmid = {39142660}, issn = {1468-4357}, support = {R01 CA277133/CA/NCI NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; R01CA277133/GF/NIH HHS/United States ; }, abstract = {Immune response decays over time, and vaccine-induced protection often wanes. Understanding how vaccine efficacy changes over time is critical to guiding the development and application of vaccines in preventing infectious diseases. The objective of this article is to develop statistical methods that assess the effect of decaying immune responses on the risk of disease and on vaccine efficacy, within the context of Cox regression with sparse sampling of immune responses, in a baseline-naive population. We aim to further disentangle the various aspects of the time-varying vaccine effect, whether direct on disease or mediated through immune responses. Based on time-to-event data from a vaccine efficacy trial and sparse sampling of longitudinal immune responses, we propose a weighted estimated induced likelihood approach that models the longitudinal immune response trajectory and the time to event separately. This approach assesses the effects of the decaying immune response, the peak immune response, and/or the waning vaccine effect on the risk of disease. The proposed method is applicable not only to standard randomized trial designs but also to augmented vaccine trial designs that re-vaccinate uninfected placebo recipients at the end of the standard trial period. We conducted simulation studies to evaluate the performance of our method and applied the method to analyze immune correlates from a phase III SARS-CoV-2 vaccine trial.}, }
@article {pmid39142425, year = {2024}, author = {Neuhouser, ML and Butt, HI and Hu, C and Shadyab, AH and Garcia, L and Follis, S and Mouton, C and Harris, HR and Wactawski-Wende, J and Gower, EW and Vitolins, M and Von Ah, D and Nassir, R and Karanth, S and Ng, T and Paskett, E and Manson, JE and Chen, Z}, title = {Risk factors for long COVID syndrome in postmenopausal women with previously reported diagnosis of COVID-19.}, journal = {Annals of epidemiology}, volume = {98}, number = {}, pages = {36-43}, pmid = {39142425}, issn = {1873-2585}, support = {75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; HHSN268201100046C/HL/NHLBI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; HHSN261201700010C/CA/NCI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; }, mesh = {Humans ; Female ; *COVID-19/epidemiology/diagnosis ; *Postmenopause ; Risk Factors ; *Post-Acute COVID-19 Syndrome ; Aged ; *SARS-CoV-2 ; Aged, 80 and over ; Middle Aged ; United States/epidemiology ; }, abstract = {PURPOSE: Long COVID-19 syndrome occurs in 10-20 % of people after a confirmed/probable SARS-COV-2 infection; new symptoms begin within three months of COVID-19 diagnosis and last > 8 weeks. Little is known about risk factors for long COVID, particularly in older people who are at greater risk of COVID complications.<br><br>METHODS: Data are from Women's Health Initiative (WHI) postmenopausal women who completed COVID surveys that included questions on whether they had ever been diagnosed with COVID and length and nature of symptoms. Long COVID was classified using standard consensus criteria. Using WHI demographic and health data collected at study enrollment (1993-98) through the present day, machine learning identified the top 20 risk factors for long COVID. These variables were tested in logistic regression models.<br><br>RESULTS: Of n&#xa0;=&#xa0;37,280 survey respondents, 1237 (mean age = 83 years) reported a positive COVID-19 test and 425 (30&#xa0;%) reported long COVID. Symptoms included an array of neurological, cardio-pulmonary, musculoskeletal, and general fatigue, and malaise symptoms. Long COVID risk factors included weight loss, physical and mobility limitations, and specific heath conditions (e.g., history of heart valve procedure, rheumatoid arthritis).<br><br>CONCLUSIONS: Knowledge of risk factors for long COVID may be the first step in understanding the etiology of this complex disease.}, }
@article {pmid39142284, year = {2024}, author = {Tervi, A and Ramste, M and Abner, E and Cheng, P and Lane, JM and Maher, M and Valliere, J and Lammi, V and Strausz, S and Riikonen, J and Nguyen, T and Martyn, GE and Sheth, MU and Xia, F and Docampo, ML and Gu, W and ,  and Esko, T and Saxena, R and Pirinen, M and Palotie, A and Ripatti, S and Sinnott-Armstrong, N and Daly, M and Engreitz, JM and Rabinovitch, M and Heckman, CA and Quertermous, T and Jones, SE and Ollila, HM}, title = {Genetic and functional analysis of Raynaud's syndrome implicates loci in vasculature and immunity.}, journal = {Cell genomics}, volume = {4}, number = {9}, pages = {100630}, pmid = {39142284}, issn = {2666-979X}, mesh = {*Raynaud Disease/genetics/immunology ; Humans ; *Quantitative Trait Loci ; *Genome-Wide Association Study ; Nitric Oxide Synthase Type III/genetics/metabolism ; Female ; Male ; }, abstract = {Raynaud's syndrome is a dysautonomia where exposure to cold causes vasoconstriction and hypoxia, particularly in the extremities. We performed meta-analysis in four cohorts and discovered eight loci (ADRA2A, IRX1, NOS3, ACVR2A, TMEM51, PCDH10-DT, HLA, and RAB6C) where ADRA2A, ACVR2A, NOS3, TMEM51, and IRX1 co-localized with expression quantitative trait loci (eQTLs), particularly in distal arteries. CRISPR gene editing further showed that ADRA2A and NOS3 loci modified gene expression and in situ RNAscope clarified the specificity of ADRA2A in small vessels and IRX1 around small capillaries in the skin. A functional contraction assay in the cold showed lower contraction in ADRA2A-deficient and higher contraction in ADRA2A-overexpressing smooth muscle cells. Overall, our study highlights the power of genome-wide association testing with functional follow-up as a method to understand complex diseases. The results indicate temperature-dependent adrenergic signaling through ADRA2A, effects at the microvasculature by IRX1, endothelial signaling by NOS3, and immune mechanisms by the HLA locus in Raynaud's syndrome.}, }
@article {pmid39141666, year = {2024}, author = {Smith, SK and Manschot, C and Kuhn, E and Laber, E and Somers, TJ and Syrjala, KL and Applebaum, AJ}, title = {Assessing the utility of the PC-PTSD-5 as a screening tool among a cancer survivor sample.}, journal = {Cancer}, volume = {130}, number = {23}, pages = {4118-4126}, pmid = {39141666}, issn = {1097-0142}, support = {R01 CA244172/CA/NCI NIH HHS/United States ; CA244172/CA/NCI NIH HHS/United States ; CA244172/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Cancer Survivors/psychology ; *Stress Disorders, Post-Traumatic/diagnosis/psychology ; Female ; Male ; Middle Aged ; Adult ; Aged ; Hematopoietic Stem Cell Transplantation/adverse effects ; Mass Screening/methods ; Neoplasms/psychology ; Checklist ; }, abstract = {INTRODUCTION: Hematopoietic stem cell transplantation (HCT) is an intensive and invasive procedure used in cancer treatment that can lead to posttraumatic stress disorder (PTSD) symptoms. These symptoms are frequently overlooked in oncology and general health care settings. The suitability and utility of the Primary Care PTSD Screen for DSM-5 (PC-PTSD-5) within the cancer population remains uncertain. This study aims to evaluate its performance as a brief (five-item) case-finding screening alternative to the longer (20-item) PTSD Checklist for DSM-5 (PCL-5) in survivors who received an HCT 1 to 5 years ago.<br><br>METHODS: A total of 817 cancer survivors completed the PC-PTSD-5 and PCL-5 during recruitment for a randomized clinical trial. Optimal cut scores for identifying probable PTSD and item performance were determined using indices correcting for chance and item response theory analyses.<br><br>RESULTS: Of the HCT sample, 10.4% screened as positive for probable DSM-5 PTSD using the PCL-5. The PC-PTSD-5 exhibited strong internal consistency and significant associations with PCL-5 scores (total, r&#xa0;=&#xa0;.82; items, rs&#xa0;=&#xa0;.56-.61). A cutoff score of 2 provided optimal sensitivity for screening (&#x3ba;[Se]&#xa0;=&#xa0;.95), whereas a cut score of 4 demonstrated the highest efficiency for detecting a probable DSM-5 PTSD diagnosis on the PCL-5 (&#x3ba;[Eff]&#xa0;=&#xa0;.39). Item response theory analyses indicated that item 4 (numbing) of the PC-PTSD-5 yielded the most informative data, with other items potentially lacking incremental utility.<br><br>CONCLUSION: Although not an instrument validation study, these findings offer efficient evidence for using the PC-PTSD-5 as a succinct screening tool among cancer survivors in a clinical context.<br><br>TRIALS REGISTRATION: ClinicalTrials.gov, NCT04058795, registered 8/16/2019.}, }
@article {pmid39141407, year = {2024}, author = {Johnston, C and Wald, A}, title = {Genital Herpes.}, journal = {JAMA}, volume = {332}, number = {10}, pages = {835-836}, doi = {10.1001/jama.2024.12743}, pmid = {39141407}, issn = {1538-3598}, mesh = {Female ; Humans ; Male ; Antiviral Agents/therapeutic use ; *Herpes Genitalis/diagnosis/drug therapy/psychology/virology ; Herpesvirus 1, Human/isolation &amp; purification ; Herpesvirus 2, Human/isolation &amp; purification ; Social Stigma ; }, }
@article {pmid39141346, year = {2024}, author = {Salisbury, NJH and Amonkar, S and Landazuri Vinueza, J and Carter, JJ and Roman, A and Galloway, DA}, title = {Polyomavirus ALTOs, but not MTs, downregulate viral early gene expression by activating the NF-κB pathway.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {34}, pages = {e2403133121}, pmid = {39141346}, issn = {1091-6490}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R35 CA209979/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *NF-kappa B/metabolism ; *Gene Expression Regulation, Viral ; *Signal Transduction ; Antigens, Viral, Tumor/genetics/metabolism ; Merkel cell polyomavirus/genetics ; Polyomavirus Infections/virology/genetics/metabolism ; Carcinoma, Merkel Cell/virology/genetics/metabolism ; Open Reading Frames/genetics ; Cell Line, Tumor ; Down-Regulation ; Alternative Splicing ; }, abstract = {Polyomaviruses are small, circular dsDNA viruses that can cause cancer. Alternative splicing of polyomavirus early transcripts generates large and small tumor antigens (LT, ST) that play essential roles in viral replication and tumorigenesis. Some polyomaviruses also express middle tumor antigens (MTs) or alternate LT open reading frames (ALTOs), which are evolutionarily related but have distinct gene structures. MTs are a splice variant of the early transcript whereas ALTOs are overprinted on the second exon of the LT transcript in an alternate reading frame and are translated via an alternative start codon. Merkel cell polyomavirus (MCPyV), the only human polyomavirus that causes cancer, encodes an ALTO but its role in the viral lifecycle and tumorigenesis has remained elusive. Here, we show MCPyV ALTO acts as a tumor suppressor and is silenced in Merkel cell carcinoma (MCC). Rescuing ALTO in MCC cells induces growth arrest and activates NF-κB signaling. ALTO activates NF-κB by binding SQSTM1 and TRAF2&amp;3 via two N-Terminal Activating Regions (NTAR1+2), resembling Epstein-Barr virus (EBV) Latent Membrane Protein 1 (LMP1). Following activation, NF-κB dimers bind the MCPyV noncoding control region (NCCR) and downregulate early transcription. Beyond MCPyV, NTAR motifs are conserved in other polyomavirus ALTOs, which activate NF-κB signaling, but are lacking in MTs that do not. Furthermore, polyomavirus ALTOs downregulate their respective viral early transcription in an NF-κB- and NTAR-dependent manner. Our findings suggest that ALTOs evolved to suppress viral replication and promote viral latency and that MCPyV ALTO must be silenced for MCC to develop.}, }
@article {pmid39140467, year = {2024}, author = {Kim, J and Xu, S and Jung, SR and Nguyen, A and Cheng, Y and Zhao, M and Fujimoto, BS and Nelson, W and Schiro, P and Franklin, JL and Higginbotham, JN and Coffey, RJ and Shi, M and Vojtech, LN and Hladik, F and Tewari, M and Tigges, J and Ghiran, I and Jovanovic-Talisman, T and Laurent, LC and Das, S and Gololobova, O and Witwer, KW and Xu, T and Charest, A and Jensen, KVK and Raffai, RL and Jones, JC and Welsh, JA and Nolan, JP and Chiu, DT}, title = {Comparison of EV characterization by commercial high-sensitivity flow cytometers and a custom single-molecule flow cytometer.}, journal = {Journal of extracellular vesicles}, volume = {13}, number = {8}, pages = {e12498}, pmid = {39140467}, issn = {2001-3078}, support = {RF1 AG068406/AG/NIA NIH HHS/United States ; UH3 TR002874/TR/NCATS NIH HHS/United States ; IK6 BX005692/BX/BLRD VA/United States ; P50 CA095103/CA/NCI NIH HHS/United States ; P30 DK058404/DK/NIDDK NIH HHS/United States ; UG3 CA241685/CA/NCI NIH HHS/United States ; //National&#xa0;Institute of Health/ ; P50 CA236733/CA/NCI NIH HHS/United States ; R35 CA197570/CA/NCI NIH HHS/United States ; UH3 TR002878/TR/NCATS NIH HHS/United States ; R33 MH118160/MH/NIMH NIH HHS/United States ; UH3 CA241685/CA/NCI NIH HHS/United States ; //VA Merit grant/ ; I01 BX003928/BX/BLRD VA/United States ; UG3 TR002878/TR/NCATS NIH HHS/United States ; }, mesh = {*Flow Cytometry/methods/instrumentation ; Humans ; *Extracellular Vesicles/metabolism ; Colorectal Neoplasms/diagnosis ; Cell Line, Tumor ; Single Molecule Imaging/methods/instrumentation ; }, abstract = {High-sensitivity flow cytometers have been developed for multi-parameter characterization of single extracellular vesicles (EVs), but performance varies among instruments and calibration methods. Here we compare the characterization of identical (split) EV samples derived from human colorectal cancer (DiFi) cells by three high-sensitivity flow cytometers, two commercial instruments, CytoFLEX/CellStream, and a custom single-molecule flow cytometer (SMFC). DiFi EVs were stained with the membrane dye di-8-ANEPPS and with PE-conjugated anti-EGFR or anti-tetraspanin (CD9/CD63/CD81) antibodies for estimation of EV size and surface protein copy numbers. The limits of detection (LODs) for immunofluorescence and vesicle size based on calibration using cross-calibrated, hard-dyed beads were ∼10 PE/∼80 nm EV diameter for CytoFLEX and ∼10 PEs/∼67 nm for CellStream. For the SMFC, the LOD for immunofluorescence was 1 PE and ≤ 35 nm for size. The population of EVs detected by each system (di-8-ANEPPS[+]/PE[+] particles) differed widely depending on the LOD of the system; for example, CellStream/CytoFLEX detected only 5.7% and 1.5% of the tetraspanin-labelled EVs detected by SMFC, respectively, and median EV diameter and antibody copy numbers were much larger for CellStream/CytoFLEX than for SMFC as measured and validated using super-resolution/single-molecule TIRF microscopy. To obtain a dataset representing a common EV population analysed by all three platforms, we filtered out SMFC and CellStream measurements for EVs below the CytoFLEX LODs as determined by bead calibration (10 PE/80 nm). The inter-platform agreement using this filtered dataset was significantly better than for the unfiltered dataset, but even better concordance between results was obtained by applying higher cutoffs (21 PE/120 nm) determined by threshold analysis using the SMFC data. The results demonstrate the impact of specifying LODs to define the EV population analysed on inter-instrument reproducibility in EV flow cytometry studies, and the utility of threshold analysis of SMFC data for providing semi-quantitative LOD values for other flow cytometers.}, }
@article {pmid39137832, year = {2024}, author = {D'Souza, A and Stowe, HB and Green, OL and Schiff, J and Hugo, GD and Ginn, J and Maraghechi, B and Kang, KH and Kim, H and Badiyan, SN and Samson, P and Robinson, CG and Price, A and Henke, LE}, title = {Dosimetric predictors of acute and late gastrointestinal toxicities in stereotactic online adaptive magnetic resonance-guided radiotherapy (SMART) for locally advanced pancreatic adenocarcinoma.}, journal = {Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology}, volume = {200}, number = {}, pages = {110473}, doi = {10.1016/j.radonc.2024.110473}, pmid = {39137832}, issn = {1879-0887}, mesh = {Humans ; *Pancreatic Neoplasms/radiotherapy ; Male ; Female ; Aged ; Middle Aged ; Retrospective Studies ; *Radiotherapy, Image-Guided/methods/adverse effects ; *Adenocarcinoma/radiotherapy/pathology ; *Radiotherapy Dosage ; *Organs at Risk/radiation effects ; *Radiosurgery/methods/adverse effects ; Radiation Injuries/etiology ; Aged, 80 and over ; Adult ; Magnetic Resonance Imaging/methods ; Radiotherapy Planning, Computer-Assisted/methods ; }, abstract = {BACKGROUND AND PURPOSE: A retrospective evaluation of dosimetric predictors and leveraged dose-volume data for gastrointestinal (GI) toxicities for locally-advanced pancreatic cancer (LAPC) treated with daily stereotactic MRI-guided online-adaptive radiotherapy (SMART).<br><br>MATERIALS AND METHODS: 147 patients with LAPC were treated with SMART at our institution between 2018 and 2021. Patients were evaluated using CTCAE V5.0 for RT-related acute (&#x2264;3 months) and late (>3 months) toxicities. Each organ at risk (OAR) was matched to a&#xa0;&#x2265;&#xa0;grade 2 (Gr2+) toxicity endpoint composite group. A least absolute shrinkage selector operator regression model was constructed by dose-volumes per OAR to account for OAR multicollinearity. A receiver operator curve (ROC) analysis was performed for the combined averages of significant toxicity groups to identify critical volumes per dose levels.<br><br>RESULTS: 18 of 147 patients experienced Gr2+ GI toxicity. 17 Gr2+ duodenal toxicities were seen; the most significant predictor was a V33Gy odds ratio (OR) of 1.69 per cc (95&#xa0;% CI 1.14-2.88). 17 Gr2+ small bowel (SB) toxicities were seen; the most significant predictor was a V33Gy OR of 1.60 per cc (95&#xa0;% CI 1.01-2.53). The AUC was 0.72 for duodenum and SB. The optimal duodenal cut-point was 1.00&#xa0;cc (true positive (TP): 17.8&#xa0;%; true negative (TN); 94.9&#xa0;%). The SB cut-point was 1.75&#xa0;cc (TP: 16.7&#xa0;%; TN: 94.3&#xa0;%). No stomach or large bowel dose toxicity predictors were identified.<br><br>CONCLUSIONS: For LAPC treated with SMART, the dose-volume threshold of V33Gy for duodenum and SB was associated with Gr2+ toxicities. These metrics can be utilized to guide future dose-volume constraints for patients undergoing upper abdominal SBRT.}, }
@article {pmid39136970, year = {2024}, author = {Appelbaum, JS and Appelbaum, FR and Percival, ME}, title = {Second chances for secondary AML.}, journal = {Blood advances}, volume = {8}, number = {15}, pages = {4221-4222}, pmid = {39136970}, issn = {2473-9537}, mesh = {Humans ; *Leukemia, Myeloid, Acute/therapy/diagnosis ; Neoplasms, Second Primary/etiology/diagnosis ; }, }
@article {pmid39136016, year = {2024}, author = {Barreto, BC and Neves, MVGD and Cardoso, CMA and Meira, CS and Daltro, PS and Figueira, CP and Santos, GC and Silva, DN and Távora, F and Neto, JDS and Macambira, SG and Lampe, PD and Coutinho, KCDS and Kasai Brunswick, TH and Ribeiro Dos Santos, R and Campos de Carvalho, AC and Soares, MBP}, title = {The effects of inflammation on connexin 43 in chronic Chagas disease cardiomyopathy.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1440662}, pmid = {39136016}, issn = {1664-3224}, support = {R01 GM055632/GM/NIGMS NIH HHS/United States ; }, mesh = {*Connexin 43/metabolism/genetics ; Animals ; *Chagas Cardiomyopathy/metabolism/pathology/immunology/parasitology ; Humans ; Mice ; *Myocytes, Cardiac/metabolism/parasitology/pathology ; *Mice, Inbred C57BL ; Inflammation/metabolism ; Phosphorylation ; Male ; Chronic Disease ; Trypanosoma cruzi ; Disease Models, Animal ; Cell Line ; Cytokines/metabolism ; Arrhythmias, Cardiac/metabolism/parasitology/immunology ; Female ; }, abstract = {BACKGROUND: Cardiac arrhythmias are the main cause of sudden death due to Chronic Chagasic Cardiomyopathy (CCC). Here we investigated alterations in connexin 43 (Cx43) expression and phosphorylation in cardiomyocytes as well as associations with cardiac arrhythmias in CCC.<br><br>METHODS: C57Bl/6 mice infected with Trypanosoma cruzi underwent cardiac evaluations at 6 and 12 months after infection via treadmill testing and EKG. Histopathology, cytokine gene expression, and distribution of total Cx43 and its phosphorylated forms Cx43[S368] and Cx43[S325/328/330] were investigated. Human heart samples obtained from subjects with CCC were submitted to immunofluorescence analysis. In vitro simulation of a pro-inflammatory microenvironment (IL-1&#x3b2;, TNF, and IFN-&#x3b3;) was performed in H9c2 cells and iPSC-derived cardiomyocytes to evaluate Cx43 distribution, action potential duration, and Lucifer Yellow dye transfer.<br><br>RESULTS: Mice chronically infected with T. cruzi exhibited impaired cardiac function associated with increased inflammation, fibrosis and upregulated IL-1&#x3b2;, TNF, and IFN-&#x3b3; gene expression. Confocal microscopy revealed altered total Cx43, Cx43[S368] and Cx43[S325/328/330] localization and phosphorylation patterns in CCC, with dispersed staining outside the intercalated disc areas, i.e., in lateral membranes and the cytoplasm. Reduced co-localization of total Cx43 and N-cadherin was observed in the intercalated discs of CCC mouse hearts compared to controls. Similar results were obtained in human CCC heart samples, which showed Cx43 distribution outside the intercalated discs. Stimulation of human iPSC-derived cardiomyocytes or H9c2 cells with IL-1&#x3b2;, TNF, and IFN-&#x3b3; induced alterations in Cx43 localization, reduced action potential duration and dye transfer between adjacent cells.<br><br>CONCLUSION: Heart inflammation in CCC affects the distribution and phosphorylation pattern of Cx43, which may contribute to the generation of conduction disturbances in Chagas disease.}, }
@article {pmid39134575, year = {2024}, author = {Lin, HY and Mazumder, H and Sarkar, I and Huang, PY and Eeles, RA and Kote-Jarai, Z and Muir, KR and ,  and Schleutker, J and Pashayan, N and Batra, J and ,  and Neal, DE and Nielsen, SF and Nordestgaard, BG and Grönberg, H and Wiklund, F and MacInnis, RJ and Haiman, CA and Travis, RC and Stanford, JL and Kibel, AS and Cybulski, C and Khaw, KT and Maier, C and Thibodeau, SN and Teixeira, MR and Cannon-Albright, L and Brenner, H and Kaneva, R and Pandha, H and ,  and Park, JY}, title = {Cluster effect for SNP-SNP interaction pairs for predicting complex traits.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {18677}, pmid = {39134575}, issn = {2045-2322}, support = {17528/CRUK_/Cancer Research UK/United Kingdom ; PC220560//U.S. Department of Defense/ ; }, mesh = {*Polymorphism, Single Nucleotide ; Humans ; *Multifactorial Inheritance/genetics ; Gene Frequency ; Genome-Wide Association Study/methods ; Cluster Analysis ; Models, Genetic ; Epistasis, Genetic ; }, abstract = {Single nucleotide polymorphism (SNP) interactions are the key to improving polygenic risk scores. Previous studies reported several significant SNP-SNP interaction pairs that shared a common SNP to form a cluster, but some identified pairs might be false positives. This study aims to identify factors associated with the cluster effect of false positivity and develop strategies to enhance the accuracy of SNP-SNP interactions. The results showed the cluster effect is a major cause of false-positive findings of SNP-SNP interactions. This cluster effect is due to high correlations between a causal pair and null pairs in a cluster. The clusters with a hub SNP with a significant main effect and a large minor allele frequency (MAF) tended to have a higher false-positive rate. In addition, peripheral null SNPs in a cluster with a small MAF tended to enhance false positivity. We also demonstrated that using the modified significance criterion based on the 3 p-value rules and the bootstrap approach (3pRule + bootstrap) can reduce false positivity and maintain high true positivity. In addition, our results also showed that a pair without a significant main effect tends to have weak or no interaction. This study identified the cluster effect and suggested using the 3pRule + bootstrap approach to enhance SNP-SNP interaction detection accuracy.}, }
@article {pmid39134521, year = {2024}, author = {Gagne, M and Flynn, BJ and Honeycutt, CC and Flebbe, DR and Andrew, SF and Provost, SJ and McCormick, L and Van Ry, A and McCarthy, E and Todd, JM and Bao, S and Teng, IT and Marciano, S and Rudich, Y and Li, C and Jain, S and Wali, B and Pessaint, L and Dodson, A and Cook, A and Lewis, MG and Andersen, H and Zahradník, J and Suthar, MS and Nason, MC and Foulds, KE and Kwong, PD and Roederer, M and Schreiber, G and Seder, RA and Douek, DC}, title = {Variant-proof high affinity ACE2 antagonist limits SARS-CoV-2 replication in upper and lower airways.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {6894}, pmid = {39134521}, issn = {2041-1723}, support = {75N93021C00017/AI/NIAID NIH HHS/United States ; P51 OD011132/OD/NIH HHS/United States ; 3814/19//Israel Science Foundation (ISF)/ ; P51 OD011132/CD/ODCDC CDC HHS/United States ; }, mesh = {Animals ; Humans ; Male ; *Angiotensin-Converting Enzyme 2/antagonists &amp; inhibitors ; *Antiviral Agents/pharmacology ; Chlorocebus aethiops ; *COVID-19/virology/immunology/prevention &amp; control ; COVID-19 Drug Treatment ; Disease Models, Animal ; Macaca mulatta ; *SARS-CoV-2/drug effects/physiology/immunology ; Spike Glycoprotein, Coronavirus/metabolism/genetics/immunology ; Vero Cells ; *Virus Replication/drug effects ; }, abstract = {SARS-CoV-2 has the capacity to evolve mutations that escape vaccine- and infection-acquired immunity and antiviral drugs. A variant-agnostic therapeutic agent that protects against severe disease without putting selective pressure on the virus would thus be a valuable biomedical tool that would maintain its efficacy despite the ongoing emergence of new variants. Here, we challenge male rhesus macaques with SARS-CoV-2 Delta-the most pathogenic variant in a highly susceptible animal model. At the time of challenge, we also treat the macaques with aerosolized RBD-62, a protein developed through multiple rounds of in vitro evolution of SARS-CoV-2 RBD to acquire 1000-fold enhanced ACE2 binding affinity. RBD-62 treatment equivalently suppresses virus replication in both upper and lower airways, a phenomenon not previously observed with clinically approved vaccines. Importantly, RBD-62 does not block the development of virus-specific T- and B-cell responses and does not elicit anti-drug immunity. These data provide proof-of-concept that RBD-62 can prevent severe disease from a highly virulent variant.}, }
@article {pmid39133932, year = {2024}, author = {Döhner, H and DiNardo, CD and Appelbaum, FR and Craddock, C and Dombret, H and Ebert, BL and Fenaux, P and Godley, LA and Hasserjian, RP and Larson, RA and Levine, RL and Miyazaki, Y and Niederwieser, D and Ossenkoppele, G and Röllig, C and Sierra, J and Stein, EM and Tallman, MS and Tien, HF and Wang, J and Wierzbowska, A and Wei, AH and Löwenberg, B}, title = {Genetic risk classification for adults with AML receiving less-intensive therapies: the 2024 ELN recommendations.}, journal = {Blood}, volume = {144}, number = {21}, pages = {2169-2173}, doi = {10.1182/blood.2024025409}, pmid = {39133932}, issn = {1528-0020}, mesh = {Humans ; *Leukemia, Myeloid, Acute/genetics/therapy/drug therapy ; Adult ; Risk Assessment ; Genetic Predisposition to Disease ; Risk Factors ; }, abstract = {The European LeukemiaNet (ELN) genetic risk classifications were developed based on data from younger adults receiving intensive chemotherapy. Emerging analyses from patients receiving less-intensive therapies prompted a proposal for an ELN genetic risk classification specifically for this patient population.}, }
@article {pmid39133891, year = {2024}, author = {Annesley, C and Lamble, AJ and Summers, C and Pulsipher, MA and Wayne, AS and Rivers, J and Huang, W and Wilson, A and Wu, Q and Seidel, KD and Mgebroff, S and Brown, CT and Lindgren, C and Park, JR and Jensen, MC and Gardner, RA}, title = {Feasibility and Favorable Responses Following Investigational CAR T-Cell Therapy for Relapsed and Refractory Infant ALL.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024012638}, pmid = {39133891}, issn = {2473-9537}, abstract = {Infants with B-cell acute lymphoblastic leukemia (B-ALL) continue to have significantly worse outcomes compared to older children with B-ALL, and those with relapsed or refractory (R/R) infant ALL have especially dismal outcomes with conventional treatment. CD19-targeting chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable success in the treatment of R/R childhood B-ALL, though the majority of reports have been in non-infant patients. Barriers to the successful implementation of CAR T-cell therapy in infant B-ALL include challenges related to apheresis, product manufacturing and disease-specific considerations such as lineage switch. We describe our experience utilizing two experimental CD19-CAR T-cell products, SCRI-CAR19 or SCRI-CAR19x22, for 19 patients with R/R infant B-ALL enrolled on three clinical trials. CAR T-cell products were successfully manufactured in 18/19 (94.7%) patients, with a median age of 22.5 months at enrollment (range, 14.5-40.1 months). Sixteen of 17 (94.1%) treated patients achieved a complete remission without detectable minimal residual disease. The 1-year leukemia free survival was 75% and 1-year overall survival was 76.5%, with a median follow up time of 35.8 months (range, 1.7-83.6 months). Cytokine release syndrome (CRS) occurred in 14/17 (82.4%) patients, with only 1 patient experiencing Grade 3 CRS. Neurotoxicity occurred in 2/17 (11.8%) patients with all events ≤ Grade 2. With the successful early clinical experience of CAR T-cell therapy in this population, more systematic evaluation specific to infant ALL is warranted.}, }
@article {pmid39133650, year = {2024}, author = {Ford, ES and Li, AZ and Laing, KJ and Dong, L and Diem, K and Jing, L and Mayer-Blackwell, K and Basu, K and Ott, M and Tartaglia, J and Gurunathan, S and Reid, JL and Ecsedi, M and Chapuis, AG and Huang, ML and Magaret, AS and Johnston, C and Zhu, J and Koelle, DM and Corey, L}, title = {Expansion of the HSV-2-specific T cell repertoire in skin after immunotherapeutic HSV-2 vaccine.}, journal = {JCI insight}, volume = {9}, number = {14}, pages = {}, pmid = {39133650}, issn = {2379-3708}, support = {K08 AI148588/AI/NIAID NIH HHS/United States ; R01 AI134878/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; 75N93019C00063/AI/NIAID NIH HHS/United States ; U19 AI113173/AI/NIAID NIH HHS/United States ; P01 AI030731/AI/NIAID NIH HHS/United States ; R01 AI042528/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Herpesvirus 2, Human/immunology ; *Skin/immunology/virology ; *Herpes Genitalis/immunology/prevention &amp; control/virology ; *CD4-Positive T-Lymphocytes/immunology ; Female ; Receptors, Antigen, T-Cell, alpha-beta/immunology/genetics ; Male ; Adult ; Vaccination ; Middle Aged ; }, abstract = {The skin at the site of HSV-2 reactivation is enriched for HSV-2-specific T cells. To evaluate whether an immunotherapeutic vaccine could elicit skin-based memory T cells, we studied skin biopsies and HSV-2-reactive CD4+ T cells from PBMCs by T cell receptor (TCR) β chain (TRB) sequencing before and after vaccination with a replication-incompetent whole-virus HSV-2 vaccine candidate (HSV529). The representation of HSV-2-reactive CD4+ TRB sequences from PBMCs in the skin TRB repertoire increased after the first vaccine dose. We found sustained expansion after vaccination of unique, skin-based T cell clonotypes that were not detected in HSV-2-reactive CD4+ T cells isolated from PBMCs. In one participant, a switch in immunodominance occurred with the emergence of a TCR αβ pair after vaccination that was not detected in blood. This TCRαβ was shown to be HSV-2 reactive by expression of a synthetic TCR in a Jurkat-based NR4A1 reporter system. The skin in areas of HSV-2 reactivation possessed an oligoclonal TRB repertoire that was distinct from the circulation. Defining the influence of therapeutic vaccination on the HSV-2-specific TRB repertoire requires tissue-based evaluation.}, }
@article {pmid39133444, year = {2024}, author = {Jones, SMW and Briant, KJ and Doody, DR and Iachan, R and Mendoza, JA}, title = {A person-reported cumulative social risk measure does not show bias by income and education.}, journal = {Journal of patient-reported outcomes}, volume = {8}, number = {1}, pages = {90}, pmid = {39133444}, issn = {2509-8020}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P30CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; Male ; *Educational Status ; *Income ; Middle Aged ; Adult ; *Social Determinants of Health ; Bias ; Aged ; Racism ; Self Report ; }, abstract = {BACKGROUND: Social risk such as housing instability, trouble affording medical care and food insecurity are a downstream effect of social determinants of health (SDOHs) and are frequently associated with worse health. SDOHs include experiences of racism, sexism and other discrimination as well as differences in income and education. The collective effects of each social risk a person reports are called cumulative social risk. Cumulative social risk has traditionally been measured through counts or sum scores that treat each social risk as equivalent. We have proposed to use item response theory (IRT) as an alternative measure of person-reported cumulative social risk as IRT accounts for the severity in each risk and allows for more efficient screening with computerized adaptive testing.<br><br>METHODS: We conducted a differential item functioning (DIF) analysis comparing IRT-based person-reported cumulative social risk scores by income and education in a population-based sample (n&#x2009;=&#x2009;2122). Six social risk items were analyzed using the two-parameter logistic model and graded response model.<br><br>RESULTS: Analyses showed no DIF on an IRT-based cumulative social risk score by education level for the six items examined. Statistically significant DIF was found on three items by income level but the ultimate effect on the scores was negligible.<br><br>CONCLUSIONS: Results suggest an IRT-based cumulative social risk score is not biased by education and income level and can be used for comparisons between groups. An IRT-based cumulative social risk score will be useful for combining datasets to examine policy factors affecting social risk and for more efficient screening of patients for social risk using computerized adaptive testing.}, }
@article {pmid39132937, year = {2024}, author = {Brown, JR and Eichhorst, B and Hillmen, P and Jurczak, W and Kaźmierczak, M and Lamanna, N and O'Brien, SM and Tam, CS and Qiu, L and Zhou, K and Simkovic, M and Mayer, J and Gillespie-Twardy, A and Ferrajoli, A and Ganly, PS and Weinkove, R and Grosicki, S and Mital, A and Robak, T and Osterborg, A and Yimer, HA and Salmi, T and Wang, MD and Fu, L and Li, J and Wu, K and Cohen, A and Shadman, M}, title = {Plain language summary of zanubrutinib or ibrutinib in chronic lymphocytic leukemia that is resistant to treatment or has come back after treatment.}, journal = {Future oncology (London, England)}, volume = {20}, number = {12}, pages = {717-726}, doi = {10.2217/fon-2023-0849}, pmid = {39132937}, issn = {1744-8301}, mesh = {Humans ; *Piperidines/therapeutic use ; *Adenine/analogs &amp; derivatives/therapeutic use ; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; *Pyrimidines/therapeutic use ; *Pyrazoles/therapeutic use ; *Drug Resistance, Neoplasm ; *Protein Kinase Inhibitors/therapeutic use/adverse effects ; Antineoplastic Agents/therapeutic use ; Pyrazines/therapeutic use ; Thiazoles/therapeutic use ; Treatment Outcome ; }, }
@article {pmid39132880, year = {2024}, author = {Simpson, S and Yu, K and Bell-Brown, A and Kimura, A and Meisner, A and Issaka, RB}, title = {Factors Associated With Mailed Fecal Immunochemical Test Completion in an Integrated Academic-Community Healthcare System.}, journal = {Clinical and translational gastroenterology}, volume = {15}, number = {10}, pages = {e1}, pmid = {39132880}, issn = {2155-384X}, support = {K08 CA241296/CA/NCI NIH HHS/United States ; K08 CA241296/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Retrospective Studies ; Female ; *Colorectal Neoplasms/diagnosis ; Middle Aged ; Male ; Aged ; *Early Detection of Cancer/methods ; *Postal Service ; *Occult Blood ; *Delivery of Health Care, Integrated ; Primary Health Care ; Feces/chemistry ; Washington ; Community Health Services ; Mass Screening/methods ; }, abstract = {INTRODUCTION: Mailed fecal immunochemical test (FIT) outreach is an effective strategy to increase colorectal cancer (CRC) screening. The aim of this study was to determine the patient-level, clinic-level, and geographic-level factors associated with CRC screening completion in a mailed FIT outreach program.<br><br>METHODS: This retrospective cohort study was conducted in the integrated healthcare system of University of Washington Medicine and included patients aged 50-75 years, who were due for CRC screening, and had a primary care encounter in the past 3 years. Eligible patients received mailed outreach that included a letter with information about CRC screening, FIT kit, and a prepaid return envelope. CRC screening and factors associated with completion were obtained from electronic health records and the CRC screening program database.<br><br>RESULTS: Of the 9,719 patients who received mailed outreach, 29.6% completed FIT mailed outreach. The median FIT return time was 27 days (interquartile range 14-54). On multivariate analysis, patients with a higher area deprivation index, insured through Medicaid, living without a partner, and whose last primary care visit was >12 months ago were less likely to complete a FIT compared with their counterparts. Over a 12-month period, overall CRC screening across the health system increased by 2 percentage points (68%-70%).<br><br>DISCUSSION: Mailed FIT outreach in an integrated academic-community practice was feasible, with 32% of invited patients completing CRC screening by FIT or colonoscopy, on par with published literature. Patient and geographic-level factors were associated with CRC screening completion. These data will inform additional interventions aimed to increase CRC screening participation in this population.}, }
@article {pmid39129757, year = {2023}, author = {Bloom, JD}, title = {Association between SARS-CoV-2 and metagenomic content of samples from the Huanan Seafood Market.}, journal = {Virus evolution}, volume = {9}, number = {2}, pages = {vead050}, pmid = {39129757}, issn = {2057-1577}, support = {S10 OD020069/OD/NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, abstract = {The role of the Huanan Seafood Market in the early severe acute respiratory syndrome virus 2 (SARS-CoV-2) outbreak remains unclear. Recently, the Chinese Centers for Disease Control (CDC) released data from deep sequencing of environmental samples collected from the market after it was closed on 1 January 2020. Prior to this release, Crits-Christoph et al. analyzed data from a subset of the samples. Both that study and the Chinese CDC study concurred that the samples contained genetic material from a variety of species, including some like raccoon dogs that are susceptible to SARS-CoV-2. However, neither study systematically analyzed the relationship between the amount of genetic material from SARS-CoV-2 and different animal species. Here I implement a fully reproducible computational pipeline that jointly analyzes the number of reads mapping to SARS-CoV-2 and the mitochondrial genomes of chordate species across the full set of samples. I validate the presence of genetic material from numerous species and calculate mammalian mitochondrial compositions similar to those reported by Crits-Christoph et al. However, the SARS-CoV-2 content of the environmental samples is generally very low: only 21 of 176 samples contain more than ten SARS-CoV-2 reads, despite most samples being sequenced to depths exceeding 10[8] total reads. None of the samples with double-digit numbers of SARS-CoV-2 reads have a substantial fraction of their mitochondrial material from any non-human susceptible species. Only one of the fourteen samples with at least a fifth of the chordate mitochondrial material from raccoon dogs contains any SARS-CoV-2 reads, and that sample only has 1 of ~200,000,000 reads mapping to SARS-CoV-2. Instead, SARS-CoV-2 reads are most correlated with reads mapping to various fish, such as catfish and largemouth bass. These results suggest that while metagenomic analysis of the environmental samples is useful for identifying animals or animal products sold at the market, co-mingling of animal and viral genetic material is unlikely to reliably indicate whether any animals were infected by SARS-CoV-2.}, }
@article {pmid39128225, year = {2024}, author = {Morrish, F and Gingras, H and Noonan, J and Huang, L and Sweet, IR and Kuok, IT and Knoblaugh, SE and Hockenbery, DM}, title = {Mitochondrial diabetes in mice expressing a dominant-negative allele of nuclear respiratory factor-1 (Nrf1) in pancreatic β-cells.}, journal = {Biochemical and biophysical research communications}, volume = {737}, number = {}, pages = {150478}, doi = {10.1016/j.bbrc.2024.150478}, pmid = {39128225}, issn = {1090-2104}, mesh = {Animals ; *Insulin-Secreting Cells/metabolism/pathology ; *Nuclear Respiratory Factor 1/metabolism/genetics ; *Mice, Transgenic ; Mice ; *Insulin/metabolism ; *Mitochondria/metabolism/genetics ; Alleles ; Diabetes Mellitus/metabolism/genetics/pathology ; Genes, Dominant ; Male ; }, abstract = {Genetic polymorphisms in nuclear respiratory factor-1 (Nrf1), a key transcriptional regulator of nuclear-encoded mitochondrial proteins, have been linked to diabetes. Homozygous deletion of Nrf1 is embryonic lethal in mice. Our goal was to generate mice with β-cell-specific reduction in NRF1 function to investigate the relationship between NRF1 and diabetes. We report the generation of mice expressing a dominant-negative allele of Nrf1 (DNNRF1) in pancreatic β-cells. Heterozygous transgenic mice had high fed blood glucose levels detected at 3 wks of age, which persisted through adulthood. Plasma insulin levels in DNNRF1 transgenic mice were reduced, while insulin sensitivity remained intact in young animals. Islet size was reduced with increased numbers of apoptotic cells, and insulin content in islets by immunohistochemistry was low. Glucose-stimulated insulin secretion in isolated islets was reduced in DNNRF1-mice, but partially rescued by KCl, suggesting that decreased mitochondrial function contributed to the insulin secretory defect. Electron micrographs demonstrated abnormal mitochondrial morphology in β-cells. Expression of NRF1 target genes Tfam, Tfb1m and Tfb2m, and islet cytochrome c oxidase and succinate dehydrogenase activities were reduced in DNNRF1-mice. Rescue of mitochondrial function with low level activation of transgenic c-Myc in β-cells was sufficient to restore β-cell mass and prevent diabetes. This study demonstrates that reduced NRF1 function can lead to loss of β-cell function and establishes a model to study the interplay between regulators of bi-genomic gene transcription in diabetes.}, }
@article {pmid39127048, year = {2024}, author = {Barrero, DJ and Wijeratne, SS and Zhao, X and Cunningham, GF and Yan, R and Nelson, CR and Arimura, Y and Funabiki, H and Asbury, CL and Yu, Z and Subramanian, R and Biggins, S}, title = {Architecture of native kinetochores revealed by structural studies utilizing a thermophilic yeast.}, journal = {Current biology : CB}, volume = {34}, number = {17}, pages = {3881-3893.e5}, pmid = {39127048}, issn = {1879-0445}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 GM145651/GM/NIGMS NIH HHS/United States ; R35 GM134842/GM/NIGMS NIH HHS/United States ; R35 GM149357/GM/NIGMS NIH HHS/United States ; }, mesh = {*Kluyveromyces/cytology ; *Kinetochores/chemistry/metabolism/ultrastructure ; Microtubule-Associated Proteins/analysis ; Fungal Proteins/analysis ; Microscopy, Atomic Force ; Microscopy, Electron, Scanning ; Microtubules/metabolism ; Electron Microscope Tomography ; }, abstract = {Eukaryotic chromosome segregation requires kinetochores, multi-megadalton protein machines that assemble on the centromeres of chromosomes and mediate attachments to dynamic spindle microtubules. Kinetochores are built from numerous complexes, and there has been progress in structural studies on recombinant subassemblies. However, there is limited structural information on native kinetochore architecture. To address this, we purified functional, native kinetochores from the thermophilic yeast Kluyveromyces marxianus and examined them by electron microscopy (EM), cryoelectron tomography (cryo-ET), and atomic force microscopy (AFM). The kinetochores are extremely large, flexible assemblies that exhibit features consistent with prior models. We assigned kinetochore polarity by visualizing their interactions with microtubules and locating the microtubule binder, Ndc80c. This work shows that isolated kinetochores are more dynamic and complex than what might be anticipated based on the known structures of recombinant subassemblies and provides the foundation to study the global architecture and functions of kinetochores at a structural level.}, }
@article {pmid39126374, year = {2024}, author = {Felker, J and Bjornard, K and Close, A and Chavez, J and Chow, EJ and Meacham, LR and Burns, K}, title = {Fertility preservation in pediatric central nervous system tumors: A report from the Children's Oncology Group.}, journal = {Pediatric blood &amp; cancer}, volume = {71}, number = {11}, pages = {e31246}, pmid = {39126374}, issn = {1545-5017}, support = {//St. Baldrick's Foundation/ ; U10CA098543/NH/NIH HHS/United States ; UG1CA189955/NH/NIH HHS/United States ; U10CA18099/NH/NIH HHS/United States ; UG1 CA189955/CA/NCI NIH HHS/United States ; U10CA098413/NH/NIH HHS/United States ; U10 CA098543/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; U10 CA180886/CA/NCI NIH HHS/United States ; //Children's Oncology&#xa0;Group/ ; U10 CA098413/CA/NCI NIH HHS/United States ; U10CA180886/NH/NIH HHS/United States ; }, mesh = {Humans ; *Fertility Preservation/methods ; Male ; *Central Nervous System Neoplasms/therapy ; Female ; Child ; Adolescent ; Child, Preschool ; Prognosis ; }, abstract = {The Oncofertility Consortium Pediatric Initiative Network has published recommendations about the risks of infertility due to gonadotoxic therapy. We abstracted gonadotoxic therapies from central nervous system (CNS) Children's Oncology Group (COG) protocols between 2000 and 2022. We assigned them as unknown, minimal, significant, or high levels of increased risk for gonadal dysfunction/infertility. Seven of 11 CNS protocols placed patients at a high level of risk in at least one treatment arm. Males (7/11) were most commonly at a high level of risk, followed by pubertal females (6/11) and prepubertal females (5/11), highlighting the importance of pre-treatment counseling regarding fertility preservation interventions in this population.}, }
@article {pmid39125034, year = {2024}, author = {Promsong, A and Chuerduangphui, J and Levy, CN and Hladik, F and Satthakarn, S and Nittayananta, W}, title = {Effects of Ellagic Acid on Vaginal Innate Immune Mediators and HPV16 Infection In Vitro.}, journal = {Molecules (Basel, Switzerland)}, volume = {29}, number = {15}, pages = {}, pmid = {39125034}, issn = {1420-3049}, mesh = {Humans ; Female ; *Ellagic Acid/pharmacology ; *Immunity, Innate/drug effects ; *Vagina/virology/immunology/drug effects ; *Human papillomavirus 16 ; *Papillomavirus Infections/immunology/virology/drug therapy ; Cytokines/metabolism ; Epithelial Cells/drug effects/virology/metabolism/immunology ; beta-Defensins/metabolism ; HEK293 Cells ; }, abstract = {Ellagic acid (EA) is a phenolic phytochemical found in many plants and their fruits. Vaginal epithelial cells are the first line of defense against pathogen invasion in the female reproductive tract and express antimicrobial peptides, including hBD2 and SLPI. This study investigated the in vitro effects of EA (1) on vaginal innate immunity using human vaginal epithelial cells, and (2) on HPV16 pseudovirus infection. Vaginal cells were cultured in the presence or absence of EA, and the expression of hBD2 and SLPI was determined at both transcriptional and translational levels. In addition, secretion of various cytokines and chemokines was measured. Cytotoxicity of EA was determined by CellTiter-blue and MTT assays. To investigate the ability of EA to inhibit HPV16 infection, EA was used to treat HEK-293FT cells in pre-attachment and adsorption steps. We found significant increases in both hBD2 mRNA (mean 2.9-fold at 12.5 µM EA, p < 0.001) and protein (mean 7.1-fold at 12.5 µM EA, p = 0.002) in response to EA. SLPI mRNA also increased significantly (mean 1.4-fold at 25 µM EA, p = 0.01), but SLPI protein did not. Secretion of IL-2 but not of other cytokines/chemokines was induced by EA in a dose-dependent manner. EA was not cytotoxic. At the pre-attachment step, EA at CC20 and CC50 showed a slight trend towards inhibiting HPV16 pseudovirus, but this was not significant. In summary, vaginal epithelial cells can respond to EA by producing innate immune factors, and at tested concentrations, EA is not cytotoxic. Thus, plant-derived EA could be useful as an immunomodulatory agent to improve vaginal health.}, }
@article {pmid39123464, year = {2024}, author = {Ebadi, M and Pankuch, M and Boyer, S and Chang, J and Stevens, C and Hall, MD and Hasan, S and Bates, JE and Flampouri, S and Kole, AJ and Mohindra, P and Rossi, C and Sanghvi, P and McGee, L and Rana, Z and Tseng, YD}, title = {Proton Pencil Beam Scanning Facilitates the Safe Treatment of Extended Radiation Targets for Hodgkin Lymphoma: A Report from the Proton Collaborative Group Registry.}, journal = {Cancers}, volume = {16}, number = {15}, pages = {}, pmid = {39123464}, issn = {2072-6694}, abstract = {Because proton beam therapy (PBT) can lower the dose of radiation to the heart, lungs, and breast, it is an established radiation modality for patients with Hodgkin lymphoma (HL). Pencil beam scanning (PBS) PBT facilitates the treatment of more extensive targets. This may be especially of value for lymphoma patients who require RT to both mediastinal and axillary targets, defined here as extended target RT (ETRT), given the target distribution and need to minimize the lung, heart, and breast dose. Using the Proton Collaborative Group registry, we identified patients with HL treated with PBT to both their mediastinum and axilla, for which DICOM-RT was available. All patients were treated with PBS. To evaluate the dosimetric impact of PBS, we compared delivered PBS plans with VMAT butterfly photon plans optimized to have the same target volume coverage, when feasible. Between 2016 and 2021, twelve patients (median 26 years) received PBS ETRT (median 30.6 Gy (RBE)). Despite the large superior/inferior (SI, median 22.2 cm) and left/right (LR, median 22.8 cm) extent of the ETRT targets, all patients were treated with one isocenter except for two patients (both with SI and LR > 30 cm). Most commonly, anterior beams, with or without posterior beams, were used. Compared to photons, PBS had greater target coverage, better conformity, and lower dose heterogeneity while achieving lower doses to the lungs and heart, but not to the breast. No acute grade 3+ toxicities were reported, including pneumonitis. Proton ETRT in this small cohort was safely delivered with PBS and was associated with an improved sparing of the heart and lungs compared to VMAT.}, }
@article {pmid39122670, year = {2024}, author = {Rachid Zaim, S and Pebworth, MP and McGrath, I and Okada, L and Weiss, M and Reading, J and Czartoski, JL and Torgerson, TR and McElrath, MJ and Bumol, TF and Skene, PJ and Li, XJ}, title = {MOCHA's advanced statistical modeling of scATAC-seq data enables functional genomic inference in large human cohorts.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {6828}, pmid = {39122670}, issn = {2041-1723}, support = {UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI069481/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *COVID-19/genetics/virology ; *Models, Statistical ; *Single-Cell Analysis/methods ; *Gene Regulatory Networks ; *Genomics/methods ; *Chromatin/genetics/metabolism ; SARS-CoV-2/genetics ; Transposases/metabolism/genetics ; Chromatin Immunoprecipitation Sequencing/methods ; Cohort Studies ; Gene Expression Regulation ; }, abstract = {Single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) is being increasingly used to study gene regulation. However, major analytical gaps limit its utility in studying gene regulatory programs in complex diseases. In response, MOCHA (Model-based single cell Open CHromatin Analysis) presents major advances over existing analysis tools, including: 1) improving identification of sample-specific open chromatin, 2) statistical modeling of technical drop-out with zero-inflated methods, 3) mitigation of false positives in single cell analysis, 4) identification of alternative transcription-starting-site regulation, and 5) modules for inferring temporal gene regulatory networks from longitudinal data. These advances, in addition to open chromatin analyses, provide a robust framework after quality control and cell labeling to study gene regulatory programs in human disease. We benchmark MOCHA with four state-of-the-art tools to demonstrate its advances. We also construct cross-sectional and longitudinal gene regulatory networks, identifying potential mechanisms of COVID-19 response. MOCHA provides researchers with a robust analytical tool for functional genomic inference from scATAC-seq data.}, }
@article {pmid39119980, year = {2024}, author = {Filigrana, P and Moon, JY and Gallo, LC and Fernández-Rhodes, L and Perreira, KM and Daviglus, ML and Thyagarajan, B and Garcia-Bedoya, OL and Cai, J and Xue, X and Kaplan, RC and Suglia, S and Isasi, CR}, title = {LifeCourse Socioeconomic Position and Ideal Cardiovascular Health in Hispanic/Latino Adults of the Hispanic Community Health Study/Study of Latinos.}, journal = {Journal of the American Heart Association}, volume = {13}, number = {16}, pages = {e035503}, doi = {10.1161/JAHA.124.035503}, pmid = {39119980}, issn = {2047-9980}, mesh = {Humans ; Male ; Female ; *Hispanic or Latino/statistics &amp; numerical data ; Adult ; Middle Aged ; United States/epidemiology ; *Cardiovascular Diseases/ethnology/epidemiology ; Longitudinal Studies ; Socioeconomic Factors ; Health Status ; Social Determinants of Health/ethnology ; Educational Status ; Social Class ; Risk Factors ; Aged ; Health Status Disparities ; Young Adult ; }, abstract = {BACKGROUND: The Hispanic/Latino population experiences socioeconomic disadvantages across the lifespan. Yet, little is known about the role of these disadvantages in cardiovascular health (CVH). We assessed the association of lifecourse socioeconomic position (SEP) with ideal CVH and change in Hispanic/Latino adults.<br><br>METHODS AND RESULTS: We used longitudinal data from the HCHS/SOL (Hispanic Community Health Study/Study of Latinos). Childhood SEP was determined using parental educational attainment. Adult SEP was determined through an index combining participants' education, occupation, income, and assets at baseline. We classified participants into 4 socioeconomic mobility categories (eg, stable low or high SEP, upward or downward mobility). Using the 4 health factors of the American Heart Association "Life's Essential 8," we built a score of ideal CVH at baseline and the 6-year follow-up. Linear mixed-effects models using inverse probability weighting were fitted to assess the main associations. Higher childhood SEP was associated with higher ideal CVH at baseline (&#x3b2; for high school versus <high school, 3.57 [95% CI, 1.76-5.57]) and (>high school versus <high school, 3.76 [95% CI, 1.99-5.52]). Middle (&#x3b2; for middle versus low SEP, 3.57 [95% CI, 1.65-5.49]) and high adult SEP (&#x3b2; for high versus low SEP, 5.05 [95% CI, 2.55-7.55]) were also associated with higher ideal CVH. Socioeconomic mobility was also associated with higher ideal CVH. No life-course SEP exposure was associated with the change in ideal CVH over a 6-year period.<br><br>CONCLUSIONS: Although high childhood and adult SEP and socioeconomic mobility were associated with higher levels of ideal CVH, they were not associated with change in ideal-CVH.}, }
@article {pmid39119731, year = {2024}, author = {Issaka, RB and Ibekwe, LN and Todd, KW and Burnett-Hartman, AN and Clark, CR and Del Vecchio, NJ and Kamineni, A and Neslund-Dudas, C and Chubak, J and Corley, DA and Haas, JS and Honda, SA and Li, CI and Winer, RL and Pruitt, SL}, title = {Association between racial residential segregation and screening uptake for colorectal and cervical cancer among Black and White patients in five US health care systems.}, journal = {Cancer}, volume = {130}, number = {24}, pages = {4287-4297}, pmid = {39119731}, issn = {1097-0142}, support = {UM1 CA221939/CA/NCI NIH HHS/United States ; UM1 CA221940/CA/NCI NIH HHS/United States ; K08 CA241296/CA/NCI NIH HHS/United States ; UM1CA221939//Division of Cancer Prevention, National Cancer Institute/ ; UM1CA222035//Division of Cancer Prevention, National Cancer Institute/ ; UM1CA221940//Division of Cancer Prevention, National Cancer Institute/ ; T32 CA057711/CA/NCI NIH HHS/United States ; K08CA241296//Division of Cancer Prevention, National Cancer Institute/ ; UM1 CA222035/CA/NCI NIH HHS/United States ; U24 CA221936/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Black or African American ; *Colorectal Neoplasms/diagnosis/ethnology/epidemiology ; *Early Detection of Cancer/statistics &amp; numerical data ; Healthcare Disparities/statistics &amp; numerical data ; Racism/statistics &amp; numerical data ; Residential Segregation ; Retrospective Studies ; *Social Segregation ; United States/epidemiology ; *Uterine Cervical Neoplasms/diagnosis ; *White ; }, abstract = {BACKGROUND: Despite increased recognition that structural racism contributes to poorer health outcomes for racial and ethnic minorities, there are knowledge gaps about how current patterns of racial residential segregation are associated with cancer screening uptake. The authors examined associations between Black residential segregation and screening for colorectal cancer (CRC) and cervical cancer among non-Hispanic Black and non-Hispanic White adults.<br><br>METHODS: This was a retrospective study of CRC and cervical cancer screening-eligible adults from five health care systems within the Population-Based Research to Optimize the Screening Process (PROSPR II) Consortium (cohort entry, 2010-2012). Residential segregation was measured using site-specific quartiles of the Black local isolation score (LIS). The outcome was receipt of CRC or cervical cancer screening within 3 years of cohort entry (2010-2015). Logistic regression was used to calculate associations between the LIS and screening completion, adjusting for patient-level covariates.<br><br>RESULTS: Among CRC (n&#xa0;=&#xa0;642,661) and cervical cancer (n&#xa0;=&#xa0;163,340) screening-eligible patients, 456,526 (71.0%) and 106,124 (65.0%), respectively, received screening. Across PROSPR sites, living in neighborhoods with higher LIS tended to be associated with lower odds of CRC screening (Kaiser Permanente Northern California: adjusted odds ratio [aOR] LIS trend in Black patients, 0.95 [p&#xa0;<&#xa0;.001]; aOR LIS trend in White patients, 0.98 [p&#xa0;<&#xa0;.001]; Kaiser Permanente Southern California: aOR LIS trend in Black patients, 0.98 [p&#xa0;=&#xa0;.026]; aOR LIS trend in White patients, 1.01 [p&#xa0;=&#xa0;.023]; Kaiser Permanente Washington: aOR LIS trend in White patients, 0.97 [p&#xa0;=&#xa0;.002]. However, for cervical cancer screening, associations with the LIS varied by site and race (Kaiser Permanente Washington: aOR LIS trend in White patients, 0.95 [p&#xa0;<&#xa0;.001]; Mass General Brigham: aOR LIS trend in Black patients, 1.12 [p&#xa0;<&#xa0;.001]; aOR LIS trend in White patients, 1.03 [p&#xa0;<&#xa0;.001]).<br><br>CONCLUSIONS: Across five diverse health care systems, the direction of the association between Black residential segregation and screening varied by PROSPR site, race, and screening type. Additional research, including studies that examine multiple dimensions of segregation and structural racism using intersectional approaches, are needed to further disentangle these relationships.}, }
@article {pmid39118035, year = {2024}, author = {Sun, V and Guthrie, KA and Arnold, KB and Antonoff, M and Erhunmwunsee, L and Borondy-Kitts, A and Johnson, J and Jones, L and Ramirez, M and Tong, BC and Moremen, JR and Yang, CJ and Ng, T and Kim, SS and Brown, LM and Blasberg, JD and Lui, NS and Kneuertz, PJ and Toloza, EM and Kim, JY and Raz, DJ}, title = {Comparative effectiveness of perioperative physical activity in older adults with lung cancer and their family caregivers: design of a multicenter pragmatic randomized trial.}, journal = {BMC cancer}, volume = {24}, number = {1}, pages = {976}, pmid = {39118035}, issn = {1471-2407}, support = {HA-2021C3-24773/PCORI/Patient-Centered Outcomes Research Institute/United States ; HA-2021C3-24773/PCORI/Patient-Centered Outcomes Research Institute/United States ; }, mesh = {Humans ; *Caregivers ; Aged ; *Lung Neoplasms/surgery ; *Quality of Life ; *Exercise ; Male ; Female ; Telephone ; Perioperative Care/methods ; }, abstract = {BACKGROUND: With a median age at diagnosis of 70, lung cancer remains a significant public health challenge for older Americans. Surgery is a key component in treating most patients with non-metastatic lung cancer. These patients experience postoperative pain, fatigue, loss of respiratory capacity, and decreased physical function. Data on quality of life (QOL) in older adults undergoing lung cancer surgery is limited, and few interventions are designed to target the needs of older adults and their family caregivers (FCGs). The primary aim of this comparative effectiveness trial is to determine whether telephone-based physical activity coaching before and after surgery will be more beneficial than physical activity self-monitoring alone for older adults and their FCGs.<br><br>METHODS: In this multicenter comparative effectiveness trial, 382 older adults (&#x2265;&#x2009;65 years) with lung cancer and their FCGs will be recruited before surgery and randomized to either telephone-based physical activity coaching or physical activity self-monitoring alone. Participants allocated to the telephone-based coaching comparator will receive five telephone sessions with coaches (1 pre and 4 post surgery), an intervention resource manual, and a wristband pedometer. Participants in the self-monitoring only arm will receive American Society of Clinical Oncology (ASCO) physical activity information and wristband pedometers. All participants will be assessed at before surgery (baseline), at discharge, and at days 30, 60, and 180 post-discharge. The primary endpoint is the 6-minute walk test (6MWT) at 30 days post-discharge. Geriatric assessment, lower extremity function, self-reported physical function, self-efficacy, and QOL will also be assessed.<br><br>DISCUSSION: The trial will determine whether this telephone-based physical activity coaching approach can enhance postoperative functional capacity and QOL outcomes for older adults with lung cancer and their FCGs. Trial results will provide critical findings to inform models of postoperative care for older adults with cancer and their FCGs.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06196008.}, }
@article {pmid39115975, year = {2024}, author = {Wong, JS and Uno, H and Tramontano, AC and Fisher, L and Pellegrini, CV and Abel, GA and Burstein, HJ and Chun, YS and King, TA and Schrag, D and Winer, E and Bellon, JR and Cheney, MD and Hardenbergh, P and Ho, A and Horst, KC and Kim, JN and Leonard, KL and Moran, MS and Park, CC and Recht, A and Soto, DE and Shiloh, RY and Stinson, SF and Snyder, KM and Taghian, AG and Warren, LE and Wright, JL and Punglia, RS}, title = {Hypofractionated vs Conventionally Fractionated Postmastectomy Radiation After Implant-Based Reconstruction: A Randomized Clinical Trial.}, journal = {JAMA oncology}, volume = {10}, number = {10}, pages = {1370-1378}, pmid = {39115975}, issn = {2374-2445}, mesh = {Humans ; Female ; Middle Aged ; *Mastectomy ; *Breast Neoplasms/radiotherapy/surgery ; *Radiation Dose Hypofractionation ; Adult ; Dose Fractionation, Radiation ; Quality of Life ; Mammaplasty/methods ; Radiotherapy, Adjuvant/adverse effects ; Aged ; Breast Implants ; Treatment Outcome ; }, abstract = {IMPORTANCE: Postmastectomy radiation therapy (PMRT) improves local-regional disease control and patient survival. Hypofractionation (HF) regimens have comparable efficacy and complication rates with improved quality of life compared with conventional fractionation (CF) schedules. However, the use of HF after mastectomy in patients undergoing breast reconstruction has not been prospectively examined.<br><br>OBJECTIVE: To compare HF and CF PMRT outcomes after implant-based reconstruction.<br><br>This randomized clinical trial assessed patients 18 years or older undergoing mastectomy and immediate expander or implant reconstruction for breast cancer (Tis, TX, or T1-3) and unilateral PMRT from March 8, 2018, to November 3, 2021 (median [range] follow-up, 40.4 [15.4-63.0] months), at 16 US cancer centers or hospitals. Analyses were conducted between September and December 2023.<br><br>INTERVENTIONS: Patients were randomized 1:1 to HF or CF PMRT. Chest wall doses were 4256 cGy for 16 fractions for HF and 5000 cGy for 25 fractions for CF. Chest wall toxic effects were defined as a grade 3 or higher adverse event.<br><br>MAIN OUTCOMES AND MEASURES: The primary outcome was the change in physical well-being (PWB) domain of the Functional Assessment of Cancer Therapy-Breast (FACT-B) quality-of-life assessment tool at 6 months after starting PMRT, controlling for age. Secondary outcomes included toxic effects and cancer recurrence.<br><br>RESULTS: Of 400 women (201 in the CF arm and 199 in the HF arm; median [range] age, 47 [23-79] years), 330 patients had PWB scores at baseline and at 6 months. There was no difference in the change in PWB between the study arms (estimate, 0.13; 95% CI, -0.86 to 1.11; P&#x2009;=&#x2009;.80), but there was a significant interaction between age group and study arm (P&#x2009;=&#x2009;.03 for interaction). Patients younger than 45 years had higher 6-month absolute PWB scores if treated with HF rather than CF regimens (23.6 [95% CI, 22.7-24.6] vs 22.0 [95% CI, 20.7-23.3]; P&#x2009;=&#x2009;.047) and reported being less bothered by adverse effects (mean [SD], 3.0 [0.9] in the HF arm and 2.6 [1.2] in the CF arm; P&#x2009;=&#x2009;.02) or nausea (mean [SD], 3.8 [0.4] in the HF arm and 3.6 [0.8] in the CF arm; P&#x2009;=&#x2009;.04). In the as-treated cohort, there were 23 distant (11 in the HF arm and 12 in the CF arm) and 2 local-regional (1 in the HF arm and 1 in the CF arm) recurrences. Chest wall toxic effects occurred in 39 patients (20 in the HF arm and 19 in the CF arm) at a median (IQR) of 7.2 (1.8-12.9) months. Fractionation was not associated with chest wall toxic effects on multivariate analysis (HF arm: hazard ratio, 1.02; 95% CI, 0.52-2.00; P&#x2009;=&#x2009;.95). Fewer patients undergoing HF vs CF regimens had a treatment break (5 [2.7%] vs 15 [7.7%]; P&#x2009;=&#x2009;.03) or required unpaid time off from work (17 [8.5%] vs 34 [16.9%]; P&#x2009;=&#x2009;.02).<br><br>CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, the HF regimen did not significantly improve change in PWB compared with the CF regimen. These data add to the increasing experience with HF PMRT in patients with implant-based reconstruction.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03422003.}, }
@article {pmid39115391, year = {2024}, author = {Di, M and Potnis, KC and Long, JB and Isufi, I and Foss, F and Seropian, S and Gross, CP and Huntington, SF}, title = {Costs of care during chimeric antigen receptor T-cell therapy in relapsed or refractory B-cell lymphomas.}, journal = {JNCI cancer spectrum}, volume = {8}, number = {4}, pages = {}, pmid = {39115391}, issn = {2515-5091}, mesh = {Humans ; *Immunotherapy, Adoptive/economics ; Male ; Middle Aged ; Female ; *Lymphoma, Large B-Cell, Diffuse/therapy/economics ; *Receptors, Chimeric Antigen ; Health Care Costs/statistics &amp; numerical data ; Lymphoma, B-Cell/therapy/economics ; Aged ; Health Expenditures ; Receptors, Antigen, T-Cell/therapeutic use ; }, abstract = {High upfront cost may be a barrier to adopting chimeric antigen receptor T-cell (CAR-T) therapy for relapsed or refractory B-cell lymphoma. Data on the real-world costs are limited. Using the Blue Cross Blue Shield Axis database, we evaluated 271 commercially insured patients who received CAR-T therapy for B-cell lymphoma (median age = 58 years; men = 68%; diffuse large B-cell lymphoma = 87%; inpatient CAR-T therapy = 85%). Our peri-CAR-T period of interest was from 41 days before to 154 days after CAR-T therapy index divided into seven 28-day intervals. Median total costs were $608 100 (interquartile range, IQR = $534 100-$732 800); 8.5% of patients had total costs exceeding $1 million. The median cost of CAR-T therapy products was $402 500, and the median out-of-pocket copayment was $510. Monthly costs were highest during the month of CAR-T therapy administration (median = $521 500), with median costs below $25 000 in all other 28-day intervals. Costs of CAR-T therapy use were substantial, largely driven by product acquisition. Future studies should examine the relationship between costs, access, and financial outcomes.}, }
@article {pmid39115038, year = {2024}, author = {Grillová, L and Romeis, E and Lieberman, NAP and Tantalo, LC and Xu, LH and Molini, B and Trejos, AT and Lacey, G and Goulding, D and Thomson, NR and Greninger, AL and Giacani, L}, title = {Bright New Resources for Syphilis Research: Genetically Encoded Fluorescent Tags for Treponema pallidum and Sf1Ep Cells.}, journal = {Molecular microbiology}, volume = {122}, number = {4}, pages = {455-464}, pmid = {39115038}, issn = {1365-2958}, support = {INV-051483//the Bill &amp; Melinda Gates Foundation/ ; /WT_/Wellcome Trust/United Kingdom ; BB/010589/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; 8394150//Open Philanthropy Project/ ; 206194/WT_/Wellcome Trust/United Kingdom ; U19 AI144133/AI/NIAID NIH HHS/United States ; U19AI144133//National Institute of Allergy and Infectious Diseases/ ; }, mesh = {*Treponema pallidum/genetics ; *Syphilis/microbiology ; *Luminescent Proteins/genetics/metabolism ; Humans ; Green Fluorescent Proteins/genetics/metabolism ; Red Fluorescent Protein ; Virulence/genetics ; Treponema ; }, abstract = {The recently discovered methodologies to cultivate and genetically manipulate Treponema pallidum subsp. pallidum (T. pallidum) have significantly helped syphilis research, allowing the in vitro evaluation of antibiotic efficacy, performance of controlled studies to assess differential treponemal gene expression, and generation of loss-of-function mutants to evaluate the contribution of specific genetic loci to T. pallidum virulence. Building on this progress, we engineered the T. pallidum SS14 strain to express a red-shifted green fluorescent protein (GFP) and Sf1Ep cells to express mCherry and blue fluorescent protein (BFP) for enhanced visualization. These new resources improve microscopy- and cell sorting-based applications for T. pallidum, better capturing the physical interaction between the host and pathogen, among other possibilities. Continued efforts to develop and share new tools and resources are required to help our overall knowledge of T. pallidum biology and syphilis pathogenesis reach that of other bacterial pathogens, including spirochetes.}, }
@article {pmid39115010, year = {2024}, author = {Peter, J and Takalani, A and Meyer, JC and Semete-Makokotlela, B and Collie, S and Seocharan, I and Goga, A and Garrett, N and Gail-Bekker, L and Gray, G}, title = {Vaccine pharmacovigilance in South Africa: successes and limitations of current approaches.}, journal = {Expert opinion on drug safety}, volume = {23}, number = {10}, pages = {1215-1225}, doi = {10.1080/14740338.2024.2387322}, pmid = {39115010}, issn = {1744-764X}, mesh = {*Pharmacovigilance ; Humans ; *COVID-19 Vaccines/adverse effects/administration &amp; dosage ; South Africa ; *COVID-19/prevention &amp; control/epidemiology ; *Adverse Drug Reaction Reporting Systems ; Mass Vaccination/methods/organization &amp; administration/adverse effects ; Vaccination/adverse effects/methods ; World Health Organization ; Public Health ; }, abstract = {INTRODUCTION: Despite the public health success of vaccination, there is an ongoing need to build public confidence in vaccines and improve systems to monitor safety while maintaining data security and patient privacy. African countries face multiple challenges in establishing systems for vaccine pharmacovigilance as was demonstrated during COVID-19 mass vaccination. We provide a framework for the development of pharmacovigilance using the COVID-19 vaccination rollout as an exemplar.<br><br>AREAS COVERED: We describe the pre-COVID-19 vaccine pharmacovigilance systems in Southern Africa and propose improvements based on our experience of COVID-19 vaccine rollout in South Africa where we implemented systems to evaluate real-world safety and effectiveness of COVID-19 vaccinations. By conducting a PubMed review of the literature on pharmacovigilance with a focus on Africa and from guidance emanating from the World Health Organization (WHO), we evaluate challenges and opportunities to improve pharmacovigilance in our setting.<br><br>EXPERT OPINION: There are ongoing efforts to improve pharmacovigilance on the African continent with improved coordination at a national level with the support of the WHO, the national regulatory authorities, and national departments of health. COVID-19 vaccine rollout provided an opportunity to improve pharmacovigilance by integrating national vaccine platforms with active and passive surveillance including hospital and death registries.}, }
@article {pmid39113782, year = {2024}, author = {Wang, CY and Hwang, WH and Song, X}, title = {Biomarker data with measurement error in medical research: A literature review.}, journal = {Wiley interdisciplinary reviews. Computational statistics}, volume = {16}, number = {1}, pages = {}, pmid = {39113782}, issn = {1939-5108}, support = {R21 AI176947/AI/NIAID NIH HHS/United States ; R21 CA239168/CA/NCI NIH HHS/United States ; R01 HL130483/HL/NHLBI NIH HHS/United States ; R21 CA201207/CA/NCI NIH HHS/United States ; R01 AG085616/AG/NIA NIH HHS/United States ; R03 CA235122/CA/NCI NIH HHS/United States ; R21 HL121347/HL/NHLBI NIH HHS/United States ; }, abstract = {A biomarker is a measurable indicator of the severity or presence of a disease or medical condition in biomedical or epidemiological research. Biomarkers may help in early diagnosis and prevention of diseases. Several biomarkers have been identified for many diseases such as carbohydrate antigen 19-9 for pancreatic cancer. However, biomarkers may be measured with errors due to many reasons such as specimen collection or day-to-day within-subject variability of the biomarker, among others. Measurement error in the biomarker leads to bias in the regression parameter estimation for the association of the biomarker with disease in epidemiological studies. In addition, measurement error in the biomarkers may affect standard diagnostic measures to evaluate the performance of biomarkers such as the receiver operating characteristic (ROC) curve, area under the ROC curve, sensitivity, and specificity. Measurement error may also have an effect on how to combine multiple cancer biomarkers as a composite predictor for disease diagnosis. In follow-up studies, biomarkers are often collected intermittently at examination times, which may be sparse and typically biomarkers are not observed at the event times. Joint modeling of longitudinal and time-to-event data is a valid approach to account for measurement error in the analysis of repeatedly measured biomarkers and time-to-event outcomes. In this article, we provide a literature review on existing methods to correct for estimation in regression analysis, diagnostic measures, and joint modeling of longitudinal biomarkers and survival outcomes when the biomarkers are measured with errors. This article is categorized under: Statistical and Graphical Methods of Data Analysis > Robust MethodsStatistical and Graphical Methods of Data Analysis > EM AlgorithmStatistical Models > Survival Models.}, }
@article {pmid39113729, year = {2024}, author = {Hirayama, AV and Wright, JH and Smythe, KS and Fiorenza, S and Shaw, AN and Gauthier, J and Maloney, DG and Naresh, KN and Yeung, CCS and Turtle, CJ}, title = {PD-L1[+] macrophage and tumor cell abundance and proximity to T cells in the pretreatment large B-cell lymphoma microenvironment impact CD19 CAR-T cell immunotherapy efficacy.}, journal = {HemaSphere}, volume = {8}, number = {8}, pages = {e142}, pmid = {39113729}, issn = {2572-9241}, abstract = {CD19-targeted chimeric antigen receptor T-cell (CAR-T) immunotherapy has transformed the management of relapsed/refractory large B-cell lymphoma (LBCL), yet durable remissions are observed in less than half of treated patients. The tumor microenvironment (TME) is a key and understudied factor impacting CD19 CAR-T therapy outcomes. Using NanoString nCounter transcriptome profiling (n = 24) and multiplex immunohistochemistry (mIHC, n = 15), we studied the TME in pretreatment biopsies from patients with LBCL undergoing CD19 CAR-T therapy. Patients who achieved complete response (CR) after CAR-T therapy demonstrated higher expression of genes associated with T-cell trafficking and function, whereas those who did not achieve CR had higher expression of genes associated with macrophages and T-cell dysfunction. Distinct patterns of immune infiltration and fibrosis in the TME were associated with CAR-T therapy outcomes, and these findings were corroborated using artificial intelligence-assisted image analyses. Patients who achieved CR had a lower proportion of the biopsy occupied by an interspersed immune infiltrate and a higher proportion of hypocellular/fibrotic regions. Furthermore, mIHC revealed lower density of CD4[+] T cells and higher densities of both macrophages and tumor cells expressing PD-L1 in non-CR patients. Spatial analysis revealed that PD-1[+] T cells were in close proximity to PD-L1[+] macrophages or PD-L1[+] tumor cells in patients who did not compared to those who did achieve CR after CAR-T therapy. These findings suggest that morphologic patterns in the TME and engagement of the PD-1/PD-L1 axis in pretreatment biopsies may impact CD19 CAR-T immunotherapy response in patients with LBCL.}, }
@article {pmid39112630, year = {2024}, author = {Kousa, AI and Jahn, L and Zhao, K and Flores, AE and Acenas, D and Lederer, E and Argyropoulos, KV and Lemarquis, AL and Granadier, D and Cooper, K and D'Andrea, M and Sheridan, JM and Tsai, J and Sikkema, L and Lazrak, A and Nichols, K and Lee, N and Ghale, R and Malard, F and Andrlova, H and Velardi, E and Youssef, S and Burgos da Silva, M and Docampo, M and Sharma, R and Mazutis, L and Wimmer, VC and Rogers, KL and DeWolf, S and Gipson, B and Gomes, ALC and Setty, M and Pe'er, D and Hale, L and Manley, NR and Gray, DHD and van den Brink, MRM and Dudakov, JA}, title = {Age-related epithelial defects limit thymic function and regeneration.}, journal = {Nature immunology}, volume = {25}, number = {9}, pages = {1593-1606}, pmid = {39112630}, issn = {1529-2916}, support = {T32-GM007270//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; 1187367//Department of Health | National Health and Medical Research Council (NHMRC)/ ; R01 CA228308/CA/NCI NIH HHS/United States ; 1158024//Department of Health | National Health and Medical Research Council (NHMRC)/ ; R01-HL145276//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01-HL147584//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01-HL165673//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01 HL123340/HL/NHLBI NIH HHS/United States ; R01 HL145276/HL/NHLBI NIH HHS/United States ; R01-CA228308//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; T32 GM007103/GM/NIGMS NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P01 CA023766/CA/NCI NIH HHS/United States ; R01 HL165673/HL/NHLBI NIH HHS/United States ; R01 HL147584/HL/NHLBI NIH HHS/United States ; P01-AG052359//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30-CA015704//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; 1090236//Department of Health | National Health and Medical Research Council (NHMRC)/ ; P30 CA008748/CA/NCI NIH HHS/United States ; P01 AG052359/AG/NIA NIH HHS/United States ; T32 GM007270/GM/NIGMS NIH HHS/United States ; 1102104//Cancer Council Victoria/ ; 1078763//Department of Health | National Health and Medical Research Council (NHMRC)/ ; 1146518//Cancer Council Victoria/ ; U01-AI70035//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; R35 HL171556/HL/NHLBI NIH HHS/United States ; ALTF-431-2017//European Molecular Biology Organization (EMBO)/ ; R01 CA228358/CA/NCI NIH HHS/United States ; F30-HL165761//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01-HL123340//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R35-HL-171556//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; 1121325//Department of Health | National Health and Medical Research Council (NHMRC)/ ; F30 HL165761/HL/NHLBI NIH HHS/United States ; }, mesh = {*Thymus Gland/immunology ; Animals ; *Epithelial Cells/immunology ; *Regeneration/immunology ; Mice ; *Aging/immunology ; *Forkhead Transcription Factors/metabolism/genetics ; Epithelial-Mesenchymal Transition/immunology ; Mice, Inbred C57BL ; Male ; Thymocytes/immunology/metabolism ; Female ; Single-Cell Analysis ; }, abstract = {The thymus is essential for establishing adaptive immunity yet undergoes age-related involution that leads to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age for unknown reasons. We applied single-cell and spatial transcriptomics, lineage-tracing and advanced imaging to define age-related changes in nonhematopoietic stromal cells and discovered the emergence of two atypical thymic epithelial cell (TEC) states. These age-associated TECs (aaTECs) formed high-density peri-medullary epithelial clusters that were devoid of thymocytes; an accretion of nonproductive thymic tissue that worsened with age, exhibited features of epithelial-to-mesenchymal transition and was associated with downregulation of FOXN1. Interaction analysis revealed that the emergence of aaTECs drew tonic signals from other functional TEC populations at baseline acting as a sink for TEC growth factors. Following acute injury, aaTECs expanded substantially, further perturbing trophic regeneration pathways and correlating with defective repair of the involuted thymus. These findings therefore define a unique feature of thymic involution linked to immune aging and could have implications for developing immune-boosting therapies in older individuals.}, }
@article {pmid39111731, year = {2024}, author = {Kozono, D and Hua, X and Wu, MC and Tolba, KA and Waqar, SN and Dragnev, KH and Cheng, H and Hirsch, FR and Mack, PC and Gray, JE and Kelly, K and Borghaei, H and Herbst, RS and Gandara, DR and Redman, MW}, title = {Lung-MAP Next-Generation Sequencing Analysis of Advanced Squamous Cell Lung Cancers (SWOG S1400).}, journal = {Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer}, volume = {19}, number = {12}, pages = {1618-1629}, pmid = {39111731}, issn = {1556-1380}, support = {U10 CA180888/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Lung Neoplasms/genetics/pathology ; *High-Throughput Nucleotide Sequencing/methods ; Male ; *Carcinoma, Squamous Cell/genetics/pathology ; Female ; Middle Aged ; Aged ; Biomarkers, Tumor/genetics ; Mutation ; }, abstract = {INTRODUCTION: Squamous cell cancer (SqCC) is a lung cancer subtype with few targeted therapy options. Molecular characterization, that is, by next-generation sequencing (NGS), is needed to identify potential targets. Lung Cancer Master Protocol Southwest Oncology Group S1400 enrolled patients with previously treated stage IV or recurrent SqCC to assess NGS biomarkers for therapeutic sub-studies.<br><br>METHODS: Tumors underwent NGS using Foundation Medicine's FoundationOne research platform, which sequenced the exons and/or introns of 313 cancer-related genes. Mutually exclusive gene set analysis and Selected Events Linked by Evolutionary Conditions across Human Tumors were performed to identify mutually exclusive and co-occurring gene alterations. Comparisons were performed with data on 495 lung SqCC downloaded from The Cancer Genome Atlas. Cox proportional hazards models were used to assess associations between genetic variants and survival.<br><br>RESULTS: NGS data are reported for 1672 patients enrolled on S1400 between 2014 and 2019. Mutually exclusive gene set analysis identified two non-overlapping sets of mutually exclusive alterations with a false discovery rate of less than 15%: NFE2L2, KEAP1, and PARP4; and CDKN2A and RB1. PARP4, a relatively uncharacterized gene, showed three frequent mutations suggesting functional significance: 3116T>C (I1039T), 3176A>G (Q1059R), and 3509C>T (T1170I). When taken together, NFE2L2 and KEAP1 alterations were associated with poorer survival.<br><br>CONCLUSIONS: As the largest dataset to date of lung SqCC profiled on a clinical trial, the S1400 NGS dataset establishes a rich resource for biomarker discovery. Mutual exclusivity of PARP4 and NFE2L2 or KEAP1 alterations suggests that PARP4 may have an uncharacterized role in a key pathway known to impact oxidative stress response and treatment resistance.}, }
@article {pmid39110181, year = {2024}, author = {Le Bihan, D and Iima, M and Partridge, SC}, title = {Fat-signal suppression in breast diffusion-weighted imaging: the Good, the Bad, and the Ugly.}, journal = {European radiology}, volume = {}, number = {}, pages = {}, pmid = {39110181}, issn = {1432-1084}, abstract = {OBJECTIVES: Fat-signal suppression is essential for breast diffusion magnetic resonance imaging (or diffusion-weighted MRI, DWI) as the very low diffusion coefficient of fat tends to decrease absolute diffusion coefficient (ADC) values. Among several methods, the STIR (short-tau inversion recovery) method is a popular approach, but signal suppression/attenuation is not specific to fat contrary to other methods such as SPAIR (spectral adiabatic (or attenuated) inversion recovery). This article focuses on those two techniques to illustrate the importance of appropriate fat suppression in breast DWI, briefly presenting the pros and cons of both approaches.<br><br>METHODS AND RESULTS: We show here through simulation and data acquired in a dedicated breast DWI phantom made of vials with water and various concentrations of polyvinylpyrrolidone (PVP) how ADC values obtained with STIR DWI may be biased toward tissue components&#xa0;with the longest T1 values: ADC values obtained with STIR fat suppression may be over/underestimated depending on the T1 and ADC profile within tissues. This bias is also illustrated in two&#xa0;clinical examples.<br><br>CONCLUSION: Fat-specific methods should be preferred over STIR for fat-signal suppression in breast DWI, such as SPAIR which also provides a higher sensitivity than STIR for lesion detection. One should remain aware, however, that efficient fat-signal suppression with SPAIR requires good B0 shimming to avoid ADC underestimation from residual fat contamination.<br><br>CLINICAL RELEVANCE STATEMENT: The spectral adiabatic (or attenuated) inversion recovery (SPAIR) method should be preferred over short-tau inversion recovery (STIR) for fat suppression in breast DWI.<br><br>KEY POINTS: Fat-signal suppression is essential for breast DWI; the SPAIR method is recommended. Short-tau inversion recovery (STIR)&#xa0;is not specific to fat; as a result, SNR is decreased and ADC values may be over- or underestimated. The STIR fat-suppression method must not be used after the injection of gadolinium-based contrast agents.}, }
@article {pmid39108244, year = {2024}, author = {Ellison, GL and Helzlsouer, KJ and Rosenfield, SM and Kim, Y and Ashare, RL and Blaes, AH and Cullen, J and Doran, N and Ebbert, JO and Egan, KM and Heffner, JL and Lee, RT and McClure, EA and McDaniels-Davidson, C and Meghani, SH and Newcomb, PA and Nugent, S and Hernandez-Ortega, N and Salz, T and Vidot, DC and Worster, B and Zylla, DM}, title = {Perceptions, prevalence, and patterns of cannabis use among cancer patients treated at 12 NCI-Designated Cancer Centers.}, journal = {Journal of the National Cancer Institute. Monographs}, volume = {2024}, number = {66}, pages = {202-217}, pmid = {39108244}, issn = {1745-6614}, support = {P30CA016520//12 NCI-Designated Cancer Centers/ ; P30 CA008748/CA/NCI NIH HHS/United States ; P30 CA016520/CA/NCI NIH HHS/United States ; P30 CA056036/CA/NCI NIH HHS/United States ; /NH/NIH HHS/United States ; /HH/HHS/United States ; }, mesh = {Humans ; *Neoplasms/epidemiology/psychology/therapy ; Female ; Male ; United States/epidemiology ; Middle Aged ; Prevalence ; Adult ; *Medical Marijuana/therapeutic use/adverse effects ; National Cancer Institute (U.S.) ; Surveys and Questionnaires ; Cancer Care Facilities/statistics &amp; numerical data ; Aged ; Perception ; }, abstract = {BACKGROUND: The legal climate for cannabis use has dramatically changed with an increasing number of states passing legislation legalizing access for medical and recreational use. Among cancer patients, cannabis is often used to ameliorate adverse effects of cancer treatment. Data are limited on the extent and type of use among cancer patients during treatment and the perceived benefits and harms. This multicenter survey was conducted to assess the use of cannabis among cancer patients residing in states with varied legal access to cannabis.<br><br>METHODS: A total of 12 NCI-Designated Cancer Centers, across states with varied cannabis-access legal status, conducted surveys with a core questionnaire to assess cannabis use among recently diagnosed cancer patients. Data were collected between September 2021 and August 2023 and pooled across 12 cancer centers. Frequencies and 95% confidence intervals for core survey measures were calculated, and weighted estimates are presented for the 10 sites that drew probability samples.<br><br>RESULTS: Overall reported cannabis use since cancer diagnosis among survey respondents was 32.9% (weighted), which varied slightly by state legalization status. The most common perceived benefits of use were for pain, sleep, stress and anxiety, and treatment side effects. Reported perceived risks were less common and included inability to drive, difficulty concentrating, lung damage, addiction, and impact on employment. A majority reported feeling comfortable speaking to health-care providers though, overall, only 21.5% reported having done so. Among those who used cannabis since diagnosis, the most common modes were eating in food, smoking, and pills or tinctures, and the most common reasons were for sleep disturbance, followed by pain and stress and anxiety with 60%-68% reporting improved symptoms with use.<br><br>CONCLUSION: This geographically diverse survey demonstrates that patients use cannabis regardless of its legal status. Addressing knowledge gaps concerning benefits and harms of cannabis use during cancer treatment is critical to enhance patient-provider communication.}, }
@article {pmid39108240, year = {2024}, author = {Jones, SMW and Ton, M and Malen, RC and Newcomb, PA and Heffner, JL}, title = {Item response theory analysis of benefits and harms of cannabis use in cancer survivors.}, journal = {Journal of the National Cancer Institute. Monographs}, volume = {2024}, number = {66}, pages = {275-281}, doi = {10.1093/jncimonographs/lgad022}, pmid = {39108240}, issn = {1745-6614}, support = {//Fred Hutchinson Cancer Center/ ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Cancer Survivors/psychology/statistics &amp; numerical data ; Female ; Male ; Middle Aged ; *Neoplasms/psychology/therapy ; *Medical Marijuana/therapeutic use/adverse effects ; Adult ; Aged ; Surveys and Questionnaires ; }, abstract = {Medical cannabis with cancer as a qualifying condition has become legalized in more states, but currently there are no standardized measures of perceived benefits and harms of cannabis use in cancer. This study surveyed a population-based sample of cancer survivors (n = 1539) with various types of cancer including breast (25%), prostate (17%), and gastrointestinal (11%) cancers. Item response theory analyses were used to evaluate the items for measuring perceived benefits and harms. Item response theory evaluates survey items by estimating the accuracy (analogous to reliability) and severity reflected by each item. Item response theory analyses showed all the items were accurate (reliable) measures of perceived benefits or harms. The perceived benefits items assessed beliefs well from low to high levels of perceived benefits. The perceived harms items assessed beliefs from moderate to high levels of perceived harms. The items can be used in future studies to standardize measurement while allowing some customization.}, }
@article {pmid39106151, year = {2024}, author = {Ji, M and Shih, YH and Huber, JH and Wang, M and Feuer, EJ and Etzioni, R and Wang, SY and Chang, SH}, title = {Asymptomatic Incidence of Monoclonal Gammopathy of Undetermined Significance and Preclinical Duration to Myeloma Diagnosis: A Modeling Study.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {33}, number = {12}, pages = {1690-1697}, pmid = {39106151}, issn = {1538-7755}, support = {R01 CA253475/CA/NCI NIH HHS/United States ; U01 CA265735/CA/NCI NIH HHS/United States ; //Alvin J. Siteman Cancer Center (SCC)/ ; //Foundation for Barnes-Jewish Hospital (FBJH)/ ; }, mesh = {Humans ; *Multiple Myeloma/epidemiology/diagnosis ; *Monoclonal Gammopathy of Undetermined Significance/epidemiology/diagnosis ; Incidence ; Middle Aged ; Aged ; Male ; Female ; United States/epidemiology ; Aged, 80 and over ; Adult ; SEER Program/statistics &amp; numerical data ; Prevalence ; }, abstract = {BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) is the premalignant condition of multiple myeloma. Given a lack of population-based screening for MGUS and its asymptomatic nature, the epidemiology of MGUS remains unknown. This study estimated age- and race/ethnicity-specific MGUS incidence and preclinical duration from MGUS to multiple myeloma in the United States.<br><br>METHODS: A previously published modeling approach was used to calculate national MGUS incidence using estimates of MGUS prevalence, multiple myeloma incidence, multiple myeloma-specific and all-cause mortality, and population age distribution from the National Health and Nutrition Examination Survey, 1999 to 2004, and Surveillance, Epidemiology, and End Results, 2000 to 2021. The estimated MGUS prevalence was divided by MGUS incidence to obtain preclinical duration of multiple myeloma.<br><br>RESULTS: MGUS incidence for non-Hispanic White (NHW) populations was 52, 86, 142, and 181 and for non-Hispanic Black (NHB) population was 110, 212, 392, and 570 per 100,000 person-years at ages 50, 60, 70, and 80 years, respectively. The average preclinical duration was 20.5 (95% confidence interval, CI, 16.5-26.1) years for the NHW population and 14.2 (95% CI, 11.5-17.6) years for the NHB population. The cumulative risk of developing MGUS in age 50 to 85 was 2.8% (95% CI, 1.7%-4.2%) for the NHW population and 6.1% (95% CI, 3.8%-10.0%) for the NHB population.<br><br>CONCLUSIONS: NHB populations had a higher MGUS incidence rate at all ages and a shorter preclinical duration of multiple myeloma compared to their NHW counterparts.<br><br>IMPACT: This study provides insights into the epidemiology of MGUS and enhances our understanding of the natural history of multiple myeloma. See related In the Spotlight, p. 1547.}, }
@article {pmid39106081, year = {2024}, author = {Coveler, AL and Reilley, MJ and Zalupski, M and Macarulla, T and Fountzilas, C and Ponz-Sarvisé, M and Nagrial, A and Uboha, NV and Frentzas, S and Overman, M and Noonan, A and Messersmith, WA and Pavlakis, N and Mettu, NB and Bisha, I and Wang, Y and Smith, P and Murtomaki, E and Bielska, AA and Bragulat, V and Cooper, ZA and Kumar, R and Spigel, DR}, title = {A Phase Ib/II Randomized Clinical Trial of Oleclumab with or without Durvalumab plus Chemotherapy in Patients with Metastatic Pancreatic Ductal Adenocarcinoma.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {30}, number = {20}, pages = {4609-4617}, pmid = {39106081}, issn = {1557-3265}, support = {//AstraZeneca (AstraZeneca PLC)/ ; }, mesh = {Humans ; Female ; Male ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Middle Aged ; *Carcinoma, Pancreatic Ductal/drug therapy/pathology/mortality ; Aged ; *Antibodies, Monoclonal/administration &amp; dosage/therapeutic use/adverse effects ; Adult ; Pancreatic Neoplasms/drug therapy/pathology/mortality ; Aged, 80 and over ; Paclitaxel/administration &amp; dosage/adverse effects/therapeutic use ; Neoplasm Metastasis ; Antibodies, Monoclonal, Humanized/administration &amp; dosage/adverse effects/therapeutic use ; Progression-Free Survival ; }, abstract = {PURPOSE: Pancreatic ductal adenocarcinoma upregulates CD73, potentially contributing to immune surveillance evasion. Combining oleclumab (CD73 inhibitor) and durvalumab with chemotherapy may identify an effective treatment option.<br><br>PATIENTS AND METHODS: We describe a multicenter phase Ib/II randomized clinical trial in patients with metastatic pancreatic ductal adenocarcinoma, untreated (cohort A) or previously received gemcitabine-based chemotherapy (cohort B; NCT03611556). During escalation, patients received oleclumab 1,500 or 3,000 mg, durvalumab 1,500 mg, and gemcitabine plus nab-paclitaxel (GnP; cohort A; n = 14) or modified FOLFOX (cohort B; n = 11). During expansion, cohort A patients (n = 170) were randomized to GnP (arm A1), oleclumab [recommended phase II dose (RP2D)] with GnP (arm A2), or oleclumab (RP2D) with durvalumab plus GnP (arm A3). Primary objectives were safety (escalation) and objective response rate (expansion). Secondary objectives included progression-free survival (PFS) and overall survival (OS).<br><br>RESULTS: During escalation, 1/11 patients from cohort B (oleclumab 3,000 mg) experienced two dose-limiting toxicities. Oleclumab's RP2D was 3,000 mg. During expansion, grade &#x2265;3 treatment-related adverse events occurred in 67.7% (42/62) of patients in A1, 73.7% (28/38) in A2, and 77.1% (54/70) in A3. The objective response rate was 29.0%, 21.1%, and 32.9% in A1, A2, and A3, respectively (A1 vs. A3; P = 0.650). PFS [HR = 0.72; 95% confidence interval (CI), 0.47, 1.11] and OS (HR = 0.75; 95% CI, 0.50-1.13) were similar for A3 versus A1. Patients with high CD73 expression had improved PFS and OS in A3 versus A1, although this should be interpreted with caution.<br><br>CONCLUSIONS: Although the safety profile was acceptable, this study did not meet its primary efficacy endpoint.}, }
@article {pmid39105648, year = {2024}, author = {Sprague, BL and Ichikawa, L and Eavey, J and Lowry, KP and Rauscher, GH and O'Meara, ES and Miglioretti, DL and Lee, JM and Stout, NK and Herschorn, SD and Perry, H and Weaver, DL and Kerlikowske, K}, title = {Performance of Supplemental US Screening in Women with Dense Breasts and Varying Breast Cancer Risk: Results from the Breast Cancer Surveillance Consortium.}, journal = {Radiology}, volume = {312}, number = {2}, pages = {e232380}, pmid = {39105648}, issn = {1527-1315}, support = {P01 CA154292/CA/NCI NIH HHS/United States ; R01 CA248068/CA/NCI NIH HHS/United States ; R01 HS018366/HS/AHRQ HHS/United States ; U54 GM115516/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Breast Neoplasms/diagnostic imaging/pathology ; Female ; Middle Aged ; Retrospective Studies ; *Breast Density ; *Early Detection of Cancer/methods ; *Ultrasonography, Mammary/methods ; Risk Assessment ; Adult ; Breast/diagnostic imaging/pathology ; United States ; Aged ; Mass Screening/methods ; Registries ; }, abstract = {Background It is unclear whether breast US screening outcomes for women with dense breasts vary with levels of breast cancer risk. Purpose To evaluate US screening outcomes for female patients with dense breasts and different estimated breast cancer risk levels. Materials and Methods This retrospective observational study used data from US screening examinations in female patients with heterogeneously or extremely dense breasts conducted from January 2014 to October 2020 at 24 radiology facilities within three Breast Cancer Surveillance Consortium (BCSC) registries. The primary outcomes were the cancer detection rate, false-positive biopsy recommendation rate, and positive predictive value of biopsies performed (PPV3). Risk classification of participants was performed using established BCSC risk prediction models of estimated 6-year advanced breast cancer risk and 5-year invasive breast cancer risk. Differences in high- versus low- or average-risk categories were assessed using a generalized linear model. Results In total, 34 791 US screening examinations from 26 489 female patients (mean age at screening, 53.9 years ± 9.0 [SD]) were included. The overall cancer detection rate per 1000 examinations was 2.0 (95% CI: 1.6, 2.4) and was higher in patients with high versus low or average risk of 6-year advanced breast cancer (5.5 [95% CI: 3.5, 8.6] vs 1.3 [95% CI: 1.0, 1.8], respectively; P = .003). The overall false-positive biopsy recommendation rate per 1000 examinations was 29.6 (95% CI: 22.6, 38.6) and was higher in patients with high versus low or average 6-year advanced breast cancer risk (37.0 [95% CI: 28.2, 48.4] vs 28.1 [95% CI: 20.9, 37.8], respectively; P = .04). The overall PPV3 was 6.9% (67 of 975; 95% CI: 5.3, 8.9) and was higher in patients with high versus low or average 6-year advanced cancer risk (15.0% [15 of 100; 95% CI: 9.9, 22.2] vs 4.9% [30 of 615; 95% CI: 3.3, 7.2]; P = .01). Similar patterns in outcomes were observed by 5-year invasive breast cancer risk. Conclusion The cancer detection rate and PPV3 of supplemental US screening increased with the estimated risk of advanced and invasive breast cancer. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Helbich and Kapetas in this issue.}, }
@article {pmid39104770, year = {2024}, author = {Marsland, P and Jain, R and Tverdek, F and Hendrie, P and Liu, C and Pergam, SA and Bourassa, L}, title = {Ceftriaxone-resistant viridans streptococci bacteraemia among patients treated at a large comprehensive cancer care centre: a retrospective eighteen-year study.}, journal = {JAC-antimicrobial resistance}, volume = {6}, number = {4}, pages = {dlae126}, pmid = {39104770}, issn = {2632-1823}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {OBJECTIVES: Viridans streptococci (VS) are opportunistic oral commensals and a common cause of bacteraemia in neutropenic patients. In this retrospective single centre cohort study, we investigated the prevalence of ceftriaxone resistance in VS (CRO-R VS) blood isolates between January 2005 and December 2022 from patients treated at a tertiary care hospital.<br><br>METHODS: Blood culture isolates were identified using biochemicals and mass spectrometry. Susceptibility testing was performed by Kirby-Bauer and Epsilometer tests. Demographic data, clinical outcomes and antimicrobial use were assessed through electronic medical record review.<br><br>RESULTS: Among 791 patients with VS bacteraemia, 31 (4%) had confirmed CRO-R VS bacteraemia over the 18-year period; 20/31 (65%) were patients also treated at the Fred Hutchinson Cancer Center and were the focus of this study. Of these 20 patients, 18 (90%) had a known haematologic malignancy; 14 (70%) had undergone haematopoietic cell transplant (HCT); 18 (90%) were neutropenic at the time of culture. Two (10%) patients died within 30 days of CRO-R VS bacteraemia. All the CRO-R isolates (20/20) were members of the Streptococcus mitis group, 12 were multi-drug resistant; all were susceptible to vancomycin. Most patients received vancomycin once blood cultures were positive for a Gram-positive organism.<br><br>CONCLUSIONS: During the study period, the frequency of VS isolate susceptibility testing increased; however, there was no concomitant increase in the percentage of CRO-R isolates at our facility. These data are important in an era where cefepime monotherapy is often used and reinforces the importance of routine resistance testing among VS bacteraemia.}, }
@article {pmid39103508, year = {2024}, author = {Lozac'hmeur, A and Danek, T and Yang, Q and Rosasco, MG and Welch, JS and Go, WY and Ng, EW and Mardiros, A and Maloney, DG and Garon, EB and Kirtane, K and Simeone, DM and Molina, JR and Salahudeen, AA and Stein, MM and Hecht, JR}, title = {Detecting HLA loss of heterozygosity within a standard diagnostic sequencing workflow for prognostic and therapeutic opportunities.}, journal = {NPJ precision oncology}, volume = {8}, number = {1}, pages = {174}, pmid = {39103508}, issn = {2397-768X}, abstract = {To enable interrogation of tumor HLA LOH as a clinical diagnostic for precision oncology, we developed and validated an assay that detects HLA LOH within the context of an FDA-approved clinical diagnostic test, Tempus xT CDx. Validation was conducted via: (1) analytical evaluation of 17 archival patient samples and 42 cell line admixtures and (2) independent clinical evaluation of LOH prevalence in the HLA-A gene (HLA-A LOH) across 10,982 patients. To evaluate the prognostic relevance of HLA-A LOH we assessed 256 immunotherapy-treated non-small cell lung cancer (NSCLC) patients. To determine the feasibility of prospectively identifying and enrolling HLA-A LOH patients into a clinical trial, we established BASECAMP-1 (NCT04981119). We observed a positive predictive agreement of 97% and a negative predictive agreement of 100% in samples with ≥ 40% tumor purity. We observed HLA-A LOH in 16.1% of patients (1771/10,982), comparable to previous reports. HLA-A LOH was associated with longer survival among NSCLC adenocarcinoma patients (HR = 0.60, 95% CI [0.37, 0.96], p = 0.032) with a trend towards shorter survival among squamous cell patients (HR = 1.64, 95% CI [0.80, 3.41], p = 0.183). In 20 months, we prospectively screened 1720 subjects using the Tempus AWARE program, identifying 26 HLA-A*02 LOH patients at 8 sites, with 14 (54%) enrolled into BASECAMP-1. In conclusion, we developed and validated an investigational assay that detects tumor HLA LOH within an FDA-approved clinical diagnostic test, enabling HLA LOH utilization in diagnostic, prognostic, and therapeutic applications.}, }
@article {pmid39102888, year = {2024}, author = {Petkov, VI and Byun, JS and Ward, KC and Schussler, NC and Archer, NP and Bentler, S and Doherty, JA and Durbin, EB and Gershman, ST and Cheng, I and Insaf, T and Gonsalves, L and Hernandez, BY and Koch, L and Liu, L and Monnereau, A and Morawski, BM and Schwartz, SM and Stroup, A and Wiggins, C and Wu, XC and Bonds, S and Negoita, S and Penberthy, L}, title = {Reporting tumor genomic test results to SEER registries via linkages.}, journal = {Journal of the National Cancer Institute. Monographs}, volume = {2024}, number = {65}, pages = {168-179}, pmid = {39102888}, issn = {1745-6614}, support = {HHSN261201800009C/CA/NCI NIH HHS/United States ; HHSN261201800005I//New York State Cancer Registry/ ; HHSN261201800041C/CA/NCI NIH HHS/United States ; HHSN261201800003I//Surveillance, Epidemiology and End Results/ ; HHSN261201800014C/CA/NCI NIH HHS/United States ; HHSN261201800012I_HHSN26100001//Surveillance, Epidemiology and End Results Program/ ; 1NU58DP006270/CC/CDC HHS/United States ; //University of California/ ; HHSN261201800012C/CA/NCI NIH HHS/United States ; HHSN261201800002I/HH/HHS/United States ; HHSN261201800001C/CA/NCI NIH HHS/United States ; HHSN261201800002C/CA/NCI NIH HHS/United States ; HHSN261201800006I/CA/NCI NIH HHS/United States ; HHSN261201800007I//chool of Public Health Louisiana State University Health New Orleans/ ; 6NU58DP006352-05-01/CC/CDC HHS/United States ; 75N99021D00009/OF/ORFDO NIH HHS/United States ; //Cancer Data Registry of Idaho/ ; HHSN261201800032C/CA/NCI NIH HHS/United States ; //Emory University/ ; HHSN261201800004C/CA/NCI NIH HHS/United States ; HHSN261201800016I/CA/NCI NIH HHS/United States ; //Keck School of Medicine/ ; HHSN261201000041C/CA/NCI NIH HHS/United States ; 75N91021D00011/CA/NCI NIH HHS/United States ; HHSN2612018000041//Division of Public Health Sciences Fred Hutchinson Cancer Center/ ; //Texas Cancer Registry/ ; HHSN261201300009I/CA/NCI NIH HHS/United States ; 75N96021D00006/ES/NIEHS NIH HHS/United States ; 75N92021D00011/HL/NHLBI NIH HHS/United States ; HHSN261201300009C/CA/NCI NIH HHS/United States ; 75N96021D00009/ES/NIEHS NIH HHS/United States ; 75N98021D00006/NH/NIH HHS/United States ; 1NU58DP007140/CC/CDC HHS/United States ; 75N95021D00011/DA/NIDA NIH HHS/United States ; //Department of Population and Public Health Sciences/ ; 75N92021D00006/HL/NHLBI NIH HHS/United States ; HHSN261201800014I/CA/NCI NIH HHS/United States ; HHSN261201000041I/CA/NCI NIH HHS/United States ; HHSN261201800032I/CA/NCI NIH HHS/United States ; 75N91021D00009//New Jersey State Cancer Registry/ ; 75N91021D00006//Illinois State Cancer Registry/ ; HHSN261201800012I/CA/NCI NIH HHS/United States ; HHSN261201800009I/CA/NCI NIH HHS/United States ; HHSN261201800002B/CA/NCI NIH HHS/United States ; 75N97021D00006/LM/NLM NIH HHS/United States ; 75N92021D00009/HL/NHLBI NIH HHS/United States ; HHSN261201800003C/CA/NCI NIH HHS/United States ; 75N90021D00009/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *SEER Program/statistics &amp; numerical data ; United States/epidemiology ; *Neoplasms/genetics/epidemiology/diagnosis ; *Genomics/methods ; *Registries/statistics &amp; numerical data ; Female ; Male ; Genetic Testing/methods/statistics &amp; numerical data ; Medical Record Linkage/methods ; National Cancer Institute (U.S.) ; }, abstract = {BACKGROUND: Precision medicine has become a mainstay of cancer care in recent years. The National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program has been an authoritative source of cancer statistics and data since 1973. However, tumor genomic information has not been adequately captured in the cancer surveillance data, which impedes population-based research on molecular subtypes. To address this, the SEER Program has developed and implemented a centralized process to link SEER registries' tumor cases with genomic test results that are provided by molecular laboratories to the registries.<br><br>METHODS: Data linkages were carried out following operating procedures for centralized linkages established by the SEER Program. The linkages used Match*Pro, a probabilistic linkage software, and were facilitated by the registries' trusted third party (an honest broker). The SEER registries provide to NCI limited datasets that undergo preliminary evaluation prior to their release to the research community.<br><br>RESULTS: Recently conducted genomic linkages included OncotypeDX Breast Recurrence Score, OncotypeDX Breast Ductal Carcinoma in Situ, OncotypeDX Genomic Prostate Score, Decipher Prostate Genomic Classifier, DecisionDX Uveal Melanoma, DecisionDX Preferentially Expressed Antigen in Melanoma, DecisionDX Melanoma, and germline tests results in Georgia and California SEER registries.<br><br>CONCLUSIONS: The linkages of cancer cases from SEER registries with genomic test results obtained from molecular laboratories offer an effective approach for data collection in cancer surveillance. By providing de-identified data to the research community, the NCI's SEER Program enables scientists to investigate numerous research inquiries.}, }
@article {pmid39102887, year = {2024}, author = {Chen, HS and Negoita, S and Schwartz, S and Hsu, E and Hafterson, J and Coyle, L and Stevens, J and Fernandez, A and Potts, M and Feuer, EJ}, title = {Toward real-time reporting of cancer incidence: methodology, pilot study, and SEER Program implementation.}, journal = {Journal of the National Cancer Institute. Monographs}, volume = {2024}, number = {65}, pages = {123-131}, doi = {10.1093/jncimonographs/lgae024}, pmid = {39102887}, issn = {1745-6614}, mesh = {Humans ; *SEER Program/statistics &amp; numerical data ; Pilot Projects ; *Neoplasms/epidemiology/diagnosis ; Incidence ; United States/epidemiology ; Registries ; National Cancer Institute (U.S.) ; }, abstract = {BACKGROUND: A lag time between cancer case diagnosis and incidence reporting impedes the ability to monitor the impact of recent events on cancer incidence. Currently, the data submission standard is 22 months after a diagnosis year ends, and the reporting standard is 27.5 months after a diagnosis year ends. This paper presents the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program's efforts to minimize the lag and achieve "real-time" reporting, operationalized as submission within 2 months from the end of a diagnosis year.<br><br>METHODS: Technology for rapidly creating a consolidated tumor case (CTC) from electronic pathology (e-path) reports is described. Statistical methods are extended to adjust for biases in incidence rates due to reporting delays for the most recent diagnosis years.<br><br>RESULTS: A registry pilot study demonstrated that real-time submissions can approximate rates obtained from 22-month submissions after adjusting for reporting delays. A plan to be implemented across the SEER Program rapidly ascertains unstructured e-path reports and uses machine learning algorithms to translate the reports into the core data items that comprise a CTC for incidence reporting. Across the program, cases were submitted 2&#x2009;months after the end of the calendar year. Registries with the most promising baseline values and a willingness to modify registry operations have joined a program to become certified as real-time reporting.<br><br>CONCLUSION: Advances in electronic reporting, natural language processing, registry operations, and statistical methodology, energized by the SEER Program's mobilization and coordination of these efforts, will make real-time reporting an achievable goal.}, }
@article {pmid39102659, year = {2024}, author = {Dei Zotti, F and Qiu, A and D'Agati, VD and Jagnarine, S and Kyritsis, E and Miller, A and Tredicine, M and Fliginger, D and Stone, EF and Panch, S and Hudson, KE}, title = {Mitigation of checkpoint inhibitor-induced autoimmune hemolytic anemia through modulation of purinergic signaling.}, journal = {Blood}, volume = {144}, number = {15}, pages = {1581-1594}, pmid = {39102659}, issn = {1528-0020}, support = {R01 HL133325/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; *Anemia, Hemolytic, Autoimmune/immunology/drug therapy/pathology ; Mice ; *Immune Checkpoint Inhibitors/adverse effects/pharmacology ; *Apyrase ; *Signal Transduction/drug effects ; T-Lymphocytes, Regulatory/immunology/drug effects ; Humans ; Autoantibodies/immunology ; Female ; Disease Models, Animal ; Mice, Inbred C57BL ; Antigens, CD ; }, abstract = {Immune checkpoint inhibitors (ICPis) have revolutionized cancer immunotherapy but also can induce autoimmune hemolytic anemia (AIHA), a severe disease with high mortality. However, the cellular and molecular mechanism(s) of AIHA secondary to ICPi therapy (ICPi-AIHA) are unclear, other than being initiated through decreased checkpoint inhibition. Herein, we report ICPi-AIHA in a novel mouse model that shows similar characteristics of known human ICPi-AIHA (eg, autoantibodies, hemolysis, and increased mortality). During ICPi-AIHA, there is the simultaneous reduction of 2 regulatory T-cell populations (FoxP3+ and Tr1 [type 1 regulatory cells]) and an increase in inflammatory T helper cell 17 (TH17). Moreover, a novel CD39+CD73-FoxP3-CD25- CD4+ T-cell subset (ie, CD39 single positive [CD39SP]) emerges, and early increases in CD39SP predict AIHA development; CD39 is an ectonuclease that breaks down adenosine triphosphate (ATP). Additionally, we found that boosting ATPase activity by injecting recombinant apyrase mitigates AIHA development and significant CD39SP reductions, both suggesting a functional role for CD39 and demonstrating a novel therapeutic approach. Importantly, CD39SP are detectable in multiple mouse models developing AIHA and in patients with AIHA, demonstrating applicability to idiopathic and secondary AIHA. Highlighting broader autoimmunity relevance, ICPi-treated NZB mice experienced accelerated onset and severity of lupus, including AIHA. Moreover, ICPi treatment of healthy B6 animals led to detectable CD39SP and development of autoantibodies against multiple autoantigens including those on red blood cells and platelets. Together, our findings provide further insight into the cellular and molecular mechanisms of ICPi-AIHA, leading to novel diagnostic and therapeutic approaches with translational potential for use in humans being treated with ICPi.}, }
@article {pmid39102335, year = {2024}, author = {Schofield, JA and Hahn, S}, title = {Transcriptional noise, gene activation, and roles of SAGA and Mediator Tail measured using nucleotide recoding single-cell RNA-seq.}, journal = {Cell reports}, volume = {43}, number = {8}, pages = {114593}, pmid = {39102335}, issn = {2211-1247}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R35 GM140823/GM/NIGMS NIH HHS/United States ; }, mesh = {*Saccharomyces cerevisiae/genetics/metabolism ; *Saccharomyces cerevisiae Proteins/metabolism/genetics ; *Single-Cell Analysis/methods ; *Transcriptional Activation ; Promoter Regions, Genetic/genetics ; Gene Expression Regulation, Fungal ; Trans-Activators/metabolism/genetics ; Transcription, Genetic ; Mediator Complex/metabolism/genetics ; RNA-Seq/methods ; Single-Cell Gene Expression Analysis ; }, abstract = {We describe a time-resolved nascent single-cell RNA sequencing (RNA-seq) approach that measures gene-specific transcriptional noise and the fraction of active genes in S. cerevisiae. Most genes are expressed with near-constitutive behavior, while a subset of genes show high mRNA variance suggestive of transcription bursting. Transcriptional noise is highest in the cofactor/coactivator-redundant (CR) gene class (dependent on both SAGA and TFIID) and strongest in TATA-containing CR genes. Using this approach, we also find that histone gene transcription switches from a low-level, low-noise constitutive mode during M and M/G1 to an activated state in S phase that shows both an increase in the fraction of active promoters and a switch to a noisy and bursty transcription mode. Rapid depletion of cofactors SAGA and MED Tail indicates that both factors play an important role in stimulating the fraction of active promoters at CR genes, with a more modest role in transcriptional noise.}, }
@article {pmid39101994, year = {2024}, author = {Karcher, MD and Zhang, C and Matsen, FA}, title = {Variational Supertrees for Bayesian Phylogenetics.}, journal = {Bulletin of mathematical biology}, volume = {86}, number = {9}, pages = {114}, pmid = {39101994}, issn = {1522-9602}, support = {U54 grant GM111274/NH/NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R01 AI162611/AI/NIAID NIH HHS/United States ; R01 grant AI162611/NH/NIH HHS/United States ; U54 GM111274/GM/NIGMS NIH HHS/United States ; CISE-1564137//National Science Foundation/ ; CISE-1561334//National Science Foundation/ ; S10OD028685//Office of Research Infrastructure Programs, National Institutes of Health/ ; }, mesh = {*Bayes Theorem ; *Phylogeny ; *Algorithms ; *Markov Chains ; *Mathematical Concepts ; *Models, Genetic ; Computer Simulation ; Probability ; }, abstract = {Bayesian phylogenetic inference is powerful but computationally intensive. Researchers may find themselves with two phylogenetic posteriors on overlapping data sets and may wish to approximate a combined result without having to re-run potentially expensive Markov chains on the combined data set. This raises the question: given overlapping subsets of a set of taxa (e.g. species or virus samples), and given posterior distributions on phylogenetic tree topologies for each of these taxon sets, how can we optimize a probability distribution on phylogenetic tree topologies for the entire taxon set? In this paper we develop a variational approach to this problem and demonstrate its effectiveness. Specifically, we develop an algorithm to find a suitable support of the variational tree topology distribution on the entire taxon set, as well as a gradient-descent algorithm to minimize the divergence from the restrictions of the variational distribution to each of the given per-subset probability distributions, in an effort to approximate the posterior distribution on the entire taxon set.}, }
@article {pmid39100381, year = {2024}, author = {Tsosie, U and Anderson, N and Woo, N and Dee, C and Echo-Hawk, A and Baker, L and Rusk, AM and Barrington, W and Parker, M and Triplette, M}, title = {Understanding determinants of lung cancer preventive care in at-risk urban American Indians and Alaska Natives: A mixed-methods study.}, journal = {Preventive medicine reports}, volume = {45}, number = {}, pages = {102822}, pmid = {39100381}, issn = {2211-3355}, support = {P50 CA228944/CA/NCI NIH HHS/United States ; }, abstract = {INTRODUCTION: Lung cancer is the leading cause of cancer death among American Indian and Alaska Native (AI/AN) people, and AI/AN people have the highest rate of smoking of any racial or ethnic group in the US. There is limited research to inform culturally-relevant strategies for lung cancer prevention inclusive of lung cancer screening (LCS). The objective of this study was to understand determinants of LCS and tobacco cessation care in at-risk urban-dwelling AI/ANs.<br><br>MATERIALS AND METHODS: This was a mixed-methods community-based participatory research study including complimentary qualitative discussions and surveys conducted in Seattle, Washington, USA from 2022 to 2023. The study measures and analytic approach integrated the Consolidated Framework for Implementation Research and Tribal Critical Race Theory and qualitative transcripts were analyzed using thematic analysis. Participants were self-identified AI/AN people who were age &#x2265; 40 and had &#x2265; 10-year history of commercial cigarette smoking.<br><br>RESULTS: Forty-five participants completed surveys and participated in discussions, 48% were female, the median age was 58 and median smoking history was 24 pack-years of commercial cigarette use. Themes revealed prominent barriers to LCS care including access, costs, awareness, and fear. Many reported previous negative and discriminatory encounters within and outside the health system which may also serve as barriers. Most participants endorsed cancer screening and increased education, recommending Indigenous-centered, delivered, and tailored programs, as well barrier-directed support.<br><br>CONCLUSIONS: In a broad sample of at-risk urban-dwelling AI/AN people, our findings suggest enthusiasm for preventive care but several complex barriers. Participants endorsed culturally-tailored programs which could provide relevant education and address barriers.}, }
@article {pmid39099206, year = {2024}, author = {Zamora, D and Dasgupta, S and Stevens-Ayers, T and Edmison, B and Winston, DJ and Razonable, RR and Mehta, AK and Lyon, GM and Boeckh, M and Singh, N and Koelle, DM and Limaye, AP}, title = {Cytomegalovirus immunity in high-risk liver transplant recipients following preemptive antiviral therapy versus prophylaxis.}, journal = {JCI insight}, volume = {9}, number = {18}, pages = {}, pmid = {39099206}, issn = {2379-3708}, support = {K23 AI163343/AI/NIAID NIH HHS/United States ; T32 AI118690/AI/NIAID NIH HHS/United States ; U01 AI163090/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Liver Transplantation ; *Cytomegalovirus Infections/immunology/prevention &amp; control ; *Antiviral Agents/therapeutic use ; Male ; *Cytomegalovirus/immunology ; Middle Aged ; Female ; *Killer Cells, Natural/immunology ; Adult ; Transplant Recipients ; Aged ; Antibodies, Neutralizing/immunology/blood ; Antibodies, Viral/immunology/blood ; Viremia/immunology ; }, abstract = {CMV-specific T cells, NK cells, and neutralizing antibodies (nAbs) were assessed in a randomized trial of CMV prevention with preemptive antiviral therapy (PET) versus prophylactic antiviral therapy (PRO) in donor-seropositive/recipient-seronegative (D+R-) liver transplant recipients (LTxR) at 100 days (end of intervention) and at 6 and 12 months after transplant. The PET group had significantly increased numbers of circulating polyfunctional T cells, NK cells, and nAbs compared with the PRO group at day 100, and several CMV immune parameters remained significantly higher by 12 months after transplant. Among PET recipients, preceding CMV viremia (vs. no preceding viremia) was associated with significantly higher levels of most CMV immune parameters at day 100. Higher numbers of CMV-specific polyfunctional T cells and NKG2C+ NK cells at day 100 were associated with a decreased incidence of CMV disease in multivariable Cox regression. The strongest associations with protection against CMV disease were with increased numbers of CMV-specific polyfunctional CD4+ T cells, CD3negCD56dimCD57negNKG2Cpos cells, and CD3negCD56dimCD57posNKG2Cpos NK cells. Our results suggest that PET is superior to PRO for CMV disease prevention by allowing low-level CMV replication and associated antigen exposure that is promptly controlled by antiviral therapy and facilitates enhanced CMV protective immunity in D+R- LTxR.}, }
@article {pmid39099090, year = {2024}, author = {Painter, CD and Sankaranarayanan, NV and Nagarajan, B and Mandel Clausen, T and West, AMV and Setiawan, NJ and Park, J and Porell, RN and Bartels, PL and Sandoval, DR and Vasquez, GJ and Chute, JP and Godula, K and Vander Kooi, CW and Gordts, PLSM and Corbett, KD and Termini, CM and Desai, UR and Esko, JD}, title = {Alteration of Neuropilin-1 and Heparan Sulfate Interaction Impairs Murine B16 Tumor Growth.}, journal = {ACS chemical biology}, volume = {19}, number = {8}, pages = {1820-1835}, pmid = {39099090}, issn = {1554-8937}, support = {R35 GM144121/GM/NIGMS NIH HHS/United States ; P01 HL151333/HL/NHLBI NIH HHS/United States ; R01 GM145913/GM/NIGMS NIH HHS/United States ; R01 ES010377/ES/NIEHS NIH HHS/United States ; P30 DK063491/DK/NIDDK NIH HHS/United States ; R33 AR073031/AR/NIAMS NIH HHS/United States ; P30 CA023100/CA/NCI NIH HHS/United States ; P01 HL131474/HL/NHLBI NIH HHS/United States ; R61 AR073031/AR/NIAMS NIH HHS/United States ; K12 HL141954/HL/NHLBI NIH HHS/United States ; K01 DK126989/DK/NIDDK NIH HHS/United States ; U01 CA241951/CA/NCI NIH HHS/United States ; P30 NS047101/NS/NINDS NIH HHS/United States ; }, mesh = {*Neuropilin-1/metabolism/genetics/chemistry ; Animals ; *Heparitin Sulfate/metabolism ; Mice ; Melanoma, Experimental/metabolism/pathology ; Protein Binding ; Binding Sites ; Mice, Inbred C57BL ; Heparin/metabolism/chemistry ; Molecular Dynamics Simulation ; Mutation ; }, abstract = {Neuropilin-1 acts as a coreceptor with vascular endothelial growth factor receptors to facilitate binding of its ligand, vascular endothelial growth factor. Neuropilin-1 also binds to heparan sulfate, but the functional significance of this interaction has not been established. A combinatorial library screening using heparin oligosaccharides followed by molecular dynamics simulations of a heparin tetradecasaccharide suggested a highly conserved binding site composed of amino acid residues extending across the b1 and b2 domains of murine neuropilin-1. Mutagenesis studies established the importance of arginine513 and lysine514 for binding of heparin to a recombinant form of Nrp1 composed of the a1, a2, b1, and b2 domains. Recombinant Nrp1 protein bearing R513A,K514A mutations showed a significant loss of heparin-binding, heparin-induced dimerization, and heparin-dependent thermal stabilization. Isothermal calorimetry experiments suggested a 1:2 complex of heparin tetradecasaccharide:Nrp1. To study the impact of altered heparin binding in vivo, a mutant allele of Nrp1 bearing the R513A,K514A mutations was created in mice (Nrp1[D]) and crossbred to Nrp1[+/-] mice to examine the impact of altered heparan sulfate binding. Analysis of tumor formation showed variable effects on tumor growth in Nrp1[D/D] mice, resulting in a frank reduction in tumor growth in Nrp1[D/-] mice. Expression of mutant Nrp1[D] protein was normal in tissues, suggesting that the reduction in tumor growth was due to the altered binding of heparin/heparan sulfate to neuropilin-1. These findings suggest that the interaction of neuropilin-1 with heparan sulfate modulates its stability and its role in tumor formation and growth.}, }
@article {pmid39098823, year = {2024}, author = {Lange, JM and Gard, CC and O'Meara, ES and Miglioretti, DL and Etzioni, R}, title = {Breast density and risk of breast cancer: masking and detection bias.}, journal = {American journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/aje/kwae245}, pmid = {39098823}, issn = {1476-6256}, abstract = {Breast density is associated with risk of breast cancer (BC) diagnosis, impacting risk prediction tools and patient notification policies. Density affects mammography sensitivity and may influence screening intensity. Therefore, the observed association between density and BC diagnosis may not reflect the relationship between density and disease risk. We investigate the association between breast density and BC risk using data sourced from 33,542 women in the Breast Cancer Surveillance Consortium, 2000-2018. We estimated mammogram sensitivity and rates of screening mammography among dense (BI-RADS c, d) and non-dense (BI-RADS a, b) breasts. We used Kaplan-Meier estimates to summarize the relative risks of BC diagnosis (RRdx) by density and fit a natural history model to estimate the relative risks of BC onset (RRonset) given density-specific sensitivities. RRdx for dense versus non-dense breasts was 1.80 (95% CI 1.46 to 2.57). Based on estimated screening sensitivities of 0.88 and .78 for non-dense and dense breasts, respectively, RRonset was 1.73 (95% CI 1.43 to 2.25). Sensitivity analyses suggested higher breast density is robustly associated with increased risk of BC onset, similar in magnitude to the increased risk of BC diagnosis. These finding support laws requiring notifications to women with dense breasts of their increased BC risk.}, }
@article {pmid39095990, year = {2024}, author = {Li, Y and Wong, KY and Howard, AG and Gordon-Larsen, P and Highland, HM and Graff, M and North, KE and Downie, CG and Avery, CL and Yu, B and Young, KL and Buchanan, VL and Kaplan, R and Hou, L and Joyce, BT and Qi, Q and Sofer, T and Moon, JY and Lin, DY}, title = {Multivariable Mendelian randomization with incomplete measurements on the exposure variables in the Hispanic Community Health Study/Study of Latinos.}, journal = {HGG advances}, volume = {5}, number = {4}, pages = {100338}, pmid = {39095990}, issn = {2666-2477}, support = {HHSN268201300005C/HL/NHLBI NIH HHS/United States ; R01 HL143885/HL/NHLBI NIH HHS/United States ; R01 HG009974/HG/NHGRI NIH HHS/United States ; N01HC65235/HL/NHLBI NIH HHS/United States ; N01HC65234/HL/NHLBI NIH HHS/United States ; T32 HL129982/HL/NHLBI NIH HHS/United States ; N01HC65233/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; N01HC65237/HL/NHLBI NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; R01 HG010297/HG/NHGRI NIH HHS/United States ; P30 AG066615/AG/NIA NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; R01 HL147853/HL/NHLBI NIH HHS/United States ; N01HC65236/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Hispanic or Latino/genetics ; *Mendelian Randomization Analysis/methods ; Algorithms ; Likelihood Functions ; Computer Simulation ; Multivariate Analysis ; }, abstract = {Multivariable Mendelian randomization allows simultaneous estimation of direct causal effects of multiple exposure variables on an outcome. When the exposure variables of interest are quantitative omic features, obtaining complete data can be economically and technically challenging: the measurement cost is high, and the measurement devices may have inherent detection limits. In this paper, we propose a valid and efficient method to handle unmeasured and undetectable values of the exposure variables in a one-sample multivariable Mendelian randomization analysis with individual-level data. We estimate the direct causal effects with maximum likelihood estimation and develop an expectation-maximization algorithm to compute the estimators. We show the advantages of the proposed method through simulation studies and provide an application to the Hispanic Community Health Study/Study of Latinos, which has a large amount of unmeasured exposure data.}, }
@article {pmid39095958, year = {2024}, author = {Asosingh, K and Bayiyana, A and Black, MC and Chakraborty, U and Clemente, MJ and Graham, AC and Gregory, MD and Hogg, KG and Van Isterdael, G and Liu, C and Martínez, L and Petersen, CC and Porat, Z and Price, KM and Prickett, LB and Rieger, AM and Roe, CE and Smit, E}, title = {Best practices for user consultation in flow cytometry shared resource laboratories.}, journal = {Cytometry. Part A : the journal of the International Society for Analytical Cytology}, volume = {105}, number = {9}, pages = {704-712}, doi = {10.1002/cyto.a.24891}, pmid = {39095958}, issn = {1552-4930}, mesh = {Humans ; *Flow Cytometry/methods/standards ; Laboratories/standards ; *Referral and Consultation/standards ; Guidelines as Topic ; }, abstract = {This "Best Practices in User Consultation" article is the result of a 2022 International Society for the Advancement of Cytometry (ISAC) membership survey that collected valuable insights from the shared research laboratory (SRL) community and of a group discussion at the CYTO 2022 workshop of the same name. One key takeaway is the importance of initiating a consultation at the outset of a flow cytometry project, particularly for trainees. This approach enables the improvement and standardization of every step, from planning experiments to interpreting data. This proactive approach effectively mitigates experimental bias and avoids superfluous trial and error, thereby conserving valuable time and resources. In addition to guidelines, the optimal approaches for user consultation specify communication channels, methods, and critical information, thereby establishing a structure for productive correspondence between SRL and users. This framework functions as an exemplar for establishing robust and autonomous collaborative relationships. User consultation adds value by providing researchers with the necessary information to conduct reproducible flow cytometry experiments that adhere to scientific rigor. By following the steps, instructions, and strategies outlined in these best practices, an SRL can readily tailor them to its own setting, establishing a personalized workflow and formalizing user consultation services. This article provides a pragmatic guide for improving the caliber and efficacy of flow cytometry research and aggregates the flow cytometry SRL community's collective knowledge regarding user consultation.}, }
@article {pmid39095638, year = {2024}, author = {Barros, G and Federico, E and Fillingham, P and Chanana, P and Kaneko, N and Zheng, Y and Kim, LJ and Levitt, MR}, title = {Endothelial Cell Transcription Modulation in Cerebral Aneurysms After Endovascular Flow Diversion.}, journal = {Annals of biomedical engineering}, volume = {52}, number = {12}, pages = {3253-3263}, pmid = {39095638}, issn = {1573-9686}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R25 NS079200/NS/NINDS NIH HHS/United States ; R01 NS105692/NS/NINDS NIH HHS/United States ; R25NS079200/NS/NINDS NIH HHS/United States ; P30CA015704//Genomics &amp; Bioinformatics Shared Resource, Fred Hutch/University of Washington/Seattle Children's Cancer Consortium/ ; UE5 NS079200/NS/NINDS NIH HHS/United States ; UL1 TR002319/TR/NCATS NIH HHS/United States ; R01NS105692/NS/NINDS NIH HHS/United States ; R01 NS121286/NS/NINDS NIH HHS/United States ; R01NS121286/NS/NINDS NIH HHS/United States ; }, mesh = {*Intracranial Aneurysm/physiopathology/surgery/metabolism ; Humans ; *Endothelial Cells/metabolism ; *Stents ; Endovascular Procedures ; Transcription, Genetic ; Male ; Hemodynamics ; Models, Cardiovascular ; }, abstract = {PURPOSE: Flow diverting stents (FDS) are used to treat cerebral aneurysms, by promoting thrombosis and occlusion of the aneurysm sac. However, retreatment is required in some cases, and the biologic basis behind treatment outcome is not known. The goal of this study was to understand how changes in hemodynamic flow after FDS placement affect aneurysmal endothelial cell (EC) activity.<br><br>METHODS: Three-dimensional models of patient-specific aneurysms were created to quantify the EC response to FDS placement. Computational fluid dynamic simulations were used to determine the hemodynamic impact of FDS. Two identical models were created for each patient; into one a FDS was inserted. Each model was then populated with human carotid ECs and subjected to patient-specific pulsatile flow for 24 h. ECs were isolated from aneurysm dome from each model and bulk RNA sequencing was performed.<br><br>RESULTS: Paired untreated and treated models were created for four patients. Aneurysm dome EC analysis revealed 366 (2.6%) significant gene changes between the untreated and FDS conditions, out of 13909 total expressed genes. Gene set enrichment analysis of the untreated models demonstrated enriched gene ontology terms related to cell adhesion, growth/tensile activity, cytoskeletal organization, and calcium ion binding. In the FDS models, enriched terms were related to cellular proliferation, ribosomal activity, RNA splicing, and protein folding.<br><br>CONCLUSION: Treatment of cerebral aneurysms with FDS induces significant EC gene transcription changes related to aneurysm hemodynamics in patient-specific in vitro 3D-printed models subjected to pulsatile flow. Further investigation is needed into the relationship between transcriptional change and treatment outcome.}, }
@article {pmid39095611, year = {2024}, author = {Cocciardi, JM and Hoffman, AM and Alvarado-Serrano, DF and Anderson, J and Blumstein, M and Boehm, EL and Bolin, LG and Borokini, IT and Bradburd, GS and Branch, HA and Brudvig, LA and Chen, Y and Collins, SL and Des Marais, DL and Gamba, D and Hanan, NP and Howard, MM and Jaros, J and Juenger, TE and Kooyers, NJ and Kottler, EJ and Lau, JA and Menon, M and Moeller, DA and Mozdzer, TJ and Sheth, SN and Smith, M and Toll, K and Ungerer, MC and Vahsen, ML and Wadgymar, SM and Waananen, A and Whitney, KD and Avolio, ML}, title = {The value of long-term ecological research for evolutionary insights.}, journal = {Nature ecology &amp; evolution}, volume = {8}, number = {9}, pages = {1584-1592}, pmid = {39095611}, issn = {2397-334X}, support = {2110351//NSF | BIO | Division of Environmental Biology (DEB)/ ; }, mesh = {*Biological Evolution ; *Ecology ; Ecosystem ; Climate Change ; }, abstract = {Scientists must have an integrative understanding of ecology and evolution across spatial and temporal scales to predict how species will respond to global change. Although comprehensively investigating these processes in nature is challenging, the infrastructure and data from long-term ecological research networks can support cross-disciplinary investigations. We propose using these networks to advance our understanding of fundamental evolutionary processes and responses to global change. For ecologists, we outline how long-term ecological experiments can be expanded for evolutionary inquiry, and for evolutionary biologists, we illustrate how observed long-term ecological patterns may motivate new evolutionary questions. We advocate for collaborative, multi-site investigations and discuss barriers to conducting evolutionary work at network sites. Ultimately, these networks offer valuable information and opportunities to improve predictions of species' responses to global change.}, }
@article {pmid39095452, year = {2024}, author = {FitzGerald, LM and Jung, CH and Wong, EM and Joo, JE and Bassett, JK and Dowty, JG and Wang, X and Dai, JY and Stanford, JL and O'Callaghan, N and Nottle, T and Pedersen, J and Giles, GG and Southey, MC}, title = {Detection of differentially methylated CpGs between tumour and adjacent benign cells in diagnostic prostate cancer samples.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {17877}, pmid = {39095452}, issn = {2045-2322}, support = {R01 CA056678/CA/NCI NIH HHS/United States ; YI 1812//Cure Cancer Australia/Prostate Cancer Foundation of Australia Young Investigators Grant/ ; 1061177//NHMRC Senior Research Fellowship/ ; }, mesh = {Humans ; *Prostatic Neoplasms/genetics/pathology/diagnosis/surgery/metabolism ; Male ; *DNA Methylation ; *CpG Islands/genetics ; Aged ; Middle Aged ; Prostatectomy ; Biomarkers, Tumor/genetics ; Gene Expression Regulation, Neoplastic ; Australia ; Prognosis ; }, abstract = {Differentially methylated CpG sites (dmCpGs) that distinguish prostate tumour from adjacent benign tissue could aid in the diagnosis and prognosis of prostate cancer. Previously, the identification of such dmCpGs has only been undertaken in radical prostatectomy (RP) samples and not primary diagnostic tumour samples (needle biopsy or transurethral resection of the prostate). We interrogated an Australian dataset comprising 125 tumour and 43 adjacent histologically benign diagnostic tissue samples, including 41 paired samples, using the Infinium Human Methylation450 BeadChip. Regression analyses of paired tumour and adjacent benign samples identified 2,386 significant dmCpGs (Bonferroni p < 0.01; delta-β ≥ 40%), with LASSO regression selecting 16 dmCpGs that distinguished tumour samples in the full Australian diagnostic dataset (AUC = 0.99). Results were validated in independent North American (npaired = 19; AUC = 0.87) and The Cancer Genome Atlas (TCGA; npaired = 50; AUC = 0.94) RP datasets. Two of the 16 dmCpGs were in genes that were significantly down-regulated in Australian tumour samples (Bonferroni p < 0.01; GSTM2 and PRKCB). Ten additional dmCpGs distinguished low (n = 34) and high Gleason (n = 88) score tumours in the diagnostic Australian dataset (AUC = 0.95), but these performed poorly when applied to the RP datasets (North American: AUC = 0.66; TCGA: AUC = 0.62). The DNA methylation marks identified here could augment and improve current diagnostic tests and/or form the basis of future prognostic tests.}, }
@article {pmid39094579, year = {2024}, author = {Voss, WN and Mallory, MA and Byrne, PO and Marchioni, JM and Knudson, SA and Powers, JM and Leist, SR and Dadonaite, B and Townsend, DR and Kain, J and Huang, Y and Satterwhite, E and Castillo, IN and Mattocks, M and Paresi, C and Munt, JE and Scobey, T and Seeger, A and Premkumar, L and Bloom, JD and Georgiou, G and McLellan, JS and Baric, RS and Lavinder, JJ and Ippolito, GC}, title = {Hybrid immunity to SARS-CoV-2 arises from serological recall of IgG antibodies distinctly imprinted by infection or vaccination.}, journal = {Cell reports. Medicine}, volume = {5}, number = {8}, pages = {101668}, pmid = {39094579}, issn = {2666-3791}, support = {R01 AI127521/AI/NIAID NIH HHS/United States ; R01 AI141707/AI/NIAID NIH HHS/United States ; U54 CA260543/CA/NCI NIH HHS/United States ; }, mesh = {*Immunoglobulin G/immunology/blood ; Humans ; *SARS-CoV-2/immunology ; *COVID-19/immunology/prevention &amp; control ; *Spike Glycoprotein, Coronavirus/immunology ; *Antibodies, Viral/immunology/blood ; *Vaccination ; *Antibodies, Neutralizing/immunology ; COVID-19 Vaccines/immunology ; Epitopes/immunology ; Female ; Antibodies, Monoclonal/immunology ; Male ; }, abstract = {We describe the molecular-level composition of polyclonal immunoglobulin G (IgG) anti-spike antibodies from ancestral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, vaccination, or their combination ("hybrid immunity") at monoclonal resolution. Infection primarily triggers S2/N-terminal domain (NTD)-reactive antibodies, whereas vaccination mainly induces anti-receptor-binding domain (RBD) antibodies. This imprint persists after secondary exposures wherein >60% of ensuing hybrid immunity derives from the original IgG pool. Monoclonal constituents of the original IgG pool can increase breadth, affinity, and prevalence upon secondary exposures, as exemplified by the plasma antibody SC27. Following a breakthrough infection, vaccine-induced SC27 gained neutralization breadth and potency against SARS-CoV-2 variants and zoonotic viruses (half-maximal inhibitory concentration [IC50] ∼0.1-1.75 nM) and increased its binding affinity to the protective RBD class 1/4 epitope (dissociation constant [KD] < 5 pM). According to polyclonal escape analysis, SC27-like binding patterns are common in SARS-CoV-2 hybrid immunity. Our findings provide a detailed molecular definition of immunological imprinting and show that vaccination can produce class 1/4 (SC27-like) IgG antibodies circulating in the blood.}, }
@article {pmid39093984, year = {2024}, author = {Elfeky, R and Builes, N and Pearce, R and Kania, S and Nademi, Z and Lucchini, G and Chiesa, R and Amrolia, P and Sorror, M and Veys, P and Rao, K}, title = {Pediatric adapted risk index to predict 2-year transplant-related mortality post-HSCT in children.}, journal = {Blood advances}, volume = {8}, number = {22}, pages = {5838-5852}, pmid = {39093984}, issn = {2473-9537}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects/methods/mortality ; Child ; Child, Preschool ; Female ; Male ; Adolescent ; Risk Assessment/methods ; Infant ; Risk Factors ; Comorbidity ; }, abstract = {Several attempts have been made to optimize pretransplant risk assessment to improve hematopoietic stem cell transplantation (HSCT) decision-making and to predict post-HSCT outcomes. However, the relevance of pretransplant risk assessment to the pediatric population remains unclear. We report the results of revalidation of the hematopoietic cell transplantation comorbidity index (HCT-CI) in 874 children who received 944 HSCTs for malignant or nonmalignant diseases at a single center. After finding the HCT-CI invalid in our patient population, we proposed a modified pediatric adapted scoring system that captures risk factors (RFs) and comorbidities (CoMs) relevant to pediatrics. Each RF/CoM was assigned an integer weight based on its hazard ratio (HR) for transplant-related mortality (TRM): 0 (HR < 1.2), 1 (1.2 ≥ HR < 1.75), 2 (1.75 ≥ HR < 2.5), and 3 (HR ≥ 2.5). Using these weights, the pediatric adapted risk index (PARI) for HSCT was devised, and patients were divided into 4 risk groups (group 1: without RF/CoM; group 2: score 1-2; group 3: score 3-4; and group 4: score ≥5). There was a linear increase in 2-year TRM from group 1 to 4 (TRM, 6.2% in group 1, 50.9% in group 4). PARI was successfully validated on an internal and external cohort of pediatric patients. Comparing models using c-statistics, PARI was found to have better performance than HCT-CI in predicting 2-year TRM in children, with Akaike and Schwarz Bayesian information criteria values of 1069.245 and 1073.269, respectively, using PARI, vs 1223.158 and 1227.051, respectively, using HCT-CI. We believe that PARI will be a valuable tool enabling better counseling and decision-making for pediatric patients with HSCT.}, }
@article {pmid39093891, year = {2024}, author = {Guenthoer, J and Garrett, ME and Lilly, M and Depierreux, DM and Ruiz, F and Chi, M and Stoddard, CI and Chohan, V and Yaffe, ZA and Sung, K and Ralph, D and Chu, HY and Matsen, FA and Overbaugh, J}, title = {The S2 subunit of spike encodes diverse targets for functional antibody responses to SARS-CoV-2.}, journal = {PLoS pathogens}, volume = {20}, number = {8}, pages = {e1012383}, pmid = {39093891}, issn = {1553-7374}, support = {R01 AI146028/AI/NIAID NIH HHS/United States ; }, mesh = {*Spike Glycoprotein, Coronavirus/immunology ; Humans ; *SARS-CoV-2/immunology ; *COVID-19/immunology/virology ; *Antibodies, Viral/immunology ; *Antibodies, Monoclonal/immunology ; Antibodies, Neutralizing/immunology ; Epitopes/immunology ; Pandemics ; Betacoronavirus/immunology ; Coronavirus Infections/immunology/virology ; Pneumonia, Viral/immunology/virology ; Antibody-Dependent Cell Cytotoxicity/immunology ; }, abstract = {The SARS-CoV-2 virus responsible for the COVID-19 global pandemic has exhibited a striking capacity for viral evolution that drives continued evasion from vaccine and infection-induced immune responses. Mutations in the receptor binding domain of the S1 subunit of the spike glycoprotein have led to considerable escape from antibody responses, reducing the efficacy of vaccines and monoclonal antibody (mAb) therapies. Therefore, there is a need to interrogate more constrained regions of spike, such as the S2 subdomain. Here, we present a collection of S2 mAbs from two SARS-CoV-2 convalescent individuals that target multiple regions in S2, including regions outside of those commonly reported. One of the S2 mAbs, C20.119, which bound to a highly conserved epitope in the fusion peptide, was able to broadly neutralize across SARS-CoV-2 variants, SARS-CoV-1, and closely related zoonotic sarbecoviruses. The majority of the mAbs were non-neutralizing; however, many of them could mediate antibody-dependent cellular cytotoxicity (ADCC) at levels similar to the S1-targeting mAb S309 that was previously authorized for treatment of SARS-CoV-2 infections. Several of the mAbs with ADCC function also bound to spike trimers from other human coronaviruses (HCoVs), such as MERS-CoV and HCoV-HKU1. Our findings suggest S2 mAbs can target diverse epitopes in S2, including functional mAbs with HCoV and sarbecovirus breadth that likely target functionally constrained regions of spike. These mAbs could be developed for potential future pandemics, while also providing insight into ideal epitopes for eliciting a broad HCoV response.}, }
@article {pmid39093355, year = {2024}, author = {Muno, BA and Islam, JY and Schwartz, R and Wallace, S and Camacho-Rivera, M and Patel, RC}, title = {Structural Racism Conceptualization and Operationalization for Research for the U.S. HIV Epidemic: Findings from a Scoping Review and Implications for Advancing Research for Structural Interventions.}, journal = {AIDS and behavior}, volume = {28}, number = {Suppl 1}, pages = {149-165}, pmid = {39093355}, issn = {1573-3254}, support = {R01MH131542/MH/NIMH NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; R01MH131542/MH/NIMH NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *HIV Infections/epidemiology/ethnology/prevention &amp; control ; United States/epidemiology ; *COVID-19/epidemiology ; SARS-CoV-2 ; Healthcare Disparities ; Systemic Racism ; Health Status Disparities ; Epidemics ; Racism ; }, abstract = {In the U.S., inequities by race/ethnicity in health outcomes, such as in the HIV epidemic, are long standing but have come to the forefront during the COVID-19 pandemic. There is growing recognition of the role of structural racism in racialized health inequities, yet the conceptualization and operationalization of structural racism in HIV research lags. We conducted a scoping review of existing published literature, between 1999-April 2024, conceptualizing and measuring structural racism's impact among people living with or at risk for HIV in the U.S. Our initial search yielded 236 unique articles, which after title and abstract screening yielded ten articles meeting full text review criteria. We then extracted key parameters, such as conceptualization, method of measurement of structural racism, study aims, design, and findings. Three of the articles were qualitative studies that conceptualized structural racism using (1) the social network model, (2) individual and structural intersectionality and (3) critical race theory. Operationalization of structural racism within the seven quantitative studies fell into three categories: (1) structural level, (2) a scale of experiences of racism, including structural racism, and (3) using explanatory demographic factors as downstream measures of the effects of structural racism. The variance in the conceptualization and operationalization of structural racism highlights the different interpretations of structural racism in its applications to the field of HIV research. Given the vast racial/ethnic inequities in HIV, we propose three overarching suggestions for next steps in improving the conduct of research on structural racism in HIV: (1) we must prioritize measuring racism past the individual and interpersonal levels to consider systemic factors at a societal level that manifest as structural racism to improve HIV outcomes in the U.S., (2) consider intergenerational effects of structural racism through the use of longitudinal data, and (3) broaden the agenda of structural racism to incorporate other systems of oppression. Additionally, broadening the scope of funding and inclusion of more researchers and individuals with lived experiences to support structural racism research to drive the scientific agenda and design of structural-level interventions will not only bolster achieving the U.S. Ending the HIV Epidemic goals but will do so by addressing inequities.}, }
@article {pmid39093129, year = {2024}, author = {Alsup, A and Nissen, E and Salas, LA and Molinaro, AM and Reiner, A and Liu, S and Madsen, TE and Liu, L and Auer, PL and Christensen, BC and Wiencke, JK and Kelsey, KT and Koestler, DC}, title = {An assessment of compositional methods for the analysis of DNA methylation-based deconvolution estimates.}, journal = {Epigenomics}, volume = {16}, number = {15-16}, pages = {1067-1080}, pmid = {39093129}, issn = {1750-192X}, support = {P20 GM103418/GM/NIGMS NIH HHS/United States ; P20 GM130423/GM/NIGMS NIH HHS/United States ; P30 CA168524/CA/NCI NIH HHS/United States ; P30 CA168524/CA/NCI NIH HHS/United States ; P20 GM103418/GM/NIGMS NIH HHS/United States ; }, mesh = {*DNA Methylation ; Humans ; Female ; Microbiota/genetics ; Computer Simulation ; }, abstract = {DNA methylation (DNAm)-based deconvolution estimates contain relative data, forming a composition, that standard methods (testing directly on cell proportions) are ill-suited to handle. In this study we examined the performance of an alternative method, analysis of compositions of microbiomes (ANCOM), for the analysis of DNAm-based deconvolution estimates. We performed two different simulation studies comparing ANCOM to a standard approach (two sample t-test performed directly on cell proportions) and analyzed a real-world data from the Women's Health Initiative to evaluate the applicability of ANCOM to DNAm-based deconvolution estimates. Our findings indicate that ANCOM can effectively account for the compositional nature of DNAm-based deconvolution estimates. ANCOM adequately controls the false discovery rate while maintaining statistical power comparable to that of standard methods.}, }
@article {pmid39091879, year = {2024}, author = {Sinnott-Armstrong, N and Strausz, S and Urpa, L and Abner, E and Valliere, J and ,  and Palta, P and Dashti, HS and Daly, M and Pritchard, JK and Saxena, R and Jones, SE and Ollila, HM}, title = {Genetic variants affect diurnal glucose levels throughout the day.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39091879}, issn = {2692-8205}, support = {/WT_/Wellcome Trust/United Kingdom ; RM1 HG010461/HG/NHGRI NIH HHS/United States ; }, abstract = {Circadian rhythms not only coordinate the timing of wake and sleep but also regulate homeostasis within the body, including glucose metabolism. However, the genetic variants that contribute to temporal control of glucose levels have not been previously examined. Using data from 420,000 individuals from the UK Biobank and replicating our findings in 100,000 individuals from the Estonian Biobank, we show that diurnal serum glucose is under genetic control. We discover a robust temporal association of glucose levels at the Melatonin receptor 1B (MTNR1B) (rs10830963, P = 1e-22) and a canonical circadian pacemaker gene Cryptochrome 2 (CRY2) loci (rs12419690, P = 1e-16). Furthermore, we show that sleep modulates serum glucose levels and the genetic variants have a separate mechanism of diurnal control. Finally, we show that these variants independently modulate risk of type 2 diabetes. Our findings, together with earlier genetic and epidemiological evidence, show a clear connection between sleep and metabolism and highlight variation at MTNR1B and CRY2 as temporal regulators for glucose levels.}, }
@article {pmid39091804, year = {2024}, author = {Nugent, PJ and Park, H and Wladyka, CL and Chen, KY and Bynum, C and Quarterman, G and Hsieh, AC and Subramaniam, AR}, title = {Decoding RNA Metabolism by RNA-linked CRISPR Screening in Human Cells.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39091804}, issn = {2692-8205}, support = {R01 GM135362/GM/NIGMS NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R35 GM119835/GM/NIGMS NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; R37 CA230617/CA/NCI NIH HHS/United States ; T32 GM008268/GM/NIGMS NIH HHS/United States ; R01 CA276308/CA/NCI NIH HHS/United States ; }, abstract = {RNAs undergo a complex choreography of metabolic processes in human cells that are regulated by thousands of RNA-associated proteins. While the effects of individual RNA-associated proteins on RNA metabolism have been extensively characterized, the full complement of regulators for most RNA metabolic events remain unknown. Here we present a massively parallel RNA-linked CRISPR (ReLiC) screening approach to measure the responses of diverse RNA metabolic events to knockout of 2,092 human genes encoding all known RNA-associated proteins. ReLiC screens highlight modular interactions between gene networks regulating splicing, translation, and decay of mRNAs. When combined with biochemical fractionation of polysomes, ReLiC reveals striking pathway-specific coupling between growth fitness and mRNA translation. Perturbing different components of the translation and proteostasis machineries have distinct effects on ribosome occupancy, while perturbing mRNA transcription leaves ribosome occupancy largely intact. Isoform-selective ReLiC screens capture differential regulation of intron retention and exon skipping by SF3b complex subunits. Chemogenomic screens using ReLiC decipher translational regulators upstream of mRNA decay and uncover a role for the ribosome collision sensor GCN1 during treatment with the anti-leukemic drug homoharringtonine. Our work demonstrates ReLiC as a versatile platform for discovering and dissecting regulatory principles of human RNA metabolism.}, }
@article {pmid39091643, year = {2024}, author = {Madut, DB and Chemaly, RF and Dadwal, SS and Hill, JA and Lee, YJ and Haidar, G and Luk, A and Drelick, A and Chin-Hong, PV and Benamu, E and Khawaja, F and Nanayakkara, D and Papanicolaou, GA and Small, CB and Fung, M and Barron, M and Davis, T and McClain, MT and Maziarz, EK and Bedoya, AD and Gilstrap, DL and Todd, JL and Barkauskas, CE and Heldman, MR and Bigelow, R and Leimberger, JD and Tsalik, EL and Wolf, O and Mughar, M and Lau, C and Noll, N and Hollemon, D and Duttagupta, R and Lupu, DS and Bercovici, S and Perkins, BA and Blauwkamp, TA and Fowler, VG and Holland, TL and Bergin, SP}, title = {Clinical Utility of Plasma Microbial Cell-Free DNA Sequencing Among Immunocompromised Patients With Pneumonia.}, journal = {Open forum infectious diseases}, volume = {11}, number = {8}, pages = {ofae425}, pmid = {39091643}, issn = {2328-8957}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Plasma microbial cell-free DNA (mcfDNA) sequencing can establish the etiology of multiple infectious syndromes by identifying microbial DNA in plasma. However, data are needed to define the clinical scenarios where this tool offers the highest clinical benefit.<br><br>METHODS: We conducted a prospective multicenter observational study that evaluated the impact of plasma mcfDNA sequencing compared with usual care testing among adults with hematologic malignancies. This is a secondary analysis of an expanded cohort that evaluated the clinical utility of plasma mcfDNA sequencing across prespecified and adjudicated outcomes. We examined the percentage of participants for whom plasma mcfDNA sequencing identified a probable cause of pneumonia or clinically relevant nonpneumonia infection. We then assessed potential changes in antimicrobial therapy based on plasma mcfDNA sequencing results and the potential for early mcfDNA testing to avoid bronchoscopy and its associated adverse events.<br><br>RESULTS: Of 223 participants, at least 1 microbial detection by plasma mcfDNA sequencing was adjudicated as a probable cause of pneumonia in 57 (25.6%) and a clinically relevant nonpneumonia infection in 88 (39.5%). A probable cause of pneumonia was exclusively identified by plasma mcfDNA sequencing in 23 (10.3%) participants. Antimicrobial therapy would have changed for 41 (18.4%) participants had plasma mcfDNA results been available in real time. Among the 57 participants with a probable cause of pneumonia identified by plasma mcfDNA sequencing, bronchoscopy identified no additional probable cause of pneumonia in 52 (91.2%).<br><br>CONCLUSIONS: Plasma mcfDNA sequencing could improve management of both pneumonia and other concurrent infections in immunocompromised patients with suspected pneumonia.}, }
@article {pmid39090779, year = {2024}, author = {Abhyankar, MM and Xu, F and Chavez, D and Goodroe, A and Mendoza, E and Chen, C and Singh, DK and Varnador, F and Sivananthan, SJ and Kinsey, R and Lykins, WR and Murphy, BM and Martin, AR and Tomai, MA and Ghosal, S and Casper, C and Pedersen, K and Petri, WA and Fox, CB}, title = {Immunogenicity and safety of an Entamoeba histolytica adjuvanted protein vaccine candidate (LecA+GLA-3M-052 liposomes) in rhesus macaques.}, journal = {Human vaccines &amp; immunotherapeutics}, volume = {20}, number = {1}, pages = {2374147}, pmid = {39090779}, issn = {2164-554X}, support = {HHSN272201800025C/AI/NIAID NIH HHS/United States ; R37 AI026649/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; *Macaca mulatta ; *Entamoeba histolytica/immunology ; *Liposomes/immunology/administration &amp; dosage ; *Protozoan Vaccines/immunology/administration &amp; dosage ; *Antibodies, Protozoan/blood/immunology ; *Leukocytes, Mononuclear/immunology ; *Entamoebiasis/prevention &amp; control/immunology ; *Administration, Intranasal ; *Interferon-gamma/immunology/metabolism ; Injections, Intramuscular ; Immunogenicity, Vaccine ; Adjuvants, Vaccine/administration &amp; dosage ; Adjuvants, Immunologic/administration &amp; dosage ; B-Lymphocytes/immunology ; Immunoglobulin G/blood/immunology ; Immunoglobulin A/immunology/blood ; Antigens, Protozoan/immunology ; Immunity, Humoral ; Immunologic Memory ; Protozoan Proteins/immunology ; }, abstract = {Entamoeba histolytica, the causative agent of amebiasis, is one of the top three parasitic causes of mortality worldwide. However, no vaccine exists against amebiasis. Using a lead candidate vaccine containing the LecA fragment of Gal-lectin and GLA-3M-052 liposome adjuvant, we immunized rhesus macaques via intranasal or intramuscular routes. The vaccine elicited high-avidity functional humoral responses as seen by the inhibition of amebic attachment to mammalian target cells by plasma and stool antibodies. Importantly, antigen-specific IFN-γ-secreting peripheral blood mononuclear cells (PBMCs) and IgG/IgA memory B cells (BMEM) were detected in immunized animals. Furthermore, antigen-specific antibody and cellular responses were maintained for at least 8 months after the final immunization as observed by robust LecA-specific BMEM as well as IFN-γ[+] PBMC responses. Overall, both intranasal and intramuscular immunizations elicited a durable and functional response in systemic and mucosal compartments, which supports advancing the LecA+GLA-3M-052 liposome vaccine candidate to clinical testing.}, }
@article {pmid39090192, year = {2024}, author = {H Elsayed, A and Cao, X and Marrero, RJ and Nguyen, NHK and Wu, H and Ni, Y and Ribeiro, RC and Tobias, H and Valk, PJ and Béliveau, F and Richard-Carpentier, G and Hébert, J and Zwaan, CM and Gamis, A and Kolb, EA and Aplenc, R and Alonzo, TA and Meshinchi, S and Rubnitz, J and Pounds, S and Lamba, JK}, title = {Integrated drug resistance and leukemic stemness gene-expression scores predict outcomes in large cohort of over 3500 AML patients from 10 trials.}, journal = {NPJ precision oncology}, volume = {8}, number = {1}, pages = {168}, pmid = {39090192}, issn = {2397-768X}, support = {R01 CA132946/CA/NCI NIH HHS/United States ; U10 CA098413/CA/NCI NIH HHS/United States ; SAP 21-061-01//American Cancer Society (American Cancer Society, Inc.)/ ; U10 CA098543/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; U10 CA180886/CA/NCI NIH HHS/United States ; P30 CA247796/CA/NCI NIH HHS/United States ; R01CA132946//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; }, abstract = {In this study, we leveraged machine-learning tools by evaluating expression of genes of pharmacological relevance to standard-AML chemotherapy (ara-C/daunorubicin/etoposide) in a discovery-cohort of pediatric AML patients (N = 163; NCT00136084) and defined a 5-gene-drug resistance score (ADE-RS5) that was predictive of outcome (high MRD1 positivity p = 0.013; lower EFS p < 0.0001 and OS p < 0.0001). ADE-RS5 was integrated with a previously defined leukemic-stemness signature (pLSC6) to classify patients into four groups. ADE-RS5, pLSC6 and integrated-score was evaluated for association with outcome in one of the largest assembly of ~3600 AML patients from 10 independent cohorts (1861 pediatric and 1773 adult AML). Patients with high ADE-RS5 had poor outcome in validation cohorts and the previously reported pLSC6 maintained strong significant association in all validation cohorts. For pLSC6/ADE-RS5-integrated-score analysis, using Group-1 (low-scores for ADE-RS5 and pLSC6) as reference, Group-4 (high-scores for ADE-RS5 and pLSC6) showed worst outcome (EFS: p < 0.0001 and OS: p < 0.0001). Groups-2/3 (one high and one low-score) showed intermediate outcome (p < 0.001). Integrated score groups remained an independent predictor of outcome in multivariable-analysis after adjusting for established prognostic factors (EFS: Group 2 vs. 1, HR = 4.68, p < 0.001, Group 3 vs. 1, HR = 3.22, p = 0.01, and Group 4 vs. 1, HR = 7.26, p < 0.001). These results highlight the significant prognostic value of transcriptomics-based scores capturing disease aggressiveness through pLSC6 and drug resistance via ADE-RS5. The pLSC6 stemness score is a significant predictor of outcome and associates with high-risk group features, the ADE-RS5 drug resistance score adds further value, reflecting the clinical utility of simultaneous testing of both for optimizing treatment strategies.}, }
@article {pmid39089815, year = {2024}, author = {Osman, MM and Iravani, A and Mitchell, C and Hicks, RJ and Perry, E and Hofman, MS}, title = {[18]F-DCFPyL PSMA PET/CT Tracheobronchial Uptake in Patients with Prostate Cancer: Incidence and Etiology.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {65}, number = {9}, pages = {1383-1386}, pmid = {39089815}, issn = {1535-5667}, mesh = {Humans ; Male ; *Positron Emission Tomography Computed Tomography ; *Prostatic Neoplasms/diagnostic imaging/metabolism ; *Trachea/diagnostic imaging/metabolism ; Aged ; *Glutamate Carboxypeptidase II/metabolism ; *Bronchi/diagnostic imaging/metabolism ; Middle Aged ; *Lysine/analogs &amp; derivatives/metabolism ; Retrospective Studies ; *Urea/analogs &amp; derivatives/metabolism ; Antigens, Surface/metabolism ; Aged, 80 and over ; Biological Transport ; Radiopharmaceuticals ; }, abstract = {We evaluated the incidence and potential etiology of tracheobronchial uptake in patients being evaluated by [18]F-DCFPyL PET/CT for prostate cancer (PCa). Methods: The study included a consecutive 100 PCa patients referred for [18]F-DCFPyL PET/CT. The PET/CT scans were retrospectively reviewed. The presence or absence of physiologic tracheobronchial uptake on PET/CT was recorded. To further evaluate tracheal prostate-specific membrane antigen (PSMA) expression, immunohistochemistry was performed on tracheal samples taken from 2 men who had surgical resection of lung cancer. Results: Tracheal uptake was present in 31 of 100 patients (31%). When tracheal uptake was present, the SUVmax was significantly higher in the left main bronchus (mean, 2.7) than in the right (mean, 2.3) (P < 0.001). Histopathologic testing of tracheobronchial samples showed PSMA expression in bronchial submucosal glands. Conclusion: In PCa patients undergoing [18]F-DCFPyL PET/CT, tracheobronchial uptake occurred in 31% of patients. This is attributed to normal physiologic PSMA expression in bronchial submucosal glands.}, }
@article {pmid39089527, year = {2024}, author = {Cheng, G and Smith, MA and Phelan, R and Brazauskas, R and Strom, J and Ahn, KW and Hamilton, B and Peterson, A and Savani, B and Schoemans, H and Schoettler, M and Sorror, M and Higham, C and Kharbanda, S and Dvorak, CC and Zinter, MS}, title = {Epidemiology of Diffuse Alveolar Hemorrhage in Pediatric Allogeneic Hematopoietic Cell Transplantation Recipients.}, journal = {Transplantation and cellular therapy}, volume = {30}, number = {10}, pages = {1017.e1-1017.e12}, doi = {10.1016/j.jtct.2024.07.022}, pmid = {39089527}, issn = {2666-6367}, mesh = {Adolescent ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Male ; Young Adult ; Graft vs Host Disease/epidemiology/etiology ; *Hematopoietic Stem Cell Transplantation/adverse effects ; *Hemorrhage/epidemiology/etiology/mortality ; Incidence ; Lung Diseases/epidemiology/etiology ; *Pulmonary Alveoli/injuries ; Retrospective Studies ; Risk Factors ; Transplantation, Homologous/adverse effects ; }, abstract = {Diffuse alveolar hemorrhage (DAH) is a life-threatening pulmonary toxicity that can arise after hematopoietic cell transplantation (HCT). Risk factors and outcomes are not well understood owing to a sparsity of cases spread across multiple centers. The objectives of this epidemiologic study were to characterize the incidence, outcomes, transplantation-related risk factors and comorbid critical care diagnoses associated with post-HCT DAH. Retrospective analysis was performed in a multicenter cohort of 6995 patients age ≤21 years who underwent allogeneic HCT between 2008 and 2014 identified through the Center for International Blood and Marrow Transplant Research registry and cross-matched with the Virtual Pediatric Systems database to obtain critical care characteristics. A multivariable Cox proportional hazard model was used to determine risk factors for DAH. Logistic regression models were used to determine critical care diagnoses associated with DAH. Survival outcomes were analyzed using both a landmark approach and Cox regression, with DAH as a time-varying covariate. DAH occurred in 81 patients at a median of 54 days post-HCT (interquartile range, 23 to 160 days), with a 1-year post-transplantation cumulative incidence probability of 1.0% (95% confidence interval [CI], .81% to 1.3%) and was noted in 7.6% of all pediatric intensive care unit patients. Risk factors included receipt of transplantation for nonmalignant hematologic disease (reference: malignant hematologic disease; hazard ratio [HR], 1.98; 95% CI, 1.22 to 3.22; P = .006), use of a calcineurin inhibitor (CNI) plus mycophenolate mofetil (MMF) as graft-versus-host disease (GVHD) prophylaxis (referent: CNI plus methotrexate; HR, 1.89; 95% CI, 1.07 to 3.34; P = .029), and grade III-IV acute GVHD (HR, 2.67; 95% CI, 1.53-4.66; P < .001). Critical care admitted patients with DAH had significantly higher rates of systemic hypertension, pulmonary hypertension, pericardial disease, renal failure, and bacterial/viral/fungal infections (P < .05) than those without DAH. From the time of DAH, median survival was 2.2 months, and 1-year overall survival was 26% (95% CI, 17% to 36%). Among all HCT recipients, the development of DAH when considered was associated with a 7-fold increase in unadjusted all-cause post-HCT mortality (HR, 6.96; 95% CI, 5.42 to 8.94; P < .001). In a landmark analysis of patients alive at 2 months post-HCT, patients who developed DAH had a 1-year overall survival of 33% (95% CI, 18% to 49%), compared to 82% (95% CI, 81% to 83%) for patients without DAH (P < .001). Although DAH is rare, it is associated with high mortality in the post-HCT setting. Our data suggest that clinicians should have a heightened index of suspicion of DAH in patients with pulmonary symptoms in the context of nonmalignant hematologic indication for HCT, use of CNI + MMF as GVHD prophylaxis, and severe acute GVHD. Further investigations and validation of modifiable risk factors are warranted given poor outcomes.}, }
@article {pmid39088271, year = {2024}, author = {Kalams, SA and Felber, BK and Mullins, JI and Scott, HM and Allen, MA and De Rosa, SC and Heptinstall, J and Tomaras, GD and Hu, J and DeCamp, AC and Rosati, M and Bear, J and Pensiero, MN and Eldridge, J and Egan, MA and Hannaman, D and McElrath, MJ and Pavlakis, GN and , }, title = {Focusing HIV-1 Gag T cell responses to highly conserved regions by DNA vaccination in HVTN 119.}, journal = {JCI insight}, volume = {9}, number = {18}, pages = {}, pmid = {39088271}, issn = {2379-3708}, support = {UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Vaccines, DNA/immunology/administration &amp; dosage ; *HIV-1/immunology ; *AIDS Vaccines/immunology/administration &amp; dosage ; Female ; Adult ; Male ; Double-Blind Method ; *HIV Infections/immunology/prevention &amp; control ; *gag Gene Products, Human Immunodeficiency Virus/immunology/genetics ; Middle Aged ; Young Adult ; T-Lymphocytes/immunology ; HIV Antibodies/immunology ; Vaccination/methods ; Immunogenicity, Vaccine ; CD4-Positive T-Lymphocytes/immunology ; }, abstract = {BACKGROUNDAn HIV-1 DNA vaccine composed of 7 highly conserved, structurally important elements (conserved elements, CE) of p24Gag was tested in a phase I randomized, double-blind clinical trial (HVTN 119, NCT03181789) in people without HIV. DNA vaccination of CE prime/CE+p55Gag boost was compared with p55Gag.METHODSTwo groups (n = 25) received 4 DNA vaccinations (CE/CE+p55Gag or p55Gag) by intramuscular injection/electroporation, including IL-12 DNA adjuvant. The placebo group (n = 6) received saline. Participants were followed for safety and tolerability. Immunogenicity was assessed for T cell and antibody responses.RESULTSBoth regimens were safe and generally well tolerated. The p24CE vaccine was immunogenic and significantly boosted by CE+p55Gag (64% CD4+, P = 0.037; 42% CD8+, P = 0.004). CE+p55Gag induced responses to 5 of 7 CE, compared with only 2 CE by p55Gag DNA, with a higher response to CE5 in 30% of individuals (P = 0.006). CE+p55Gag induced significantly higher CD4+ CE T cell breadth (0.68 vs. 0.22 CE; P = 0.029) and a strong trend for overall T cell breadth (1.14 vs. 0.52 CE; P = 0.051). Both groups developed high cellular and humoral responses. p24CE vaccine-induced CD4+ CE T cell responses correlated (P = 0.007) with p24Gag antibody responses.CONCLUSIONThe CE/CE+p55Gag DNA vaccine induced T cell responses to conserved regions in p24Gag, increasing breadth and epitope recognition throughout p55Gag compared with p55Gag DNA. Vaccines focusing immune responses by priming responses to highly conserved regions could be part of a comprehensive HIV vaccine strategy.TRIAL REGISTRATIONClinical Trials.gov NCT03181789FUNDINGHVTN, NIAID/NIH.}, }
@article {pmid39088246, year = {2024}, author = {Kepper, MM and Fowler, LA and Kusters, IS and Davis, JW and Baqer, M and Sagui-Henson, S and Xiao, Y and Tarfa, A and Yi, JC and Gibson, B and Heron, KE and Alberts, NM and Burgermaster, M and Njie-Carr, VP and Klesges, LM}, title = {Expanding a Behavioral View on Digital Health Access: Drivers and Strategies to Promote Equity.}, journal = {Journal of medical Internet research}, volume = {26}, number = {}, pages = {e51355}, pmid = {39088246}, issn = {1438-8871}, support = {K01 HL167993/HL/NHLBI NIH HHS/United States ; K01 MD017630/MD/NIMHD NIH HHS/United States ; P50 CA244431/CA/NCI NIH HHS/United States ; U48 DP006395/DP/NCCDPHP CDC HHS/United States ; }, mesh = {Humans ; *Health Equity ; *COVID-19/epidemiology ; *Health Services Accessibility ; *Telemedicine ; Pandemics ; SARS-CoV-2 ; Digital Technology ; Digital Health ; }, abstract = {The potential and threat of digital tools to achieve health equity has been highlighted for over a decade, but the success of achieving equitable access to health technologies remains challenging. Our paper addresses renewed concerns regarding equity in digital health access that were deepened during the COVID-19 pandemic. Our viewpoint is that (1) digital health tools have the potential to improve health equity if equitable access is achieved, and (2) improving access and equity in digital health can be strengthened by considering behavioral science-based strategies embedded in all phases of tool development. Using behavioral, equity, and access frameworks allowed for a unique and comprehensive exploration of current drivers of digital health inequities. This paper aims to present a compilation of strategies that can potentially have an actionable impact on digital health equity. Multilevel factors drive unequal access, so strategies require action from tool developers, individual delivery agents, organizations, and systems to effect change. Strategies were shaped with a behavioral medicine focus as the field has a unique role in improving digital health access; arguably, all digital tools require the user (individual, provider, and health system) to change behavior by engaging with the technology to generate impact. This paper presents a model that emphasizes using multilevel strategies across design, delivery, dissemination, and sustainment stages to advance digital health access and foster health equity.}, }
@article {pmid39087765, year = {2024}, author = {Alwine, J and Goodrum, F and Banfield, B and Bloom, D and Britt, WJ and Broadbent, AJ and Campos, SK and Casadevall, A and Chan, GC and Cliffe, AR and Dermody, T and Duprex, P and Enquist, LW and Frueh, K and Geballe, AP and Gaglia, M and Goldstein, S and Greninger, AL and Gronvall, GK and Jung, JU and Kamil, JP and Lakdawala, S and Liu, S-L and Luftig, M and Moore, JP and Moscona, A and Neuman, BW and Nikolich, J&#x17d; and O'Connor, C and Pekosz, A and Permar, S and Pfeiffer, J and Purdy, J and Rasmussen, A and Semler, B and Smith, GA and Stein, DA and Van Doorslaer, K and Weller, SK and Whelan, SPJ and Yurochko, A}, title = {The harms of promoting the lab leak hypothesis for SARS-CoV-2 origins without evidence.}, journal = {Journal of virology}, volume = {98}, number = {9}, pages = {e0124024}, pmid = {39087765}, issn = {1098-5514}, support = {P20 GM134974/GM/NIGMS NIH HHS/United States ; }, mesh = {*SARS-CoV-2 ; Humans ; *COVID-19/virology/transmission ; Pandemics ; Animals ; }, abstract = {Science is humanity's best insurance against threats from nature, but it is a fragile enterprise that must be nourished and protected. The preponderance of scientific evidence indicates a natural origin for SARS-CoV-2. Yet, the theory that SARS-CoV-2 was engineered in and escaped from a lab dominates media attention, even in the absence of strong evidence. We discuss how the resulting anti-science movement puts the research community, scientific research, and pandemic preparedness at risk.}, }
@article {pmid39086310, year = {2024}, author = {Loriot, Y and Balar, AV and Petrylak, DP and Kalebasty, AR and Grivas, P and Fléchon, A and Jain, RK and Swami, U and Bupathi, M and Barthélémy, P and Beuzeboc, P and Palmbos, P and Kyriakopoulos, CE and Pouessel, D and Sternberg, CN and Tonelli, J and Sierecki, M and Zavodovskaya, M and Elboudwarej, E and Diehl, L and Jürgensmeier, JM and Tagawa, ST}, title = {Sacituzumab Govitecan Demonstrates Efficacy across Tumor Trop-2 Expression Levels in Patients with Advanced Urothelial Cancer.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {30}, number = {15}, pages = {3179-3188}, doi = {10.1158/1078-0432.CCR-23-3924}, pmid = {39086310}, issn = {1557-3265}, mesh = {Humans ; *Cell Adhesion Molecules/metabolism ; *Antigens, Neoplasm ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Female ; Male ; Aged ; Middle Aged ; *Camptothecin/analogs &amp; derivatives/therapeutic use ; *Immunoconjugates/therapeutic use ; Aged, 80 and over ; Adult ; Biomarkers, Tumor/metabolism ; Urologic Neoplasms/drug therapy/pathology/mortality/metabolism ; Treatment Outcome ; Neoplasm Staging ; }, abstract = {PURPOSE: Human trophoblast cell surface antigen 2 (Trop-2) is a protein highly expressed in urothelial cancer (UC). Sacituzumab govitecan (SG) is a Trop-2-directed antibody drug conjugate with a hydrolysable linker and a potent SN-38 payload. This study explored Trop-2 expression in tumors treated with SG in cohorts 1 to 3 (C1-3) from the TROPHY-U-01 study and evaluated whether efficacy was associated with Trop-2 expression.<br><br>PATIENTS AND METHODS: TROPHY-U-01 (NCT03547973) is an open-label phase II study that assessed the efficacy and safety of SG (alone or in combinations) in patients with unresectable locally advanced or metastatic UC (mUC). Archival tumor samples collected at enrollment for C1-3 were analyzed for Trop-2 membrane expression by considering histological scores (H-scores; scale 0-300) and the percentage of membrane positive tumor cells at low magnification (4&#xd7;). The association of Trop-2 with clinical endpoints [objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)] was evaluated.<br><br>RESULTS: In C1-3, tissue was collected from 158 (82%) of 192 treated patients, and 146 (76%) had evaluable Trop-2 data. Trop-2 was highly expressed in tumor samples. The median [interquartile range (IQR)] Trop-2 H-score was 215 (180-246), and the median (IQR) percentage of membrane positive tumor cells was 91% (80-98). Trop-2 expression at any level was observed in 98% of patients. Furthermore, ORR, PFS, and OS benefits were observed across all Trop-2 expression levels.<br><br>CONCLUSIONS: Trop-2 protein is highly expressed in UC, as confirmed by examining tumors from patients enrolled in the TROPHY-U-01 trial. The results indicate that SG demonstrates efficacy in mUC across Trop-2 expression levels.}, }
@article {pmid39085897, year = {2024}, author = {Lau, N and Steineck, A and Walsh, C and Fladeboe, KM and Yi-Frazier, JP and Rosenberg, AR and Barton, K}, title = {Social support resources in adolescents and young adults with advanced cancer: a qualitative analysis.}, journal = {BMC palliative care}, volume = {23}, number = {1}, pages = {193}, pmid = {39085897}, issn = {1472-684X}, support = {K08 CA263474/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; Male ; *Neoplasms/psychology/therapy ; *Social Support ; Adolescent ; *Qualitative Research ; Young Adult ; Quality of Life/psychology ; Adaptation, Psychological ; Adult ; }, abstract = {PURPOSE: Adolescents and Young Adults (AYAs) with cancer are an at-risk group with unique palliative and supportive care needs. Social support in AYAs with cancer is associated with better coping, quality of life, and psychosocial well-being. Here, we extend existing research to examine the sources and types of support received by AYAs with advanced cancer.<br><br>METHODS: AYAs participated in a semi-structured, 1:1 interview on communication and psychosocial support needs. The present analysis focused on social support experiences for AYAs with advanced cancer. Directed content analysis was used to develop the codebook. Established social support constructs provided a coding framework. We presented our qualitative findings as a code frequency report with quantified frequency counts of all "source of support" and "type of support" codes. We assigned a global "sufficiency of support code" to each AYA.<br><br>RESULTS: We interviewed 32 AYAs with advanced cancer (Mage&#x2009;=&#x2009;18, SDage&#x2009;=&#x2009;3.2, 41% female). Most AYAs identified family (namely, caregivers) as their primary source of support and stated that family universally provided all types of support: emotional, informational, instrumental, and social companionship. They received informational and emotional support from clinicians, and received emotional support and social companionship from healthy peers, cancer peers, and their existing community. One-third of participants were coded as having "mixed support" and described a lack of support in some domains.<br><br>CONCLUSION: AYAs with advanced cancer described caregivers as their universal source of support, and that other support sources provided support for specific needs. Future research should continue to evaluate social support needs and family-based palliative and supportive care interventions to bolster social support resources in this high-risk group.}, }
@article {pmid39084844, year = {2024}, author = {McCulloch, DJ and Pottinger, PS}, title = {Infectious Disease Updates for Primary Care.}, journal = {The Medical clinics of North America}, volume = {108}, number = {5}, pages = {965-979}, doi = {10.1016/j.mcna.2024.02.003}, pmid = {39084844}, issn = {1557-9859}, mesh = {Humans ; *Primary Health Care ; COVID-19/epidemiology/prevention &amp; control ; Female ; Sexually Transmitted Diseases/diagnosis/drug therapy/prevention &amp; control/therapy ; Male ; Candidiasis, Vulvovaginal/drug therapy/diagnosis ; Influenza, Human/epidemiology/prevention &amp; control ; SARS-CoV-2 ; Communicable Diseases/epidemiology/drug therapy ; }, abstract = {This article summarizes the situation with public health threats for primary care patients as of early 2024 and provides updates on strategies for the prevention, diagnosis, and treatment of common infections where new treatments and vaccines are available. For flu and COVID, an update on treatment is also provided-along with pearls useful for the busy primary care provider. The authors also discuss a new treatment option for drug-resistant vulvovaginal candidiasis and provide a balanced view of the increasingly popular technique of preventing bacterial sexually transmitted infections using doxycycline after condomless sex among men who have sex with men.}, }
@article {pmid39084517, year = {2024}, author = {Murphy, NR and Crothers, K and Snidarich, M and Budak, JZ and Brown, MC and Weiner, BJ and Giustini, N and Caverly, T and Durette, K and DeCell, K and Triplette, M}, title = {The Use of a Tailored Decision Aid to Improve Understanding of Lung Cancer Screening in People With HIV.}, journal = {Chest}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.chest.2024.07.147}, pmid = {39084517}, issn = {1931-3543}, abstract = {BACKGROUND: People with HIV are at increased risk for lung cancer and multimorbidity, complicating the balance of risks and benefits of lung cancer screening. We previously adapted Decision Precision (screenlc.com) to guide shared decision-making for lung cancer screening in people with HIV.<br><br>RESEARCH QUESTION: Does an HIV-adapted and personally tailored decision aid improve shared decision-making regarding lung cancer screening in people with HIV as measured by knowledge, decisional conflict, and acceptability?<br><br>STUDY DESIGN AND METHODS: This was a single-arm pilot trial of the decision aid in 40 participants with HIV eligible for lung cancer screening. The decision aid included personalized screening recommendations and HIV-specific, 5-year risk estimates of lung cancer and all-cause mortality. Participants reviewed the decision aid at shared decision-making visits and completed previsit and postvisit surveys with measures of knowledge about lung cancer screening, acceptability, and decisional conflict.<br><br>RESULTS: The 40 enrolled participants were a median age of 62 years, 60%&#xa0;currently smoked, and they had median 5-year risks of lung cancer and all-cause mortality of 2.0%&#xa0;(IQR, 1.4%-3.3%) and 4.1%&#xa0;(IQR, 3.3%-7.9%), respectively. Personalized recommendations included "Encourage Screening" for 53%&#xa0;of participants and "Preference Sensitive" recommendations for the remainder. Participants showed improvement in two validated knowledge measures with relative improvement of 60%&#xa0;(P&#xa0;< 0.001) on the 12-question lung cancer screening knowledge test and 27%&#xa0;(P&#xa0;< .001) on the seven-question lung cancer screening knowledge score, with significant improvement on questions regarding false-positive and false-negative findings, incidental findings, lung cancer-specific mortality benefit, and the possible harms of screening. Participants reported low scores on the decisional conflict scale (median score, 0; interquartile range, 0-5) and high acceptability. Ninety percent of patients ultimately underwent screening within 1&#xa0;month of the visit.<br><br>INTERPRETATION: In our study, this HIV-adapted and personally tailored decision aid improved participants' knowledge of risks, benefits, and characteristics of screening with low decisional conflict and high acceptability. Our results indicate that this decision aid can enable high-quality shared decision-making in this high-risk population.<br><br>CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04682301; URL: www.<br><br>CLINICALTRIALS: gov.}, }
@article {pmid39084261, year = {2024}, author = {Shahid, Z and Jain, T and Dioverti, V and Pennisi, M and Mikkilineni, L and Thiruvengadam, SK and Shah, NN and Dadwal, S and Papanicolaou, G and Hamadani, M and Carpenter, PA and Alfaro, GM and Seo, SK and Hill, JA}, title = {Best Practice Considerations by The American Society of Transplant and Cellular Therapy: Infection Prevention and Management After Chimeric Antigen Receptor T Cell Therapy for Hematological Malignancies.}, journal = {Transplantation and cellular therapy}, volume = {30}, number = {10}, pages = {955-969}, doi = {10.1016/j.jtct.2024.07.018}, pmid = {39084261}, issn = {2666-6367}, mesh = {Humans ; *Hematologic Neoplasms/therapy/immunology ; *Immunotherapy, Adoptive/methods/adverse effects ; Practice Guidelines as Topic ; *Receptors, Chimeric Antigen/immunology/therapeutic use ; Societies, Medical/standards ; United States/epidemiology ; }, abstract = {Chimeric antigen receptor (CAR) T-cell therapy is rapidly advancing, offering promising treatments for patients with hematological malignancy. However, associated infectious complications remain a significant concern because of their contribution to patient morbidity and non-relapse mortality. Recent epidemiological insights shed light on risk factors for infections after CAR T-cell therapy. However, the available evidence is predominantly retrospective, highlighting a need for further prospective studies. Institutions are challenged with managing infections after CAR T-cell therapy but variations in the approaches taken underscore the importance of standardizing infection prevention and management protocols across different healthcare settings. Therefore, the Infectious Diseases Special Interest Group of the American Society of Transplantation and Cellular Therapy assembled an expert panel to develop best practice considerations. The aim was to guide healthcare professionals in optimizing infection prevention and management for CAR T-cell therapy recipients and advocates for early consultation of Infectious Diseases during treatment planning phases given the complexities involved. By synthesizing current evidence and expert opinion these best practice considerations provide the basis for understanding infection risk after CAR T-cell therapies and propose risk-mitigating strategies in children, adolescents, and adults. Continued research and collaboration will be essential to refining and effectively implementing these recommendations.}, }
@article {pmid39080017, year = {2024}, author = {Navarro, SL and Pinto, N and Hawkins, DS and Park, JR and Dilmaghani, S and Rimorin, C and Wurscher, M and McCune, JS}, title = {Pharmacogenomic associations of cyclophosphamide pharmacokinetic candidate genes with 4hydroxycyclophosphamide formation in children with Cancer.}, journal = {Cancer chemotherapy and pharmacology}, volume = {94}, number = {4}, pages = {627-633}, pmid = {39080017}, issn = {1432-0843}, support = {R01 GM129863/GM/NIGMS NIH HHS/United States ; R03 CA178104/CA/NCI NIH HHS/United States ; M01 RR000037/RR/NCRR NIH HHS/United States ; R21 CA162059/CA/NCI NIH HHS/United States ; R01 HL091744/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Cyclophosphamide/pharmacokinetics/administration &amp; dosage/analogs &amp; derivatives ; Child ; Female ; *Neoplasms/drug therapy/genetics ; Male ; *Polymorphism, Single Nucleotide ; Child, Preschool ; *Pharmacogenetics ; Adolescent ; Infant ; Area Under Curve ; Age Factors ; }, abstract = {PURPOSE: 4-hydroxycyclophosphamide (4HCY) is the principal precursor to the cytotoxic metabolite of cyclophosphamide (CY), which is often used as first-line treatment of children with cancer. There is conflicting data regarding the relationship between CY efficacy, toxicity, and pharmacokinetics with the genes encoding proteins involved in 4HCY pharmacokinetics, specifically its formation and elimination.<br><br>METHODS: We evaluated germline pharmacogenetics in children with various malignancies receiving their first CY dose. Using linear regression, we analyzed the associations between two pharmacokinetic outcomes - how fast a child cleared CY (i.e., CY clearance) and the ratio of the 4HCY/CY exposure, specifically area under the plasma concentration-time curve (AUC), and 372 single nucleotide polymorphisms (SNP) in 14 drug-metabolizing transporters or enzymes involved in 4HCY formation or elimination.<br><br>RESULTS: Age was associated with the ratio of 4HCY/CY AUC (P&#x2009;=&#x2009;0.004); Chemotherapy regimen was associated with CY clearance (P&#x2009;=&#x2009;0.003). No SNPs were associated with CY clearance or the ratio of 4HCY/CY AUC after controlling for a false discovery rate.<br><br>CONCLUSION: Age and chemotherapy regimen, but not germline pharmacogenomics, were associated with CY clearance or the ratio of 4HCY/CY AUC. Other methods, such as metabolomics or lipidomics, should be explored.}, }
@article {pmid39079612, year = {2024}, author = {Beight, LJ and Mendoza, JA and Leisenring, WM and Collier, W and Olsen, ME and Ross, WL and Santiago-Rivera, Y and Bryant, S and Rotatori, J and Ness, KK and Hurtado-de-Mendoza, A and Baker, KS and Chow, EJ and Kadan-Lottick, NS}, title = {Design and methods of the StepByStep randomized trial of a mobile health and social media physical activity intervention among adolescent and young adult survivors of childhood cancer: A report from the Children's Oncology Group.}, journal = {Contemporary clinical trials}, volume = {145}, number = {}, pages = {107645}, pmid = {39079612}, issn = {1559-2030}, support = {U01 CA246665/CA/NCI NIH HHS/United States ; U10 CA180886/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; UG1 CA189955/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Adolescent ; *Social Media ; *Cancer Survivors/psychology ; *Exercise ; *Quality of Life ; Young Adult ; Male ; Female ; *Telemedicine ; Prospective Studies ; Neoplasms/therapy/psychology ; Fitness Trackers ; Research Design ; }, abstract = {BACKGROUND: Interventions to increase physical activity are needed in adolescent and young adult survivors of childhood cancer who are largely inactive but at lifelong elevated risk of multiple chronic conditions improved by physical activity. The goals of the StepByStep study are to evaluate the effects of a 48-week distance-based, multi-component mobile health and social media behavioral intervention on physical activity, biomarkers of cardiometabolic health, and health-related quality of life.<br><br>METHODS: This ongoing study is a two-arm, prospective, multi-site randomized controlled trial. 384 childhood cancer survivors age&#xa0;&#x2265;&#xa0;15&#xa0;years and&#xa0;<&#xa0;21&#xa0;years who were 3-36&#xa0;months off therapy and not meeting physical activity guidelines were enrolled. The trial will test the efficacy of a 24-week intensive multi-component physical activity intervention combining a wearable physical activity tracker, social media peer support group, and individualized goal setting followed by a 24-week maintenance phase of the intervention to improve outcomes. The control group receives the wearable physical activity tracker only.<br><br>CONCLUSION: There is a growing need for novel, developmentally appropriate interventions to increase physical activity and improve the health trajectory of adolescent and young adult survivors of childhood cancer. If efficacious, this portable and scalable intervention would be a much-needed tool to reduce the morbidity from cancer treatment and improve quality of life among survivors after treatment ends.<br><br>CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04089358; COG Identifier: ALTE2031.}, }
@article {pmid39079559, year = {2024}, author = {Halpern, AB and Sugalski, JM and Bandini, L and Othus, M and Stewart, FM and Walter, RB}, title = {Care Patterns and Barriers to Outpatient Care for Adults With AML Following Intensive Chemotherapy at NCCN Member Institutions.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {7}, pages = {469-474}, doi = {10.6004/jnccn.2024.7026}, pmid = {39079559}, issn = {1540-1413}, mesh = {Humans ; *Leukemia, Myeloid, Acute/drug therapy/therapy ; *Ambulatory Care/standards/methods/statistics &amp; numerical data ; Adult ; Hospitalization/statistics &amp; numerical data ; Female ; Health Services Accessibility/standards/statistics &amp; numerical data ; Male ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Patient Discharge/standards/statistics &amp; numerical data ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: Prolonged hospitalization following intensive (re)induction chemotherapy for acute myeloid leukemia (AML), while standard, is costly and resource intense, limits inpatient bed capacity, and negatively impacts quality of life. Early hospital discharge (EHD) following completion of chemotherapy has proven safe as an alternative at select institutions, but is not widely implemented.<br><br>PATIENTS AND METHODS: From February 2023 through May 2023, the NCCN Best Practices Committee conducted a survey evaluating AML hospitalization patterns, care models, and barriers to EHD at its 33 member institutions.<br><br>RESULTS: A total of 30 (91%) institutions completed the survey; two-thirds treat >100 patients with AML annually and 45% treat more than half of these with intensive chemotherapy. In the (re)induction setting, 80% of institutions keep patients hospitalized until blood count recovery, whereas 20% aim to discharge patients after completion of chemotherapy if medically stable and logistically feasible. The predominant reasons for the perceived need for ongoing hospitalization were high risk of infection, treatment toxicities, and lack of nearby/accessible housing. There was no significant association between ability to practice EHD and annual AML volume or treatment intensity patterns (P=.60 and P=.11, respectively). In contrast, in the postremission setting, 87% of centers support patients following chemotherapy in the outpatient setting unless toxicities arise requiring readmission. Survey responses showed that 80% of centers were interested in exploring EHD after (re)induction but noted significant barriers, including accessible housing (71%), transportation (50%), high toxicity/infection rate (50%), high transfusion burden (50%), and limited bed availability for rehospitalization (50%).<br><br>CONCLUSIONS: Hospitalization and care patterns following intensive AML therapy vary widely across major US cancer institutions. Although only 20% of surveyed centers practice EHD following intensive (re)induction chemotherapy, 87% do so following postremission therapy. Given the interest in exploring the EHD approach given potential advantages of EHD for both patients and health care systems, strategies to address identified medical and logistical barriers should be explored.}, }
@article {pmid39079108, year = {2024}, author = {Lau, N and Palermo, TM and Zhou, C and Badillo, I and Hong, S and Aalfs, H and Yi-Frazier, JP and McCauley, E and Chow, EJ and Weiner, BJ and Ben-Zeev, D and Rosenberg, AR}, title = {Mobile App Promoting Resilience in Stress Management for Adolescents and Young Adults With Cancer: Protocol for a Pilot Randomized Controlled Trial.}, journal = {JMIR research protocols}, volume = {13}, number = {}, pages = {e57950}, pmid = {39079108}, issn = {1929-0748}, support = {K08 CA263474/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Adolescent ; *Mobile Applications ; Pilot Projects ; *Resilience, Psychological ; Young Adult ; *Neoplasms/therapy/psychology ; *Stress, Psychological/therapy ; Male ; Female ; Adult ; Child ; Telemedicine ; Quality of Life/psychology ; }, abstract = {BACKGROUND: Adolescents and young adults (AYAs) with cancer are at risk of poor psychosocial outcomes. AYAs grew up with the internet and digital technology, and mobile Health (mHealth) psychosocial interventions have the potential to overcome care access barriers.<br><br>OBJECTIVE: This pilot randomized controlled trial (RCT) aimed to establish the feasibility, acceptability, and preliminary efficacy of a fully automated mobile app version of the Promoting Resilience in Stress Management intervention (mPRISM). Promoting Resilience in Stress Management is an evidence-based intervention developed in collaboration with AYAs, based on stress and coping theory, resilience theory, and evidence-based coping strategies. We hypothesized that mPRISM would be feasible, acceptable, and appropriate.<br><br>METHODS: This is a parallel, 2-arm, single-site pilot RCT with a waitlist control design. The study will recruit 80 AYAs with cancer from a clinic. Eligible AYAs are aged 12 to 25 years, within 12 months of a new cancer diagnosis, receiving chemotherapy or radiation therapy, speak, read, or write in English, and are cognitively able to participate in study procedures. Recruitment by clinical research coordinators will occur remotely by phone, video, or text. Participants will be randomized to psychosocial usual care (UC) alone or UC plus mPRISM for an 8-week intervention period, and will remain unblinded to study condition. Enrolled participants will complete surveys at baseline before randomization, 8 weeks, and 3-month follow-up. Using a waitlist design, the UC arm will receive mPRISM upon completion of 3-month follow-up surveys. Those in the UC arm will complete 2 additional measurement points at immediate posttreatment and 3 months later. The primary outcomes of interest are feasibility, defined as &#x2265;60% enrollment and &#x2265;70% retention (ie, percentage of participants who completed the study), and "feasibility, acceptability, and appropriateness" as defined by cut-off scores &#x2265;4/5 on 3 brief validated implementation outcome measures (feasibility of implementation measure, acceptability of intervention measure [AIM], intervention appropriateness measure [IAM]). We will apply top-box scoring for the implementation measures. Exploratory outcomes of interest include patient-reported health-related quality of life, resilience, distress, anxiety, depression, pain, and sleep. We will conduct an intention-to-treat analysis to compare the outcomes of the mPRISM arm versus the control arm with covariate-adjusted regression models. We will summarize individual digital usage metrics using descriptive statistics.<br><br>RESULTS: Since September 2023, we have enrolled 20 participants and recruitment is ongoing.<br><br>CONCLUSIONS: Although our previous work suggests AYAs with cancer are interested in mHealth psychosocial interventions, such interventions have not yet been sufficiently evaluated or implemented among AYA oncology patients. mPRISM may serve as a potential mHealth intervention to fill this gap. In this study, we will test the feasibility, acceptability, and preliminary efficacy of mPRISM. This work will inform future larger-scale RCTs powered for efficacy outcomes.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT05842902; https://clinicaltrials.gov/study/NCT05842902.<br><br>DERR1-10.2196/57950.}, }
@article {pmid39078947, year = {2024}, author = {Raymundo, C and Cella, D and Wagner, L and Hippe, DS and Di, M and Guitart, J and Rosen, ST and Querfeld, C and Shinohara, MM}, title = {Development and psychometric properties of the Functional Assessment of Cancer Therapy-Cutaneous T-Cell Lymphoma (FACT-CTCL).}, journal = {The British journal of dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1093/bjd/ljae308}, pmid = {39078947}, issn = {1365-2133}, abstract = {BACKGROUND: Patients with Mycosis Fungoides (MF)/Sézary Syndrome (SS) can experience impacted health-related quality of life (HRQoL).<br><br>OBJECTIVES: To validate the CTCL-S, a novel subscale of the Functional Assessment of Cancer Therapy - General (FACT-G), in patients with MF/SS.<br><br>METHODS: Qualitative interviews were conducted with expert clinicians and MF/SS patients. Thematic analysis identified the most common concerns, and 19 items were selected.MF/SS patients were recruited from a single center. FACT-G, CTCL-S (collectively "FACT-CTCL"), Skindex29, and Visual Analogue Scale-Pruritis (VAS itch) were administered. A subset repeated FACT-CTCL and VAS itch after &#x2248;2 weeks. Patient demographics and clinical characteristics were obtained via review of the electronic medical record.Psychometric properties were assessed. Internal consistency was estimated using Cronbach's alpha (&#x3b1;). Convergent and discriminant validity were assessed by comparing CTCL-S to disease stage, age, VAS itch, FACT-G, and SkinDex29. Exploratory factor analysis (EFA) was used to preliminarily assess CTCL-S dimensionality. Test-retest repeatability was summarized using intraclass correlation coefficient (ICC), within-subject standard deviation (wSD), and within-subject coefficient of variation.<br><br>RESULTS: Seventy-two patients completed the initial survey, and 35 repeated the FACT-CTCL and VAS itch after &#x2248;2 weeks. Two-thirds were male, most were white (78%). The majority (85%) had MF, 15% SS, and 75% early (stage IA-IIA) and 25% advanced (&#x2265; stage IIB) disease. Preliminary EFA found a single predominant factor, supporting a hypothesis of unidimensionality of the CTCL-S. Internal consistency of the CTCL-S was high (&#x3b1;: 0.95 [95% CI: 0.93-0.96]). There was no significant change in CTCL-S average test-retest scores (ICC of 0.93 (p = 0.63)). CTCL-S was significantly lower in advanced vs early stage disease (median[IQR]: 34[26, 48] vs. 59[44, 68], p < 0.001) and strongly correlated with VAS itch (Spearman's r (rs): -0.70, 95% CI: -0.81, -0.55), FACT-G (rs: 0.77, 95% CI: 0.65, 0.85), and Skindex29 (rs: -0.90, 95% CI: -0.94, -0.84), supporting convergent validity. CTCL-S scores had little correlation with age (rs: 0.19, 95% CI: -0.05, 0.41, p = 0.12), supporting discriminant validity.<br><br>CONCLUSIONS: The FACT-CTCL is a disease specific instrument for assessing HRQoL with high reproducibility and good performance in a cohort of patients with MF/SS.}, }
@article {pmid39078720, year = {2024}, author = {Hall, AG and Duenas, DM and Voutsinas, J and Wu, Q and Lamble, AJ and Gruber, E and Wilfond, B and Park, JR and Agrawal, AK and Marron, JM}, title = {Perspectives of pediatric oncologists on referral for CAR-T therapy: a mixed methods pilot study.}, journal = {JNCI cancer spectrum}, volume = {8}, number = {4}, pages = {}, pmid = {39078720}, issn = {2515-5091}, support = {U01 TR002487/TR/NCATS NIH HHS/United States ; U01TR002487/NH/NIH HHS/United States ; /NH/NIH HHS/United States ; //Conquer Cancer Foundation/ ; }, mesh = {Humans ; *Referral and Consultation/statistics &amp; numerical data ; *Oncologists ; Pilot Projects ; Male ; Female ; *Immunotherapy, Adoptive ; Hispanic or Latino/statistics &amp; numerical data ; Attitude of Health Personnel ; Hospitals, Pediatric ; Receptors, Chimeric Antigen ; Child ; Neoplasms/therapy ; Medical Oncology ; Surveys and Questionnaires ; Practice Patterns, Physicians'/statistics &amp; numerical data ; Pediatrics ; Adult ; }, abstract = {BACKGROUND: Receipt of chimeric antigen receptor T-cell (CAR-T) therapy at an institution different from the primary oncologist's institution is a complex, multistep process. Referral by oncologists plays an important role in the process but may be susceptible to bias.<br><br>METHODS: Oncologists who previously referred patients for CAR-T therapy at 5 pediatric hospitals were sent surveys by email exploring their CAR-T referral practices. Descriptive statistics were generated, and multivariate analyses examined associations among oncologist characteristics, familiarity with CAR-T therapy, and referral practices. We conducted semistructured interviews with a subset of participants and used thematic analysis to code transcripts.<br><br>RESULTS: Sixty-eight oncologists completed the survey; 77% expressed being "very familiar" with CAR-T therapy. Hispanic oncologists and oncologists at institutions with 50 or fewer new diagnoses per year were more likely to identify as less familiar with CAR-T therapy (odds ratio [OR]&#x2009;=&#x2009;64.3, 95% confidence interval [CI]&#x2009;=&#x2009;2.45 to 10&#x200a;452.50, P&#x2009;=&#x2009;.04 and OR&#x2009;=&#x2009;24.5, 95% CI&#x2009;=&#x2009;3.3 to 317.3, P&#x2009;=&#x2009;.005, respectively). In total, 38% of respondents considered nonclinical features (compliance, social support, resources, insurance, language, education, and race or ethnicity) influential in referral decisions. Oncologists who were Hispanic and oncologists who had been practicing for 20 or more years were more likely to consider these features significantly influential (OR&#x2009;=&#x2009;14.52, 95% CI&#x2009;=&#x2009;1.49 to 358.66, P&#x2009;=&#x2009;.04 and OR&#x2009;=&#x2009;6.76, 95% CI&#x2009;=&#x2009;1.18 to 50.5, P&#x2009;=&#x2009;.04). Nine oncologists completed in-depth interviews; common themes included barriers and concerns regarding CAR-T therapy referral, the value of an established relationship with a CAR-T therapy center, and poor communication after CAR-T therapy.<br><br>CONCLUSIONS: Nearly 40% of oncologists consider nonclinical features significantly influential when deciding to refer patients for CAR-T therapy, raising concern for bias in the referral process. Establishing formal partnerships with CAR-T therapy centers may help address physician barriers in referral.}, }
@article {pmid39076249, year = {2024}, author = {Kwak, JW and Nguyen, HQ and Camai, A and Huffman, GM and Mekvanich, S and Kenney, NN and Zhu, X and Randolph, TW and Houghton, AM}, title = {CXCR1/2 antagonism inhibits neutrophil function and not recruitment in cancer.}, journal = {Oncoimmunology}, volume = {13}, number = {1}, pages = {2384674}, pmid = {39076249}, issn = {2162-402X}, mesh = {*Receptors, Interleukin-8B/antagonists &amp; inhibitors/metabolism ; *Receptors, Interleukin-8A/antagonists &amp; inhibitors/metabolism ; *Neutrophils/drug effects/immunology/metabolism ; Animals ; Mice ; Humans ; Neutrophil Infiltration/drug effects ; Neoplasms/drug therapy/immunology/pathology/metabolism ; Immune Checkpoint Inhibitors/pharmacology/therapeutic use ; Cell Line, Tumor ; Mice, Inbred C57BL ; Female ; }, abstract = {The level of tumor and circulating CXCR1/2-expressing neutrophils and CXCR1/2 ligands correlate with poor patient outcomes, inversely correlate with tumoral lymphocyte content, and predict immune checkpoint inhibitor (ICI) treatment failure. Accordingly, CXCR2-selective and CXCR1/2 dual inhibitors exhibit activity both as single agents and in combination with ICI treatment in mouse tumor models. Based on such reports, clinical trials combining CXCR1/2 axis antagonists with ICI treatment for cancer patients are underway. It has been assumed that CXCR1/2 blockade impacts tumors by blocking neutrophil chemotaxis and reducing neutrophil content in tumors. Here, we show that while CXCR2 antagonism does slow tumor growth, it does not preclude neutrophil recruitment into tumor. Instead, CXCR1/2 inhibition alters neutrophil function by blocking the polarization of transcriptional programs toward immune suppressive phenotypes and rendering neutrophils incapable of suppressing lymphocyte proliferation. This is associated with decreased release of reactive oxygen species and Arginase-1 into the extracellular milieu. Remarkably, these therapeutics do not impact the ability of neutrophils to phagocytose and kill ingested bacteria. Taken together, these results mechanistically explain why CXCR1/2 inhibition has been active in cancer but without infectious complications.}, }
@article {pmid39076160, year = {2024}, author = {Davidsen, K and Sullivan, LB}, title = {A robust method for measuring aminoacylation through tRNA-Seq.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, pmid = {39076160}, issn = {2050-084X}, support = {R35 GM147118/GM/NIGMS NIH HHS/United States ; R35GM147118/GM/NIGMS NIH HHS/United States ; }, mesh = {*RNA, Transfer/genetics/metabolism ; Transfer RNA Aminoacylation ; Sequence Analysis, RNA/methods ; Aminoacylation/genetics ; }, abstract = {Current methods to quantify the fraction of aminoacylated tRNAs, also known as the tRNA charge, are limited by issues with either low throughput, precision, and/or accuracy. Here, we present an optimized charge transfer RNA sequencing (tRNA-Seq) method that combines previous developments with newly described approaches to establish a protocol for precise and accurate tRNA charge measurements. We verify that this protocol provides robust quantification of tRNA aminoacylation and we provide an end-to-end method that scales to hundreds of samples including software for data processing. Additionally, we show that this method supports measurements of relative tRNA expression levels and can be used to infer tRNA modifications through reverse transcription misincorporations, thereby supporting multipurpose applications in tRNA biology.}, }
@article {pmid39074152, year = {2024}, author = {Smukowski, SN and Danyko, C and Somberg, J and Kaufman, EJ and Course, MM and Postupna, N and Barker-Haliski, M and Keene, CD and Valdmanis, PN}, title = {mRNA and circRNA mislocalization to synapses are key features of Alzheimer's disease.}, journal = {PLoS genetics}, volume = {20}, number = {7}, pages = {e1011359}, pmid = {39074152}, issn = {1553-7404}, support = {R21 AG082032/AG/NIA NIH HHS/United States ; R61 NS126626/NS/NINDS NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; U19 AG066567/AG/NIA NIH HHS/United States ; R01 AG067788/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease/genetics/metabolism ; *RNA, Circular/genetics/metabolism ; Humans ; Animals ; *Synapses/metabolism/genetics ; *RNA, Messenger/genetics/metabolism ; Mice ; *tau Proteins/metabolism/genetics ; Phosphorylation ; Disease Models, Animal ; Brain/metabolism/pathology ; Male ; Neurons/metabolism ; Mice, Transgenic ; Synaptosomes/metabolism ; Female ; Aged ; }, abstract = {Proper transport of RNAs to synapses is essential for localized translation of proteins in response to synaptic signals and synaptic plasticity. Alzheimer's disease (AD) is a neurodegenerative disease characterized by accumulation of amyloid aggregates and hyperphosphorylated tau neurofibrillary tangles followed by widespread synapse loss. To understand whether RNA synaptic localization is impacted in AD, we performed RNA sequencing on synaptosomes and brain homogenates from AD patients and cognitively healthy controls. This resulted in the discovery of hundreds of mislocalized mRNAs in AD among frontal and temporal brain regions. Similar observations were found in an APPswe/PSEN1dE9 mouse model. Furthermore, major differences were observed among circular RNAs (circRNAs) localized to synapses in AD including two overlapping isoforms of circGSK3β, one upregulated, and one downregulated. Expression of these distinct isoforms affected tau phosphorylation in neuronal cells substantiating the importance of circRNAs in the brain and pointing to a new class of therapeutic targets.}, }
@article {pmid39074144, year = {2024}, author = {Wang, R and Senay, TE and Luo, TT and Liu, W and Regan, JM and Salisbury, NJH and Galloway, DA and You, J}, title = {Merkel cell polyomavirus protein ALTO modulates TBK1 activity to support persistent infection.}, journal = {PLoS pathogens}, volume = {20}, number = {7}, pages = {e1012170}, pmid = {39074144}, issn = {1553-7374}, support = {P50 CA174523/CA/NCI NIH HHS/United States ; R01 CA187718/CA/NCI NIH HHS/United States ; R01 CA284690/CA/NCI NIH HHS/United States ; R21 CA267803/CA/NCI NIH HHS/United States ; }, mesh = {*Protein Serine-Threonine Kinases/metabolism ; *Merkel cell polyomavirus ; *Polyomavirus Infections/metabolism/immunology/virology ; Humans ; *Tumor Virus Infections/metabolism/immunology/virology ; Carcinoma, Merkel Cell/virology/metabolism ; Membrane Proteins/metabolism ; Signal Transduction ; Viral Proteins/metabolism ; Virus Replication ; Skin Neoplasms/virology/metabolism/immunology ; Animals ; }, abstract = {While Merkel cell polyomavirus (MCPyV or MCV) is an abundant virus frequently shed from healthy skin, it is one of the most lethal tumor viruses in immunocompromised individuals, highlighting the crucial role of host immunity in controlling MCPyV oncogenic potential. Despite its prevalence, very little is known about how MCPyV interfaces with the host immune response to maintain asymptomatic persistent infection and how inadequate control of MCPyV infection triggers MCC tumorigenesis. In this study, we discovered that the MCPyV protein, known as the Alternative Large Tumor Open Reading Frame (ALTO), also referred to as middle T, effectively primes and activates the STING signaling pathway. It recruits Src kinase into the complex of STING downstream kinase TBK1 to trigger its autophosphorylation, which ultimately activates the subsequent antiviral immune response. Combining single-cell analysis with both loss- and gain-of-function studies of MCPyV infection, we demonstrated that the activity of ALTO leads to a decrease in MCPyV replication. Thus, we have identified ALTO as a crucial viral factor that modulates the STING-TBK1 pathway, creating a negative feedback loop that limits viral infection and maintains a delicate balance with the host immune system. Our study reveals a novel mechanism by which a tumorigenic virus-encoded protein can link Src function in cell proliferation to the activation of innate immune signaling, thereby controlling viral spread, and sustaining persistent infection. Our previous findings suggest that STING also functions as a tumor suppressor in MCPyV-driven oncogenesis. This research provides a foundation for investigating how disruptions in the finely tuned virus-host balance, maintained by STING, could alter the fate of MCPyV infection, potentially encouraging malignancy.}, }
@article {pmid39072755, year = {2024}, author = {Parrish, AG and Szulzewsky, F}, title = {TRKing down drug resistance in NTRK fusion-positive cancers[†].}, journal = {The Journal of pathology}, volume = {264}, number = {2}, pages = {129-131}, doi = {10.1002/path.6341}, pmid = {39072755}, issn = {1096-9896}, mesh = {Humans ; *Drug Resistance, Neoplasm/genetics ; *Protein Kinase Inhibitors/therapeutic use/pharmacology ; Neurofibromin 2/genetics ; Oncogene Proteins, Fusion/genetics ; Benzamides/therapeutic use/pharmacology ; Receptor, trkA/genetics/metabolism ; Signal Transduction/genetics ; Indazoles/therapeutic use/pharmacology ; Mutation ; Sarcoma/genetics/drug therapy/pathology ; Antineoplastic Agents/therapeutic use/pharmacology ; TOR Serine-Threonine Kinases/genetics/metabolism ; }, abstract = {In a recent issue of The Journal of Pathology, Chen and colleagues established novel patient-derived ex vivo models of NTRK fusion-positive soft tissue sarcoma to characterize resistance mechanisms against targeted therapy with tyrosine kinase inhibitors. Prolonged exposure to escalating concentrations of the tyrosine kinase inhibitor, entrectinib, ultimately led to the occurrence of resistant clones that harbored an inactivating mutation in the NF2 gene, not previously described in this context, accompanied by increased PI3K/AKT/mTOR and Ras/Raf/MEK/ERK signaling. Finally, an inhibitor screen identified, among others, MEK and mTOR inhibitors as potential combination agents. © 2024 The Pathological Society of Great Britain and Ireland.}, }
@article {pmid39072356, year = {2024}, author = {Hamilton, EP and Ma, C and De Laurentiis, M and Iwata, H and Hurvitz, SA and Wander, SA and Danso, M and Lu, DR and Perkins Smith, J and Liu, Y and Tran, L and Anderson, S and Campone, M}, title = {VERITAC-2: a Phase III study of vepdegestrant, a PROTAC ER degrader, versus fulvestrant in ER+/HER2- advanced breast cancer.}, journal = {Future oncology (London, England)}, volume = {20}, number = {32}, pages = {2447-2455}, pmid = {39072356}, issn = {1744-8301}, support = {//Pfizer,&#xa0;Inc./ ; //Arvinas Estrogen Receptor, Inc./ ; }, mesh = {Humans ; Female ; *Breast Neoplasms/drug therapy/mortality/pathology ; *Fulvestrant/therapeutic use/administration &amp; dosage ; *Receptor, ErbB-2/metabolism ; *Receptors, Estrogen/metabolism ; Adult ; Middle Aged ; Estrogen Receptor alpha/genetics/metabolism ; }, abstract = {Vepdegestrant (ARV-471) is an oral PROTAC ER degrader that binds an E3 ubiquitin ligase and ER to directly trigger ubiquitination of ER and its subsequent proteasomal degradation. In a first-in-human Phase I/II study, vepdegestrant monotherapy was well tolerated with clinical activity in pretreated patients with ER+/HER2- advanced breast cancer. The global, randomized Phase III VERITAC-2 study compares efficacy and safety of vepdegestrant versus fulvestrant in adults with ER+/HER2- advanced breast cancer after treatment with a CDK4/6 inhibitor plus endocrine therapy. Progression-free survival by blinded independent central review (primary end point) will be assessed in the intention-to-treat population and ESR1 mutation-positive subpopulation. Secondary end points include overall survival, tumor response, safety, pharmacokinetics, patient-reported outcomes, and circulating tumor DNA biomarkers.Clinical trial registration: NCT05654623 (ClinicalTrials.gov).}, }
@article {pmid39071941, year = {2024}, author = {Pete, D and Salama, NR and Lampe, JW and Wu, MC and Phipps, AI}, title = {The prevalence and risk factors of Helicobacter pylori infection and cagA virulence gene carriage in adults in the Navajo Nation.}, journal = {Microbiota in health and disease}, volume = {6}, number = {}, pages = {}, pmid = {39071941}, issn = {2704-8845}, support = {F99 CA253685/CA/NCI NIH HHS/United States ; R01 AI054423/AI/NIAID NIH HHS/United States ; S06 GM123543/GM/NIGMS NIH HHS/United States ; }, abstract = {BACKGROUND: American Indian and Alaska Native people in the United States experience high rates of stomach cancer. Helicobacter pylori infection is a significant risk factor for stomach cancer, and H. pylori strains that carry the cagA gene are linked to greater gastrointestinal disease severity. Yet, little is known about H. pylori and cagA infections in American Indian and Alaska Native people, particularly at the tribal level. We assessed the prevalence and risk factors of H. pylori infection and cagA gene carriage in tribal members from the Navajo Nation.<br><br>MATERIALS AND METHODS: We conducted a cross-sectional study with adults from the Navajo Nation. Stool samples collected from participants were analyzed with droplet digital PCR for H. pylori 16S ribosomal and cagA virulence genes. Self-administered health and food questionnaires were mailed to participants to collect information on sociodemographic, health, lifestyle, and environmental risk factors for H. pylori infection. Logistic regression assessed the association between risk factors and H. pylori infection and cagA gene carriage.<br><br>RESULTS: Among 99 adults, the median age was 45 (age range: 18 to 79 years), and 73.7% were female. About 56.6% (95% CI: 46.2-66.5) of participants were infected with H. pylori. Of H. pylori-infected participants, 78.6% (95% CI: 65.6-88.4) were cagA-gene positive. No significant associations of relevant risk factors with H. pylori and cagA-gene positive infections were noted.<br><br>CONCLUSIONS: In a community-based study population, a substantial proportion of adult tribal members had H. pylori and cagA-gene positive infections. Given these high proportions, culturally appropriate prevention strategies and interventions addressing H. pylori infections present an avenue for additional research and stomach cancer prevention in the Navajo Nation.}, }
@article {pmid39071407, year = {2024}, author = {Estevam, GO and Linossi, EM and Rao, J and Macdonald, CB and Ravikumar, A and Chrispens, KM and Capra, JA and Coyote-Maestas, W and Pimentel, H and Collisson, EA and Jura, N and Fraser, JS}, title = {Mapping kinase domain resistance mechanisms for the MET receptor tyrosine kinase via deep mutational scanning.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39071407}, issn = {2692-8205}, support = {R01 CA239604/CA/NCI NIH HHS/United States ; T32 GM149436/GM/NIGMS NIH HHS/United States ; S10 OD028511/OD/NIH HHS/United States ; R35 GM145238/GM/NIGMS NIH HHS/United States ; R01 LM013434/LM/NLM NIH HHS/United States ; }, abstract = {Mutations in the kinase and juxtamembrane domains of the MET Receptor Tyrosine Kinase are responsible for oncogenesis in various cancers and can drive resistance to MET-directed treatments. Determining the most effective inhibitor for each mutational profile is a major challenge for MET-driven cancer treatment in precision medicine. Here, we used a deep mutational scan (DMS) of ~5,764 MET kinase domain variants to profile the growth of each mutation against a panel of 11 inhibitors that are reported to target the MET kinase domain. We identified common resistance sites across type I, type II, and type I ½ inhibitors, unveiled unique resistance and sensitizing mutations for each inhibitor, and validated non-cross-resistant sensitivities for type I and type II inhibitor pairs. We augment a protein language model with biophysical and chemical features to improve the predictive performance for inhibitor-treated datasets. Together, our study demonstrates a pooled experimental pipeline for identifying resistance mutations, provides a reference dictionary for mutations that are sensitized to specific therapies, and offers insights for future drug development.}, }
@article {pmid39071291, year = {2024}, author = {Frank, S and Persse, T and Coleman, I and Bankhead, A and Li, D and De-Sarkar, N and Wilson, D and Rudoy, D and Vashisth, M and Galipeau, P and Yang, M and Hanratty, B and Dumpit, R and Morrissey, C and Corey, E and Montgomery, RB and Haffner, MC and Pritchard, C and Vasioukhin, V and Ha, G and Nelson, PS}, title = {Molecular consequences of acute versus chronic CDK12 loss in prostate carcinoma nominates distinct therapeutic strategies.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39071291}, issn = {2692-8205}, support = {F32 CA243286/CA/NCI NIH HHS/United States ; R21 CA277368/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; DP2 CA280624/CA/NCI NIH HHS/United States ; P01 CA163227/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; R01 CA280056/CA/NCI NIH HHS/United States ; }, abstract = {Genomic loss of the transcriptional kinase CDK12 occurs in ~6% of metastatic castration-resistant prostate cancers (mCRPC) and correlates with poor patient outcomes. Prior studies demonstrate that acute CDK12 loss confers a homologous recombination (HR) deficiency (HRd) phenotype via premature intronic polyadenylation (IPA) of key HR pathway genes, including ATM. However, mCRPC patients have not demonstrated benefit from therapies that exploit HRd such as inhibitors of polyADP ribose polymerase (PARP). Based on this discordance, we sought to test the hypothesis that an HRd phenotype is primarily a consequence of acute CDK12 loss and the effect is greatly diminished in prostate cancers adapted to CDK12 loss. Analyses of whole genome sequences (WGS) and RNA sequences (RNAseq) of human mCRPCs determined that tumors with biallelic CDK12 alterations (CDK12 [BAL]) lack genomic scar signatures indicative of HRd, despite carrying bi-allelic loss and the appearance of the hallmark tandem-duplicator phenotype (TDP). Experiments confirmed that acute CDK12 inhibition resulted in aberrant polyadenylation and downregulation of long genes (including BRCA1 and BRCA2) but such effects were modest or absent in tumors adapted to chronic CDK12 [BAL] . One key exception was ATM, which did retain transcript shortening and reduced protein expression in the adapted CDK12 [BAL] models. However, CDK12 [BAL] cells demonstrated intact HR as measured by RAD51 foci formation following irradiation. CDK12 [BAL] cells showed a vulnerability to targeting of CDK13 by sgRNA or CDK12/13 inhibitors and in vivo treatment of prostate cancer xenograft lines showed that tumors with CDK12 [BAL] responded to the CDK12/13 inhibitor SR4835, while CDK12-intact lines did not. Collectively, these studies show that aberrant polyadenylation and long HR gene downregulation is primarily a consequence of acute CDK12 deficiency, which is largely compensated for in cells that have adapted to CDK12 loss. These results provide an explanation for why PARPi monotherapy has thus far failed to consistently benefit patients with CDK12 alterations, though alternate therapies that target CDK13 or transcription are candidates for future research and testing.}, }
@article {pmid39070544, year = {2024}, author = {Hashemi, A and Moradi Alamdarloo, S and Vafaei, H and Barzegar, H and Jafari, F and Haseli, S and Abbaspour, E}, title = {Multiple giant placental chorioangioma: A case report.}, journal = {Clinical case reports}, volume = {12}, number = {8}, pages = {e9219}, pmid = {39070544}, issn = {2050-0904}, abstract = {KEY CLINICAL MESSAGE: Giant chorioangiomas, despite being rare, pose significant fetal and maternal risks. Timely and individualized treatment plans are crucial to reduce morbidity and mortality when fetal compromise occurs. Additionally, successful conservative management relies on consistent ultrasound monitoring, Doppler flowmetry assessments, and amniotic fluid level measurements.<br><br>ABSTRACT: Chorioangiomas are benign placental tumors that manifest in approximately 1% of pregnancies. Giant chorioangiomas, characterized by tumors exceeding 4&#x2009;cm, are exceptionally rare and pose substantial risks to maternal and fetal health. This case report details a patient with multiple giant chorioangiomas, emphasizing the rarity and consequential complications associated with these tumors. A 23-year-old woman, G3P2, at 28&#x2009;weeks gestational age, was diagnosed with multiple large, well-defined placental masses with increased vascularity, indicative of giant placental chorioangiomas. Subsequent ultrasound revealed various fetal anomalies such as cleft palate and lip, as well as lung and heart abnormalities. At 34[+5]&#x2009;weeks of gestation, an emergency cesarean section was performed due to preeclampsia. Subsequently, a female neonate was born with hydrops fetalis. Unfortunately, she passed away within the first hour of her life. Complications associated with chorioangiomas primarily arise from arteriovenous shunts, which potentially lead to compromised fetal perfusion and cardiac failure. Although small-sized chorioangiomas are often discovered incidentally, Doppler ultrasound and magnetic resonance imaging can reliably distinguish these tumors from other placental lesions. Additionally, management strategies tailored to gestational age and maternal-fetal symptoms typically necessitate a multidisciplinary approach. However, additional research is essential to understand the mechanisms of chorioangiomas and to develop comprehensive management guidelines.}, }
@article {pmid39068857, year = {2024}, author = {Canton, G and Baylam Geleri, D and Hippe, DS and Sun, J and Guo, Y and Balu, N and Chu, B and Pimentel, K and Akçiçek, H and Yaman Akçiçek, E and Tirschwell, D and Tang, G and Kohler, T and Shibata, D and Ferguson, MS and Yuan, C and Hatsukami, TS}, title = {Pathophysiology of carotid atherosclerosis: Calcification, intraplaque haemorrhage and pulse pressure as key players.}, journal = {European journal of radiology}, volume = {178}, number = {}, pages = {111647}, pmid = {39068857}, issn = {1872-7727}, support = {R01 HL103609/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; *Carotid Artery Diseases/diagnostic imaging/complications/physiopathology ; Aged ; Middle Aged ; *Hemorrhage/diagnostic imaging/physiopathology ; *Blood Pressure ; Disease Progression ; Risk Factors ; Vascular Calcification/diagnostic imaging/physiopathology/complications ; Plaque, Atherosclerotic/diagnostic imaging ; Reproducibility of Results ; Sensitivity and Specificity ; Magnetic Resonance Imaging/methods ; Magnetic Resonance Angiography ; }, abstract = {PURPOSE: Intraplaque haemorrhage (IPH) is a well-known risk factor for faster plaque progression (volume increase); however, its etiology is unclear. We aimed at determining what other local plaque- and systemic factors contribute to plaque progression and to the development and progression of IPH.<br><br>METHODS: We examined 98 asymptomatic participants with carotid plaque using serial multi-contrast magnetic resonance imaging. We measured the percent of wall volume (%WV=100&#xa0;x&#xa0;[wall volume] / [total vessel volume]) and measured IPH and calcification volumes. We used generalized estimating equations-based regression to analyze predictors of %WV change and new IPH while accounting for covariates (sex, age and statin use), and multiple non-independent observations per participant.<br><br>RESULTS: Total follow-up was 1.8&#xa0;&#xb1;&#xa0;0.8&#xa0;years on average. The presence of IPH (&#x3b2;: 0.6&#xa0;%/y, p&#xa0;=&#xa0;0.033) and calcification (&#x3b2;: 1.2&#xa0;%/y, p&#xa0;=&#xa0;0.028) were each associated with faster plaque progression. New IPH, detected on a subsequent scan in 4&#xa0;% of arteries that did not initially have IPH, was associated with larger calcification (odds ratio [OR]: 2.6 per 1-SD increase, p&#xa0;=&#xa0;0.038) and higher pulse pressure (OR: 2.3 per 1-SD increase, p&#xa0;=&#xa0;0.016). Larger calcification was associated with greater increases in pulse pressure (&#x3b2;: 1.4&#xa0;mm Hg/y per 1-SD increase, p&#xa0;=&#xa0;0.040).<br><br>CONCLUSIONS: IPH and calcification are each independently associated with faster plaque progression. The association of carotid calcification to increased pulse pressure and new IPH development suggests a possible mechanism by which calcification drives IPH development and plaque progression.}, }
@article {pmid39068651, year = {2024}, author = {Showman, S and Talbert, PB and Xu, Y and Henikoff, S}, title = {Protocol to measure centromeric array size changes using droplet digital PCR-based quantification of higher-order repeats.}, journal = {STAR protocols}, volume = {5}, number = {3}, pages = {103218}, pmid = {39068651}, issn = {2666-1667}, support = {R01 HG010492/HG/NHGRI NIH HHS/United States ; }, mesh = {*Centromere/genetics ; *Polymerase Chain Reaction/methods ; Humans ; Repetitive Sequences, Nucleic Acid/genetics ; }, abstract = {Centromere length changes occurring during somatic cell divisions can be estimated by quantifying the copy numbers (CNs) of higher-order repeats (HORs), which are nested repeats of monomers that comprise centromeric arrays. Here, we present a protocol for single-cell isolation for clonal evolution followed by droplet digital PCR-based quantification. The assay measures HOR CNs across subclones to determine the frequency and degree of changes in HOR CNs. This protocol tests the underlying molecular mechanisms responsible for rapid centromere sequence evolution. For complete details on the use and execution of this protocol, please refer to Showman et al.[1].}, }
@article {pmid39067873, year = {2024}, author = {Patel, SP and Othus, M and Chae, YK and Huynh, T and Tan, B and Kuzel, T and McLeod, C and Lopez, G and Chen, HX and Sharon, E and Streicher, H and Ryan, CW and Blanke, C and Kurzrock, R}, title = {Phase II basket trial of Dual Anti-CTLA-4 and Anti-PD-1 blockade in Rare Tumors (DART) SWOG S1609: adrenocortical carcinoma cohort.}, journal = {Journal for immunotherapy of cancer}, volume = {12}, number = {7}, pages = {}, pmid = {39067873}, issn = {2051-1426}, support = {UG1 CA233331/CA/NCI NIH HHS/United States ; UG1 CA233320/CA/NCI NIH HHS/United States ; U10 CA180821/CA/NCI NIH HHS/United States ; U10 CA180828/CA/NCI NIH HHS/United States ; UG1 CA233198/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; U10 CA180819/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; Middle Aged ; Male ; Adult ; *Adrenocortical Carcinoma/drug therapy/mortality ; Aged ; *CTLA-4 Antigen/antagonists &amp; inhibitors ; Immune Checkpoint Inhibitors/therapeutic use/adverse effects/administration &amp; dosage ; Ipilimumab/therapeutic use/administration &amp; dosage/adverse effects ; Prospective Studies ; Programmed Cell Death 1 Receptor/antagonists &amp; inhibitors ; Adrenal Cortex Neoplasms/drug therapy/mortality ; Nivolumab/therapeutic use/administration &amp; dosage/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; }, abstract = {OBJECTIVES: Multiple common cancers benefit from immunotherapy; however, less is known about efficacy in rare tumors. We report the results of the adrenocortical carcinoma cohort of NCI/SWOG S1609 Dual Anti-CTLA-4 and Anti-PD-1 blockade in Rare Tumors.<br><br>DESIGN/SETTING: A prospective, phase 2 clinical trial of ipilimumab plus nivolumab was conducted by the SWOG Early Therapeutics and Rare Cancers Committee for multiple rare tumor cohorts across >1,000 National Clinical Trial Network sites.<br><br>PARTICIPANTS: 21 eligible patients were registered. Median age was 53 years (range 26-69); 16 (76%) were women.<br><br>INTERVENTIONS: Ipilimumab 1&#x2009;mg/kg intravenously every 6 weeks with nivolumab 240&#x2009;mg intravenously every 2 weeks was administered until disease progression, symptomatic deterioration, treatment delay for any reason >56&#x2009;days, unacceptable or immune-related toxicity with inability to decrease prednisone to <10&#x2009;mg daily, or per patient request.<br><br>MAIN OUTCOME MEASURES: The primary endpoint was the overall response rate (ORR) (RECIST V.1.1). Secondary endpoints include clinical benefit rate (CBR) (includes stable disease (SD)>6 months), progression-free survival (PFS), overall survival (OS), and toxicity. Immune-related outcomes included immune ORR (iORR), immune CBR (iCBR), and immune PFS (iPFS). A two-stage design was used assuming: null=5% alternative=30%, n=6 in the first stage, 16 max, one-sided alpha=13%.<br><br>RESULTS: The median number of prior therapy lines was 2 (range: 1-9). 3 of 21 patients attained confirmed partial response (PR) (ORR=14%). In addition, one patient had an unconfirmed PR; one, stable disease (SD)>6 months; one, immune-related RECIST (iRECIST) PR (iPR); and one patient attained iSD>6 months: clinical benefit rate (response or SD>6 months)=5/21 (24%), iORR=4/21 (19%), iCBR=7/21 (33%). The 6-month PFS was 24%; 6-month iPFS, 33%. The PFS for patients (N=7) with iRECIST clinical benefit were 57, 52, 18, 15, 13, 7, and 7 months. The 6-month OS was 76%; the median OS, was 15.8 months. The most common toxicities were fatigue (62%) and rash (38%), and the most common grade 3/4 immune-related adverse events were hepatic dysfunction (9.5%) and adrenal insufficiency (9.5%). Treatment-related adverse events leading to discontinuation of therapy in four patients (21%). There were no grade 5 adverse events.<br><br>CONCLUSIONS: Ipilimumab plus nivolumab is active in refractory metastatic adrenocortical cancer meeting the primary endpoint of the study, with a 19% iORR and 33% iCBR (includes SD/iSD>6 months) and with the longest PFS/iPFS of 52 and 57 months.<br><br>TRIAL REGISTRATION NUMBER: NCT02834013 (registered 15 July, 2016; https://clinicaltrials.gov/ct2/show/NCT02834013).}, }
@article {pmid39067790, year = {2024}, author = {Dandoy, CE and Adams, J and Artz, A and Bredeson, C and Dahi, PB and Dodd, T and Jaglowski, S and Lehmann, L and LeMaistre, CF and Mian, A and Neal, A and Page, K and Rizzo, JD and Rotz, S and Sorror, M and Steinberg, A and Viswabandya, A and Howard, DS and , }, title = {In Pursuit of Optimal Outcomes: A Framework for Quality Standards in Immune Effector Cell Therapy.}, journal = {Transplantation and cellular therapy}, volume = {30}, number = {10}, pages = {942-954}, doi = {10.1016/j.jtct.2024.07.011}, pmid = {39067790}, issn = {2666-6367}, mesh = {Humans ; *Neoplasms/immunology/therapy ; Cell- and Tissue-Based Therapy/standards/methods ; Quality Assurance, Health Care ; Treatment Outcome ; Immunotherapy/methods/standards ; }, abstract = {Immune effector cell (IEC) therapy represents a transformative advancement in oncology, leveraging the immune system to combat various malignancies. This article outlines a comprehensive framework for establishing and maintaining quality standards in IEC therapy amidst rapid scientific and clinical advancements. We emphasize the integration of structured process measures, robust quality assurance, and meticulous outcome evaluation to ensure treatment efficacy and safety. Key components include multidisciplinary expertise, stringent accreditation protocols, and advanced data management systems, which facilitate standardized reporting and continual innovation. The collaborative effort among stakeholders-ranging from patients and healthcare providers to regulatory bodies-is crucial in delivering high-quality IEC therapies. This framework aims to enhance patient outcomes and cement the role of IEC therapy as a cornerstone of modern oncology, promoting continuous improvement and adherence to high standards across the therapeutic spectrum.}, }
@article {pmid39067061, year = {2024}, author = {Tantalo, LC and Luetkemeyer, A and Lieberman, NAP and Nunley, BE and Avendaño, C and Greninger, AL and Celum, C and Giacani, L}, title = {Long-term in vitro exposure of Treponema pallidum to sub-bactericidal doxycycline did not induce resistance: Implications for doxy-PEP and syphilis.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiae381}, pmid = {39067061}, issn = {1537-6613}, support = {R01 AI143439/AI/NIAID NIH HHS/United States ; }, abstract = {Doxycycline post-exposure prophylaxis (doxy-PEP) could significantly reduce syphilis incidence. However, the increase in intermittent doxycycline usage might select resistant Treponema pallidum (T. pallidum) strains. To assess whether resistance to doxycycline could be induced in this pathogen, we exposed the SS14 strain in vitro both intermittently and continuously to a sub-bactericidal doxycycline concentration that still exerts antibiotic pressure. During and after each exposure experiment, we assessed the doxycycline minimal inhibitory concentration in test and control treponemes and performed whole genome sequencing, concluding that no resistance developed. This work suggests that doxycycline-resistant T. pallidum is not an immediate threat for doxy-PEP implementation.}, }
@article {pmid39067017, year = {2024}, author = {Afiaz, A and Ivanov, AA and Chamberlin, J and Hanauer, D and Savonen, CL and Goldman, MJ and Morgan, M and Reich, M and Getka, A and Holmes, A and Pati, S and Knight, D and Boutros, PC and Bakas, S and Caporaso, JG and Del Fiol, G and Hochheiser, H and Haas, B and Schloss, PD and Eddy, JA and Albrecht, J and Fedorov, A and Waldron, L and Hoffman, AM and Bradshaw, RL and Leek, JT and Wright, C}, title = {Best practices to evaluate the impact of biomedical research software-metric collection beyond citations.}, journal = {Bioinformatics (Oxford, England)}, volume = {40}, number = {8}, pages = {}, pmid = {39067017}, issn = {1367-4811}, support = {UE5 CA254170/CA/NCI NIH HHS/United States ; U24 CA248265/CA/NCI NIH HHS/United States ; U01 CA242871/CA/NCI NIH HHS/United States ; U24 CA274582/CA/NCI NIH HHS/United States ; U54 HG012517/HG/NHGRI NIH HHS/United States ; /NH/NIH HHS/United States ; R33 CA263703/CA/NCI NIH HHS/United States ; }, mesh = {*Software ; *Biomedical Research/methods ; Humans ; United States ; Computational Biology/methods ; }, abstract = {MOTIVATION: Software is vital for the advancement of biology and medicine. Impact evaluations of scientific software have primarily emphasized traditional citation metrics of associated papers, despite these metrics inadequately capturing the dynamic picture of impact and despite challenges with improper citation.<br><br>RESULTS: To understand how software developers evaluate their tools, we conducted a survey of participants in the Informatics Technology for Cancer Research (ITCR) program funded by the National Cancer Institute (NCI). We found that although developers realize the value of more extensive metric collection, they find a lack of funding and time hindering. We also investigated software among this community for how often infrastructure that supports more nontraditional metrics were implemented and how this impacted rates of papers describing usage of the software. We found that infrastructure such as social media presence, more in-depth documentation, the presence of software health metrics, and clear information on how to contact developers seemed to be associated with increased mention rates. Analysing more diverse metrics can enable developers to better understand user engagement, justify continued funding, identify novel use cases, pinpoint improvement areas, and ultimately amplify their software's impact. Challenges are associated, including distorted or misleading metrics, as well as ethical and security concerns. More attention to nuances involved in capturing impact across the spectrum of biomedical software is needed. For funders and developers, we outline guidance based on experience from our community. By considering how we evaluate software, we can empower developers to create tools that more effectively accelerate biological and medical research progress.<br><br>More information about the analysis, as well as access to data and code is available at https://github.com/fhdsl/ITCR_Metrics_manuscript_website.}, }
@article {pmid39066181, year = {2024}, author = {Zhu, J and Miner, MD}, title = {Local Power: The Role of Tissue-Resident Immunity in Human Genital Herpes Simplex Virus Reactivation.}, journal = {Viruses}, volume = {16}, number = {7}, pages = {}, pmid = {39066181}, issn = {1999-4915}, mesh = {Humans ; *Herpes Genitalis/immunology/virology ; *Virus Activation/immunology ; *Herpesvirus 2, Human/immunology/physiology ; *CD8-Positive T-Lymphocytes/immunology ; *Virus Latency/immunology ; Immunologic Memory ; Adaptive Immunity ; Skin/immunology/virology ; Immunity, Innate ; Animals ; }, abstract = {From established latency, human herpes virus type 2 (HSV-2) frequently reactivates into the genital tract, resulting in symptomatic ulcers or subclinical shedding. Tissue-resident memory (TRM) CD8+ T cells that accumulate and persist in the genital skin at the local site of recrudescence are the "first responders" to viral reactivation, performing immunosurveillance and containment and aborting the ability of the virus to induce clinical lesions. This review describes the unique spatiotemporal characteristics, transcriptional signatures, and noncatalytic effector functions of TRM CD8+ T cells in the tissue context of human HSV-2 infection. We highlight recent insights into the intricate overlaps between intrinsic resistance, innate defense, and adaptive immunity in the tissue microenvironment and discuss how rapid virus-host dynamics at the skin and mucosal level influence clinical outcomes of genital herpes diseases.}, }
@article {pmid39066177, year = {2024}, author = {Giorgi, EE and Li, H and Hora, B and Shaw, GM and Wagh, K and Williams, WB}, title = {Viral Envelope Evolution in Simian-HIV-Infected Neonate and Adult-Dam Pairs of Rhesus Macaques.}, journal = {Viruses}, volume = {16}, number = {7}, pages = {}, pmid = {39066177}, issn = {1999-4915}, support = {R37 AI150590/AI/NIAID NIH HHS/United States ; AI140897//NIH, NIAID/ ; SP30 AI064518/GF/NIH HHS/United States ; AI160607//NIH, NIAID/ ; }, mesh = {Animals ; *Macaca mulatta ; *Simian Immunodeficiency Virus/genetics/immunology ; *Simian Acquired Immunodeficiency Syndrome/virology ; *Phylogeny ; *HIV-1/genetics/immunology/classification ; *Antibodies, Neutralizing/immunology/blood ; *Evolution, Molecular ; Genetic Variation ; Animals, Newborn ; HIV Antibodies/immunology/blood ; Viral Envelope Proteins/genetics/immunology ; HIV Infections/virology ; }, abstract = {We recently demonstrated that Simian-HIV (SHIV)-infected neonate rhesus macaques (RMs) generated heterologous HIV-1 neutralizing antibodies (NAbs) with broadly-NAb (bNAb) characteristics at a higher frequency compared with their corresponding dam. Here, we characterized genetic diversity in Env sequences from four neonate or adult/dam RM pairs: in two pairs, neonate and dam RMs made heterologous HIV-1 NAbs; in one pair, neither the neonate nor the dam made heterologous HIV-1 NAbs; and in another pair, only the neonate made heterologous HIV-1 NAbs. Phylogenetic and sequence diversity analyses of longitudinal Envs revealed that a higher genetic diversity, within the host and away from the infecting SHIV strain, was correlated with heterologous HIV-1 NAb development. We identified 22 Env variable sites, of which 9 were associated with heterologous HIV-1 NAb development; 3/9 sites had mutations previously linked to HIV-1 Env bNAb development. These data suggested that viral diversity drives heterologous HIV-1 NAb development, and the faster accumulation of viral diversity in neonate RMs may be a potential mechanism underlying bNAb induction in pediatric populations. Moreover, these data may inform candidate Env immunogens to guide precursor B cells to bNAb status via vaccination by the Env-based selection of bNAb lineage members with the appropriate mutations associated with neutralization breadth.}, }
@article {pmid39059381, year = {2024}, author = {Wang, LT and Cooper, AJR and Farrell, B and Miura, K and Diouf, A and Müller-Sienerth, N and Crosnier, C and Purser, L and Kirtley, PJ and Maciuszek, M and Barrett, JR and McHugh, K and Ogwang, R and Tucker, C and Li, S and Doumbo, S and Doumtabe, D and Pyo, CW and Skinner, J and Nielsen, CM and Silk, SE and Kayentao, K and Ongoiba, A and Zhao, M and Nguyen, DC and Lee, FE and Minassian, AM and Geraghty, DE and Traore, B and Seder, RA and Wilder, BK and Crompton, PD and Wright, GJ and Long, CA and Draper, SJ and Higgins, MK and Tan, J}, title = {Natural malaria infection elicits rare but potent neutralizing antibodies to the blood-stage antigen RH5.}, journal = {Cell}, volume = {187}, number = {18}, pages = {4981-4995.e14}, pmid = {39059381}, issn = {1097-4172}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Antibodies, Neutralizing/immunology ; *Plasmodium falciparum/immunology ; *Malaria, Falciparum/immunology/prevention &amp; control/parasitology ; *Malaria Vaccines/immunology ; *Antibodies, Protozoan/immunology ; *Antigens, Protozoan/immunology ; Immunoglobulin G/immunology/blood ; Protozoan Proteins/immunology ; Antibodies, Monoclonal/immunology ; Adult ; B-Lymphocytes/immunology ; Epitopes/immunology ; Female ; Mali ; Carrier Proteins/immunology ; Male ; Adolescent ; }, abstract = {Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) is the most advanced blood-stage malaria vaccine candidate and is being evaluated for efficacy in endemic regions, emphasizing the need to study the underlying antibody response to RH5 during natural infection, which could augment or counteract responses to vaccination. Here, we found that RH5-reactive B cells were rare, and circulating immunoglobulin G (IgG) responses to RH5 were short-lived in malaria-exposed Malian individuals, despite repeated infections over multiple years. RH5-specific monoclonal antibodies isolated from eight malaria-exposed individuals mostly targeted non-neutralizing epitopes, in contrast to antibodies isolated from five RH5-vaccinated, malaria-naive UK individuals. However, MAD8-151 and MAD8-502, isolated from two malaria-exposed Malian individuals, were among the most potent neutralizers out of 186 antibodies from both cohorts and targeted the same epitopes as the most potent vaccine-induced antibodies. These results suggest that natural malaria infection may boost RH5-vaccine-induced responses and provide a clear strategy for the development of next-generation RH5 vaccines.}, }
@article {pmid39058785, year = {2024}, author = {Wertman, RS and Yost, W and Herrmann, BI and Bourne, CM and Sorobetea, D and Go, CK and Saller, BS and Groß, O and Scott, P and Rongvaux, A and Taabazuing, CY and Brodsky, IE}, title = {Distinct sequential death complexes regulate pyroptosis and IL-1β release in response to Yersinia blockade of immune signaling.}, journal = {Science advances}, volume = {10}, number = {30}, pages = {eadl3629}, pmid = {39058785}, issn = {2375-2548}, support = {F31 AI172200/AI/NIAID NIH HHS/United States ; R00 AI148598/AI/NIAID NIH HHS/United States ; R01 AI128530/AI/NIAID NIH HHS/United States ; R01 AI139102/AI/NIAID NIH HHS/United States ; }, mesh = {*Pyroptosis ; *Interleukin-1beta/metabolism ; *Caspase 8/metabolism ; *Signal Transduction ; Animals ; *Caspase 1/metabolism ; *Inflammasomes/metabolism ; *Yersinia/metabolism ; *Phosphate-Binding Proteins/metabolism ; Mice ; Humans ; Bacterial Proteins/metabolism ; Intracellular Signaling Peptides and Proteins/metabolism ; Yersinia Infections/immunology/microbiology/metabolism ; Gasdermins ; }, abstract = {Pathogen infection of host cells triggers an inflammatory cell death termed pyroptosis via activation of inflammatory caspases. However, blockade of immune signaling kinases by the Yersinia virulence factor YopJ triggers cell death involving both apoptotic caspase-8 and pyroptotic caspase-1. While caspase-1 is normally activated within inflammasomes, Yersinia-induced caspase-1 activation is independent of known inflammasome components. We report that caspase-8 is an essential initiator, while caspase-1 is an essential amplifier of its own activation through two feed-forward loops involving caspase-1 auto-processing and caspase-1-dependent activation of gasdermin D and NLPR3. Notably, while Yersinia-induced caspase-1 activation and cell death are inflammasome-independent, IL-1β release requires NLPR3 inflammasome activation. Mechanistically, caspase-8 is rapidly activated within multiple foci throughout the cell, followed by assembly of a canonical inflammasome speck, indicating that caspase-8 and canonical inflammasome complex assemblies are kinetically and spatially distinct. Our findings reveal that functionally interconnected but distinct death complexes mediate pyroptosis and IL-1β release in response to pathogen blockade of immune signaling.}, }
@article {pmid39056362, year = {2024}, author = {Wen, J and Sun, Q and Huang, L and Zhou, L and Doyle, MF and Ekunwe, L and Durda, P and Olson, NC and Reiner, AP and Li, Y and Raffield, LM}, title = {Gene expression and splicing QTL analysis of blood cells in African American participants from the Jackson Heart Study.}, journal = {Genetics}, volume = {228}, number = {1}, pages = {}, pmid = {39056362}, issn = {1943-2631}, support = {HHSN268201800012C/HL/NHLBI NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; R01 HL129132/NH/NIH HHS/United States ; HHSN268201800014I/HB/NHLBI NIH HHS/United States ; T32 ES007018/ES/NIEHS NIH HHS/United States ; R01 AG075884/AG/NIA NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; R01 HL163972/HL/NHLBI NIH HHS/United States ; HHSN268201800014C/HL/NHLBI NIH HHS/United States ; HHSN268201800012I/HL/NHLBI NIH HHS/United States ; HHSN268201800011C/HL/NHLBI NIH HHS/United States ; HHSN268201800015I/HB/NHLBI NIH HHS/United States ; HHSN268201800010I/HB/NHLBI NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; HHSN268201800011I/HB/NHLBI NIH HHS/United States ; 5T32ES007018/GF/NIH HHS/United States ; HHSN268201100037C/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; HHSN268201800013I/MD/NIMHD NIH HHS/United States ; }, mesh = {*Quantitative Trait Loci ; Humans ; *Black or African American/genetics ; Alternative Splicing ; Male ; Gene Frequency ; Leukocytes, Mononuclear/metabolism ; Female ; Genome-Wide Association Study ; Polymorphism, Single Nucleotide ; }, abstract = {Most gene expression and alternative splicing quantitative trait loci (eQTL/sQTL) studies have been biased toward European ancestry individuals. Here, we performed eQTL and sQTL analyses using TOPMed whole-genome sequencing-derived genotype data and RNA-sequencing data from stored peripheral blood mononuclear cells in 1,012 African American participants from the Jackson Heart Study (JHS). At a false discovery rate of 5%, we identified 17,630 unique eQTL credible sets covering 16,538 unique genes; and 24,525 unique sQTL credible sets covering 9,605 unique genes, with lead QTL at P < 5e-8. About 24% of independent eQTLs and independent sQTLs with a minor allele frequency > 1% in JHS were rare (minor allele frequency < 0.1%), and therefore unlikely to be detected, in European ancestry individuals. Finally, we created an open database, which is freely available online, allowing fast query and bulk download of our QTL results.}, }
@article {pmid39055240, year = {2024}, author = {Rehwald, CM and Hippe, DS and Princing, T and Horneber, E and Sheehan, K and Cohen, W and Bresnahan, B}, title = {Spinal infection: Assessing comorbidities and costs to inform patient management and resource use strategies.}, journal = {North American Spine Society journal}, volume = {19}, number = {}, pages = {100335}, pmid = {39055240}, issn = {2666-5484}, abstract = {BACKGROUND: Spinal Infection (SI) is associated with various comorbidities. The interaction of these comorbidities and their impact on costs and complexity of care has not been fully assessed.<br><br>METHODS: This is a retrospective cohort study of SI patients in an urban hospital system to characterize comorbidities and outcomes in adult patients with SI. Adult patients in our hospital system who were hospitalized with an initial diagnosis of SI between July 1, 2017 and June 30, 2019 were included. Outcomes measures included length of stay (LOS) of the index hospitalization for SI, charges and payments for the index hospitalization, and hospital readmissions within one year after discharge from the index hospitalization. Data was obtained by querying our Electronic Data Warehouse (EDW) using ICD-10-CM and CPT procedure codes. Spearman's correlation was used to summarize the relationships between LOS, charges, and payments. Multivariable linear regression was used to evaluate associations of demographics, comorbidities, and other factors with LOS. Multivariable Cox regression was used to evaluate associations of demographics, comorbidities, and other factors with hospital readmissions.<br><br>RESULTS: 403 patients with a first diagnosis of SI were identified. The average number of comorbidities per patient was 1.3. 294 (73%) had at least 1 medical comorbidity, and 54 (13%) had 3 or more comorbidities. The most common medical comorbidities were diabetes mellitus (26%), intravenous drug use (IVDU, 26%), and malnutrition (20%). 112 patients (28%) had a surgical site infection (SSI). DM (p<.001) and SSI (p=.016) were more common among older patients while IVDU was more common among younger patients (p<.001). Median LOS was 12 days. A larger number of medical comorbidities was associated with a longer LOS (p<.001) while the presence of a SSI was associated with a shorter LOS (p=.007) after multivariable adjustment. LOS was positively correlated with both charges (r=0.83) and payments (r=0.61). Among 389 patients discharged after the index hospitalization, 36% had a readmission within 1 year. The rate of readmission was twice as high for patients with three or more comorbidities than patients with zero comorbidities (hazard ratio: 1.95, p=.017).<br><br>CONCLUSIONS: Patients with SI often have multiple comorbidities, and the specific type of comorbidity is associated with the patient's age. The presence of multiple comorbidities correlates with initial LOS, cost of care, and readmission rate. Readmission in the first year post-discharge is high.}, }
@article {pmid39054491, year = {2024}, author = {Necchi, A and Van der Heijden, MS and Trukhin, D and Peer, A and Gurney, H and Alekseev, BY and Parnis, FX and Leibowitz, R and De Santis, M and Grivas, P and Clark, J and Munteanu, M and Kataria, R and Jia, C and Balar, AV and de Wit, R}, title = {Pembrolizumab plus either epacadostat or placebo for cisplatin-ineligible urothelial carcinoma: results from the ECHO-307/KEYNOTE-672 study.}, journal = {BMC cancer}, volume = {23}, number = {Suppl 1}, pages = {1252}, pmid = {39054491}, issn = {1471-2407}, mesh = {Humans ; *Antibodies, Monoclonal, Humanized/therapeutic use/administration &amp; dosage/adverse effects ; Male ; Female ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Aged ; *Sulfonamides/therapeutic use/administration &amp; dosage/adverse effects ; *Cisplatin/therapeutic use/administration &amp; dosage/adverse effects ; Double-Blind Method ; Middle Aged ; Urologic Neoplasms/drug therapy/pathology ; Aged, 80 and over ; Carcinoma, Transitional Cell/drug therapy/pathology ; Adult ; Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists &amp; inhibitors/metabolism ; Oximes ; }, abstract = {BACKGROUND: Indoleamine 2,3- dioxygenase 1 (IDO1) is an immunosuppressive enzyme that has been correlated with shorter disease-specific survival in patients with urothelial carcinoma (UC). IDO1 may counteract the antitumor effects of immune checkpoint inhibitors. Epacadostat is a potent and highly selective inhibitor of IDO1. In the phase I/II ECHO-202/KEYNOTE-037 study, epacadostat plus pembrolizumab resulted in a preliminary objective response rate (ORR) of 35% in a cohort of patients with advanced UC.<br><br>METHODS: ECHO-307/KEYNOTE-672 was a double-blinded, randomized, phase III study. Eligible adults had confirmed locally advanced/unresectable or metastatic UC of the urinary tract and were ineligible to receive cisplatin-based chemotherapy. Participants were randomly assigned (1:1) to receive epacadostat (100&#xa0;mg twice daily) plus pembrolizumab (200&#xa0;mg every 3&#xa0;weeks) or placebo plus pembrolizumab for up to 35 pembrolizumab infusions. The primary endpoint was investigator-assessed ORR per Response Evaluation Criteria in Solid Tumors (version 1.1).<br><br>RESULTS: A total of 93 patients were randomized (epacadostat plus pembrolizumab, n&#x2009;=&#x2009;44; placebo plus pembrolizumab, n&#x2009;=&#x2009;49). Enrollment was stopped early due to emerging data from the phase III ECHO-301/KEYNOTE-252 study. The median duration of follow-up was 64&#xa0;days in both arms. Based on all available data at cutoff, ORR (unconfirmed) was 31.8% (95% CI, 22.46-55.24%) for epacadostat plus pembrolizumab and 24.5% (95% CI, 15.33-43.67%) for placebo plus pembrolizumab. Circulating kynurenine levels numerically increased from C1D1 to C2D1 in the placebo-plus-pembrolizumab arm and decreased in the epacadostat-plus-pembrolizumab arm. Epacadostat-plus-pembrolizumab combination treatment was well tolerated with a safety profile similar to the placebo arm. Treatment discontinuations due to treatment-related adverse events were more frequent with epacadostat (11.6% vs. 4.1%).<br><br>CONCLUSIONS: Treatment with epacadostat plus pembrolizumab resulted in a similar ORR and safety profile as placebo plus pembrolizumab in cisplatin-ineligible patients with previously untreated locally advanced/unresectable or metastatic UC. At a dose of 100&#xa0;mg twice daily, epacadostat did not appear to completely normalize circulating kynurenine levels when administered with pembrolizumab. Larger studies with longer follow-up and possibly testing higher doses of epacadostat, potentially in different therapy settings, may be warranted.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03361865, retrospectively registered December 5, 2017.}, }
@article {pmid39054323, year = {2024}, author = {Quintanal-Villalonga, A and Kawasaki, K and Redin, E and Uddin, F and Rakhade, S and Durani, V and Sabet, A and Shafer, M and Karthaus, WR and Zaidi, S and Zhan, YA and Manoj, P and Sridhar, H and Kinyua, D and Zhong, H and Mello, BP and Ciampricotti, M and Bhanot, UK and Linkov, I and Qiu, J and Patel, RA and Morrissey, C and Mehta, S and Barnes, J and Haffner, MC and Socci, ND and Koche, RP and de Stanchina, E and Molina-Pinelo, S and Salehi, S and Yu, HA and Chan, JM and Rudin, CM}, title = {CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation.}, journal = {Signal transduction and targeted therapy}, volume = {9}, number = {1}, pages = {189}, pmid = {39054323}, issn = {2059-3635}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; NA//Yasuda Memorial Medical Foundation (Yasuda Medical Foundation)/ ; }, mesh = {Humans ; Male ; *Cell Cycle Proteins/genetics/metabolism ; *Prostatic Neoplasms/genetics/pathology/metabolism/drug therapy ; *Lung Neoplasms/genetics/pathology/metabolism/drug therapy ; *Proto-Oncogene Proteins c-myc/genetics/metabolism ; Cell Transformation, Neoplastic/genetics/metabolism ; Cell Line, Tumor ; Protein Serine-Threonine Kinases/genetics/metabolism/antagonists &amp; inhibitors ; Tumor Suppressor Protein p53/genetics/metabolism ; Mice ; Animals ; Neuroendocrine Tumors/genetics/pathology/metabolism/drug therapy ; Proteolysis/drug effects ; Retinoblastoma Binding Proteins/genetics/metabolism ; Ubiquitin-Protein Ligases ; }, abstract = {Neuroendocrine (NE) transformation is a mechanism of resistance to targeted therapy in lung and prostate adenocarcinomas leading to poor prognosis. Up to date, even if patients at high risk of transformation can be identified by the occurrence of Tumor Protein P53 (TP53) and Retinoblastoma Transcriptional Corepressor 1 (RB1) mutations in their tumors, no therapeutic strategies are available to prevent or delay histological transformation. Upregulation of the cell cycle kinase Cell Division Cycle 7 (CDC7) occurred in tumors during the initial steps of NE transformation, already after TP53/RB1 co-inactivation, leading to induced sensitivity to the CDC7 inhibitor simurosertib. CDC7 inhibition suppressed NE transdifferentiation and extended response to targeted therapy in in vivo models of NE transformation by inducing the proteasome-mediated degradation of the MYC Proto-Oncogen (MYC), implicated in stemness and histological transformation. Ectopic overexpression of a degradation-resistant MYC isoform reestablished the NE transformation phenotype observed on targeted therapy, even in the presence of simurosertib. CDC7 inhibition also markedly extended response to standard cytotoxics (cisplatin, irinotecan) in lung and prostate small cell carcinoma models. These results nominate CDC7 inhibition as a therapeutic strategy to constrain lineage plasticity, as well as to effectively treat NE tumors de novo or after transformation. As simurosertib clinical efficacy trials are ongoing, this concept could be readily translated for patients at risk of transformation.}, }
@article {pmid39054321, year = {2024}, author = {Greenlee, H and Rillamas-Sun, E and Yung, RL and Cobos, S and Donzella, SM and Huang, Y and Schattenkerk, L and Ueland, K and VanDoren, M and Myers, SA and Garcia, G and King, T and Santiago-Torres, M and Di, C and Dey, N and Guthrie, KA and Davidson, NE}, title = {Cook and Move for Your Life, an eHealth intervention for women with breast cancer.}, journal = {NPJ breast cancer}, volume = {10}, number = {1}, pages = {62}, pmid = {39054321}, issn = {2374-4677}, support = {BCRF 20-035//Carol M. Baldwin Breast Cancer Research Fund (Carol M. Baldwin Breast Cancer Research Fund, Inc.)/ ; NIH P30CA01574//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; }, abstract = {We tested the feasibility and preliminary efficacy of an online diet and physical activity program for women with early-stage breast cancer who had completed surgery, chemotherapy, and radiation therapy (ongoing endocrine therapy allowed). Participants with low fruit and vegetable (F/V) consumption and/or low moderate-to-vigorous physical activity (MVPA) levels were randomized to one of two doses - low (one Zoom group session) or high (12 Zoom group sessions) - of an online lifestyle program with the goal of improving F/V intake and MVPA. All participants received eHealth communications (text messages, study website access), a Fitbit, and a WiFi-enabled scale. Primary objectives evaluated feasibility. Secondary objectives compared the 6-month change in F/V intake and MVPA between the two dose groups. Seventy-four women (mean age = 58.4 years; 87% non-Hispanic White; mean time since diagnosis = 4.6 years) were accrued. Among women in the low dose group, 94% attended the single session; among women in the high dose group, 84% attended at least 8 of the 12 sessions. Retention at 6 months was 93%. High relative to low dose participants consumed 1.5 more servings/day of F/V at 6 months (P = 0.007) but MVPA levels did not differ between groups. We successfully implemented an online lifestyle program for early-stage breast cancer survivors. The high dose intervention demonstrated preliminary efficacy in improving F/V consumption in early-stage breast cancer survivors. Future trials can test the intervention in a larger and more diverse population of breast cancer survivors.}, }
@article {pmid39053946, year = {2024}, author = {Akaike, T and Jabbour, AJ and Goff, PH and Park, SY and Bhatia, S and Nghiem, P}, title = {Merkel cell carcinoma refractory to anti-PD(L)1: utility of adding ipilimumab for salvage therapy.}, journal = {Journal for immunotherapy of cancer}, volume = {12}, number = {7}, pages = {}, pmid = {39053946}, issn = {2051-1426}, support = {P01 CA225517/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Ipilimumab/therapeutic use ; *Carcinoma, Merkel Cell/drug therapy ; *Salvage Therapy/methods ; Male ; Female ; Skin Neoplasms/drug therapy ; Aged ; Immune Checkpoint Inhibitors/therapeutic use/pharmacology/adverse effects ; Middle Aged ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Aged, 80 and over ; Retrospective Studies ; }, abstract = {Merkel cell carcinoma (MCC) incidence has risen to approximately 3,000 cases annually in the USA. Although anti-programmed cell death (ligand) 1 (PD-(L)1) agents are now the first-line treatment for advanced MCC, approximately 50% of such patients do not persistently benefit. In PD-(L)1-refractory cases, ipilimumab (anti-cytotoxic T lymphocyte antigen-4) is often added; however, the extent of the clinical benefit of this combination is controversial. We identified one prospective study, three retrospective studies, and three case reports regarding this combination in refractory MCC. The aggregate response rate from retrospective studies was 32% (13 of 41 patients) with 4 complete responses (CR) and 9 partial responses (PR). In the prospective study, the response rate was very similar at 31% (8 of 26 patients; 4 CR, 4 PR). Response durability was highly variable (range 2 to >43 months), with patients achieving CR having greater durability. Immune-related adverse events (irAEs) were ≥grade III in 29% (retrospective cohort, N=41) and 36% (prospective cohort, N=50). While these aggregate data indicate adding ipilimumab should be considered in this setting, many patients with refractory MCC are ineligible due to comorbidities/irAEs, and approximately 70% will not benefit from this regimen. There is thus a significant unmet need in PD-(L)1-refractory MCC and clinical trials in this setting should be encouraged.}, }
@article {pmid39053567, year = {2024}, author = {He, Q and Zhang, S and LeBlanc, ML and Zhao, YQ}, title = {Estimating individualized treatment rules by optimizing the adjusted probability of a longer survival.}, journal = {Statistical methods in medical research}, volume = {33}, number = {9}, pages = {1517-1530}, doi = {10.1177/09622802241262525}, pmid = {39053567}, issn = {1477-0334}, mesh = {Humans ; *Precision Medicine/statistics &amp; numerical data ; Survival Analysis ; *Probability ; Models, Statistical ; Proportional Hazards Models ; Computer Simulation ; }, abstract = {Individualized treatment rules inform tailored treatment decisions based on the patient's information, where the goal is to optimize clinical benefit for the population. When the clinical outcome of interest is survival time, most of current approaches typically aim to maximize the expected time of survival. We propose a new criterion for constructing Individualized treatment rules that optimize the clinical benefit with survival outcomes, termed as the adjusted probability of a longer survival. This objective captures the likelihood of living longer with being on treatment, compared to the alternative, which provides an alternative and often straightforward interpretation to communicate with clinicians and patients. We view it as an alternative to the survival analysis standard of the hazard ratio and the increasingly used restricted mean survival time. We develop a new method to construct the optimal Individualized treatment rule by maximizing a nonparametric estimator of the adjusted probability of a longer survival for a decision rule. Simulation studies demonstrate the reliability of the proposed method across a range of different scenarios. We further perform data analysis using data collected from a randomized Phase III clinical trial (SWOG S0819).}, }
@article {pmid39052958, year = {2024}, author = {Akaike, T and Thakuria, M and Silk, AW and Hippe, DS and Park, SY and So, NA and Maloney, NJ and Gunnell, L and Eschholz, A and Kim, EY and Sinha, S and Hall, ET and Bhatia, S and Reddy, S and Rodriguez, AA and Aleshin, A and Choi, JS and Tsai, KY and Yom, SS and Yu, SS and Choi, J and Chandra, S and Nghiem, P and Zaba, LC}, title = {Circulating Tumor DNA Assay Detects Merkel Cell Carcinoma Recurrence, Disease Progression, and Minimal Residual Disease: Surveillance and Prognostic Implications.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {42}, number = {26}, pages = {3151-3161}, pmid = {39052958}, issn = {1527-7755}, mesh = {Humans ; *Carcinoma, Merkel Cell/blood/genetics/pathology ; Male ; Female ; *Circulating Tumor DNA/blood/genetics ; Aged ; *Neoplasm Recurrence, Local/genetics/blood/diagnosis ; *Skin Neoplasms/blood/genetics/pathology/diagnosis ; Prospective Studies ; Middle Aged ; *Disease Progression ; Prognosis ; Aged, 80 and over ; *Neoplasm, Residual ; Biomarkers, Tumor/blood/genetics ; Adult ; }, abstract = {PURPOSE: Merkel cell carcinoma (MCC) is an aggressive skin cancer with a 40% recurrence rate, lacking effective prognostic biomarkers and surveillance methods. This prospective, multicenter, observational study aimed to evaluate circulating tumor DNA (ctDNA) as a biomarker for detecting MCC recurrence.<br><br>METHODS: Plasma samples, clinical data, and imaging results were collected from 319 patients. A tumor-informed ctDNA assay was used for analysis. Patients were divided into discovery (167 patients) and validation (152 patients) cohorts. Diagnostic performance, including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), was assessed.<br><br>RESULTS: ctDNA showed high sensitivity, 95% (discovery; 95% CI, 87 to 99) and 94% (validation; 95% CI, 85 to 98), for detecting disease at enrollment, with corresponding specificities of 90% (95% CI, 82 to 95) and 86% (95% CI, 77 to 93). A positive ctDNA during surveillance indicated increased recurrence risk, with hazard ratios (HRs) of 6.8 (discovery; 95% CI, 2.9 to 16) and 20 (validation; 95% CI, 8.3 to 50). The PPV for clinical recurrence at 1 year after a positive ctDNA test was 69% (discovery; 95% CI, 32 to 91) and 94% (validation; 95% CI, 71 to 100), respectively. The NPV at 135 days after a negative ctDNA test was 94% (discovery; 95% CI, 90 to 97) and 93% (validation; 95% CI, 89 to 97), respectively. Patients positive for ctDNA within 4 months after treatment had higher rates of recurrence, with 1-year rates of 74% versus 21% (adjusted HR, 7.4 [95% CI, 2.7 to 20]).<br><br>CONCLUSION: ctDNA testing exhibited high prognostic accuracy in detecting MCC recurrence, suggesting its potential to reduce frequent surveillance imaging. ctDNA also identifies high-risk patients who need more frequent imaging and may be best suited for adjuvant therapy trials.}, }
@article {pmid39052736, year = {2024}, author = {Munch, MM and Strenk, SM and Srinivasan, S and Fiedler, TL and Proll, S and Fredricks, DN}, title = {Gardnerella Species and Their Association With Bacterial Vaginosis.}, journal = {The Journal of infectious diseases}, volume = {230}, number = {1}, pages = {e171-e181}, pmid = {39052736}, issn = {1537-6613}, support = {R01 AI061628/AI/NIAID NIH HHS/United States ; R01 AI061628/NH/NIH HHS/United States ; }, mesh = {Humans ; *Vaginosis, Bacterial/microbiology ; Female ; Adult ; *Gardnerella/isolation &amp; purification/genetics ; Young Adult ; Vagina/microbiology ; Washington/epidemiology ; Gardnerella vaginalis/isolation &amp; purification/genetics ; Gram-Positive Bacterial Infections/microbiology ; Adolescent ; Prevalence ; Middle Aged ; DNA, Bacterial/genetics ; Chaperonin 60/genetics ; Real-Time Polymerase Chain Reaction ; }, abstract = {BACKGROUND: Bacterial vaginosis (BV) is a condition marked by high vaginal bacterial diversity. Gardnerella vaginalis has been implicated in BV but is also detected in healthy women. The Gardnerella genus has been expanded to encompass 6 validly named species and several genomospecies. We hypothesized that particular Gardnerella species may be more associated with BV.<br><br>METHODS: Quantitative polymerase chain reaction (PCR) assays were developed targeting the cpn60 gene of species groups including G. vaginalis, G. piotii/pickettii, G. swidsinskii/greenwoodii, and G. leopoldii. These assays were applied to vaginal swabs from individuals with (n = 101) and without BV (n = 150) attending a sexual health clinic in Seattle, Washington. Weekly swabs were collected from 42 participants for up to 12 weeks.<br><br>RESULTS: Concentrations and prevalence of each Gardnerella species group were significantly higher in participants with BV; 91.1% of BV-positive participants had 3 or more Gardnerella species groups detected compared to 32.0% of BV-negative participants (P < .0001). BV-negative participants with 3 or more species groups detected were more likely to develop BV within 100 days versus those with fewer (60.5% vs 3.7%, P < .0001).<br><br>CONCLUSIONS: These results suggest that BV reflects a state of high Gardnerella species diversity. No Gardnerella species group was a specific marker for BV.}, }
@article {pmid39052420, year = {2024}, author = {Carlson, LE and Tripathy, D and Zick, SM and Balneaves, LG and Lee, RT and Greenlee, H}, title = {The Society for Integrative Oncology-American Society of Clinical Oncology Joint Guidelines on Integrative Therapies for Symptom Management-Overview and Key Recommendations.}, journal = {Journal of integrative and complementary medicine}, volume = {30}, number = {7}, pages = {596-601}, doi = {10.1089/jicm.2024.0452}, pmid = {39052420}, issn = {2768-3613}, mesh = {Humans ; *Integrative Oncology/methods ; *Neoplasms/therapy ; Societies, Medical ; Complementary Therapies/methods ; United States ; Integrative Medicine/methods ; Medical Oncology/methods ; Practice Guidelines as Topic ; }, }
@article {pmid39052387, year = {2024}, author = {Moorthi, S and Paguirigan, A and Itagi, P and Ko, M and Pettinger, M and Hoge, AC and Nag, A and Patel, NA and Wu, F and Sather, C and Levine, KM and Fitzgibbon, MP and Thorner, AR and Anderson, GL and Ha, G and Berger, AH}, title = {The genomic landscape of lung cancer in never-smokers from the Women's Health Initiative.}, journal = {JCI insight}, volume = {9}, number = {17}, pages = {}, pmid = {39052387}, issn = {2379-3708}, support = {R37 CA252050/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; T32 CA009515/CA/NCI NIH HHS/United States ; R01 CA284585/CA/NCI NIH HHS/United States ; K22 CA237746/CA/NCI NIH HHS/United States ; R01 CA262556/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Lung Neoplasms/genetics/epidemiology ; Aged ; Middle Aged ; *Mutation ; Smoking/genetics/epidemiology/adverse effects ; Women's Health ; Adenocarcinoma of Lung/genetics/epidemiology ; Non-Smokers/statistics &amp; numerical data ; Genomics/methods ; DNA Copy Number Variations ; United States/epidemiology ; ErbB Receptors/genetics ; Exome Sequencing ; Proto-Oncogene Proteins p21(ras)/genetics ; Smokers/statistics &amp; numerical data ; }, abstract = {Over 200,000 individuals are diagnosed with lung cancer in the United States every year, with a growing proportion of cases, especially lung adenocarcinoma, occurring in individuals who have never smoked. Women over the age of 50 comprise the largest affected demographic. To understand the genomic drivers of lung adenocarcinoma and therapeutic response in this population, we performed whole genome and/or whole exome sequencing on 73 matched lung tumor/normal pairs from postmenopausal women who participated in the Women's Health Initiative. Somatic copy number alterations showed little variation by smoking status, suggesting that aneuploidy may be a general characteristic of lung cancer regardless of smoke exposure. Similarly, clock-like and APOBEC mutation signatures were prevalent but did not differ in tumors from smokers and never-smokers. However, mutations in both EGFR and KRAS showed unique allelic differences determined by smoking status that are known to alter tumor response to targeted therapy. Mutations in the MYC-network member MGA were more prevalent in tumors from smokers. Fusion events in ALK, RET, and ROS1 were absent, likely due to age-related differences in fusion prevalence. Our work underscores the profound effect of smoking status, age, and sex on the tumor mutational landscape and identifies areas of unmet medical need.}, }
@article {pmid39052289, year = {2024}, author = {Phelan, EA and Williamson, BD and Balderson, BH and Cook, AJ and Piccorelli, AV and Fujii, MM and Nakata, KG and Graham, VF and Theis, MK and Turner, JP and Tannenbaum, C and Gray, SL}, title = {Reducing Central Nervous System-Active Medications to Prevent Falls and Injuries Among Older Adults: A Cluster Randomized Clinical Trial.}, journal = {JAMA network open}, volume = {7}, number = {7}, pages = {e2424234}, pmid = {39052289}, issn = {2574-3805}, mesh = {Humans ; *Accidental Falls/prevention &amp; control/statistics &amp; numerical data ; Female ; Male ; Aged ; Deprescriptions ; Middle Aged ; Central Nervous System Agents/therapeutic use ; Aged, 80 and over ; Washington ; Primary Health Care ; Wounds and Injuries/prevention &amp; control ; }, abstract = {IMPORTANCE: High-risk medications that contribute to adverse health outcomes are frequently prescribed to older adults. Deprescribing interventions reduce their use, but studies are often not designed to examine effects on patient-relevant health outcomes.<br><br>OBJECTIVE: To test the effect of a health system-embedded deprescribing intervention targeting older adults and their primary care clinicians for reducing the use of central nervous system-active drugs and preventing medically treated falls.<br><br>In this cluster randomized, parallel-group, clinical trial, 18 primary care practices from an integrated health care delivery system in Washington state were recruited from April 1, 2021, to June 16, 2022, to participate, along with their eligible patients. Randomization occurred at the clinic level. Patients were community-dwelling adults aged 60 years or older, prescribed at least 1 medication from any of 5 targeted medication classes (opioids, sedative-hypnotics, skeletal muscle relaxants, tricyclic antidepressants, and first-generation antihistamines) for at least 3 consecutive months.<br><br>INTERVENTION: Patient education and clinician decision support. Control arm participants received usual care.<br><br>MAIN OUTCOMES AND MEASURES: The primary outcome was medically treated falls. Secondary outcomes included medication discontinuation, sustained medication discontinuation, and dose reduction of any and each target medication. Serious adverse drug withdrawal events involving opioids or sedative-hypnotics were the main safety outcome. Analyses were conducted using intent-to-treat analysis.<br><br>RESULTS: Among 2367 patient participants (mean [SD] age, 70.6 [7.6] years; 1488 women [63%]), the adjusted cumulative incidence rate of a first medically treated fall at 18 months was 0.33 (95% CI, 0.29-0.37) in the intervention group and 0.30 (95% CI, 0.27-0.34) in the usual care group (estimated adjusted hazard ratio, 1.11 (95% CI, 0.94-1.31) (P&#x2009;=&#x2009;.11). There were significant differences favoring the intervention group in discontinuation, sustained discontinuation, and dose reduction of tricyclic antidepressants at 6 months (discontinuation adjusted rate: intervention group, 0.23 [95% CI, 0.18-0.28] vs usual care group, 0.13 [95% CI, 0.09-0.17]; adjusted relative risk, 1.79 [95% CI, 1.29-2.50]; P&#x2009;=&#x2009;.001) and secondary time points (9, 12, and 15 months).<br><br>CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of a health system-embedded deprescribing intervention targeting community-dwelling older adults prescribed central nervous system-active medications and their primary care clinicians, the intervention was no more effective than usual care in reducing medically treated falls. For health systems that attend to deprescribing as part of routine clinical practice, additional interventions may confer modest benefits on prescribing without a measurable effect on clinical outcomes.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05689554.}, }
@article {pmid39052272, year = {2024}, author = {Scott, BL}, title = {Change is not always good.}, journal = {Blood}, volume = {144}, number = {4}, pages = {355-357}, doi = {10.1182/blood.2024024824}, pmid = {39052272}, issn = {1528-0020}, }
@article {pmid39052257, year = {2024}, author = {Cheng, HH and Shevach, JW and Castro, E and Couch, FJ and Domchek, SM and Eeles, RA and Giri, VN and Hall, MJ and King, MC and Lin, DW and Loeb, S and Morgan, TM and Offit, K and Pritchard, CC and Schaeffer, EM and Szymaniak, BM and Vassy, JL and Katona, BW and Maxwell, KN}, title = {BRCA1, BRCA2, and Associated Cancer Risks and Management for Male Patients: A Review.}, journal = {JAMA oncology}, volume = {10}, number = {9}, pages = {1272-1281}, doi = {10.1001/jamaoncol.2024.2185}, pmid = {39052257}, issn = {2374-2445}, support = {I01 CX002635/CX/CSRD VA/United States ; I01 HX003627/HX/HSRD VA/United States ; T32 HG009495/HG/NHGRI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Genetic Predisposition to Disease ; *BRCA2 Protein/genetics ; *BRCA1 Protein/genetics ; Risk Factors ; Genetic Testing ; Neoplasms/genetics/epidemiology ; Breast Neoplasms, Male/genetics/therapy ; Early Detection of Cancer ; Germ-Line Mutation ; Risk Assessment ; }, abstract = {IMPORTANCE: Half of all carriers of inherited cancer-predisposing variants in BRCA1 and BRCA2 are male, but the implications for their health are underrecognized compared to female individuals. Germline variants in BRCA1 and BRCA2 (also known as pathogenic or likely pathogenic variants, referred to here as BRCA1/2 PVs) are well known to significantly increase the risk of breast and ovarian cancers in female carriers, and knowledge of BRCA1/2 PVs informs established cancer screening and options for risk reduction. While risks to male carriers of BRCA1/2 PVs are less characterized, there is convincing evidence of increased risk for prostate cancer, pancreatic cancer, and breast cancer in males. There has also been a rapid expansion of US Food and Drug Administration-approved targeted cancer therapies, including poly ADP ribose polymerase (PARP) inhibitors, for breast, pancreatic, and prostate cancers associated with BRCA1/2 PVs.<br><br>OBSERVATIONS: This narrative review summarized the data that inform cancer risks, targeted cancer therapy options, and guidelines for early cancer detection. It also highlighted areas of emerging research and clinical trial opportunities for male BRCA1/2 PV carriers. These developments, along with the continued relevance to family cancer risk and reproductive options, have informed changes to guideline recommendations for genetic testing and strengthened the case for increased genetic testing for males.<br><br>CONCLUSIONS AND RELEVANCE: Despite increasing clinical actionability for male carriers of BRCA1/2 PVs, far fewer males than female individuals undergo cancer genetic testing. Oncologists, internists, and primary care clinicians should be vigilant about offering appropriate genetic testing to males. Identifying more male carriers of BRCA1/2 PVs will maximize opportunities for cancer early detection, targeted risk management, and cancer treatment for males, along with facilitating opportunities for risk reduction and prevention in their family members, thereby decreasing the burden of hereditary cancer.}, }
@article {pmid39052225, year = {2024}, author = {Whiteaker, JR and Zhao, L and Kennedy, JJ and Ivey, RG and Paulovich, AG}, title = {Targeted Mass Spectrometry for Quantification of Receptor Tyrosine Kinase Signaling.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2823}, number = {}, pages = {253-267}, pmid = {39052225}, issn = {1940-6029}, support = {R01 CA235575/CA/NCI NIH HHS/United States ; R50 CA211499/CA/NCI NIH HHS/United States ; U01 CA214114/CA/NCI NIH HHS/United States ; U01 CA271407/CA/NCI NIH HHS/United States ; }, mesh = {*Proteomics/methods ; Humans ; *Signal Transduction ; *Mass Spectrometry/methods ; Receptor Protein-Tyrosine Kinases/metabolism ; Isotope Labeling/methods ; Phosphorylation ; Phosphopeptides/metabolism/analysis ; Protein Processing, Post-Translational ; Tandem Mass Spectrometry/methods ; }, abstract = {Targeted proteomics enables sensitive and specific quantification of proteins and post-translational modifications. By coupling peptide immunoaffinity enrichment with targeted mass spectrometry, we have developed the methodology for multiplexed quantification of proteins and phosphosites involved in the RAS/MAPK signaling network. The method uses anti-peptide antibodies to enrich analytes and heavy stable isotope-labeled internal standards, spiked in at known concentrations. The enriched peptides are directly measured by multiple-reaction monitoring (MRM), a well-characterized quantitative mass spectrometry-based method. The analyte (light) peptide response is measured relative to the heavy standard. The method described provides quantitative measurements of phospho-signaling and is generally applicable to other phosphopeptides and sample types.}, }
@article {pmid39052199, year = {2024}, author = {Young, AM and Stoner, MCD and Mathebula, F and Mohuba, R and Baez, A and Seyama, L and Mutero, P and Etima, J and Fabiano, Z and Fairlie, L and Mayo, AJ and Balkus, JE and Song, M and Bunge, K and Piper, J and Balan, IC and van der Straten, A and Montgomery, ET}, title = {Acceptability of the Dapivirine Vaginal Ring and Daily Oral Pre-exposure Prophylaxis (PrEP) during Pregnancy in Malawi, South Africa, Uganda, and Zimbabwe.}, journal = {AIDS and behavior}, volume = {28}, number = {11}, pages = {3615-3628}, pmid = {39052199}, issn = {1573-3254}, support = {U01 AI069463/AI/NIAID NIH HHS/United States ; U01 AI068632/AI/NIAID NIH HHS/United States ; UM1AI068615//Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ ; UM1 AI106707/AI/NIAID NIH HHS/United States ; UM1AI106707//Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ ; UM1AI068633//Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ ; }, mesh = {Humans ; Female ; Pregnancy ; *Pre-Exposure Prophylaxis/methods ; *HIV Infections/prevention &amp; control ; Adult ; *Contraceptive Devices, Female ; *Anti-HIV Agents/administration &amp; dosage/therapeutic use ; *Pyrimidines/administration &amp; dosage ; *Qualitative Research ; *Patient Acceptance of Health Care ; Malawi ; Pregnancy Complications, Infectious/prevention &amp; control ; Uganda ; Interviews as Topic ; Zimbabwe ; South Africa ; Administration, Oral ; Young Adult ; Adolescent ; Administration, Intravaginal ; Sexual Behavior ; }, abstract = {Pregnant and lactating persons in sub-Saharan Africa face a heightened risk of HIV acquisition, due to biological and behavioral factors, combined with limited access to prevention and treatment services. Oral pre-exposure prophylaxis (PrEP) and the dapivirine vaginal ring are promising tools for HIV prevention, and the ring's recent approval in multiple African countries represents a significant advancement in expanding access to HIV prevention. In a nested qualitative study within the MTN-042 trial, we explored the acceptability of study products among pregnant persons in the second and early third trimesters. Interviews were conducted privately, using a semi-structured guide with 77 participants, in participants' preferred language. Topics explored included product acceptability (using the theoretical framework of acceptability), user experience, satisfaction, disclosure, community attitudes, and sexual activity during pregnancy. Interview transcripts were analyzed using Dedoose software. We observed positive attitudes among participants towards the study products, which they found generally user-friendly, despite the added complexities of using them during pregnancy. Participants recognized that consistent and correct use would provide protection for both them and their unborn children. Although initial concerns existed, most of these worries dissipated over time, with study staff support and increased product use experience. These findings emphasize the importance of continued surveillance, support, and education to ensure the successful rollout of new HIV prevention measures during pregnancy.}, }
@article {pmid39049159, year = {2024}, author = {Ghosh, N and Manzoor, BS and Fakhri, B and Emechebe, N and Alhasani, H and Skarbnik, A and Jawaid, D and Shadman, M}, title = {Real-world comparative effectiveness of venetoclax-obinutuzumab versus Bruton tyrosine kinase inhibitors for frontline chronic lymphocytic leukaemia.}, journal = {British journal of haematology}, volume = {205}, number = {4}, pages = {1395-1403}, doi = {10.1111/bjh.19613}, pmid = {39049159}, issn = {1365-2141}, support = {//AbbVie, Inc./ ; }, mesh = {Humans ; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/mortality ; *Bridged Bicyclo Compounds, Heterocyclic/therapeutic use/administration &amp; dosage ; *Sulfonamides/therapeutic use/administration &amp; dosage ; Male ; Aged ; Female ; *Agammaglobulinaemia Tyrosine Kinase/antagonists &amp; inhibitors ; Middle Aged ; Retrospective Studies ; *Antibodies, Monoclonal, Humanized/therapeutic use/administration &amp; dosage ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; *Protein Kinase Inhibitors/therapeutic use/administration &amp; dosage ; Aged, 80 and over ; Treatment Outcome ; Adult ; Tyrosine Kinase Inhibitors ; }, abstract = {Real-world evidence comparing clinical outcomes between venetoclax and Bruton tyrosine kinase inhibitors (BTKis) in patients with frontline (1 L) chronic lymphocytic leukaemia (CLL) is lacking. We compared treatment effectiveness of 1 L venetoclax plus obinutuzumab (VenO) versus BTKi-based regimens. This retrospective observational study using Optum Clinformatics Data Mart® included adult patients with CLL (≥2 outpatient or ≥1 inpatient claim) who received VenO or BTKi-based regimens in 1 L (1/2019-9/2022). Baseline characteristics were balanced using stabilised inverse probability weighting. Outcomes included duration of therapy (DoT), persistence, time to next treatment or death (TTNT-D), and time off-treatment. Among 1506 eligible patients (VenO: 203; BTKi: 1303), the median follow-up duration was 12.6 (VenO) and 16.2 months (BTKi). Median DoT for VenO was 12.3 months; persistence remained higher in VenO versus BTKi through expected 1 L fixed treatment duration. Median TTNT-D was not reached for VenO; however, more VenO- versus BTKi-treated patients had not switched therapies/experienced death through Month 12 (87.1% vs. 75.3%). Among patients that discontinued, median time to discontinuation was 11.7 vs. 5.9 months for VenO versus BTKi and median time off-treatment was 11.3 vs. 4.3 months. In this real-world study, VenO was associated with better effectiveness outcomes than BTKi-based regimens in 1 L CLL.}, }
@article {pmid39048762, year = {2024}, author = {Raber-Durlacher, JE and Treister, NS and Zadik, Y and Dean, DR and Miranda-Silva, W and Fregnani, ER and Epstein, JB and Elad, S}, title = {MASCC/ISOO Clinical Practice Statement: The risk of secondary oral cancer following hematopoietic cell transplantation.}, journal = {Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer}, volume = {32}, number = {8}, pages = {545}, pmid = {39048762}, issn = {1433-7339}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects/methods ; *Mouth Neoplasms/etiology ; *Graft vs Host Disease/etiology ; Risk Factors ; Carcinoma, Squamous Cell/etiology ; Neoplasms, Second Primary/etiology ; }, abstract = {PURPOSE: A MASCC/ISOO Clinical Practice Statement (CPS) is aimed at generating a concise tool for clinicians that concentrates practical information needed for the management of oral complications of cancer patients. This CPS is focused on the risk of secondary oral cancer following hematopoietic cell transplantation (HCT).<br><br>METHODS: This CPS was developed based on critical evaluation of the literature followed by a structured discussion of a group of leading experts, members of the Oral Care Study Group of MASCC/ISOO. The information is presented in the form of succinct bullets to generate a short manual about the best standard of care.<br><br>RESULTS: Studies described a 7-16-fold higher risk of secondary oral cancer (mainly squamous cell carcinoma) in allogeneic HCT (alloHCT) recipients, particularly in those who developed chronic graft versus host disease (cGVHD). Risk increases over time and is influenced by several risk factors. In autologous HCT, oral cancer risk seemed only slightly elevated.<br><br>CONCLUSION: Clinicians should be aware of the higher oral cancer risk in alloHCT survivors, and emphasize the importance of lifelong oral cancer surveillance (at least every 6-12 months) and avoiding cancer promoting lifestyle factors in an empathic way, particularly of those with (a history of) cGVHD. Post-HCT for Fanconi anemia or dyskeratosis congenita, education and rigorous follow-up is even more crucial. In case of suspected oral lesions in the presence of oral mucosal cGVHD, a GVHD intervention may facilitate diagnosis. Suspected lesions should be biopsied. More research is needed on the role of HPV in oral cancer post-HCT.}, }
@article {pmid39046350, year = {2024}, author = {Landovitz, RJ and Delany-Moretlwe, S and Fogel, JM and Marzinke, MA and Piwowar-Manning, E and Richardson, P and Halvas, EK and Mellors, JW and Persaud, D and Kofron, R and McCauley, M and Rose, S and Rinehart, AR and Rooney, JF and Adeyeye, A and Cohen, MS and Donnell, D and Hosseinipour, MC and Grinsztejn, B and Eshleman, SH and , }, title = {Features of HIV Infection in the Context of Long-Acting Cabotegravir Preexposure Prophylaxis.}, journal = {The New England journal of medicine}, volume = {391}, number = {13}, pages = {1253-1256}, pmid = {39046350}, issn = {1533-4406}, support = {U01 AI068619/AI/NIAID NIH HHS/United States ; UM1 AI069424/AI/NIAID NIH HHS/United States ; U01 AI069463/AI/NIAID NIH HHS/United States ; UM1 AI068619/AI/NIAID NIH HHS/United States ; UM1 AI068613/AI/NIAID NIH HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; }, }
@article {pmid39046263, year = {2024}, author = {Nelson, GW and van Duijn, J and Yuki, Y and Pau, MG and Tomaka, F and Lavreys, L and DeRosa, SC and McElrath, MJ and Kirk, GD and Michael, NL and Haas, DW and Deeks, SG and Wolinsky, S and Walker, B and Barouch, DH and Stieh, D and Carrington, M}, title = {Prediction of differential Gag versus Env responses to a mosaic HIV-1 vaccine regimen by HLA class I alleles.}, journal = {Journal of virology}, volume = {98}, number = {8}, pages = {e0028124}, pmid = {39046263}, issn = {1098-5514}, support = {75N91019D00024/CA/NCI NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *AIDS Vaccines/immunology/administration &amp; dosage ; *HIV-1/immunology/genetics ; *HIV Infections/immunology/virology/genetics/prevention &amp; control ; *gag Gene Products, Human Immunodeficiency Virus/immunology/genetics ; *env Gene Products, Human Immunodeficiency Virus/immunology/genetics ; *Alleles ; Histocompatibility Antigens Class I/immunology/genetics ; Male ; Viral Load ; Adult ; Female ; CD8-Positive T-Lymphocytes/immunology ; }, abstract = {HLA class I variation has the strongest effect genome-wide on outcome after HIV infection, and as such, an understanding of the impact of HLA polymorphism on response to HIV vaccination may inform vaccine design. We sought HLA associations with HIV-directed immunogenicity in the phase 1/2a APPROACH vaccine trial, which tested vaccine regimens containing mosaic inserts in Ad26 and MVA vectors, with or without a trimeric gp140 protein. While there were no HLA allelic associations with the overall cellular immune response to the vaccine assessed by ELISpot (Gag, Pol, and Env combined), significant associations with differential response to Gag compared to Env antigens were observed. Notably, HLA class I alleles known to associate with disease susceptibility in HIV natural history cohorts are associated with stronger Env-directed responses, whereas protective alleles are associated with stronger Gag-directed responses. Mean viral loads determined for each HLA allele in untreated individuals correlated negatively with the strength of the Gag response minus the Env response in Black vaccinees based on both ELISpot and CD8[+] T cell ICS responses. As the association of T cell responses to conserved Gag epitopes with lower viral load in untreated individuals is well established, our data raise the possibility that the Ad26.Mos.HIV vaccine may induce more effective cellular responses in those with HLA alleles that confer improved virologic control in untreated HIV infection.IMPORTANCENo vaccine tested to date has shown sufficient efficacy against HIV infection. A vaccine that induces robust responses in one individual may fail to do so in another individual due to variation in HLA class I genes, loci central to the immune response. Extensive data have shown the strong effect of HLA variation on outcome after HIV infection, but very little is known about the effect of such variation on HIV vaccine success. Here, we identify a link between the effect of HLA variation on HIV disease outcome and immune responses to an HIV vaccine. HLA variants associated with better HIV control after infection also induce stronger responses against the HIV Gag protein relative to the Env protein after vaccination. Given the virologic control conferred by responses to Gag in natural history of HIV infection, these data suggest that HLA alleles conferring protection after HIV infection may also support a more effective cellular response to HIV vaccination.}, }
@article {pmid39046245, year = {2024}, author = {Cui, N and Perez, YL and Hume, AJ and Nunley, BE and Kong, K and Mills, MG and Xie, H and Greninger, AL}, title = {A high-throughput, polymerase-targeted RT-PCR for broad detection of mammalian filoviruses.}, journal = {Microbiology spectrum}, volume = {12}, number = {9}, pages = {e0101024}, pmid = {39046245}, issn = {2165-0497}, support = {U19 AI171403/AI/NIAID NIH HHS/United States ; 1U19AI171403-01//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; }, mesh = {*Filoviridae/genetics/isolation &amp; purification/classification ; Humans ; Animals ; *Filoviridae Infections/virology ; *Reverse Transcriptase Polymerase Chain Reaction/methods ; RNA, Viral/genetics ; Sensitivity and Specificity ; High-Throughput Nucleotide Sequencing/methods ; Mammals/virology ; High-Throughput Screening Assays/methods ; Viral Proteins/genetics ; }, abstract = {Filoviruses are some of the most lethal viruses in the modern world, and increasing numbers of filovirus species and genera have been discovered in recent years. Despite the potential severity of filovirus outbreaks in the human population, comparably few sensitive pan-filovirus RT-PCR assays have been described that might facilitate early detection and prevention. Here, we present a new pan-filovirus RT-PCR assay targeting the L polymerase gene for detection of all known mammalian filoviruses. We demonstrate the detection of 10 synthetic filovirus RNA templates with analytical sensitivity ranging from 178 to 3,354 copies/mL, without cross-reactivity on 10 non-filoviral human viral species. We verified assay performance on 10 inactivated filovirus isolates, yielding initial sensitivities of 0.012-44.17 TCID50/mL. We coupled this broadly reactive RT-PCR with a deep sequencing workflow that is amenable to high-throughput pooling to maximize detection and discovery potential. In summary, this pan-filovirus RT-PCR assay targets the most conserved filovirus gene, offers the widest breadth of coverage to date, and may help in the detection and discovery of novel filoviruses.IMPORTANCEFiloviruses remain some of the most mysterious viruses known to the world, with extremely high lethality rates and significant pandemic potential. Yet comparably few filovirus species and genera have been discovered to date and questions surround the definitive host species for zoonotic infections. Here, we describe a novel broadly reactive RT-PCR assay targeting the conserved L polymerase gene for high-throughput screening for filoviruses in a variety of clinical and environmental specimens. We demonstrate the assay can detect all known mammalian filoviruses and determine the sensitivity and specificity of the assay on synthetic RNA sequences, inactivated filovirus isolates, and non-filoviral species.}, }
@article {pmid39045125, year = {2024}, author = {Chung, E and Wang, Y and Chow, EJ and Emanuels, A and Heimonen, J and Ogokeh, CE and Rolfes, MA and Hughes, JP and Uyeki, TM and Starita, LM and Hoag, S and Boeckh, M and Englund, JA and Chu, HY and , }, title = {Absenteeism and Health Behavior Trends Associated With Acute Respiratory Illness Before and During the COVID-19 Pandemic in a Community Household Cohort, King County, Washington.}, journal = {AJPM focus}, volume = {3}, number = {4}, pages = {100248}, pmid = {39045125}, issn = {2773-0654}, abstract = {INTRODUCTION: Longitudinal data on how acute respiratory illness (ARI) affects behavior, namely school or work participation, and nonpharmaceutical intervention (NPI) usage before and during the COVID-19 pandemic is limited. The authors assessed how ARIs and specific symptoms affected school, work, and health-related behaviors over time.<br><br>METHODS: From November 2019 to June 2021, participating households with children in King County, Washington, were remotely monitored for ARI symptoms weekly. Following ARIs, participants reported illness-related effects on school, work, and NPI use. Using logistic regression with generalized estimating equations, the authors examined associations between symptoms and behaviors.<br><br>RESULTS: Of 1,861 participants, 581 (31%) from 293 households reported 884 ARIs and completed one-week follow-up surveys. Compared with the prepandemic period, during the period of the pandemic pre-COVID-19 vaccine, ARI-related school (56% vs 10%, p<0.001) absenteeism decreased and masking increased (3% vs 28%, p<0.001). After vaccine authorization in December 2020, more ARIs resulted in masking (3% vs 48%, p<0.001), avoiding contact with non-household members (26% vs 58%, p<0.001), and staying home (37% vs 69%, p<0.001) compared with the prepandemic period. Constitutional symptoms such as fever were associated with work disruptions (OR=1.91; 95% CI=1.06, 3.43), staying home (OR=1.55; 95% CI=1.06, 2.27), and decreased contact with non-household members (OR=1.58; 95% CI=1.05, 2.36).<br><br>CONCLUSIONS: This remote household study permitted uninterrupted tracking of behavioral changes in families with children before and during the COVID-19 pandemic, identifying increased use of some NPIs when ill but no additional illness-associated work or school disruptions.}, }
@article {pmid39044861, year = {2024}, author = {Shyamsundar, S and Pierson, SK and Connolly, CM and Teles, M and Segev, DL and Werbel, WA and van Rhee, F and Casper, C and Brandstadter, JD and Noy, A and Fajgenbaum, DC}, title = {Castleman disease patients report mild COVID-19 symptoms and mount a humoral response to SARS-CoV-2 vaccination.}, journal = {Blood neoplasia}, volume = {1}, number = {1}, pages = {}, pmid = {39044861}, issn = {2950-3280}, support = {R01 FD007632/FD/FDA HHS/United States ; R01 HL141408/HL/NHLBI NIH HHS/United States ; }, abstract = {The coronavirus disease of 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in increased morbidity and mortality in patients with impaired immunity, hematologic malignancies, and immunosuppressive regimens. COVID-19 can cause a cytokine storm with some patients benefiting from blockade of the pro-inflammatory cytokine, interleukin 6 (IL6). As Castleman disease (CD) is an atypical lymphoproliferative disorder that can involve a cytokine storm and often requires immunosuppressive therapies, including IL6 inhibition, we sought to evaluate outcomes following COVID-19 and SARS-CoV-2 vaccination in CD patients. We administered a survey in April 2021 to characterize experiences with COVID-19 and SARS-CoV-2 vaccination among 300 CD patients enrolled in ACCELERATE, a natural history registry of CD patients. Among 128 respondents, the prevalence of SARS-CoV-2 infection (16/95, 17%), severe disease (1/16, 6%), vaccination rates (112/128, 88%), and vaccine adverse effects after dose one (62/112, 55%) were comparable to the general U.S. population. While there were two cases of CD flares occurring shortly after SARS-CoV-2 infection (N=1) and vaccination (N=1), over 100 patients in this study that were infected and/or vaccinated did not experience CD flares. The median anti-spike titer six months after the second dose among CD patients was comparable to individuals with other immune-related diseases and healthy populations. Data from this small cohort suggest that, despite being on immunosuppressive therapies, CD patients do not appear to be at increased risk of poor COVID-19 outcomes and can mount a humoral response to SARS-CoV-2 vaccination. This study was registered on clinicaltrials.gov (#NCT02817997).}, }
@article {pmid39042564, year = {2024}, author = {Dai, J and Nianogo, R and Wong, ND and Moin, T and McClain, AC and Alver, S and Cordero, C and Daviglus, ML and Qi, Q and Sotres-Alvarez, D and Chen, L}, title = {Energy Intake and Dietary Glycemic Load in Late Morning and Risk of Type 2 Diabetes: The Hispanic Community Health Study/Study of Latinos-A Multicenter Prospective Cohort Study.}, journal = {Diabetes care}, volume = {47}, number = {9}, pages = {1673-1681}, pmid = {39042564}, issn = {1935-5548}, support = {/DE/NIDCR NIH HHS/United States ; HHSN268201300003I/HL/NHLBI NIH HHS/United States ; N01-HC65237//San Diego State University/ ; N01HC65234/HL/NHLBI NIH HHS/United States ; N01HC65233/HL/NHLBI NIH HHS/United States ; K01 HL150406/HL/NHLBI NIH HHS/United States ; N01HC65237/HL/NHLBI NIH HHS/United States ; /NS/NINDS NIH HHS/United States ; HHSN268201300003C/HL/NHLBI NIH HHS/United States ; //National Center on Minority Health and Health Disparities, the National Institute of Deafness/ ; //Office of Dietary Supplements/ ; /DK/NIDDK NIH HHS/United States ; N01-HC65233//National Heart, Lung, and Blood Institute (NHLBI)/ ; N01-HC65235//Albert Einstein College of Medicine/ ; N01HC65236/HL/NHLBI NIH HHS/United States ; N01HC65235/HL/NHLBI NIH HHS/United States ; N01-HC65236//Northwestern University/ ; N01-HC65234//University of Miami/ ; }, mesh = {Humans ; *Diabetes Mellitus, Type 2/epidemiology/ethnology ; Female ; Male ; Prospective Studies ; *Hispanic or Latino/statistics &amp; numerical data ; Adult ; *Energy Intake ; *Glycemic Load ; Middle Aged ; Risk Factors ; }, abstract = {OBJECTIVE: To evaluate the association between meal timing and type 2 diabetes risk in U.S. Hispanic/Latino adults.<br><br>RESEARCH DESIGN AND METHODS: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) is a multicenter, community-based, prospective cohort study. This study included 8,868 HCHS/SOL adults without diabetes at baseline (2008-2011) and attending the visit 2 examination (2014-2017). Energy intake and glycemic load (GL) in each meal timing were assessed at baseline using two 24-h dietary recalls. Incident diabetes was identified through annual follow-up calls or at visit 2. Hazard ratios (HRs) for incident diabetes were estimated using Cox models, accounting for the complex survey design.<br><br>RESULTS: The study population (50.9% female) had a baseline mean age of 39.0 (95% CI, 38.4-39.5) years. Over a median (range) follow-up of 5.8 (0.8-9.6) years, 1,262 incident diabetes cases were documented. Greater energy intake and GL in late morning (9:00-11:59 a.m.) were associated with a lower diabetes risk, whereas greater energy intake and GL in other meal timings were not. After accounting for diet quantity and quality, sociodemographic characteristics, lifestyle factors, and chronic conditions, the HRs were 0.94 (95% CI, 0.91-0.97) per 100-kcal energy intake increment and 0.93 (0.89-0.97) per 10-unit GL increment in late morning. Replacing energy intake or GL from early morning (6:00-8:59 a.m.), afternoon (12:00-5:59 p.m.), or evening (6:00-11:59 p.m.) with late-morning equivalents was associated with a comparably lower diabetes risk.<br><br>CONCLUSIONS: This study identified late morning as a favorable meal timing in Hispanic/Latino adults, providing a novel perspective on type 2 diabetes prevention that warrants confirmation.}, }
@article {pmid39042383, year = {2024}, author = {Appelbaum, FR}, title = {Soiled soil.}, journal = {Blood advances}, volume = {8}, number = {14}, pages = {3847-3848}, pmid = {39042383}, issn = {2473-9537}, }
@article {pmid39041868, year = {2024}, author = {Gwin, WR and Davidson, NE}, title = {TAILORing Estimates of Late Breast Cancer Recurrence with the RSClin Tool.}, journal = {NEJM evidence}, volume = {3}, number = {8}, pages = {EVIDe2400191}, doi = {10.1056/EVIDe2400191}, pmid = {39041868}, issn = {2766-5526}, mesh = {Humans ; *Breast Neoplasms/pathology/genetics ; Female ; *Neoplasm Recurrence, Local/pathology ; }, }
@article {pmid39041385, year = {2024}, author = {Ljungman, P and Chemaly, RF and Khawaya, F and Alain, S and Avery, R and Badshah, C and Boeckh, M and Fournier, M and Hodowanec, A and Komatsu, T and Limaye, AP and Manuel, O and Natori, Y and Navarro, D and Pikis, A and Razonable, RR and Westman, G and Miller, V and Griffiths, PD and Kotton, CN and , }, title = {Consensus Definitions of Cytomegalovirus (CMV) Infection and Disease in Transplant Patients Including Resistant and Refractory CMV for Use in Clinical Trials: 2024 Update From the Transplant Associated Virus Infections Forum.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {79}, number = {3}, pages = {787-794}, pmid = {39041385}, issn = {1537-6591}, support = {//Forum/ ; //AiCuris/ ; //AlloVir/ ; //Evrys Bio/ ; //HHV-6 Foundation/ ; //Merck/ ; //Takeda/ ; //Symbio/ ; //Qiagen/ ; //Vera Therapeutics/ ; //Eurofins Viracor/ ; }, mesh = {Humans ; *Cytomegalovirus Infections/drug therapy/virology/diagnosis ; *Antiviral Agents/therapeutic use ; *Cytomegalovirus/drug effects ; *Transplant Recipients ; *Clinical Trials as Topic ; *Consensus ; Drug Resistance, Viral ; Organ Transplantation/adverse effects ; }, abstract = {Cytomegalovirus (CMV) infection and disease are important causes of morbidity and mortality in transplant recipients. For the purpose of developing consistent reporting of CMV outcomes in clinical trials, definitions of CMV infection and disease were developed and most recently published in 2017. Since then, there have been major developments, including registration of new antiviral agents. Therefore, the Transplant Associated Virus Infections Forum, which consists of scientists, clinicians, regulators, and industry representatives, has produced an updated version of these definitions that incorporates recent knowledge with the aim of supporting clinical research and drug development. This also includes an update regarding the definition of resistant and refractory CMV infections previously published in 2019. As the field evolves, the need for updates of these definitions is clear, and collaborative efforts among clinicians, scientists, regulators, and industry representatives can provide a platform for this work.}, }
@article {pmid39041028, year = {2024}, author = {Zheng, Y and Caron, DP and Kim, JY and Jun, SH and Tian, Y and Florian, M and Stuart, KD and Sims, PA and Gottardo, R}, title = {ADTnorm: Robust Integration of Single-cell Protein Measurement across CITE-seq Datasets.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39041028}, issn = {2693-5015}, support = {U19 AI128949/AI/NIAID NIH HHS/United States ; T32 AI106711/AI/NIAID NIH HHS/United States ; K99 HG012797/HG/NHGRI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R00 HG012797/HG/NHGRI NIH HHS/United States ; U19 AI128914/AI/NIAID NIH HHS/United States ; }, abstract = {CITE-seq enables paired measurement of surface protein and mRNA expression in single cells using antibodies conjugated to oligonucleotide tags. Due to the high copy number of surface protein molecules, sequencing antibody-derived tags (ADTs) allows for robust protein detection, improving cell-type identification. However, variability in antibody staining leads to batch effects in the ADT expression, obscuring biological variation, reducing interpretability, and obstructing cross-study analyses. Here, we present ADTnorm (https://github.com/yezhengSTAT/ADTnorm), a normalization and integration method designed explicitly for ADT abundance. Benchmarking against 14 existing scaling and normalization methods, we show that ADTnorm accurately aligns populations with negative- and positive-expression of surface protein markers across 13 public datasets, effectively removing technical variation across batches and improving cell-type separation. ADTnorm enables efficient integration of public CITE-seq datasets, each with unique experimental designs, paving the way for atlas-level analyses. Beyond normalization, ADTnorm includes built-in utilities to aid in automated threshold-gating as well as assessment of antibody staining quality for titration optimization and antibody panel selection. Applying ADTnorm to a published COVID-19 CITE-seq dataset allowed for identifying previously undetected disease-associated markers, illustrating a broad utility in biological applications.}, }
@article {pmid39040640, year = {2024}, author = {Visani, GM and Pun, MN and Galvin, W and Daniel, E and Borisiak, K and Wagura, U and Nourmohammad, A}, title = {HERMES: Holographic Equivariant neuRal network model for Mutational Effect and Stability prediction.}, journal = {ArXiv}, volume = {}, number = {}, pages = {}, pmid = {39040640}, issn = {2331-8422}, support = {R35 GM142795/GM/NIGMS NIH HHS/United States ; }, abstract = {Predicting the stability and fitness effects of amino acid mutations in proteins is a cornerstone of biological discovery and engineering. Various experimental techniques have been developed to measure mutational effects, providing us with extensive datasets across a diverse range of proteins. By training on these data, traditional computational modeling and more recent machine learning approaches have advanced significantly in predicting mutational effects. Here, we introduce HERMES, a 3D rotationally equivariant structure-based neural network model for mutational effect and stability prediction. Pre-trained to predict amino acid propensity from its surrounding 3D structure, HERMES can be fine-tuned for mutational effects using our open-source code. We present a suite of HERMES models, pre-trained with different strategies, and fine-tuned to predict the stability effect of mutations. Benchmarking against other models shows that HERMES often outperforms or matches their performance in predicting mutational effect on stability, binding, and fitness. HERMES offers versatile tools for evaluating mutational effects and can be fine-tuned for specific predictive objectives.}, }
@article {pmid39040204, year = {2024}, author = {Stafford, E and Dimitrov, D and Trinidad, SB and Matrajt, L}, title = {Evaluating equity-promoting interventions to prevent race-based inequities in influenza outcomes.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39040204}, support = {NU38OT000297/CC/CDC HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI148684/AI/NIAID NIH HHS/United States ; }, abstract = {IMPORTANCE: Seasonal influenza hospitalizations pose a considerable burden in the United States, with BIPOC (Black, Indigenous, and other People of Color) communities being disproportionately affected.<br><br>OBJECTIVE: To determine and quantify the effects of different types of mitigation strategies on inequities in influenza outcomes (symptomatic infections and hospitalizations).<br><br>DESIGN: In this simulation study, we fit a race-stratified agent-based model of influenza transmission to demographic and hospitalization data of the United States.<br><br>PARTICIPANTS: We consider five racial-ethnic groups: non-Hispanic White persons, non- Hispanic Black persons, non-Hispanic Asian persons, non-Hispanic American Indian or Alaska Native persons, and Hispanic or Latino persons.<br><br>SETTING: We tested five idealized equity-promoting interventions to determine their effectiveness in reducing inequity in influenza outcomes. The interventions assumed (i) equalized vaccination rates, (ii) equalized comorbidities, (iii) work-risk distribution proportional to the distribution of the population, (iv) reduced work contacts for all, or (v) a combination of equalizing vaccination rates and comorbidities and reducing work contacts.<br><br>MAIN OUTCOMES AND MEASURES: Reduction in symptomatic or hospitalization risk ratios, defined as the ratio of the number of symptomatic infections (hospitalizations respectively) in each age- and racial-ethnic group and their corresponding white counterpart. We also evaluated the reduction in the absolute mean number of symptomatic infections or hospitalizations in each age- and racial-ethnic group compared to the fitted scenario (baseline).<br><br>RESULTS: Our analysis suggests that symptomatic infections were equalized and reduced (by up to 17% in BIPOC adults aged 18-49) by strategies reducing work contacts or equalizing vaccination rates. Reducing comorbidities resulted in significant decreases in hospitalizations, with a reduction of over 40% in BIPOC groups. All tested interventions reduced the inequity in influenza hospitalizations in all racial-ethnic groups, but interventions reducing comorbidities in marginalized populations were the most effective. Notably, these interventions resulted in better outcomes across all racial-ethnic groups, not only those prioritized by the interventions.<br><br>CONCLUSIONS AND RELEVANCE: In this simulation modeling study, equalizing vaccination rates and reducing number of work contacts (which are relatively simple strategies to implement) reduced the both the inequity in hospitalizations and the absolute number of symptomatic infections and hospitalizations in all age and racial-ethnic groups.}, }
@article {pmid39040045, year = {2024}, author = {Iovino, L and Krenning, G and Hadland, B}, title = {Editorial: Unconventional roles of endothelial cells.}, journal = {Frontiers in cell and developmental biology}, volume = {12}, number = {}, pages = {1439419}, pmid = {39040045}, issn = {2296-634X}, }
@article {pmid39039279, year = {2024}, author = {Majumder, MA and Leek, JT and Hansen, KD and Razi, A and McGuire, AL}, title = {Large-scale genotype prediction from RNA sequence data necessitates a new ethical and policy framework.}, journal = {Nature genetics}, volume = {56}, number = {8}, pages = {1537-1540}, pmid = {39039279}, issn = {1546-1718}, support = {R01GM121459//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R35GM149323//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; U24HG010263//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R35GM144128//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; }, mesh = {Humans ; *Genotype ; Sequence Analysis, RNA/methods ; RNA/genetics ; }, }
@article {pmid39038701, year = {2024}, author = {Hamilton, BK and Onstad, L and Carpenter, PA and Pidala, J and El Jurdi, N and Farhadfar, N and Kitko, CL and Lee, CJ and Mehta, R and Chen, GL and Cutler, C and Lee, SJ}, title = {Study Protocol: Predicting the Quality of Response to Specific Treatments (PQRST) in Chronic Graft-versus-Host Disease.}, journal = {Contemporary clinical trials}, volume = {145}, number = {}, pages = {107637}, doi = {10.1016/j.cct.2024.107637}, pmid = {39038701}, issn = {1559-2030}, mesh = {*Graft vs Host Disease ; Humans ; Prospective Studies ; Chronic Disease ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Research Design ; Immunosuppressive Agents/therapeutic use ; Treatment Outcome ; COVID-19 ; Bronchiolitis Obliterans Syndrome ; }, abstract = {BACKGROUND: Chronic graft-versus-host disease (GVHD) is a leading cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation. Despite significant progress in chronic GVHD therapies, challenges remain in understanding pleomorphic phenotypes and varying response to treatment. The goal of the Predicting the Quality of Response to Specific Treatments (PQRST) in chronic GVHD study is to identify predictors of treatment response. This report describing the study design seeks to raise awareness and invite collaborations with investigators who wish to access clinical data and research samples from this study.<br><br>METHODS: This is a prospective, observational cohort study involving data collection from patients who are beginning first-, second-, or third-line systemic therapy for chronic GVHD with defined agents. Evaluable participants will have baseline assessments and research samples prior to starting the index therapy, and 1&#xa0;month after starting treatment. Response assessments occur at 3 and 6&#xa0;months after start of treatment, or if a new systemic therapy is started before 6&#xa0;months. Target enrollment is approximately 200 patients at 8 institutions, with at least 6&#xa0;months of follow up to determine response to index therapy.<br><br>RESULTS: Enrollment started in July 2020 and was delayed due to the COVID-19 pandemic; as of 3/1/2024, 137 evaluable participants have been enrolled.<br><br>DISCUSSION: The Chronic GVHD Consortium "PQRST" is a large longitudinal cohort study that aims to investigate predictors of treatment response by identifying biologically and clinically defined patient subgroups. We welcome investigators to collaborate in the use of these data.<br><br>TRIAL REGISTRATION: NCT04431479.}, }
@article {pmid39038477, year = {2024}, author = {Gray, GE and Mngadi, K and Lavreys, L and Nijs, S and Gilbert, PB and Hural, J and Hyrien, O and Juraska, M and Luedtke, A and Mann, P and McElrath, MJ and Odhiambo, JA and Stieh, DJ and van Duijn, J and Takalani, AN and Willems, W and Tapley, A and Tomaras, GD and Van Hoof, J and Schuitemaker, H and Swann, E and Barouch, DH and Kublin, JG and Corey, L and Pau, MG and Buchbinder, S and Tomaka, F and , }, title = {Mosaic HIV-1 vaccine regimen in southern African women (Imbokodo/HVTN 705/HPX2008): a randomised, double-blind, placebo-controlled, phase 2b trial.}, journal = {The Lancet. Infectious diseases}, volume = {24}, number = {11}, pages = {1201-1212}, pmid = {39038477}, issn = {1474-4457}, support = {UM1 AI069423/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI154463/AI/NIAID NIH HHS/United States ; UM1 AI069453/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; Z01 AI000686/ImNIH/Intramural NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Female ; *HIV Infections/prevention &amp; control ; *AIDS Vaccines/administration &amp; dosage/immunology ; *HIV-1/immunology ; Double-Blind Method ; Adult ; Young Adult ; Adolescent ; HIV Antibodies/blood ; Vaccine Efficacy ; Africa, Southern ; Adjuvants, Immunologic/administration &amp; dosage ; }, abstract = {BACKGROUND: HIV type 1 (HIV-1) remains a global health concern, with the greatest burden in sub-Saharan Africa. Despite 40 years of research, no vaccine candidate has shown durable and protective efficacy against HIV-1 acquisition. Although pre-exposure prophylaxis in groups with high vulnerability can be very effective, barriers to its use, such as perceived low acquisition risk, fear of stigma, and concerns about side-effects, remain. Thus, a population-based approach, such as an HIV-1 vaccine, is needed. The current study aimed to evaluate the efficacy and safety of a heterologous HIV-1 vaccine regimen, consisting of a tetravalent mosaic adenovirus 26-based vaccine (Ad26.Mos4.HIV) and aluminium phosphate-adjuvanted clade C glycoprotein (gp) 140, in young women at risk of acquiring HIV-1 in southern Africa.<br><br>METHODS: This randomised, double-blind, phase 2b study enrolled sexually active women without HIV-1 or HIV-2 aged 18-35 years at 23 clinical research sites in Malawi, Mozambique, South Africa, Zambia, and Zimbabwe. Participants were centrally randomly assigned (1:1) to receive intramuscular injections of vaccine or saline placebo in stratified permuted blocks via an interactive web response system. Study participants, study site personnel (except those with primary responsibility for study vaccine preparation and dispensing), and investigators were masked to treatment group allocation. The vaccine regimen consisted of Ad26.Mos4.HIV administered at months 0 and 3 followed by Ad26.Mos4.HIV administered concurrently with aluminium phosphate-adjuvanted clade C gp140 at months 6 and 12. The primary efficacy outcome was vaccine efficacy in preventing laboratory-confirmed HIV-1 acquisition diagnosed between visits at month 7 and month 24 after the first vaccination (VE[7-24]) in the per-protocol population, which included participants who had not acquired HIV-1 4 weeks after the third vaccination, received all planned vaccinations at the first three vaccination visits within the protocol-specified windows, and had no major protocol deviations that could affect vaccine efficacy. Primary safety outcomes were assessed in randomly assigned participants who received one study injection or more based on the actual injection received. The primary safety endpoints were the incidences of unsolicited adverse events (AEs), solicited local and systemic AEs, serious AEs, AEs of special interest, and AEs leading to discontinuation of vaccination. This trial is registered with ClinicalTrials.gov, NCT03060629, and is complete.<br><br>FINDINGS: Between Nov 3, 2017, and June 30, 2019, 2654 women were randomly assigned, of whom 2636 women (median age of 23 years [IQR 20-25]) were enrolled and received at least one study injection (1313 assigned vaccine, 1323 placebo; 1317 received vaccine, 1319 placebo). Analysis of the primary efficacy outcome in the per-protocol cohort included 1080 women in the vaccine group and 1108 women in the placebo group; the incidence of HIV-1 acquisition per 100 person-years over months 7-24 after the first vaccination was 3&#xb7;38 (95% CI 2&#xb7;54-4&#xb7;41) in the vaccine group and 3&#xb7;94 (3&#xb7;04-5&#xb7;03) in the placebo group, with an estimated VE(7-24) of 14&#xb7;10% (95% CI -22&#xb7;00 to 39&#xb7;51; p=0&#xb7;40). There were no serious unsolicited AEs, AEs of special interest, or deaths related to the study vaccine. In the vaccine group, 663 (50&#xb7;3%) of 1317 participants had grade 1 or 2 solicited local AEs and ten (0&#xb7;8%) of 1317 participants had grade 3 or 4 solicited local AEs. In the placebo group, 305 (23&#xb7;1%) of 1319 participants had grade 1 or 2 solicited local AEs and three (0&#xb7;2%) of 1319 participants had grade 3 or 4 solicited local AEs. 863 (65&#xb7;5%) of 1317 participants in the vaccine group had grade 1 or 2 solicited systemic AEs and 34 (2&#xb7;6%) of 1317 participants had grade 3 or 4 solicited systemic AEs. 763 (57&#xb7;8%) of 1319 participants in the placebo group had grade 1 or 2 solicited systemic AEs and 20 (1&#xb7;5%) of 1319 participants had grade 3 or 4 solicited systemic AEs. Overall, three (0&#xb7;2%) of 1317 participants in the vaccine group and three (0&#xb7;2%) of 1319 participants in the placebo group discontinued vaccination due to an unsolicited AE, and three (0&#xb7;2%) of 1317 participants in the vaccine group and one (0&#xb7;1%) of 1319 participants in the placebo group discontinued vaccination due to a solicited AE.<br><br>INTERPRETATION: The heterologous Ad26.Mos4.HIV and clade C gp140 vaccine regimen was safe and well tolerated but did not show efficacy in preventing HIV-1 acquisition in a population of young women in southern Africa at risk of HIV-1.<br><br>FUNDING: Division of AIDS at the National Institute of Allergy and Infectious Diseases through the HIV Vaccine Trials Network, Bill &amp; Melinda Gates Foundation, Janssen Vaccines &amp; Prevention, US Army Medical Materiel Development Activity, and Ragon Institute.}, }
@article {pmid39038011, year = {2024}, author = {Demedis, J and Reedy, J and Miller, K and Hu, J and Klosky, JL and Dorsey Holliman, B and Peterson, PN and Chow, EJ and Studts, C}, title = {Testing effectiveness and implementation of a standardized approach to sexual dysfunction screening among adolescent and young adult-aged survivors of childhood cancer: A type I hybrid, mixed methods trial protocol.}, journal = {PloS one}, volume = {19}, number = {7}, pages = {e0305677}, pmid = {39038011}, issn = {1932-6203}, support = {K08 CA263192/CA/NCI NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Female ; Humans ; Male ; Young Adult ; *Cancer Survivors/psychology ; Mass Screening/methods ; Neoplasms/diagnosis ; Patient Reported Outcome Measures ; Quality of Life ; Sexual Dysfunction, Physiological/diagnosis/therapy ; Multicenter Studies as Topic ; }, abstract = {BACKGROUND: Approximately 20-50% of adolescent and young adult-aged childhood cancer survivors (AYA-CCS) experience sexual dysfunction (SD), although this healthcare need is widely underrecognized. Previous research from both AYA-CCS patients and their providers report that SD needs are unaddressed despite patient desires for SD discussions to be incorporated as part of their care. Patients and providers agree that standardized use of a patient-reported outcome measure may facilitate SD discussions; an SD screening approach was developed with patient and provider input. This study will measure the effectiveness of a standardized SD screening intervention and assess implementation outcomes and multilevel barriers and facilitators to guide future research.<br><br>METHODS: This multi-site, mixed methods, type 1 effectiveness-implementation hybrid trial will be evaluated using a pre-post design (NCT05524610). The trial will enroll 86 AYA-CCS (ages 15-39) from two cancer centers in the United States. The SD intervention consists of core fundamental functions with a "menu" of intervention options to allow for flexibility in delivery and tailoring in variable contexts. Effectiveness of the intervention on facilitating SD communication will be measured through patient surveys and clinical data; multivariable logistic regression will be used for the binary outcome of self-reported SD screening, controlling for patient-level predictors. Implementation outcomes will be assessed using mixed methods (electronic health record abstraction, patient and provider surveys, and provider interviews. Quantitative and qualitative findings will be merged using a joint display to understand factors affecting intervention success.<br><br>IMPLICATIONS: Identification and treatment of SD in AYA-CCS is an important and challenging quality of life concern. The type 1 hybrid design will facilitate rapid translation from research to practice by testing the effects of the intervention while simultaneously identifying multilevel barriers and facilitators to real-world implementation. This approach will inform future testing and dissemination of the SD screening intervention.}, }
@article {pmid39037853, year = {2024}, author = {Forbes, SP and Yay Donderici, E and Zhang, N and Sharif, B and Tremblay, G and Schafer, G and Raymond, VM and Talasaz, A and Eagle, C and Das, AK and Grady, WM}, title = {Population health outcomes of blood-based screening for colorectal cancer in comparison to current screening modalities: insights from a discrete-event simulation model incorporating longitudinal adherence.}, journal = {Journal of medical economics}, volume = {27}, number = {1}, pages = {991-1002}, doi = {10.1080/13696998.2024.2382036}, pmid = {39037853}, issn = {1941-837X}, mesh = {Humans ; *Colorectal Neoplasms/diagnosis ; Middle Aged ; Aged ; *Early Detection of Cancer/methods ; Male ; Female ; *Patient Compliance ; *Occult Blood ; *Colonoscopy ; Cost-Benefit Analysis ; }, abstract = {AIM: Insufficient adherence to colorectal cancer (CRC) screening impedes individual and population health benefits, with about one-third of individuals non-adherent to available screening options. The impact of poor adherence is inadequately considered in most health economics models, limiting the evaluation of real-world population-level screening outcomes. This study introduces the CAN-SCREEN (Colorectal cANcer SCReening Economics and adherENce) model, utilizing real-world adherence scenarios to assess the effectiveness of a blood-based test (BBT) compared to existing strategies.<br><br>MATERIALS AND METHODS: The CAN-SCREEN model evaluates various CRC screening strategies per 1,000 screened individuals for ages 45-75. Adherence is modeled in two ways: (1) full adherence and (2) longitudinally declining adherence. BBT performance is based on recent pivotal trial data while existing strategies are informed using literature. The full adherence model is calibrated using previously published Cancer Intervention and Surveillance Modeling Network (CISNET) models. Outcomes, including life-years gained (LYG), CRC cases averted, CRC deaths averted, and colonoscopies, are compared to no screening.<br><br>RESULTS: Longitudinal adherence modeling reveals differences in the relative ordering of health outcomes and resource utilization, as measured by the number of colonoscopies performed per 1,000, between screening modalities. BBT outperforms the fecal immunochemical test (FIT) and the multitarget stool DNA (mtsDNA) test with more CRC deaths averted (13) compared to FIT and mtsDNA (7, 11), more CRC cases averted (27 vs. 16, 22) and higher LYG (214 vs. 157, 199). BBT yields fewer CRC deaths averted compared to colonoscopy (13, 15) but requires fewer colonoscopies (1,053 vs. 1,928).<br><br>LIMITATIONS: Due to limited data, the CAN-SCREEN model with longitudinal adherence leverages evidence-informed assumptions for the natural history and real-world longitudinal adherence to screening.<br><br>CONCLUSIONS: The CAN-SCREEN model demonstrates that amongst non-invasive CRC screening strategies, those with higher adherence yield more favorable health outcomes as measured by CRC deaths averted, CRC cases averted, and LYG.}, }
@article {pmid39037433, year = {2024}, author = {Moore, M and Chen, X and Sadigh, S and Seifert, R and Mindiola Romero, AE and Pozdnyakova, O and Courville, EL}, title = {Evaluating pathologist practices in peripheral blood smear review: A comprehensive practice survey.}, journal = {American journal of clinical pathology}, volume = {}, number = {}, pages = {}, doi = {10.1093/ajcp/aqae091}, pmid = {39037433}, issn = {1943-7722}, abstract = {OBJECTIVES: Widely accepted standardized criteria for peripheral blood (PB) smear review do not exist. The aim of this study was to collect data regarding PB smear review practices across multiple institutions, with a focus on pathologist review.<br><br>METHODS: A 23-question survey was developed by members of the Society for Hematopathology (SH) Education Committee and distributed to SH members. The survey included questions on practice environment and PB smear review practices, including trainee involvement.<br><br>RESULTS: Of 725 members contacted, 137 (19%) completed the entire survey. Over half of practices examined 5 to 20 smears a day. All respondents reported using complete blood count/differential leukocyte count data and clinical history as part of smear review. The reported proportion of laboratory-initiated vs clinician-requested reviews varied across respondents. Clinician-requested smear reviews were more likely to be billed and issued as a separate pathology report. Glass slide review (as opposed to digital microscopy) was used by most respondents. All respondents affirmed that PB smear review is an essential component of pathology training programs. Numerous free-text comments were submitted by respondents regarding their own experiences with PB smear review and suggested improvements.<br><br>CONCLUSIONS: This survey elucidated the spectrum of practice patterns for pathologist review of blood smears and identified potential areas for process improvement.}, }
@article {pmid39035572, year = {2024}, author = {Cantos, VD and Neradilek, M and Huang, Y and Roxby, AC and Gillespie, K and deCamp, AC and Karuna, ST and Edupuganti, S and Gallardo-Cartagena, J and Sanchez, J and Del Rio, C and Veloso, V and Cohen, MS and Donnell, DJ and Corey, L and Kelley, CF}, title = {Oral Preexposure Prophylaxis Uptake and Discontinuation in the HIV Vaccine Trials Network 704/HIV Prevention Trials Network 085 Study: Implications for Biomedical Human Immunodeficiency Virus Prevention Trials.}, journal = {Open forum infectious diseases}, volume = {11}, number = {7}, pages = {ofae387}, pmid = {39035572}, issn = {2328-8957}, support = {UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: HIV Vaccine Trials Network (HVTN) 704/085, a placebo-controlled clinical trial assessing the efficacy of VRC01 broadly neutralizing antibody infusion for HIV prevention, offered oral preexposure prophylaxis (PrEP) as the standard of prevention at no cost to participants.<br><br>METHODS: We characterized features of- identified factors associated with- PrEP initiation and discontinuation, and the effects of PrEP initiation on HIV incidence.<br><br>RESULTS: Of 2221 participants, 31.8% initiated oral PrEP during study follow-up, with the highest proportion of PrEP initiations in Brazil (83.2%) and the United States (US) (54.2%). Prior PrEP use was associated with PrEP initiation (hazard ratio [HR], 2.22 [95% confidence interval {CI}, 1.25-3.95]). Participants from Switzerland (HR, 0.5 [95% CI, .3-1.0]) and Peru (HR, 0.08 [95% CI, .06-.1]) had lower likelihood of PrEP initiation compared to the US, while participants from Brazil had higher likelihood (HR, 2.6 [95% CI, 2.0-3.3]). In the US, PrEP initiation was lower in areas with higher unmet need for PrEP (HR, 0.9 per 5 units [95% CI, 0.8-1.0]). PrEP initiators had 58% less risk of acquiring HIV than PrEP noninitiators. Among PrEP initiators, 34.4% discontinued PrEP during study follow-up. Brazil had 63% less likelihood of PrEP discontinuation than the US (HR, 0.37 [95% CI, .22-.60]).<br><br>CONCLUSIONS: When included as standard of prevention in HVTN 704/085, oral PrEP utilization patterns mirrored those observed in real-life settings. Variable effects of oral PrEP on HIV outcomes in clinical trials may be expected based on regional differences in oral PrEP use.}, }
@article {pmid39034203, year = {2024}, author = {Gagelmann, N and Bose, P and Gupta, V and McLornan, DP and Vachhani, P and Al-Ali, HK and Ali, H and Treskes, P and Buckley, S and Roman-Torres, K and Scott, B}, title = {Consistency of Spleen and Symptom Reduction Regardless of Cytopenia in Patients With Myelofibrosis Treated With Pacritinib.}, journal = {Clinical lymphoma, myeloma &amp; leukemia}, volume = {24}, number = {11}, pages = {796-803}, doi = {10.1016/j.clml.2024.06.012}, pmid = {39034203}, issn = {2152-2669}, mesh = {Humans ; *Primary Myelofibrosis/drug therapy/complications ; Male ; Female ; Middle Aged ; *Spleen/pathology/drug effects ; Aged ; Protein Kinase Inhibitors/therapeutic use/pharmacology/adverse effects ; Pyrimidines/therapeutic use/pharmacology ; Treatment Outcome ; Aged, 80 and over ; Adult ; Bridged-Ring Compounds/therapeutic use/pharmacology ; Platelet Count ; Thrombocytopenia/drug therapy/etiology ; Cytopenia ; }, abstract = {BACKGROUND: Pacritinib is a JAK2/IRAK1/ACVR1 inhibitor that is approved in the United States for the treatment of patients with myelofibrosis who have a platelet count < 50 × 109/L. Phase 3 clinical studies of pacritinib included patients across a wide range of baseline platelet and hemoglobin levels.<br><br>PATIENTS AND METHODS: In order to assess the impact of baseline blood counts on pacritinib efficacy, an analysis of efficacy outcomes by baseline platelet and hemoglobin levels was performed using data pooled from 2 Phase 3 studies of pacritinib in patients with MF (PERSIST-1 and PERSIST-2).<br><br>RESULTS: Of 276 patients evaluable for spleen response, spleen volume reduction occurred consistently across platelet subgroups (< 100 &#xd7; 109/L or &#x2265; 100 &#xd7; 109/L) and hemoglobin subgroups (< 8 g/dL, &#x2265; 8 to < 10 g/dL, or > 10 g/dL), with no diminution in treatment effect in patients with severe thrombocytopenia or anemia. Among 159 patients evaluable for symptoms response, improvement in total symptom score (TTS) was similar across platelet subgroups. A &#x2265; 50% improvement of TSS occurred more frequently in patients with baseline hemoglobin < 8 g/dL compared with those with baseline hemoglobin &#x2265; 8 to < 10 g/dL or > 10 g/dL. Patients with baseline hemoglobin < 8 g/dL also experienced improved hemoglobin sustained over 24 weeks, whereas subgroups with less severe anemia had stable hemoglobin levels over time. Symptom improvement as assessed using the Patient Global Impression of Change instrument was generally consistent across platelet and hemoglobin subgroups.<br><br>CONCLUSION: Pacritinib demonstrates consistent efficacy in patients with MF regardless of baseline platelet and hemoglobin counts.}, }
@article {pmid39033978, year = {2024}, author = {Ballen, K and Wang, T and He, N and Knight, JM and Hong, S and Frangoul, H and Verdonck, LF and Steinberg, A and Diaz, MA and LeMaistre, CF and Badawy, SM and Pu, JJ and Hashem, H and Savani, B and Sharma, A and Lazarus, HM and Abid, MB and Tay, J and Rangarajan, HG and Kindwall-Keller, T and Freytes, CO and Beitinjaneh, A and Winestone, LE and Gergis, U and Farhadfar, N and Bhatt, NS and Schears, RM and Gómez-Almaguer, D and Aljurf, M and Agrawal, V and Kuwatsuka, Y and Seo, S and Marks, DI and Lehmann, L and Wood, WA and Hashmi, S and Saber, W}, title = {Impact of Race and Ethnicity on Outcomes After Umbilical Cord Blood Transplantation.}, journal = {Transplantation and cellular therapy}, volume = {30}, number = {10}, pages = {1027.e1-1027.e14}, doi = {10.1016/j.jtct.2024.07.009}, pmid = {39033978}, issn = {2666-6367}, mesh = {Adolescent ; Adult ; Aged ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Male ; Middle Aged ; Young Adult ; *Cord Blood Stem Cell Transplantation ; Disease-Free Survival ; Ethnicity ; *Graft vs Host Disease/ethnology ; Hispanic or Latino ; Leukemia, Myeloid, Acute/therapy/mortality/ethnology ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy/ethnology/mortality ; Racial Groups/statistics &amp; numerical data ; Retrospective Studies ; Transplantation Conditioning/methods ; Treatment Outcome ; White ; Black or African American ; Asian ; }, abstract = {BACKGROUND: Umbilical cord blood transplant (UCBT) improves access to transplant for patients lacking a fully matched donor. Previous Center for International Blood and Marrow Transplant Research (CIBMTR) showed that Black patients had a lower overall survival (OS) than White patients following single UCBT. The current study draws on a larger modern cohort and compares outcomes among White, Latinx, Black, and Asian patients.<br><br>OBJECTIVE: To compare outcomes by social determinants of health.<br><br>STUDY DESIGN: We designed a retrospective study using CIBMTR data. US patients were between ages 1 and 80; 983 received single and 1529 double UCBT as reported to CIBMTR, following either a myeloablative (N = 1752) or reduced intensity conditioning (N = 759) for acute myeloid leukemia, acute lymphoid leukemia, or myelodysplasia. The primary outcome was 2-year OS. Secondary outcomes included disease free survival, transplant related mortality (TRM), acute and chronic graft vs host disease (GVHD), and GVHD free, relapse free survival (GRFS).<br><br>RESULTS: For 1705 adults, in univariate analysis, 2-year OS was 41.5% (99% CI, 37.6 to 45.3) for Whites, 36.1% (99% CI, 28.2 to 44.5) for Latinx, 45.8% (99% CI, 36.7 to 55.1) for Blacks, and 44.5% (99% CI, 33.6 to 55.6) for Asians. In multivariate analysis of adults, Latinx patients had inferior OS compared to black patients (p = .0005, HR 1.45, 99% CI 1.18 to 1.79). OS improved over time for all racial/ethnic groups. GVHD rates were comparable among the different racial/ethnic groups. In the 807 children, the 2-year OS in univariate analysis was 66.1% (99% CI, 59.7 to 72.2) for Whites, 57.1% (99%CI, 49 to 64.9) for Latinx, 46.8% (99%CI, 35.3 to 58.4) for Blacks, and 53.8% (99%CI, 32.7 to 74.2) for Asians. In multivariate analysis, no difference in OS was observed among racial/ethnic groups (p = .051). Grade III/IV acute GVHD was higher in Blacks compared with Whites (p = .0016, HR 2.25, 99% CI 1.36 to 3.74) and Latinx (p = .0016, HR 2.17, 99% CI 1.43 to 3.30). There was no survival advantage to receiving a UCB unit from a donor of similar race and ethnicity, for any racial/ethnic groups, for both children and adults. Black and Latinx adult patients were more likely to live in areas defined as high poverty. Patients from high poverty level areas had worse OS (p = .03), due to a higher rate of TRM (p=0.04). Educational level, and type of insurance did not impact overall survival, GVHD, TRM or other transplant outcomes. Children from areas with a higher poverty level had higher TRM, regardless of race and ethnicity (p = .02). Public health insurance, such as Medicaid, was also associated with a higher TRM (p = .02). However, poverty did not impact pediatric OS, DFS, or other post-transplant outcomes.<br><br>CONCLUSIONS: OS for UCBT has improved over time. In adults, OS is comparable among Whites, Blacks, and Asians and lower for Latinx patients. In children, OS is comparable among Whites, Blacks, Latinx, and Asians, but Grade III/IV acute GVHD was higher in Black patients. There was no survival benefit to matching UCB unit and patient by race and ethnicity for adults and children.}, }
@article {pmid39033157, year = {2024}, author = {Oesterreich, S and Pate, L and Lee, AV and Chen, F and Jankowitz, RC and Mukhtar, R and Metzger, O and Sikora, MJ and Li, CI and Sotiriou, C and Shah, OS and Koorman, T and Ulaner, G and Reis-Filho, JS and Davidson, NM and Van Baelen, K and Hutcheson, L and Freeney, S and Migyanka, F and Turner, C and Derksen, P and Bear, T and Desmedt, C}, title = {International survey on invasive lobular breast cancer identifies priority research questions.}, journal = {NPJ breast cancer}, volume = {10}, number = {1}, pages = {61}, pmid = {39033157}, issn = {2374-4677}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; P30 CA047904/CA/NCI NIH HHS/United States ; P50 CA247749/CA/NCI NIH HHS/United States ; }, abstract = {There is growing awareness of the unique etiology, biology, and clinical presentation of invasive lobular breast cancer (ILC), but additional research is needed to ensure translation of findings into management and treatment guidelines. We conducted a survey with input from breast cancer physicians, laboratory-based researchers, and patients to analyze the current understanding of ILC, and identify consensus research questions. 1774 participants from 66 countries respondents self-identified as clinicians (N = 413), researchers (N = 376), and breast cancer patients and advocates (N = 1120), with some belonging to more than one category. The majority of physicians reported being very/extremely (41%) to moderately (42%) confident in describing the differences between ILC and invasive breast cancer of no special type (NST). Knowledge of histology was seen as important (73%) and as affecting treatment decisions (51%), and most agreed that refining treatment guidelines would be valuable (76%). 85% of clinicians have never powered a clinical trial to allow subset analysis for histological subtypes, but the majority would consider it, and would participate in an ILC clinical trials consortium. The majority of laboratory researchers, reported being and very/extremely (48%) to moderately (29%) confident in describing differences between ILC and NST. They reported that ILCs are inadequately presented in large genomic data sets, and that ILC models are insufficient. The majority have adequate access to tissue or blood from patients with ILC. The majority of patients and advocates (52%) thought that their health care providers did not sufficiently explain the unique features of ILC. They identified improvement of ILC screening/early detection, and identification of better imaging tools as top research priorities. In contrast, both researchers and clinicians identified understanding of endocrine resistance and identifying novel drugs that can be tested in clinical trials as top research priority. In summary, we have gathered information from an international community of physicians, researchers, and patients/advocates that we expect will lay the foundation for a community-informed collaborative research agenda, with the goal of improving management and personalizing treatment for patients with ILC.}, }
@article {pmid39032493, year = {2024}, author = {Welsh, FC and Eguia, RT and Lee, JM and Haddox, HK and Galloway, J and Van Vinh Chau, N and Loes, AN and Huddleston, J and Yu, TC and Quynh Le, M and Nhat, NTD and Thi Le Thanh, N and Greninger, AL and Chu, HY and Englund, JA and Bedford, T and Matsen, FA and Boni, MF and Bloom, JD}, title = {Age-dependent heterogeneity in the antigenic effects of mutations to influenza hemagglutinin.}, journal = {Cell host &amp; microbe}, volume = {32}, number = {8}, pages = {1397-1411.e11}, pmid = {39032493}, issn = {1934-6069}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R01 AI146028/AI/NIAID NIH HHS/United States ; T32 GM007270/GM/NIGMS NIH HHS/United States ; 75N93021C00015/AI/NIAID NIH HHS/United States ; R01 AI165821/AI/NIAID NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Hemagglutinin Glycoproteins, Influenza Virus/genetics/immunology ; *Influenza A Virus, H3N2 Subtype/genetics/immunology ; *Mutation ; Adult ; *Antibodies, Viral/immunology/blood ; *Influenza, Human/virology/immunology ; Age Factors ; Middle Aged ; Young Adult ; Antibodies, Neutralizing/immunology/blood ; Antigens, Viral/genetics/immunology ; Adolescent ; Evolution, Molecular ; Aged ; Child ; }, abstract = {Human influenza virus evolves to escape neutralization by polyclonal antibodies. However, we have a limited understanding of how the antigenic effects of viral mutations vary across the human population and how this heterogeneity affects virus evolution. Here, we use deep mutational scanning to map how mutations to the hemagglutinin (HA) proteins of two H3N2 strains, A/Hong Kong/45/2019 and A/Perth/16/2009, affect neutralization by serum from individuals of a variety of ages. The effects of HA mutations on serum neutralization differ across age groups in ways that can be partially rationalized in terms of exposure histories. Mutations that were fixed in influenza variants after 2020 cause greater escape from sera from younger individuals compared with adults. Overall, these results demonstrate that influenza faces distinct antigenic selection regimes from different age groups and suggest approaches to understand how this heterogeneous selection shapes viral evolution.}, }
@article {pmid39032121, year = {2024}, author = {Taneja, S and Heddle, NM and Hillis, C and Lane, S and Karunakaran, M and Maze, D and Modi, D and Khalaf, D and Arnold, DM and Zahreddine, H and Webert, K and Hess, L and Cook, R and Stanworth, S and Gernsheimer, T and Vanstone, M}, title = {Healthcare provider's perceptions of bleeding in patients with acute leukaemia undergoing induction chemotherapy: A qualitative study.}, journal = {Transfusion medicine (Oxford, England)}, volume = {34}, number = {4}, pages = {268-277}, doi = {10.1111/tme.13070}, pmid = {39032121}, issn = {1365-3148}, support = {#2358/CAPMC/CIHR/Canada ; //Canada Graduate Scholarship - Master's program/ ; #2358/CAPMC/CIHR/Canada ; }, mesh = {Humans ; *Hemorrhage/chemically induced ; Male ; Female ; Induction Chemotherapy ; Qualitative Research ; Middle Aged ; Adult ; Leukemia/therapy/drug therapy ; Health Personnel/psychology ; }, abstract = {BACKGROUND: Bleeding is a primary outcome for many transfusion-related trials in acute leukaemia (AL) patients, typically graded using the World Health Organisation (WHO) bleeding scale (clinically significant bleed (CSB) is ≥grade 2). This composite outcome fails to differentiate minor bleeds that may not be significant, poorly represents the total burden of bleeding and lacks input from healthcare providers (HCPs) and patients. As part of a multi-step project to create a better bleeding tool for trials, our objective was to identify HCPs' perspectives on the components of CSB in AL patients.<br><br>STUDY DESIGN AND METHODS: Using qualitative description, we interviewed 19 physicians and nurses who care for AL patients undergoing induction chemotherapy. Participants were recruited from professional organisations, networks and social media. An inductive approach to conventional content analysis was used.<br><br>RESULTS: HCPs identified features of CSB as the anatomical site of bleeding, amount of bleeding, need for intervention and changes in vital signs. Using these characteristics, bleeding events were categorised into three groups: clinically significant, could evolve into a CSB and not clinically significant. HCPs considered the patient's condition, bleeding history and clinical intuitions when deciding whether a bleed could escalate into serious bleeding.<br><br>DISCUSSION: Using data from HCPs, we categorised bleeds as clinically significant, could evolve into a CSB, and not significant. A study of patients' perspectives on the importance of different kinds of bleeding is the next step to creating a bleeding definition that is informed by evidence, clinicians and patients.}, }
@article {pmid39031841, year = {2024}, author = {Rosenberg, AR and Taylor, MR and Fladeboe, KM and Zhou, C and Levine, DR and Johnston, EE and Freyer, DR and Comiskey, L and Junkins, CC and Bradford, M and Odom, JN and Baker, KS and Yi-Frazier, JP}, title = {Resilience and distress among adolescents and young adults receiving hematopoietic cell transplantation: The Promoting Resilience in Stress Management randomized trial.}, journal = {Cancer}, volume = {130}, number = {20}, pages = {3519-3529}, doi = {10.1002/cncr.35440}, pmid = {39031841}, issn = {1097-0142}, support = {R01 CA225629/NH/NIH HHS/United States ; R01 CA225629/NH/NIH HHS/United States ; }, mesh = {Humans ; Adolescent ; *Hematopoietic Stem Cell Transplantation/psychology ; Female ; Male ; *Resilience, Psychological ; Young Adult ; *Quality of Life ; *Depression/psychology ; *Stress, Psychological/therapy/psychology ; *Anxiety/psychology/therapy ; Child ; Psychological Distress ; Adult ; }, abstract = {BACKGROUND: Adolescents and young adults (AYAs) receiving hematopoietic cell transplantation (HCT) are at high risk of poor psychosocial health. This study aimed to determine whether the Promoting Resilience in Stress Management (PRISM) intervention mitigated these risks during the first 6 months posttransplant.<br><br>METHODS: This multisite, parallel, randomized trial was conducted from April 2019 to March 2023. Eligible AYAs were aged 12-24 years, English speaking, and within 1 month of HCT for cancer or cancer predisposition syndrome. They were assigned 1:1 to PRISM (a brief, skills-based intervention targeting "resilience resources" [stress management, goal setting, cognitive reframing, and meaning making]) or usual care (UC). Outcomes included total symptoms of depression and anxiety (Hospital Anxiety and Depression Scale; primary outcome), hope (Snyder Hope Scale), resilience (10-item Connor-Davidson Resilience Scale), and health-related quality of life (HRQOL; Pediatric Quality of Life Inventory Cancer Module). Analyses leveraged multivariable linear regressions; exploratory analyses assessed the influence of baseline depression or anxiety.<br><br>RESULTS: Of 94 enrolled and randomized AYAs, the mean age was 16.7 years (SD,&#xa0;4.2); 43 (46%) were female, 56 (60%) were non-Hispanic White, 22 (23%) were Hispanic, and nine (10%) were Black. Most (77%) had leukemia. Of n&#xa0;=&#xa0;50 randomized to PRISM and n&#xa0;=&#xa0;44 to UC, 37 (74%) and 33 (73%) completed all study procedures, respectively. In intention-to-treat analyses, PRISM did not affect 6-month depression and anxiety (&#x3b2;&#xa0;=&#xa0;-1.1; 95% CI, -3.7 to 1.5), hope (&#x3b2;&#xa0;=&#xa0;0.83; 95% CI, -3.3 to 4.9), resilience (&#x3b2;&#xa0;=&#xa0;-0.01; 95% CI, -3.0 to 3.0), or HRQOL (&#x3b2;&#xa0;=&#xa0;1.5; 95% CI, -4.7 to 7.9). Among AYAs with preexisting anxiety or depression, PRISM recipients reported greater 6-month improvements in hope (score change, +3.71; SD,&#xa0;6.9) versus UC recipients (score change, -2.76; SD,&#xa0;6.5) (p&#xa0;=&#xa0;.04).<br><br>CONCLUSIONS: Resilience coaching did not influence outcomes in this sample. Exploratory findings suggest it may be more effective when directed toward those with concurrent distress.}, }
@article {pmid39029743, year = {2024}, author = {Cuthbertson, CC and Evenson, KR and Wen, F and Moore, CC and Howard, AG and Di, C and Parada, H and Matthews, CE and Manson, JE and Buring, J and Shiroma, EJ and LaCroix, AZ and Lee, IM}, title = {Associations of steps per day and step intensity with the risk of cancer: Findings from the Women's Health Accelerometry Collaboration cohort.}, journal = {Preventive medicine}, volume = {186}, number = {}, pages = {108070}, pmid = {39029743}, issn = {1096-0260}, support = {75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; R01 CA227122/CA/NCI NIH HHS/United States ; R01 HL043851/HL/NHLBI NIH HHS/United States ; R01 HL130483/HL/NHLBI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; UM1 CA182913/CA/NCI NIH HHS/United States ; U54 CA132379/CA/NCI NIH HHS/United States ; U01 CA182913/CA/NCI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; R01 HL105065/HL/NHLBI NIH HHS/United States ; P30 AG059299/AG/NIA NIH HHS/United States ; U54 CA132384/CA/NCI NIH HHS/United States ; K01 CA234317/CA/NCI NIH HHS/United States ; R01 CA047988/CA/NCI NIH HHS/United States ; R01 HL080467/HL/NHLBI NIH HHS/United States ; R01 CA154647/CA/NCI NIH HHS/United States ; T32 HL007055/HL/NHLBI NIH HHS/United States ; RC1 HL099355/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Accelerometry ; Aged ; *Neoplasms/epidemiology/mortality ; *Women's Health ; Middle Aged ; Exercise ; Risk Factors ; Cohort Studies ; Walking ; Proportional Hazards Models ; Prospective Studies ; }, abstract = {OBJECTIVE: Accumulating more steps/day is associated with a lower risk of cancer mortality and composite cancer outcomes. However, less is known about the relationship of steps/day with the risk of multiple site-specific cancers.<br><br>METHODS: This study included >22,000 women from the Women's Health Accelerometry Collaboration Cohort (2011-2022), comprised of women from the Women's Health Study and Women's Health Initiative Objective Physical Activity and Cardiovascular Health Study. Steps/day and step intensity were collected with accelerometry. Incident cancer cases and deaths were adjudicated. Stratified Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of the associations of steps/day and step intensity with incident breast, colon, endometrial, lung, and ovarian cancers, a composite of 13 physical activity-related cancers, total invasive cancer, and fatal cancer.<br><br>RESULTS: On average, women were 73.4&#xa0;years old, accumulated 4993 steps/day, and had 7.9&#xa0;years of follow-up. There were small nonsignificant inverse associations with the risks of colon cancer (HR&#xa0;=&#xa0;0.94, 95% CI: 0.83, 1.05), endometrial cancer (HR&#xa0;=&#xa0;0.91, 95% CI: 0.82, 1.01), and fatal cancer (HR&#xa0;=&#xa0;0.95 95% CI: 0.90, 1.00) per 1000 steps/day. More minutes at &#x2265;40 steps/min and a faster peak 10- and 30-min step cadence were associated with a lower risk of endometrial cancer, but findings were attenuated after adjustment for body mass index and steps/day.<br><br>CONCLUSIONS: Among women 62-97&#xa0;years, there were small nonsignificant inverse associations of colon, endometrial, and fatal cancer with more steps/day. Epidemiologic studies with longer follow-up and updated assessments are needed to further explore these associations.}, }
@article {pmid39028936, year = {2024}, author = {Boothby, AB and Tanner, MK and Alswied, A and Youngs, D and Bribiesca Rodriguez, J and Bikkani, T and Cha, N and Gernsheimer, T and Gimferrer, I and Hess, JR and Sokol-Hessner, L and Marivada, S and Nash, MG and Flegel, WA and Vassallo, RR and Stroncek, DF and Tsang, HC and Panch, SR}, title = {Cumulative donor-specific antibody threshold predicts platelet transfusion response in HLA-alloimmunized patients.}, journal = {Blood advances}, volume = {8}, number = {17}, pages = {4689-4699}, pmid = {39028936}, issn = {2473-9537}, support = {T32 HL007093/HL/NHLBI NIH HHS/United States ; ZIC CL002128/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Humans ; *Platelet Transfusion/adverse effects ; *HLA Antigens/immunology ; *Isoantibodies/immunology/blood ; Male ; Female ; Retrospective Studies ; Middle Aged ; Adult ; Aged ; Blood Donors ; Blood Platelets/immunology ; }, abstract = {Up to a third of patients with hemato-oncologic conditions who have received multiply transfusions develop immune-mediated platelet transfusion refractoriness. Yet factors that influence posttransfusion platelet corrected count increments (CCI) in patients with HLA-alloimmune platelet transfusion refractoriness remain less well elucidated. Recent advances in HLA antibody characterization using fluorescent bead-based platforms enable the study of donor-specific antibody (DSA) avidity (as measured by mean fluorescence intensity [MFI]) and its impact on HLA-alloimmune platelet transfusion refractoriness. In this large retrospective study of 2012 platelet transfusions among 73 HLA-alloimmunized patients, we evaluated the impact of cumulative HLA DSA-MFI alongside other donor, platelet component, and patient characteristics on CCI at 2 and 24 hours after transfusion. As part of a quality improvement initiative, we also developed and tested a computerized algorithm to optimize donor-recipient histocompatibility based on cumulative DSA-MFI and sought other actionable predictors of CCI. In multivariate analyses, cumulative HLA DSA-MFI of ≥10 000, major/bidirectional ABO-mismatch, splenomegaly, transfusion reactions, and platelet storage in additive solution negatively affected 2-hour but not 24-hour posttransfusion CCI. The DSA-MFI threshold of 10 000 was corroborated by greater antibody-mediated complement activation and significantly more CCI failures above this threshold, suggesting the usefulness of this value to inform "permissive platelet mismatching" and to optimize CCI. Furthermore, DSA-MFI decreases were deemed feasible by the computer-based algorithm for HLA-platelet selection in a pilot cohort of 8 patients (122 transfusions) evaluated before and after algorithm implementation. When HLA-selected platelets are unavailable, ABO-identical/minor-mismatched platelet concentrates may enhance 2-hour CCI in heavily HLA-alloimmunized patients with platelet transfusion refractoriness.}, }
@article {pmid39028918, year = {2024}, author = {Chlebowski, RT and Aragaki, AK and Pan, K and Luo, J and Rohan, TE and Johnson, KC and Wactawski-Wende, J and Jung, SY and Xiao, Q and Lavasani, S and Manson, JE and Simon, MS}, title = {Estrogen Plus Progestin and Colorectal Cancer: Long-Term Findings From the Women's Health Initiative Randomized Clinical Trial.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {42}, number = {30}, pages = {3530-3536}, doi = {10.1200/JCO.23.02092}, pmid = {39028918}, issn = {1527-7755}, mesh = {Humans ; Female ; *Colorectal Neoplasms/mortality/drug therapy ; Middle Aged ; *Medroxyprogesterone Acetate/administration &amp; dosage/adverse effects ; Aged ; *Estrogens, Conjugated (USP)/administration &amp; dosage/adverse effects/therapeutic use ; Postmenopause ; Women's Health ; Estrogen Replacement Therapy/adverse effects ; }, abstract = {Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We report long-term colorectal cancer findings from the Women's Health Initiative trial where 16,608 postmenopausal women with a uterus were randomly assigned to daily conjugated equine estrogen (CEE) 0.625 mg, plus medroxyprogesterone acetate (MPA) 2.5 mg, or placebo. When intervention ended after 5.6 years, although there were 44% fewer colorectal cancers in the intervention group (43 v 72, P = .003), the cancers were more commonly lymph node-positive (59.0% v 29.4%, P = .003). Now after cumulative 24-year follow-up, with 431 colorectal cancers, CEE plus MPA no longer influenced colorectal cancer incidence (215 [0.15, annualized rate %] v 216 [0.15], hazard ratio [HR], 0.95 [95% CI, 0.79 to 1.15]). Although not statistically significant, there were more colorectal cancer deaths with CEE plus MPA (87 [0.049] v 69 [0.041] deaths, HR, 1.20 [95% CI, 0.87 to 1.65], P = .26). Vaginal bleeding (54.1% v 5.2% at 6 months) and breast changes were more frequent in the intervention group. After adjusting for postrandomization vaginal bleeding and breast changes, bowel examinations were significantly delayed in intervention group participants (P = .005), potentially contributing to diagnostic delay. Taken together, the findings suggest no clinically meaningful benefit for about 5 years of CEE plus MPA use on colorectal cancer outcome.}, }
@article {pmid39028203, year = {2024}, author = {Hsu, VP and Pergam, SA and Shenoy, ES and Banach, DB and Jones Batshon, L and Branch-Elliman, W and Dumyati, G and Haessler, S and Jump, RLP and Malani, AN and Mathew, TA and Murthy, RK and Weber, DJ}, title = {SHEA position statement on pandemic preparedness for policymakers: emerging infectious threats.}, journal = {Infection control and hospital epidemiology}, volume = {45}, number = {7}, pages = {818-820}, doi = {10.1017/ice.2024.64}, pmid = {39028203}, issn = {1559-6834}, mesh = {Humans ; *Pandemics/prevention &amp; control ; Communicable Diseases, Emerging/prevention &amp; control/epidemiology ; COVID-19/prevention &amp; control/epidemiology ; Disaster Planning/organization &amp; administration ; Health Policy ; Pandemic Preparedness ; }, }
@article {pmid39026838, year = {2024}, author = {Visani, GM and Pun, MN and Galvin, W and Daniel, E and Borisiak, K and Wagura, U and Nourmohammad, A}, title = {HERMES: Holographic Equivariant neuRal network model for Mutational Effect and Stability prediction.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39026838}, issn = {2692-8205}, support = {R35 GM142795/GM/NIGMS NIH HHS/United States ; }, abstract = {Predicting the stability and fitness effects of amino-acid mutations in proteins is a cornerstone of biological discovery and engineering. Various experimental techniques have been developed to measure mutational effects, providing us with extensive datasets across a diverse range of proteins. By training on these data, machine learning approaches have advanced significantly in predicting mutational effects. Here, we introduce HERMES, a 3D rotationally equivariant structure-based neural network model for mutation effect prediction. Pre-trained to predict amino-acid propensities from their surrounding 3D structure atomic environments, HERMES can be efficiently fine-tuned to predict mutational effects, thanks to its symmetry-aware parameterization of the output space. Benchmarking against other models demonstrates that HERMES often outperforms or matches their performance in predicting mutation effects on stability, binding, and fitness, using either computationally or experimentally resolved protein structures. HERMES offers a versatile suit of tools for evaluating mutation effects and can be easily fine-tuned for specific predictive objectives using our open-source code.}, }
@article {pmid39026837, year = {2024}, author = {Grosely, R and Alvarado, C and Ivanov, IP and Nicholson, OB and Puglisi, JD and Dever, TE and Lapointe, CP}, title = {eIF1 and eIF5 dynamically control translation start site fidelity.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39026837}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R35 GM145306/GM/NIGMS NIH HHS/United States ; R00 GM144678/GM/NIGMS NIH HHS/United States ; RF1 AG064690/AG/NIA NIH HHS/United States ; R01 AG064690/AG/NIA NIH HHS/United States ; }, abstract = {Translation initiation defines the identity of a synthesized protein through selection of a translation start site on a messenger RNA. This process is essential to well-controlled protein synthesis, modulated by stress responses, and dysregulated in many human diseases. The eukaryotic initiation factors eIF1 and eIF5 interact with the initiator methionyl-tRNAi [Met] on the 40S ribosomal subunit to coordinate start site selection. Here, using single-molecule analysis of in vitro reconstituted human initiation combined with translation assays in cells, we examine eIF1 and eIF5 function. During translation initiation on a panel of RNAs, we monitored both proteins directly and in real time using single-molecule fluorescence. As expected, eIF1 loaded onto mRNAs as a component of the 43S initiation complex. Rapid (~ 2 s) eIF1 departure required a translation start site and was delayed by alternative start sites and a longer 5' untranslated region (5'UTR). After its initial departure, eIF1 rapidly and transiently sampled initiation complexes, with more prolonged sampling events on alternative start sites. By contrast, eIF5 only transiently bound initiation complexes late in initiation immediately prior to association of eIF5B, which allowed joining of the 60S ribosomal subunit. eIF5 association required the presence of a translation start site and was inhibited and destabilized by alternative start sites. Using both knockdown and overexpression experiments in human cells, we validated that eIF1 and eIF5 have opposing roles during initiation. Collectively, our findings demonstrate how multiple eIF1 and eIF5 binding events control start-site selection fidelity throughout initiation, which is tuned in response to changes in the levels of both proteins.}, }
@article {pmid39026820, year = {2024}, author = {Krishnamoorthy, GP and Glover, AR and Untch, BR and Sigcha-Coello, N and Xu, B and Vukel, D and Liu, Y and Tiedje, V and Berman, K and Tamarapu, PP and Acuña-Ruiz, A and Saqcena, M and de Stanchina, E and Boucai, L and Ghossein, RA and Knauf, JA and Abdel-Wahab, O and Bradley, RK and Fagin, JA}, title = {RBM10 loss induces aberrant splicing of cytoskeletal and extracellular matrix mRNAs and promotes metastatic fitness.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39026820}, issn = {2692-8205}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; R01 CA050706/CA/NCI NIH HHS/United States ; R01 CA249663/CA/NCI NIH HHS/United States ; R01 CA255211/CA/NCI NIH HHS/United States ; }, abstract = {RBM10 modulates transcriptome-wide cassette exon splicing. Loss-of-function RBM10 mutations are enriched in thyroid cancers with distant metastases. Analysis of transcriptomes and genes mis-spliced by RBM10 loss showed pro-migratory and RHO/RAC signaling signatures. RBM10 loss increases cell velocity. Cytoskeletal and ECM transcripts subject to exon-inclusion events included vinculin (VCL), tenascin C (TNC) and CD44. Knockdown of the VCL exon inclusion transcript in RBM10-null cells reduced cell velocity, whereas knockdown of TNC and CD44 exon-inclusion isoforms reduced invasiveness. RAC1-GTP levels were increased in RBM10-null cells. Mouse Hras [G12V] /Rbm1O [KO] thyrocytes develop metastases that are reversed by RBM10 or by combined knockdown of VCL, CD44 and TNC inclusion isoforms. Thus, RBM10 loss generates exon inclusions in transcripts regulating ECM-cytoskeletal interactions, leading to RAC1 activation and metastatic competency. Moreover, a CRISPR-Cas9 screen for synthetic lethality with RBM10 loss identified NFkB effectors as central to viability, providing a therapeutic target for these lethal thyroid cancers.}, }
@article {pmid39026080, year = {2024}, author = {Nagle, CM and Ibiebele, TI and Bandera, EV and Cramer, D and Doherty, JA and Giles, GG and Goodman, MT and Hanley, GE and Harris, HR and Jensen, A and Kjaer, SK and Lee, AW and Milne, RL and Qin, B and Richardson, J and Sasamoto, N and Sieh, W and Terry, KL and Titus, L and Trabert, B and Wentzensen, N and Wu, AH and Berchuck, A and Pike, M and Pearce, CL and Webb, PM}, title = {Pre-diagnosis tea and coffee consumption and survival after a diagnosis of ovarian cancer: results from the Ovarian Cancer Association Consortium.}, journal = {British journal of cancer}, volume = {131}, number = {6}, pages = {1043-1049}, pmid = {39026080}, issn = {1532-1827}, support = {//Rutgers Cancer Institute of New Jersey (Cancer Institute of New Jersey)/ ; K22 CA138563/CA/NCI NIH HHS/United States ; R01-CA112523, R01-CA87538//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; 209057, 396414, 1074383//Department of Health | National Health and Medical Research Council (NHMRC)/ ; W81XWH-10-1-02802//U.S. Department of Defense (United States Department of Defense)/ ; P30 CA008748/CA/NCI NIH HHS/United States ; W81XSH-16-2-0010//United States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research Programs (CDMRP)/ ; NIH-K07-CA095666, R01-CA83918, NIH-K22-CA138563, P30-CA072720//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01 CA054419/CA/NCI NIH HHS/United States ; Intramural Research Program//U.S. Department of Health &amp; Human Services | NIH | NCI | Division of Cancer Epidemiology and Genetics, National Cancer Institute (National Cancer Institute Division of Cancer Epidemiology and Genetics)/ ; R01-CA58598, N01-CN-55424, N01-PC-67001//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; P01 CA017054/CA/NCI NIH HHS/United States ; P01-CA17054, P30-CA14089, R01-CA61132, N01-PC67010, R03-CA113148, R03-CA115195, N01-CN025403//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; K07 CA095666/CA/NCI NIH HHS/United States ; R01 CA112523/CA/NCI NIH HHS/United States ; N01 CN025403/CN/NCI NIH HHS/United States ; N01 PC067010/PC/NCI NIH HHS/United States ; R01-CA61107//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R03 CA113148/CA/NCI NIH HHS/United States ; R01 CA058598/CA/NCI NIH HHS/United States ; P30 CA014089/CA/NCI NIH HHS/United States ; R01 CA083918/CA/NCI NIH HHS/United States ; R03 CA115195/CA/NCI NIH HHS/United States ; R01-CA54419, P50-CA105009//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; }, mesh = {Humans ; Female ; *Ovarian Neoplasms/mortality/diagnosis ; *Tea ; *Coffee ; Middle Aged ; Aged ; Proportional Hazards Models ; Adult ; Caffeine/administration &amp; dosage ; }, abstract = {BACKGROUND: Tea and coffee are the most frequently consumed beverages in the world. Green tea in particular contains compounds with potential anti-cancer effects, but its association with survival after ovarian cancer is uncertain.<br><br>METHODS: We investigated the associations between tea and coffee consumption before diagnosis and survival using data from 10 studies in the Ovarian Cancer Association Consortium. Data on tea (green, black, herbal), coffee and caffeine intake were available for up to 5724 women. We used Cox proportional hazards regression to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI).<br><br>RESULTS: Compared with women who did not drink any green tea, consumption of one or more cups/day was associated with better overall survival (aHR = 0.84, 95% CI 0.71-1.00, p-trend = 0.04). A similar association was seen for ovarian cancer-specific survival in five studies with this information (aHR = 0.81, 0.66-0.99, p-trend = 0.045). There was no consistent variation between subgroups defined by clinical or lifestyle characteristics and adjustment for other aspects of lifestyle did not appreciably alter the estimates. We found no evidence of an association between coffee, black or herbal tea, or caffeine intake and survival.<br><br>CONCLUSION: The observed association with green tea consumption before diagnosis raises the possibility that consumption after diagnosis might improve patient outcomes.}, }
@article {pmid39025648, year = {2024}, author = {Frost, SHL and Orozco, JJ and Bäck, TA and Miller, BW and Santos, EB and Kenoyer, A and Knoblaugh, SE and Hamlin, DK and Wilbur, DS and Sandmaier, BM}, title = {[211]At-Labeled Anti-CD45 Antibody as a Nonmyeloablative Conditioning for Canine DLA-Haploidentical Stem Cell Transplantation.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {65}, number = {9}, pages = {1443-1449}, pmid = {39025648}, issn = {1535-5667}, mesh = {Animals ; Dogs ; *Leukocyte Common Antigens/metabolism ; *Transplantation Conditioning/methods ; *Astatine ; *Hematopoietic Stem Cell Transplantation ; Antibodies, Monoclonal ; Histocompatibility Antigens Class I ; }, abstract = {The α-emitter [211]At deposits a high amount of energy within a few cell diameters, resulting in irreparable DNA double-strand breaks while minimizing off-target toxicity. We investigated the use of the [211]At-labeled anti-CD45 monoclonal antibody (mAb) [211]At-CD45-B10 as a nonmyeloablative conditioning regimen for dog-leukocyte-antigen-haploidentical hematopoietic cell transplantation. Methods: Seventeen healthy dogs were injected with either a 0.50 (n = 14) or 0.75 (n = 3) mg/kg dose of anti-CD45 mAb labeled with [211]At (8.436-23.199 MBq [0.228-0.627 mCi/kg]) on day -3. Peripheral blood stem cells from dog-leukocyte-antigen-haploidentical donors were given on day 0. Peripheral blood chimerism was calculated by polymerase chain reaction assays, and blood clearance of the radioimmunoconjugate was studied using enzyme-linked immunosorbent assay and radioactivity measurements of serial blood samples. Results: All dogs achieved donor chimerism by day 28 (range, 27%-100%). The hematopoietic engraftment rate was 100%, though engraftment durability was variable. No difference in absorbed dose to blood was seen for the 2 mAb dosing levels studied. Neutropenia (0-29 cells/μL), lymphocytopenia (36-130 cells/μL), and thrombocytopenia (1.5-9 × 10[3]/μL) with prompt recovery were observed. The main adverse nonhematologic event related to [211]At-CD45-B10 was mild reversible transaminitis. Graft-versus-host disease was not seen. Twelve of the 17 dogs survived over 30 d, with donor chimerism ranging from 3% to 99%. Conclusion: The results suggest that nonmyeloablative conditioning with [211]At-CD45-B10 could be used in haploidentical hematopoietic cell transplantation though with variable engraftment.}, }
@article {pmid39025327, year = {2024}, author = {Aglago, EK and Qu, C and Harlid, S and Phipps, AI and Steinfelder, RS and Ogino, S and Thomas, CE and Hsu, L and Toland, AE and Brenner, H and Berndt, SI and Buchanan, DD and Campbell, PT and Cao, Y and Chan, AT and Drew, DA and Figueiredo, JC and French, AJ and Gallinger, S and Georgeson, P and Giannakis, M and Goode, EL and Gruber, SB and Gunter, MJ and Harrison, TA and Hoffmeister, M and Huang, WY and Hullar, MA and Huyghe, JR and Jenkins, MA and Lynch, BM and Moreno, V and Murphy, N and Newton, CC and Nowak, JA and Obón-Santacana, M and Sun, W and Ugai, T and Um, CY and Zaidi, SH and Tsilidis, KK and van Guelpen, B and Peters, U}, title = {Folate intake and colorectal cancer risk according to genetic subtypes defined by targeted tumor sequencing.}, journal = {The American journal of clinical nutrition}, volume = {120}, number = {3}, pages = {664-673}, pmid = {39025327}, issn = {1938-3207}, support = {001/WHO_/World Health Organization/International ; P30 CA015083/CA/NCI NIH HHS/United States ; R01 CA201407/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Colorectal Neoplasms/genetics/epidemiology ; *Folic Acid/administration &amp; dosage ; Female ; Male ; Middle Aged ; Aged ; *Mutation ; Case-Control Studies ; Risk Factors ; Diet ; Dietary Supplements ; Signal Transduction ; Adult ; Logistic Models ; }, abstract = {BACKGROUND: Folate is involved in multiple genetic, epigenetic, and metabolic processes, and inadequate folate intake has been associated with an increased risk of cancer.<br><br>OBJECTIVE: We examined whether folate intake is differentially associated with colorectal cancer (CRC) risk according to somatic mutations in genes linked to CRC using targeted sequencing.<br><br>DESIGN: Participants within 2 large CRC consortia with available information on dietary folate, supplemental folic acid, and total folate intake were included. Colorectal tumor samples from cases were sequenced for the presence of nonsilent mutations in 105 genes and 6 signaling pathways (IGF2/PI3K, MMR, RTK/RAS, TGF-&#x3b2;, WNT, and TP53/ATM). Multinomial logistic regression models were analyzed comparing mutated/nonmutated CRC cases to controls to compute multivariable-adjusted odds ratios (ORs) with 95% confidence interval (CI). Heterogeneity of associations of mutated compared with nonmutated CRC cases was tested in case-only analyses using logistic regression. Analyses were performed separately in hypermutated and nonhypermutated tumors, because they exhibit different clinical behaviors.<br><br>RESULTS: We included 4339 CRC cases (702 hypermutated tumors, 16.2%) and 11,767 controls. Total folate intake was inversely associated with CRC risk (OR = 0.93; 95% CI: 0.90, 0.96). Among hypermutated tumors, 12 genes (AXIN2, B2M, BCOR, CHD1, DOCK3, FBLN2, MAP3K21, POLD1, RYR1, TET2, UTP20, and ZNF521) showed nominal statistical significance (P < 0.05) for heterogeneity by mutation status, but none remained significant after multiple testing correction. Among these genetic subtypes, the associations between folate variables and CRC were mostly inverse or toward the null, except for tumors mutated for DOCK3 (supplemental folic acid), CHD1 (total folate), and ZNF521 (dietary folate) that showed positive associations. We did not observe differential associations in analyses among nonhypermutated tumors, or according to the signaling pathways.<br><br>CONCLUSIONS: Folate intake was not differentially associated with CRC risk according to mutations in the genes explored. The nominally significant differential mutation effects observed in a few genes warrants further investigation.}, }
@article {pmid39024506, year = {2024}, author = {DeMartino, PC and Haag, MB and Caughey, AB and Roth, JA}, title = {A budget impact analysis of gene therapy for sickle cell disease: an updated analysis.}, journal = {Blood advances}, volume = {8}, number = {17}, pages = {4658-4661}, pmid = {39024506}, issn = {2473-9537}, mesh = {*Anemia, Sickle Cell/therapy/genetics/economics ; Humans ; *Genetic Therapy/economics/methods ; Cost-Benefit Analysis ; Budgets ; }, }
@article {pmid39024224, year = {2024}, author = {Wilkens, LR and Castelfranco, AM and Monroe, KR and Kristal, BS and Cheng, I and Maskarinec, G and Hullar, MA and Lampe, JW and Shepherd, JA and Franke, AA and Ernst, T and Le Marchand, L and Lim, U}, title = {Prediction of future visceral adiposity and application to cancer research: The Multiethnic Cohort Study.}, journal = {PloS one}, volume = {19}, number = {7}, pages = {e0306606}, pmid = {39024224}, issn = {1932-6203}, support = {P30 CA071789/CA/NCI NIH HHS/United States ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Adiposity ; Body Mass Index ; Case-Control Studies ; Cohort Studies ; Ethnicity ; *Intra-Abdominal Fat/diagnostic imaging ; Magnetic Resonance Imaging ; Neoplasms/diagnostic imaging ; Racial Groups ; }, abstract = {BACKGROUND: We previously developed a prediction score for MRI-quantified abdominal visceral adipose tissue (VAT) based on concurrent measurements of height, body mass index (BMI), and nine blood biomarkers, for optimal performance in five racial/ethnic groups. Here we evaluated the VAT score for prediction of future VAT and examined if enhancement with additional biomarkers, lifestyle behavior information, and medical history improves the prediction.<br><br>METHODS: We examined 500 participants from the Multiethnic Cohort (MEC) with detailed data (age 50-66) collected 10 years prior to their MRI assessment of VAT. We generated three forecasted VAT prediction models: first by applying the original VAT equation to the past data on the predictors ("original"), second by refitting the past data on anthropometry and biomarkers ("refit"), and third by building a new prediction model based on the past data enhanced with lifestyle and medical history ("enhanced"). We compared the forecasted prediction scores to future VAT using the coefficient of determination (R2). In independent nested case-control data in MEC, we applied the concurrent and forecasted VAT models to assess association of the scores with subsequent incident breast cancer (950 pairs) and colorectal cancer (831 pairs).<br><br>RESULTS: Compared to the VAT prediction by the concurrent VAT score (R2 = 0.70 in men, 0.68 in women), the forecasted original VAT score (R2 = 0.54, 0.48) performed better than past anthropometry alone (R2 = 0.47, 0.40) or two published scores (VAI, METS-VF). The forecasted refit (R2 = 0.61, 0.51) and enhanced (R2 = 0.62, 0.55) VAT scores each showed slight improvements. Similar to the concurrent VAT score, the forecasted VAT scores were associated with breast cancer, but not colorectal cancer. Both the refit score (adjusted OR for tertile 3 vs. 1 = 1.27; 95% CI: 1.00-1.62) and enhanced score (1.27; 0.99-1.62) were associated with breast cancer independently of BMI.<br><br>CONCLUSIONS: Predicted VAT from midlife data can be used as a surrogate to assess the effect of VAT on incident diseases associated with obesity, as illustrated for postmenopausal breast cancer.}, }
@article {pmid39023913, year = {2024}, author = {Neuhouser, ML and Schenk, JM and Wright, JL}, title = {Exercise for Prostate Cancer-Worthy Goals but Suboptimal Trial Designs.}, journal = {JAMA oncology}, volume = {10}, number = {9}, pages = {1177-1178}, doi = {10.1001/jamaoncol.2024.2057}, pmid = {39023913}, issn = {2374-2445}, mesh = {Humans ; *Prostatic Neoplasms/therapy ; Male ; *Research Design ; Clinical Trials as Topic ; Exercise ; Exercise Therapy/methods ; }, }
@article {pmid39023869, year = {2024}, author = {Radich, J}, title = {Transplant, MRD, and predicting relapse in AML.}, journal = {Blood}, volume = {144}, number = {3}, pages = {245-247}, doi = {10.1182/blood.2024024870}, pmid = {39023869}, issn = {1528-0020}, mesh = {Humans ; *Leukemia, Myeloid, Acute/pathology/diagnosis ; *Neoplasm, Residual/diagnosis ; *Hematopoietic Stem Cell Transplantation ; Recurrence ; Prognosis ; Male ; }, }
@article {pmid39022903, year = {2024}, author = {Rosen, EA and Stohs, EJ}, title = {Changing the culture of blood cultures: Opportunities for diagnostic stewardship in febrile neutropenia.}, journal = {Transplant infectious disease : an official journal of the Transplantation Society}, volume = {26}, number = {4}, pages = {e14346}, pmid = {39022903}, issn = {1399-3062}, support = {T32 AI118690/AI/NIAID NIH HHS/United States ; /NH/NIH HHS/United States ; T32AI118690//National Institute of Allergy and Infectious Diseases of the National Institutes of Health/ ; }, mesh = {Humans ; *Blood Culture/methods ; *Febrile Neutropenia/diagnosis/microbiology/drug therapy ; Anti-Bacterial Agents/therapeutic use ; Antimicrobial Stewardship ; }, }
@article {pmid39021245, year = {2024}, author = {Zang, PD and Seylani, A and Yu, EY and Dorff, TB}, title = {PROTACing the androgen receptor and other emerging therapeutics in prostate cancer.}, journal = {Expert review of anticancer therapy}, volume = {24}, number = {9}, pages = {829-835}, doi = {10.1080/14737140.2024.2379913}, pmid = {39021245}, issn = {1744-8328}, mesh = {Humans ; Male ; *Receptors, Androgen/metabolism/genetics ; *Prostatic Neoplasms/drug therapy/pathology/genetics ; *Androgen Receptor Antagonists/pharmacology ; Animals ; *Molecular Targeted Therapy ; *Drug Resistance, Neoplasm ; Signal Transduction/drug effects ; Mutation ; Proteolysis ; Disease Progression ; }, abstract = {INTRODUCTION: The androgen receptor (AR) is a critical driver of prostate cancer progression, and the advent of androgen receptor pathway inhibitors (ARPIs) has transformed the treatment landscape of metastatic prostate cancer. However, resistance to ARPIs eventually develops via mutations in AR, AR overexpression, and alternative AR signaling which have required novel approaches to target effectively.<br><br>AREAS COVERED: The mechanism of action and early clinical results of proteolysis targeting chimera (PROTAC) agents targeting AR are reviewed. Preclinical and early clinical data for other emerging AR-targeting therapeutics, including dual-action androgen receptor inhibitors (DAARIs) and anitens that target the N-terminal domain of AR, were also identified through literature search for agents which may circumvent resistance through AR splice variants and AR ligand-binding domain mutations. The literature search utilized PubMed to identify articles that were relevant to this review from 2000 to 2024.<br><br>EXPERT OPINION: PROTACs, DAARIs, and anitens represent novel and promising AR-targeting therapeutics that may become an important part of prostate cancer treatment in the future. Elucidating mechanisms of resistance, including ability of these agents to target full length AR, may yield further insights into maximal therapeutic efficacy aimed at silencing AR signaling.}, }
@article {pmid39020019, year = {2024}, author = {Gjærde, LK and Brück, O and Gagelmann, N and Gavriilaki, E and Inngjerdingen, M and Keranen, M and Kisch, A and Myhre, AE and Olivieri, A and Perez-Simon, JA and Perovic, D and Perovic, V and Piekarska, A and Pulanic, D and Rathje, K and Van Veen, S and Dachy, G and Moiseev, I and Penack, O and Peric, Z and Greinix, H and Lee, SJ and Wolff, D and Schoemans, H}, title = {Standardized translations of the Lee Chronic GvHD Symptom Scale to 12 European languages: an EU COST Action cGvHD Eurograft project.}, journal = {Bone marrow transplantation}, volume = {59}, number = {10}, pages = {1477-1479}, pmid = {39020019}, issn = {1476-5365}, mesh = {Humans ; *Graft vs Host Disease ; Chronic Disease ; Male ; Female ; Europe ; Language ; Translations ; Adult ; }, }
@article {pmid39019980, year = {2024}, author = {Broderick, A and Pan, E and Li, J and Chu, A and Hwang, C and Barata, PC and Cackowski, FC and Labriola, M and Ghose, A and Bilen, MA and Kilari, D and Thapa, B and Piero, M and Graham, L and Tripathi, A and Garje, R and Koshkin, VS and Hernandez, E and Dorff, TB and Schweizer, MT and Alva, AS and McKay, RR and Armstrong, AJ}, title = {Clinical implications of Wnt pathway genetic alterations in men with advanced prostate cancer.}, journal = {Prostate cancer and prostatic diseases}, volume = {}, number = {}, pages = {}, pmid = {39019980}, issn = {1476-5608}, support = {R01 CA256157/CA/NCI NIH HHS/United States ; R01 1R01CA233585//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; }, abstract = {BACKGROUND: Aberrant Wnt signaling has been implicated in prostate cancer tumorigenesis and metastasis in preclinical models but the impact of genetic alterations in Wnt signaling genes in men with advanced prostate cancer is unknown.<br><br>METHODS: We utilized the Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) clinical-genomic database for this retrospective analysis. Patients with activating mutations in CTNNB1 or RSPO2 or inactivating mutations in APC, RNF43, or ZNRF3 were defined as Wnt-altered, while those lacking such alterations were defined as Wnt non-altered. We compared patient characteristics and clinical outcomes as well as co-occurring genetic alterations according to Wnt alteration status.<br><br>RESULTS: Of the 1498 patients included, 193 (12.9%) were Wnt-altered. These men had a statistically significant 2-fold increased prevalence of liver and lung metastases as compared with Wnt non-altered patients at the time of initial diagnosis, (4.66% v 2.15% ; 6.22% v 3.07%), first metastatic disease diagnosis (10.88% v 5.29%; 13.99% v 6.21%), and CRPC development (11.40% v 6.36%; 12.95% v 5.29%). Wnt alterations were associated with more co-occurring alterations in RB1 (10.4% v 6.2%), AR (38.9% vs 25.7%), SPOP (13.5% vs 4.1%), FOXA1 (6.7% vs 2.8%), and PIK3CA (10.9% vs 5.1%). We found no significant differences in overall survival or other clinical outcomes from initial diagnosis, first metastatic disease, diagnosis of CRPC, or with AR inhibition for mCRPC between the Wnt groups.<br><br>CONCLUSIONS: Wnt-altered patients with prostate cancer have a higher prevalence of visceral metastases and are enriched in RB1, AR, SPOP, FOXA1, and PIK3CA alterations. Despite these associations, Wnt alterations were not associated with worse survival or treatment outcomes in men with advanced prostate cancer.}, }
@article {pmid39019209, year = {2024}, author = {Barbour, AB and Upadhyay, R and Anderson, AC and Kutuk, T and Kumar, R and Wang, SJ and Psutka, SP and Fekrmandi, F and Skalina, KA and Bruynzeel, AME and Correa, RJM and Dal Pra, A and Biancia, CD and Hannan, R and Louie, A and Singh, AK and Swaminath, A and Tang, C and Teh, BS and Zaorsky, NG and Lo, SS and Siva, S}, title = {Stereotactic Body Radiation Therapy for Primary Renal Cell Carcinoma: A Case-Based Radiosurgery Society Practice Guide.}, journal = {Practical radiation oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.prro.2024.06.012}, pmid = {39019209}, issn = {1879-8519}, abstract = {Traditionally, renal cell carcinoma (RCC) was considered a radioresistant tumor, thereby limiting definitive radiation therapy management options. However, several recent studies have demonstrated that stereotactic body radiation therapy (SBRT) can achieve high rates of local control for the treatment of primary RCC. In the setting of expanding use of SBRT for primary RCC, it is crucial to provide guidance on practical considerations such as patient selection, fractionation, target delineation, and response assessment. This is particularly important in challenging scenarios where a paucity of evidence exists, such as in patients with a solitary kidney, bulky tumors, or tumor thrombus. The Radiosurgery Society endorses this case-based guide to provide a practical framework for delivering SBRT to primary RCC, exemplified by 3 cases. This article explores topics of tumor size and dose fractionation, impact on renal function and treatment in the setting of a solitary kidney, and radiation's role in the management of inferior vena cava tumor thrombus. Additionally, we review existing evidence and expert opinion on target delineation, advanced techniques such as magnetic resonance imaging guided SBRT, and SBRT response assessment.}, }
@article {pmid39019058, year = {2024}, author = {Gradishar, WJ and Moran, MS and Abraham, J and Abramson, V and Aft, R and Agnese, D and Allison, KH and Anderson, B and Bailey, J and Burstein, HJ and Chen, N and Chew, H and Dang, C and Elias, AD and Giordano, SH and Goetz, MP and Jankowitz, RC and Javid, SH and Krishnamurthy, J and Leitch, AM and Lyons, J and McCloskey, S and McShane, M and Mortimer, J and Patel, SA and Rosenberger, LH and Rugo, HS and Santa-Maria, C and Schneider, BP and Smith, ML and Soliman, H and Stringer-Reasor, EM and Telli, ML and Wei, M and Wisinski, KB and Yeung, KT and Young, JS and Schonfeld, R and Kumar, R}, title = {Breast Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {5}, pages = {331-357}, doi = {10.6004/jnccn.2024.0035}, pmid = {39019058}, issn = {1540-1413}, mesh = {Humans ; *Breast Neoplasms/therapy/diagnosis/pathology ; Female ; Medical Oncology/standards/methods ; Combined Modality Therapy/standards ; }, abstract = {Breast cancer is treated with a multidisciplinary approach involving surgical oncology, radiation oncology, and medical oncology. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget's disease, Phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The content featured in this issue focuses on the recommendations for overall management of systemic therapy (preoperative and adjuvant) options for nonmetastatic breast cancer. For the full version of the NCCN Guidelines for Breast Cancer, visit NCCN.org.}, }
@article {pmid39019054, year = {2024}, author = {Swetter, SM and Johnson, D and Albertini, MR and Barker, CA and Bateni, S and Baumgartner, J and Bhatia, S and Bichakjian, C and Boland, G and Chandra, S and Chmielowski, B and DiMaio, D and Dronca, R and Fields, RC and Fleming, MD and Galan, A and Guild, S and Hyngstrom, J and Karakousis, G and Kendra, K and Kiuru, M and Lange, JR and Lanning, R and Logan, T and Olson, D and Olszanski, AJ and Ott, PA and Ross, MI and Rothermel, L and Salama, AK and Sharma, R and Skitzki, J and Smith, E and Tsai, K and Wuthrick, E and Xing, Y and McMillian, N and Espinosa, S}, title = {NCCN Guidelines® Insights: Melanoma: Cutaneous, Version 2.2024.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {5}, pages = {290-298}, doi = {10.6004/jnccn.2024.0036}, pmid = {39019054}, issn = {1540-1413}, mesh = {Humans ; *Melanoma/therapy/diagnosis/pathology ; *Skin Neoplasms/therapy/diagnosis/pathology ; Neoplasm Staging ; Medical Oncology/standards/methods ; }, abstract = {The NCCN Guidelines for Cutaneous Melanoma (termed Melanoma: Cutaneous) provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients. These NCCN Guidelines Insights focus on the update to neoadjuvant systemic therapy options and summarize the new clinical data evaluated by the NCCN panel for the recommended therapies in Version 2.2024 of the NCCN Guidelines for Cutaneous Melanoma.}, }
@article {pmid39018351, year = {2024}, author = {Hammermeister Suger, A and Harrison, TA and Henning, B and Turman, C and Kraft, P and Lindström, S}, title = {Nonadditive Effects of Common Genetic Variants Have a Negligent Contribution to Cancer Heritability.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {33}, number = {10}, pages = {1383-1388}, pmid = {39018351}, issn = {1538-7755}, support = {R01 CA134444/CA/NCI NIH HHS/United States ; U01 CA164930/CA/NCI NIH HHS/United States ; R01 CA059045/CA/NCI NIH HHS/United States ; U19 CA148127/CA/NCI NIH HHS/United States ; R01 CA197350/CA/NCI NIH HHS/United States ; P20 GM103534/GM/NIGMS NIH HHS/United States ; UL1 TR000445/TR/NCATS NIH HHS/United States ; R01 CA076366/CA/NCI NIH HHS/United States ; R01 CA188214/CA/NCI NIH HHS/United States ; Z01 CP010119/ImNIH/Intramural NIH HHS/United States ; U01 HG004438/HG/NHGRI NIH HHS/United States ; U01 HG004446/HG/NHGRI NIH HHS/United States ; R01 CA084979/CA/NCI NIH HHS/United States ; U01 CA074799/CA/NCI NIH HHS/United States ; U10 CA037429/CA/NCI NIH HHS/United States ; R01 CA121060/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; P50 CA140388/CA/NCI NIH HHS/United States ; U01 CA194393/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; UM1 CA176726/CA/NCI NIH HHS/United States ; CA194393//National Cancer Institute (NCI)/ ; U54 CA096297/CA/NCI NIH HHS/United States ; U24 CA074783/CA/NCI NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; R37 CA070867/CA/NCI NIH HHS/United States ; R01 CA058598/CA/NCI NIH HHS/United States ; R01 CA092447/CA/NCI NIH HHS/United States ; R01 HL034595/HL/NHLBI NIH HHS/United States ; R01 CA189184/CA/NCI NIH HHS/United States ; U54 MD007587/MD/NIMHD NIH HHS/United States ; U01 CA086402/CA/NCI NIH HHS/United States ; U01 CA137088/CA/NCI NIH HHS/United States ; Z01 CP010200/ImNIH/Intramural NIH HHS/United States ; U24 CA074794/CA/NCI NIH HHS/United States ; UM1 CA173640/CA/NCI NIH HHS/United States ; U24 CA074806/CA/NCI NIH HHS/United States ; U01 CA206110/CA/NCI NIH HHS/United States ; R01 CA068578/CA/NCI NIH HHS/United States ; R01 CA140561/CA/NCI NIH HHS/United States ; HHSN268201200008C/HL/NHLBI NIH HHS/United States ; R01 CA155101/CA/NCI NIH HHS/United States ; R01 CA137178/CA/NCI NIH HHS/United States ; U24 CA097735/CA/NCI NIH HHS/United States ; U01 CA074794/CA/NCI NIH HHS/United States ; P30 CA023108/CA/NCI NIH HHS/United States ; R01 CA056678/CA/NCI NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; R03 CA130034/CA/NCI NIH HHS/United States ; P30 CA014089/CA/NCI NIH HHS/United States ; U19 CA148537/CA/NCI NIH HHS/United States ; R01 CA148667/CA/NCI NIH HHS/United States ; R01 CA081488/CA/NCI NIH HHS/United States ; T32 CA009168/CA/NCI NIH HHS/United States ; R01 CA201407/CA/NCI NIH HHS/United States ; R01 CA063464/CA/NCI NIH HHS/United States ; P01 CA033619/CA/NCI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; U54 CA096300/CA/NCI NIH HHS/United States ; R01 CA133891/CA/NCI NIH HHS/United States ; R01 CA082664/CA/NCI NIH HHS/United States ; R01 CA144040/CA/NCI NIH HHS/United States ; R01 CA042182/CA/NCI NIH HHS/United States ; P30 ES007784/ES/NIEHS NIH HHS/United States ; R01 HL026490/HL/NHLBI NIH HHS/United States ; R01 CA132839/CA/NCI NIH HHS/United States ; P30 CA068485/CA/NCI NIH HHS/United States ; R01 CA128813/CA/NCI NIH HHS/United States ; U01 CA097735/CA/NCI NIH HHS/United States ; T32 ES013678/ES/NIEHS NIH HHS/United States ; HHSN261201000006C/CA/NCI NIH HHS/United States ; U19 CA148112/CA/NCI NIH HHS/United States ; U01 CA196386/CA/NCI NIH HHS/United States ; UM1 CA167552/CA/NCI NIH HHS/United States ; R01 CA149429/CA/NCI NIH HHS/United States ; N01RC37004/RC/CCR NIH HHS/United States ; U01 CA122839/CA/NCI NIH HHS/United States ; HHSN261201500005C/CA/NCI NIH HHS/United States ; U19 CA148065/CA/NCI NIH HHS/United States ; P30 CA054174/CA/NCI NIH HHS/United States ; UL1 RR024975/RR/NCRR NIH HHS/United States ; G12 MD007600/MD/NIMHD NIH HHS/United States ; R01 CA040360/CA/NCI NIH HHS/United States ; U01 CA074783/CA/NCI NIH HHS/United States ; R01 CA194393/CA/NCI NIH HHS/United States ; N01 CN045165/CN/NCI NIH HHS/United States ; U24 CA074799/CA/NCI NIH HHS/United States ; P01 CA196569/CA/NCI NIH HHS/United States ; R01 CA092579/CA/NCI NIH HHS/United States ; U01 CA074806/CA/NCI NIH HHS/United States ; UM1 CA182910/CA/NCI NIH HHS/United States ; U24 CA074800/CA/NCI NIH HHS/United States ; P50 CA127003/CA/NCI NIH HHS/United States ; UM1 CA182883/CA/NCI NIH HHS/United States ; T32CA09168//National Cancer Institute (NCI)/ ; HHSN268201200008I/HL/NHLBI NIH HHS/United States ; R01 CA097193/CA/NCI NIH HHS/United States ; U01 CA164973/CA/NCI NIH HHS/United States ; R37 CA054281/CA/NCI NIH HHS/United States ; U01 CA074800/CA/NCI NIH HHS/United States ; R01 CA034944/CA/NCI NIH HHS/United States ; R01 CA141298/CA/NCI NIH HHS/United States ; U19 CA148107/CA/NCI NIH HHS/United States ; U01 HG004726/HG/NHGRI NIH HHS/United States ; N01 CN043302/CN/NCI NIH HHS/United States ; }, mesh = {Humans ; *Neoplasms/genetics ; *Genome-Wide Association Study ; *Genetic Predisposition to Disease ; Genetic Variation ; Female ; Male ; Polymorphism, Single Nucleotide ; Case-Control Studies ; }, abstract = {BACKGROUND: Contribution of dominance effects to cancer heritability is unknown. We leveraged existing genome-wide association data for seven cancers to estimate the contribution of dominance effects to the heritability of individual cancer types.<br><br>METHODS: We estimated the proportion of phenotypic variation caused by dominance genetic effects using genome-wide association data for seven cancers (breast, colorectal, lung, melanoma, nonmelanoma skin, ovarian, and prostate) in a total of 166,772 cases and 284,824 controls.<br><br>RESULTS: We observed no evidence of a meaningful contribution of dominance effects to cancer heritability. By contrast, additive effects ranged between 0.11 and 0.34.<br><br>CONCLUSIONS: In line with studies of other human traits, the dominance effects of common genetic variants play a minimal role in cancer etiology.<br><br>IMPACT: These results support the assumption of an additive inheritance model when conducting cancer association studies with common genetic variants.}, }
@article {pmid39018074, year = {2024}, author = {Shen, MJ and Stokes, T and Yarborough, S and Harrison, J}, title = {Improving Pain Self-Management Among Rural Older Adults With Cancer.}, journal = {JAMA network open}, volume = {7}, number = {7}, pages = {e2421298}, pmid = {39018074}, issn = {2574-3805}, mesh = {Humans ; Aged ; Female ; Male ; *Self-Management/methods ; *Rural Population/statistics &amp; numerical data ; *Pain Management/methods ; *Neoplasms/complications/psychology/therapy ; Cancer Pain/therapy/psychology ; Tennessee ; Aged, 80 and over ; Feasibility Studies ; Patient Education as Topic/methods ; }, abstract = {IMPORTANCE: Undertreated cancer pain is a major public health concern among older adults in rural communities. Interventions to improve pain management among this vulnerable population are needed.<br><br>OBJECTIVE: To test the feasibility, acceptability, and changes in pain outcomes from exposure to an adapted intervention, Cancer Health Empowerment for Living without Pain (CA-HELP), to improve patients' communication about pain to their clinicians.<br><br>Older adults with cancer (aged &#x2265;65 years) who were residing in a noninstitutional rural setting and receiving outpatient care at a rural-based clinic in Tennessee were enrolled in the study, in which everyone received the intervention, in May 2022. All patients were given assessments at baseline and 1 week after intervention. Mean score differences were analyzed using 1-tailed paired sample t tests (&#x3b1;&#x2009;=&#x2009;.05). Data were analyzed in June 2022.<br><br>EXPOSURE: The adapted version of CA-HELP included an 18-page patient-facing workbook and a 30-minute telephone coaching call with a registered nurse to coach patients on pain education and communication techniques to discuss pain with their medical team.<br><br>MAIN OUTCOMES AND MEASURES: Feasibility was examined through accrual and completion rates. Acceptability was measured by helpfulness, difficulty, and satisfaction with the intervention. Changes in outcomes were measured using mean score differences from pre-post assessments of pain self-management, self-efficacy for communicating with clinicians about pain, patient-reported pain, and misconceptions about pain.<br><br>RESULTS: Among the 30 total participants, the mean (SD) age was 73.0 (5.1) years; 17 participants (56.7%) were female, 5 (16.7%) were Black or African American, 30 (100%) were non-Hispanic or non-Latino, 24 (80.0%) were White, 16 (53.3%) had less than a high school education, and 15 (50.0%) reported income less than $21&#x202f;000 per year. Based on accrual and completion rates of 100%, this intervention was highly feasible. Fidelity rates for delivering intervention components (100%) and communication competence (27 participants [90%]) were also high. Regarding acceptability, all patients rated the intervention as helpful, with the majority (24 participants [80%]) rating it as "very helpful." Most patients rated the intervention as "not at all difficult" (27 participants [90%]), enjoyed participating (21 participants [70%]), and reported being "very satisfied" (25 participants [83.3%]). Pre-post changes in outcomes suggested significant improvements in pain self-management and self-efficacy for communicating with clinicians about pain, as well as significant reductions in patient-reported pain and pain misconceptions.<br><br>CONCLUSIONS AND RELEVANCE: In this case-series study of CA-HELP, results suggested the adapted version of CA-HELP was feasible and acceptable and showed changes in pain-related outcome measures among older adults with cancer in a rural setting.}, }
@article {pmid39017661, year = {2024}, author = {Rashidi, A and Pidala, J and Hamilton, BK and Pavletic, SZ and Kim, K and Zevin, A and Mays, JW and Lee, SJ}, title = {Oral and Gut Microbiome Alterations in Oral Chronic GVHD Disease: Results from Close Assessment and Testing for Chronic GVHD (CATCH Study).}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {30}, number = {18}, pages = {4240-4250}, pmid = {39017661}, issn = {1557-3265}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; U01 CA236229/CA/NCI NIH HHS/United States ; ZIA DE000747/ImNIH/Intramural NIH HHS/United States ; U01 CA118953/CA/NCI NIH HHS/United States ; CA118953//National Cancer Institute (NCI)/ ; CA236229//National Institute of Dental and Craniofacial Research (NIDCR)/ ; R01 CA118953/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Graft vs Host Disease/microbiology/diagnosis ; *Gastrointestinal Microbiome ; Female ; Male ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Middle Aged ; Adult ; Chronic Disease ; *Mouth/microbiology ; Transplantation, Homologous ; Aged ; Feces/microbiology ; Prospective Studies ; Metagenomics/methods ; Young Adult ; }, abstract = {PURPOSE: Whether and how the oral microbiome and its changes in allogeneic hematopoietic cell transplantation (alloHCT) recipients may contribute to oral chronic GVHD (cGVHD) pathogenesis is unknown. In addition, although the oral and colonic microbiota are distinct in healthy adults, whether oral microbes may ectopically colonize the gut in alloHCT patients is unknown.<br><br>EXPERIMENTAL DESIGN: To address these knowledge gaps, longitudinal oral and fecal samples were collected prospectively in the multicenter Close Assessment and Testing for Chronic GVHD study (NCT04188912). Through shotgun metagenomic sequencing of the samples collected at baseline, oral cGVHD onset, first post-cGVHD onset visit, and 1-year post-HCT time points in patients with oral cGVHD (cases; N = 29) or without any cGVHD (controls; N = 51), we examined whether (i) oral and/or gut microbiomes and their longitudinal trajectories differ between cases and controls and (ii) oral and gut microbiomes overlap in alloHCT recipients, especially those developing cGVHD.<br><br>RESULTS: A total of 195 samples were analyzed. The onset of oral cGVHD was characterized by an expansion of Streptococcus salivarius and Veillonella parvula in the oral microbiome. High levels of oral/gut microbiota overlap were observed, particularly in patients with oral cGVHD, suggesting ectopic colonization of the gut by oral bacteria.<br><br>CONCLUSIONS: The unusual coalescence of two distant niches in these patients may result in short- or long-term consequences for the host, a novel avenue for future research. In addition, this study suggests a contribution of the oral microbiome to oral cGVHD pathogenesis.}, }
@article {pmid39014324, year = {2024}, author = {Huo, Y and Yang, Y and Halloran, ME and Longini, IM and Dean, NE}, title = {Hypothesis testing and sample size considerations for the test-negative design.}, journal = {BMC medical research methodology}, volume = {24}, number = {1}, pages = {151}, pmid = {39014324}, issn = {1471-2288}, mesh = {Humans ; Sample Size ; Case-Control Studies ; *Research Design ; Vaccine Efficacy/statistics &amp; numerical data ; Logistic Models ; Computer Simulation ; Odds Ratio ; Vaccination/statistics &amp; numerical data ; Observational Studies as Topic/methods/statistics &amp; numerical data ; }, abstract = {The test-negative design (TND) is an observational study design to evaluate vaccine effectiveness (VE) that enrolls individuals receiving diagnostic testing for a target disease as part of routine care. VE is estimated as one minus the adjusted odds ratio of testing positive versus negative comparing vaccinated and unvaccinated patients. Although the TND is related to case-control studies, it is distinct in that the ratio of test-positive cases to test-negative controls is not typically pre-specified. For both types of studies, sparse cells are common when vaccines are highly effective. We consider the implications of these features on power for the TND. We use simulation studies to explore three hypothesis-testing procedures and associated sample size calculations for case-control and TND studies. These tests, all based on a simple logistic regression model, are a standard Wald test, a continuity-corrected Wald test, and a score test. The Wald test performs poorly in both case-control and TND when VE is high because the number of vaccinated test-positive cases can be low or zero. Continuity corrections help to stabilize the variance but induce bias. We observe superior performance with the score test as the variance is pooled under the null hypothesis of no group differences. We recommend using a score-based approach to design and analyze both case-control and TND. We propose a modification to the TND score sample size to account for additional variability in the ratio of controls over cases. This work enhances our understanding of the data generating mechanism in a test-negative design (TND) and how it is distinct from that of a case-control study due to its passive recruitment of controls.}, }
@article {pmid39013466, year = {2024}, author = {Carr, CR and Crawford, KHD and Murphy, M and Galloway, JG and Haddox, HK and Matsen, FA and Andersen, KG and King, NP and Bloom, JD}, title = {Deep mutational scanning reveals functional constraints and antibody-escape potential of Lassa virus glycoprotein complex.}, journal = {Immunity}, volume = {57}, number = {9}, pages = {2061-2076.e11}, pmid = {39013466}, issn = {1097-4180}, support = {R01 AI141707/AI/NIAID NIH HHS/United States ; U19 AI135995/AI/NIAID NIH HHS/United States ; }, mesh = {*Lassa virus/immunology/genetics ; Humans ; *Antibodies, Viral/immunology ; *Mutation ; *Antibodies, Neutralizing/immunology ; Animals ; *Antibodies, Monoclonal/immunology ; *Lassa Fever/immunology/virology ; Virus Internalization ; Viral Envelope Proteins/immunology/genetics ; Glycoproteins/immunology/genetics ; Immune Evasion/immunology/genetics ; HEK293 Cells ; }, abstract = {Lassa virus is estimated to cause thousands of human deaths per year, primarily due to spillovers from its natural host, Mastomys rodents. Efforts to create vaccines and antibody therapeutics must account for the evolutionary variability of the Lassa virus's glycoprotein complex (GPC), which mediates viral entry into cells and is the target of neutralizing antibodies. To map the evolutionary space accessible to GPC, we used pseudovirus deep mutational scanning to measure how nearly all GPC amino-acid mutations affected cell entry and antibody neutralization. Our experiments defined functional constraints throughout GPC. We quantified how GPC mutations affected neutralization with a panel of monoclonal antibodies. All antibodies tested were escaped by mutations that existed among natural Lassa virus lineages. Overall, our work describes a biosafety-level-2 method to elucidate the mutational space accessible to GPC and shows how prospective characterization of antigenic variation could aid the design of therapeutics and vaccines.}, }
@article {pmid39012906, year = {2024}, author = {Desai, P and Zhou, Y and Grenet, J and Handelman, SK and Crispino, CM and Tarbay, LN and Whitsel, EA and Roboz, G and Barac, A and Honigberg, M and Bick, A and Anderson, G and Wactawski-Wende, J and Jakubek Swartzlander, YA and Bacon, J and Wong, J and Ma, X and Scheet, P and Li, Z and Kasi, P and Prentice, R and Auer, P and Manson, JE and Reiner, A and Simon, M}, title = {Association of clonal hematopoiesis and mosaic chromosomal alterations with solid malignancy incidence and mortality.}, journal = {Cancer}, volume = {130}, number = {22}, pages = {3879-3887}, doi = {10.1002/cncr.35455}, pmid = {39012906}, issn = {1097-0142}, support = {1 R01 CA248747-01A1/CA/NCI NIH HHS/United States ; 1 R01 CA248747-01A1/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Clonal Hematopoiesis/genetics ; Aged ; *Breast Neoplasms/genetics/mortality/pathology ; Middle Aged ; *Colorectal Neoplasms/genetics/mortality/pathology ; *Chromosome Aberrations ; Incidence ; *Mosaicism ; Lung Neoplasms/genetics/mortality/pathology ; Male ; Neoplasms/genetics/mortality/pathology/epidemiology ; Whole Genome Sequencing ; }, abstract = {BACKGROUND: Understanding the impact of clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) on solid tumor risk and mortality can shed light on novel cancer pathways.<br><br>METHODS: The authors analyzed whole genome sequencing data from the Trans-Omics for Precision Medicine Women's Health Initiative study (n&#xa0;=&#xa0;10,866). They investigated the presence of CHIP and mCA and their association with the development and mortality of breast, lung, and colorectal cancers.<br><br>RESULTS: CHIP was associated with higher risk of breast (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.03-1.64; p&#xa0;=&#xa0;.02) but not colorectal (p&#xa0;=&#xa0;.77) or lung cancer (p&#xa0;=&#xa0;.32). CHIP carriers who developed colorectal cancer also had a greater risk for advanced-stage (p&#xa0;=&#xa0;.01), but this was not seen in breast or lung cancer. CHIP was associated with increased colorectal cancer mortality both with (HR, 3.99; 95% CI, 2.41-6.62; p&#xa0;<&#xa0;.001) and without adjustment (HR, 2.50; 95% CI, 1.32-4.72; p&#xa0;=&#xa0;.004) for advanced-stage and a borderline higher breast cancer mortality (HR, 1.53; 95% CI, 0.98-2.41; p&#xa0;=&#xa0;.06). Conversely, mCA (cell fraction [CF] >3%) did not correlate with cancer risk. With higher CFs (mCA >5%), autosomal mCA was associated with increased breast cancer risk (HR, 1.39; 95% CI, 1.06-1.83; p&#xa0;=&#xa0;.01). There was no association of mCA (>3%) with breast, colorectal, or lung mortality except higher colon cancer mortality (HR, 2.19; 95% CI, 1.11-4.3; p&#xa0;=&#xa0;.02) with mCA >5%.<br><br>CONCLUSIONS: CHIP and mCA (CF >5%) were associated with higher breast cancer risk and colorectal cancer mortality individually. These data could inform on novel pathways that impact cancer risk and lead to better risk stratification.}, }
@article {pmid39010324, year = {2024}, author = {Fischer, MD and Green, ML and Selke, S and Limaye, AP and Wald, A and Boeckh, MJ and Phipps, AI and Pergam, SA and Johnston, C}, title = {Evaluation of oral herpes simplex virus shedding among solid organ transplant recipients: A pilot study.}, journal = {Transplant infectious disease : an official journal of the Transplantation Society}, volume = {26}, number = {4}, pages = {e14335}, pmid = {39010324}, issn = {1399-3062}, support = {K23 AI097234/AI/NIAID NIH HHS/United States ; T32 AI007044/AI/NIAID NIH HHS/United States ; T32 AI 007044//National Institute of Allergy and Infectious Diseases/ ; K-23AI097234//National Institute of Allergy and Infectious Diseases/ ; }, mesh = {Humans ; *Virus Shedding ; Pilot Projects ; Male ; Middle Aged ; Female ; *Transplant Recipients/statistics &amp; numerical data ; Aged ; *Herpesvirus 1, Human/isolation &amp; purification ; Adult ; Organ Transplantation/adverse effects ; Herpes Simplex/virology ; Virus Activation ; Kidney Transplantation/adverse effects ; Immunosuppression Therapy/adverse effects ; Liver Transplantation/adverse effects ; }, abstract = {BACKGROUND: Herpes simplex viruses (HSVs) frequently reactivate during immunosuppression and may be a risk factor for adverse outcomes after solid organ transplant (SOT). While suppressive antiviral therapy reduces the risk of symptomatic HSV reactivation, the kinetics of asymptomatic viral shedding with chronic immunosuppression after transplant are not well understood. We report the characteristics of oral HSV shedding among 15 HSV-1 seropositive SOT recipients (n = 8 liver, n = 7 kidney, median age 58.5 years, median 20 months post-transplant) who were not taking daily antiviral suppressive therapy.<br><br>METHODS: Participants self-collected oral swabs three times daily for 6 weeks for HSV quantification and recorded the presence of oral symptoms or lesions in a diary.<br><br>RESULTS: Sample collection adherence was high (median 122 swabs/person, range: 85.7%-101.6% of expected swabs). Most participants (n = 12, 80%) experienced at least one shedding episode, with a median shedding rate of 8.9% (range: 0%-33.6%). There were 32 total shedding episodes, 24 (75%) of which occurred without symptoms or lesions. For episodes of known duration, the median length was 21.8 hrs (interquartile range: 10.8-46.1 hrs).<br><br>CONCLUSION: Most shedding episodes (78.1%) lasted >12 hrs, suggesting that twice-daily sampling may be sufficient to detect most episodes. These data show that self-collection of oral swabs is feasible for patients who have undergone SOTs and can provide insight into the frequency of oral HSV reactivation, which can be used to design future studies in this population.}, }
@article {pmid39010279, year = {2024}, author = {Becktell, K and Chen, Y and Yasui, Y and Phelan, R and Armstrong, GT and Link, M and Oeffinger, K and Snyder, C and Daw, N and Weil, B and Weldon, C and Chow, EJ and Schwartz, CL}, title = {Long-term outcomes among survivors of childhood osteosarcoma: A report from the Childhood Cancer Survivor Study (CCSS).}, journal = {Pediatric blood &amp; cancer}, volume = {71}, number = {10}, pages = {e31189}, pmid = {39010279}, issn = {1545-5017}, support = {U24 CA055727/CA/NCI NIH HHS/United States ; //American Lebanese-Syrian Associated Charities/ ; P30 CA021765/CA/NCI NIH HHS/United States ; CA55727/CA/NCI NIH HHS/United States ; CA21765//Cancer Center Support/ ; CA55727/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Osteosarcoma/mortality/therapy/drug therapy ; Female ; Male ; Child ; *Cancer Survivors/statistics &amp; numerical data ; Adolescent ; *Bone Neoplasms/mortality/therapy/pathology ; Child, Preschool ; Adult ; Young Adult ; Follow-Up Studies ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Survival Rate ; Infant ; }, abstract = {PURPOSE: Treatment strategies for osteosarcoma evolving between 1970 and 1999 improved 5-year survival and continue as standard of care today. This report evaluates the impact of these evolving therapies on long-term health outcomes.<br><br>METHODS: Five-year survivors of childhood osteosarcoma in CCSS treated from 1970 to 1999 were evaluated for late (>5&#xa0;years from diagnosis) mortality, chronic health conditions (CHCs), and health status using piecewise-exponential and logistical models. Comparisons were made between survivors and siblings without cancer, and among survivors examining historical and current standard chemotherapies (e.g., methotrexate/doxorubicin/cisplatin [MAP] vs. others), specific chemotherapy agents and surgical approaches (amputation vs. limb salvage [LS]). Models were evaluated adjusting for attained age, sex, race, ethnicity, and age at diagnosis.<br><br>RESULTS: A total of 1257 survivors of osteosarcoma were followed on average for 24.4&#xa0;years. Twenty-year all-cause late mortality was 13.3% (95% confidence interval [CI]: 11.7%-14.9%) overall and 11.7% (95% CI: 6.9%-16.5%) for the subset treated with MAP plus LS. Survivors were at higher risk of CHCs (rate ratio [RR] 3.7, 95% CI: 3.2-4.3) than the sibling cohort, most notably having more serious cardiac, musculoskeletal, and hearing CHCs. Within the survivor cohort, the risk of severe CHCs was twice as high with MAP versus no chemotherapy (RR 2.1, 95% CI: 1.3-3.4). Compared with primary amputation, serious musculoskeletal CHCs were higher after LS (RR 6.6, 95% CI: 3.6-13.4), without discernable differences in health status.<br><br>CONCLUSION: Contemporary osteosarcoma therapy with MAP plus LS, while improving 5-year disease-free survival, continues to be associated with a high burden of late mortality, CHCs, and health status limitations.}, }
@article {pmid39009580, year = {2024}, author = {Wacker, JN and Woods, JJ and Rupert, PB and Peterson, A and Allaire, M and Lukens, WW and Gaiser, AN and Minasian, SG and Strong, RK and Abergel, RJ}, title = {Actinium chelation and crystallization in a macromolecular scaffold.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {5741}, pmid = {39009580}, issn = {2041-1723}, support = {P30 GM124169/GM/NIGMS NIH HHS/United States ; DE-AC02-05CH11231//U.S. Department of Energy (DOE)/ ; }, mesh = {*Actinium/chemistry ; *Chelating Agents/chemistry ; Crystallization ; Radiopharmaceuticals/chemistry ; Humans ; Ligands ; }, abstract = {Targeted alpha therapy (TAT) pairs the specificity of antigen targeting with the lethality of alpha particles to eradicate cancerous cells. Actinium-225 [[225]Ac; t1/2 = 9.920(3) days] is an alpha-emitting radioisotope driving the next generation of TAT radiopharmaceuticals. Despite promising clinical results, a fundamental understanding of Ac coordination chemistry lags behind the rest of the Periodic Table due to its limited availability, lack of stable isotopes, and inadequate systems poised to probe the chemical behavior of this radionuclide. In this work, we demonstrate a platform that combines an 8-coordinate synthetic ligand and a mammalian protein to characterize the solution and solid-state behavior of the longest-lived Ac isotope, [227]Ac [t1/2 = 21.772(3) years]. We expect these results to direct renewed efforts for [225]Ac-TAT development, aid in understanding Ac coordination behavior relative to other +3 lanthanides and actinides, and more broadly inform this element's position on the Periodic Table.}, }
@article {pmid39009417, year = {2024}, author = {Arends, T and Hamm, DC and van der Maarel, S and Tapscott, SJ}, title = {Facioscapulohumeral Dystrophy: Molecular Basis and Therapeutic Opportunities.}, journal = {Cold Spring Harbor perspectives in biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/cshperspect.a041492}, pmid = {39009417}, issn = {1943-0264}, support = {P50 AR065139/AR/NIAMS NIH HHS/United States ; R01 AR045203/AR/NIAMS NIH HHS/United States ; }, abstract = {Facioscapulohumeral dystrophy (FSHD) is caused by misexpression of the early embryonic transcription factor Double Homeobox Protein 4 (DUX4) in skeletal muscle. DUX4 is normally expressed at the 4-cell stage of the human embryo and initiates a portion of the first wave of embryonic gene expression that establishes the totipotent cells of the embryo. Following brief expression, the DUX4 locus is suppressed by epigenetic silencing and remains silenced in nearly all somatic cells. Mutations that cause FSHD decrease the efficiency of epigenetic silencing of the DUX4 locus and result in aberrant expression of this transcription factor in skeletal muscles. DUX4 expression in these skeletal muscles reactivates part of the early totipotent program and suppresses the muscle program-resulting in a progressive muscular dystrophy that affects some muscles earlier than others. These advances in understanding the cause of FSHD have led to multiple therapeutic strategies that are now entering clinical trials.}, }
@article {pmid39009001, year = {2024}, author = {Donnell, D}, title = {Reassuring long-term safety, resistance, and efficacy data for two daily formulations of PrEP.}, journal = {The lancet. HIV}, volume = {11}, number = {8}, pages = {e496-e497}, doi = {10.1016/S2352-3018(24)00158-9}, pmid = {39009001}, issn = {2352-3018}, mesh = {Humans ; *HIV Infections/prevention &amp; control/drug therapy ; *Pre-Exposure Prophylaxis/methods ; *Anti-HIV Agents/administration &amp; dosage/therapeutic use ; Drug Resistance, Viral ; Treatment Outcome ; }, }
@article {pmid39008818, year = {2024}, author = {Pidala, JA and Gooley, TA and Luznik, L and Blazar, BR}, title = {Chronic graft-versus-host disease: unresolved complication or ancient history?.}, journal = {Blood}, volume = {144}, number = {13}, pages = {1363-1373}, pmid = {39008818}, issn = {1528-0020}, support = {P01 CA015396/CA/NCI NIH HHS/United States ; P01 CA065493/CA/NCI NIH HHS/United States ; P01 HL158505/HL/NHLBI NIH HHS/United States ; R01 HL110879/HL/NHLBI NIH HHS/United States ; R01 HL155114/HL/NHLBI NIH HHS/United States ; P01 AI056299/AI/NIAID NIH HHS/United States ; R37 AI034495/AI/NIAID NIH HHS/United States ; }, mesh = {*Graft vs Host Disease/etiology ; Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Chronic Disease ; Transplantation, Homologous/adverse effects ; }, abstract = {Chronic graft-versus-host disease (cGVHD) is associated with morbidity, mortality, impaired quality of life, prolonged immunosuppressive therapy, and infection risk after allogeneic hematopoietic cell transplantation (HCT). Major strides have occurred in the understanding of cGVHD biology; National Institutes of Health Consensus meetings have refined rigorous approaches to diagnosis, staging, and response criteria; major interventional trials have established standard benchmarks for treatment outcome; and 3 agents to date have been US Food and Drug Administration approved for treating corticosteroid-refractory cGVHD. Promising results from several recent trials have led some, but not others, to conclude that the risk of developing cGVHD is sufficiently low to be considered a major post-HCT complication of the past. We propose that it is time to critically examine the results of contemporary graft-versus-host disease (GVHD) prophylaxis regimens and discuss the state of the science and associated controversies in the spectrum of conclusions reached as to the risk of cGVHD. With these data, the current cGVHD incidence can be most precisely determined, and the present and future burden of cGVHD-affected patients can be accurately modeled. Through review of existing evidence, we highlight unresolved needs and opportunities to refine best GVHD prophylaxis or preemptive therapy approaches and optimize established cGVHD therapy, and make the argument that support of preclinical and clinical research is critical in improving patient outcomes.}, }
@article {pmid39008789, year = {2024}, author = {Leonard, S and Helstrom, E and Correa, A and Sindhani, M and Uzzo, N and Jia, AY and Kutikov, A and Uzzo, R and Psutka, SP and Calaway, A and Klaassen, Z and Staehler, M and Smaldone, M and Wallis, CJD and Bukavina, L}, title = {Financial Distress in Genitourinary Cancer: Insights From CDC National Health Interview Survey.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2300733}, doi = {10.1200/OP.23.00733}, pmid = {39008789}, issn = {2688-1535}, abstract = {PURPOSE: This study leverages CDC National Health Interview Survey data to examine Financial Distress (FD) among genitourinary (GU) cancer survivors, specifically prostate cancer (PC), kidney cancer (KC), and bladder cancer (BC). It investigates the economic impacts faced by these patients, especially in relation to disparities in insurance coverage and its effects on material, psychological, and behavioral aspects of FD.<br><br>METHODS: We retrospectively analyzed responses from GU cancer survivors, stratifying by cancer status and age (18-64 years, &#x2265;65 years). Medical financial hardship was divided into three domains: material, psychological, and behavioral. Associations between cancer history, hardship, and clinical factors were assessed using generalized ordinal logistic regressions.<br><br>RESULTS: Significant health care access disparities were found, particularly for mental health services, with 25% of younger BC survivors and 4.7% of younger KC survivors reporting affordability issues, in contrast to 2.7% of noncancer individuals. Dental care was also problematic, with higher avoidance rates among younger BC (27%) and KC (15%) survivors compared with the general population. Surprisingly, noncancer individuals reported more difficulty in affording prescriptions than BC survivors across both age groups. PC survivors, however, showed lower FD across all domains versus noncancer controls, indicating fewer concerns about medical bills and a lesser tendency to forgo care.<br><br>CONCLUSION: The study underscores significant gaps in the financial support system for GU cancer survivors, with urgent needs in mental and dental health care access. Policy interventions, including comprehensive insurance reforms, are imperative to alleviate the financial burdens on these individuals.}, }
@article {pmid39008717, year = {2024}, author = {Mehta, RS and Petersdorf, EW and Wang, T and Spellman, SR and Lee, SJ}, title = {Interplay between donor age and HLA-DP matching in 10/10 HLA-matched unrelated donor HCT.}, journal = {Blood advances}, volume = {8}, number = {20}, pages = {5438-5449}, pmid = {39008717}, issn = {2473-9537}, support = {R01 CA231838/CA/NCI NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; R01 CA100019/CA/NCI NIH HHS/United States ; U01 AI069197/AI/NIAID NIH HHS/United States ; R01 CA218285/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/methods ; *Unrelated Donors ; Adult ; *Histocompatibility Testing ; Female ; Age Factors ; Middle Aged ; Male ; HLA Antigens/immunology ; Aged ; Young Adult ; }, abstract = {In 10/10 HLA-matched unrelated donor (MUD) hematopoietic cell transplantation (HCT) with calcineurin-inhibitor (CNI)-based prophylaxis, T-cell epitope DP-matched and permissive mismatched donors are associated with similar overall survival (OS) whereas donors with nonpermissive mismatches should be avoided. Younger unrelated donors are also favored over older donors. We explored outcomes associated with different combinations of DP-matching and donor age (dichotomized at 35 years) to further guide donor selection. Using a Center for International Blood and Marrow Transplant Research data set, we categorized 10 783 patients into 6 groups: DP-matched/younger donor (n = 1591), DP-matched/older donor (n = 526), permissive-mismatched/younger donor (n = 3845), permissive-mismatched/older donor (n = 1184), nonpermissive mismatched/younger donor (n = 2659), and nonpermissive mismatched/older donor (n = 978). We noted that younger donor age, rather than DP matching, was associated with better OS. Younger donors with permissive mismatches were associated with improved OS compared with older matched donors. Furthermore, younger donors with nonpermissive mismatches were associated with improved OS compared with older donors with permissive mismatches. Our study adds further information about the association of DP matching and donor age with HCT outcomes. Donor age should be prioritized over DP matching in patients undergoing 10/10 HLA-MUD with CNI prophylaxis. Among those with younger donors, permissive-mismatched or DP-matched donors are preferred over nonpermissive mismatched donors.}, }
@article {pmid39008559, year = {2024}, author = {Wang, Y and Chen, GC and Wang, Z and Luo, K and Zhang, Y and Li, Y and McClain, AC and Jankowska, MM and Perreira, KM and Mattei, J and Isasi, CR and Llabre, MM and Thyagarajan, B and Daviglus, ML and Van Horn, L and Goldsztajn Farelo, D and Maldonado, LE and Levine, SR and Yu, B and Boerwinkle, E and Knight, R and Burk, RD and Kaplan, RC and Qi, Q and Peters, BA}, title = {Dietary Acculturation Is Associated With Altered Gut Microbiome, Circulating Metabolites, and Cardiovascular Disease Risk in US Hispanics and Latinos: Results From HCHS/SOL.}, journal = {Circulation}, volume = {150}, number = {3}, pages = {215-229}, pmid = {39008559}, issn = {1524-4539}, support = {HHSN268201300003I/HL/NHLBI NIH HHS/United States ; R01 DK119268/DK/NIDDK NIH HHS/United States ; N01HC65236/HL/NHLBI NIH HHS/United States ; N01HC65234/HL/NHLBI NIH HHS/United States ; K01 HL169019/HL/NHLBI NIH HHS/United States ; K01 HL150406/HL/NHLBI NIH HHS/United States ; N01HC65237/HL/NHLBI NIH HHS/United States ; R01 HL140976/HL/NHLBI NIH HHS/United States ; HHSN268201300003C/HL/NHLBI NIH HHS/United States ; R01 HL148094/HL/NHLBI NIH HHS/United States ; R01 DK126698/DK/NIDDK NIH HHS/United States ; R01 MD011389/MD/NIMHD NIH HHS/United States ; K01 HL160146/HL/NHLBI NIH HHS/United States ; N01HC65235/HL/NHLBI NIH HHS/United States ; P30 DK111022/DK/NIDDK NIH HHS/United States ; N01HC65233/HL/NHLBI NIH HHS/United States ; U01 HL146204/HL/NHLBI NIH HHS/United States ; R01 HL141824/HL/NHLBI NIH HHS/United States ; U01 HL146202/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Gastrointestinal Microbiome ; Male ; Female ; *Acculturation ; *Cardiovascular Diseases/blood/ethnology ; *Hispanic or Latino ; Middle Aged ; United States/epidemiology ; Adult ; *Diet/adverse effects ; Risk Factors ; Incidence ; }, abstract = {BACKGROUND: Dietary acculturation, or adoption of dominant culture diet by migrant groups, influences human health. We aimed to examine dietary acculturation and its relationships with cardiovascular disease (CVD), gut microbiota, and blood metabolites among US Hispanic and Latino adults.<br><br>METHODS: In the HCHS/SOL (Hispanic Community Health Study/Study of Latinos), US exposure was defined by years in the United States (50 states and Washington, DC) and US nativity. A dietary acculturation pattern was derived from 14&#x2009;172 participants with two 24-hour dietary recalls at baseline (2008-2011) using least absolute shrinkage and selection operator regression, with food groups as predictors of US exposure. We evaluated associations of dietary acculturation with incident CVD across &#x2248;7 years of follow-up (n=211/14&#x2009;172 cases/total) and gut microbiota (n=2349; visit 2, 2014 to 2017). Serum metabolites associated with both dietary acculturation-related gut microbiota (n=694) and incident CVD (n=108/5256 cases/total) were used as proxy measures to assess the association of diet-related gut microbiome with incident CVD.<br><br>RESULTS: We identified an empirical US-oriented dietary acculturation score that increased with US exposure. Higher dietary acculturation score was associated with higher risk of incident CVD (hazard ratio per SD, 1.33 [95% CI, 1.13-1.57]), adjusted for sociodemographic, lifestyle, and clinical factors. Sixty-nine microbial species (17 enriched from diverse species, 52 depleted mainly from fiber-utilizing Clostridia and Prevotella species) were associated with dietary acculturation, driven by lower intakes of whole grains, beans, and fruits and higher intakes of refined grains. Twenty-five metabolites, involved predominantly in fatty acid and glycerophospholipid metabolism (eg, branched-chain 14:0 dicarboxylic acid** and glycerophosphoethanolamine), were associated with both diet acculturation-related gut microbiota and incident CVD. Proxy association analysis based on these metabolites suggested a positive relationship between diet acculturation-related microbiome and risk of CVD (r=0.70, P<0.001).<br><br>CONCLUSIONS: Among US Hispanic and Latino adults, greater dietary acculturation was associated with elevated CVD risk, possibly through alterations in gut microbiota and related metabolites. Diet and microbiota-targeted interventions may offer opportunities to mitigate CVD burdens of dietary acculturation.}, }
@article {pmid39007490, year = {2024}, author = {Kumar, A and Rara, M and Yu, M and Wen, KW and Grady, WM and Chak, A and Iyer, PG and Rustgi, AK and Wang, TC and Rubenstein, JH and Liu, Y and Kresty, L and Westerhoff, M and Kwon, RS and Wamsteker, E and Wang, T and Berry, L and Canto, MI and Shaheen, NJ and Wang, KK and Abrams, JA and Stachler, MD}, title = {Molecular Analysis of Persistent and Recurrent Barrett's Esophagus in the Setting of Endoscopic Therapy.}, journal = {Clinical and translational gastroenterology}, volume = {15}, number = {8}, pages = {e00751}, pmid = {39007490}, issn = {2155-384X}, support = {Clinician Scientist Development Award/DDCF/Doris Duke Charitable Foundation/United States ; U54CA163004/CA/NCI NIH HHS/United States ; U54 CA163059/CA/NCI NIH HHS/United States ; U24 CA163056/CA/NCI NIH HHS/United States ; Professorship Fund//Russ and Kathy Van Cleve/ ; R50 CA233042/CA/NCI NIH HHS/United States ; U54CA163059/CA/NCI NIH HHS/United States ; R37 CA269649/CA/NCI NIH HHS/United States ; U24CA163056/CA/NCI NIH HHS/United States ; R01 CA272898/CA/NCI NIH HHS/United States ; P30DK132710/DK/NIDDK NIH HHS/United States ; R37CA269649/CA/NCI NIH HHS/United States ; R01CA272898/CA/NCI NIH HHS/United States ; R01 CA238433/CA/NCI NIH HHS/United States ; P30 DK132710/DK/NIDDK NIH HHS/United States ; R01 CA241164/CA/NCI NIH HHS/United States ; R01 CA255298/CA/NCI NIH HHS/United States ; U54 CA163060/CA/NCI NIH HHS/United States ; R01CA255298/CA/NCI NIH HHS/United States ; U54 CA163004/CA/NCI NIH HHS/United States ; R01CA238433/CA/NCI NIH HHS/United States ; U54CA163060/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Barrett Esophagus/genetics/pathology ; Male ; Female ; Middle Aged ; Aged ; *Esophageal Neoplasms/genetics/pathology ; Esophagoscopy ; Recurrence ; Neoplasm Recurrence, Local/genetics/epidemiology ; Disease Progression ; Esophagus/pathology/surgery ; Adenocarcinoma/genetics/pathology ; Sequence Analysis, DNA ; Mutation ; }, abstract = {INTRODUCTION: Early neoplastic progression of Barrett's esophagus (BE) is often treated with endoscopic therapy. Although effective, some patients are refractory to therapy or recur after apparent eradication of the BE. The goal of this study was to determine whether genomic alterations within the treated BE may be associated with persistent or recurrent disease.<br><br>METHODS: We performed DNA sequencing on pre-treatment esophageal samples from 45 patients who were successfully treated by endoscopic therapy and did not recur as well as pre-treatment and post-treatment samples from 40 patients who had persistent neoplasia and 21 patients who had recurrent neoplasia. The genomic alterations were compared between groups.<br><br>RESULTS: The genomic landscape was similar between all groups. Patients with persistent disease were more likely to have pre-treatment alterations involving the receptor tyrosine kinase pathway (P = 0.01), amplifications of oncogenes (P = 0.01), and deletions of tumor suppressor genes (P = 0.02). These associations were no longer significant after adjusting for patient age and BE length. More than half of patients with persistent (52.5%) or recurrent (57.2%) disease showed pre-treatment and post-treatment samples that shared at least 50% of their driver mutations.<br><br>DISCUSSION: Pre-treatment samples were genomically similar between those who responded to endoscopic therapy and those who had persistent or recurrent disease, suggesting there is not a strong genomic component to treatment response. Although it was expected to find shared driver mutations in pre-treatment and post-treatment samples in patients with persistent disease, the finding that an equal number of patients with recurrent disease also showed this relation suggests that many recurrences represent undetected minimal residual disease.}, }
@article {pmid39006423, year = {2024}, author = {Asano, Y and Veatch, J and McAfee, M and Bakhtiari, J and Lee, B and Martin, L and Zhang, S and Mazziotta, F and Paulson, KG and Schmitt, TM and Munkbhat, A and Young, C and Seaton, B and Hunter, D and Horst, N and Lindberg, M and Miller, N and Stone, M and Bielas, J and Koelle, D and Voillet, V and Gottardo, R and Gooley, T and Oda, S and Greenberg, PD and Nghiem, P and Chapuis, AG}, title = {Tumor Regression Following Engineered Polyomavirus-Specific T Cell Therapy in Immune Checkpoint Inhibitor-Refractory Merkel Cell Carcinoma.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39006423}, support = {P01 CA225517/CA/NCI NIH HHS/United States ; }, abstract = {Although immune check-point inhibitors (CPIs) revolutionized treatment of Merkel cell carcinoma (MCC), patients with CPI-refractory MCC lack effective therapy. More than 80% of MCC express T-antigens encoded by Merkel cell polyomavirus, which is an ideal target for T-cell receptor (TCR)-based immunotherapy. However, MCC often repress HLA expression, requiring additional strategies to reverse the downregulation for allowing T cells to recognize their targets. We identified TCRMCC1 that recognizes a T-antigen epitope restricted to human leukocyte antigen (HLA)-A*02:01. Seven CPI-refractory metastatic MCC patients received CD4 and CD8 T cells transduced with TCRMCC1 (TTCR-MCC1) preceded either by lymphodepleting chemotherapy or an HLA-upregulating regimen (single-fraction radiation therapy (SFRT) or systemic interferon gamma (IFNγ)) with concurrent avelumab. Two patients who received preceding SFRT and IFNγ respectively experienced tumor regression. One experienced regression of 13/14 subcutaneous lesions with 1 'escape' lesion and the other had delayed tumor regression in all lesions after initial progression. Although TTCR-MCC1 cells with an activated phenotype infiltrated tumors including the 'escape' lesion, all progressing lesions transcriptionally lacked HLA expression. While SFRT/IFNγ did not immediately upregulate tumor HLA expression, a secondary endogenous antigen-specific T cell infiltrate was detected in one of the regressing tumors and associated with HLA upregulation, indicating in situ immune responses have the potential to reverse HLA downregulation. Indeed, supplying a strong co-stimulatory signal via a CD200R-CD28 switch receptor allows TTCR-MCC1 cells to control HLA-downregulated MCC cells in a xenograft mouse model, upregulating HLA expression. Our results demonstrate the potential of TCR gene therapy for metastatic MCC and propose a next strategy for overcoming epigenetic downregulation of HLA in MCC.}, }
@article {pmid39005399, year = {2024}, author = {Briney, CA and Henriksen, JC and Lin, C and Jones, LA and Benner, L and Rains, AB and Gutierrez, R and Gafken, PR and Rissland, OS}, title = {Muskelin acts as a substrate receptor of the highly regulated Drosophila CTLH E3 ligase during the maternal-to-zygotic transition.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39005399}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R35 GM128680/GM/NIGMS NIH HHS/United States ; P40 OD010949/OD/NIH HHS/United States ; T32 GM141742/GM/NIGMS NIH HHS/United States ; T32 GM136444/GM/NIGMS NIH HHS/United States ; S10 OD030225/OD/NIH HHS/United States ; }, abstract = {The maternal-to-zygotic transition (MZT) is a conserved developmental process where the maternally-derived protein and mRNA cache is replaced with newly made zygotic gene products. We have previously shown that in Drosophila the deposited RNA-binding proteins ME31B, Cup, and Trailer Hitch (TRAL) are ubiquitylated by the CTLH E3 ligase and cleared. However, the organization and regulation of the CTLH complex remain poorly understood in flies. In particular, Drosophila lacks an identifiable substrate adaptor, and the mechanisms restricting degradation of ME31B and its cofactors to the MZT are unknown. Here, we show that the developmental specificity of the CTLH complex is mediated by multipronged regulation, including transcriptional control by the transcription factor OVO and autoinhibition of the E3 ligase. One major regulatory target is the subunit Muskelin, which we demonstrate acts as a substrate adaptor for the Drosophila CTLH complex. Although conserved, Muskelin has structural roles in other species, suggesting a surprising functional plasticity. Finally, we find that Muskelin has few targets beyond the three known RNA binding proteins, showing exquisite target specificity. Thus, multiple levels of integrated regulation restrict the activity of the embryonic CTLH complex to early embryogenesis, seemingly with the goal of regulating three important RNA binding proteins.}, }
@article {pmid39005374, year = {2024}, author = {Wu, P and Becker, FB and Ogelman, R and Camci, ED and Linbo, TH and Simon, JA and Rubel, EW and Raible, DW}, title = {Multiple mechanisms of aminoglycoside ototoxicity are distinguished by subcellular localization of action.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39005374}, issn = {2692-8205}, support = {R01 DC005987/DC/NIDCD NIH HHS/United States ; }, abstract = {Mechanosensory hair cells of the inner ears and lateral line of vertebrates display heightened vulnerability to environmental insult, with damage resulting in hearing and balance disorders. An important example is hair cell loss due to exposure to toxic agents including therapeutic drugs such as the aminoglycoside antibiotics such as neomycin and gentamicin and antineoplastic agents. We describe two distinct cellular pathways for aminoglycoside-induced hair cell death in zebrafish lateral line hair cells. Neomycin exposure results in death from acute exposure with most cells dying within 1 hour of exposure. By contrast, exposure to gentamicin results primarily in delayed hair cell death, taking up to 24 hours for maximal effect. Washout experiments demonstrate that delayed death does not require continuous exposure, demonstrating two mechanisms where downstream responses differ in their timing. Acute damage is associated with mitochondrial calcium fluxes and can be alleviated by the mitochondrially-targeted antioxidant mitoTEMPO, while delayed death is independent of these factors. Conversely delayed death is associated with lysosomal accumulation and is reduced by altering endolysosomal function, while acute death is not sensitive to lysosomal manipulations. These experiments reveal the complexity of responses of hair cells to closely related compounds, suggesting that intervention focusing on early events rather than specific death pathways may be a successful therapeutic strategy.}, }
@article {pmid39005367, year = {2024}, author = {Gao, Y and Feder, AF}, title = {Detecting branching rate heterogeneity in multifurcating trees with applications in lineage tracing data.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39005367}, issn = {2692-8205}, support = {DP2 CA280623/CA/NCI NIH HHS/United States ; }, abstract = {Understanding cellular birth rate differences is crucial for predicting cancer progression and interpreting tumor-derived genetic data. Lineage tracing experiments enable detailed reconstruction of cellular genealogies, offering new opportunities to measure branching rate heterogeneity. However, the lineage tracing process can introduce complex tree features that complicate this effort. Here, we examine tree characteristics in lineage tracing-derived genealogies and find that editing window placement leads to multifurcations at a tree's root or tips. We propose several ways in which existing tree topology-based metrics can be extended to test for rate heterogeneity on trees even in the presence of lineage-tracing associated distortions. Although these methods vary in power and robustness, a test based on the J 1 statistic effectively detects branching rate heterogeneity in simulated lineage tracing data. Tests based on other common statistics (s ^ and the Sackin index) show interior performance to J 1 . We apply our validated methods to xenograft experimental data and find widespread rate heterogeneity across multiple study systems. Our results demonstrate the potential of tree topology statistics in analyzing lineage tracing data, and highlight the challenges associated with adapting phylogenetic methods to these systems.}, }
@article {pmid39005354, year = {2024}, author = {MacLean, F and Tsegaye, AT and Graham, JB and Swarts, JL and Vick, SC and Potchen, N and Talavera, IC and Warrier, L and Dubrulle, J and Schroeder, LK and Mar, C and Thomas, KK and Mack, M and Sabo, MC and Chohan, BH and Ngure, K and Mugo, N and Lingappa, JR and Lund, JM and , }, title = {Bacterial vaginosis-driven changes in vaginal T cell phenotypes and their implications for HIV susceptibility.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39005354}, issn = {2692-8205}, support = {T32 AI007509/AI/NIAID NIH HHS/United States ; T32 AI007140/AI/NIAID NIH HHS/United States ; R01 AI131914/AI/NIAID NIH HHS/United States ; R01 AI141435/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; T32 AI083203/AI/NIAID NIH HHS/United States ; R01 AI129715/AI/NIAID NIH HHS/United States ; }, abstract = {Bacterial vaginosis (BV) is a dysbiosis of the vaginal microbiome that is prevalent in reproductive-age women worldwide. Adverse outcomes associated with BV include an increased risk of sexually acquired Human Immunodeficiency Virus (HIV), yet the immunological mechanisms underlying this association are not well understood. To investigate BV driven changes to cervicovaginal tract (CVT) and circulating T cell phenotypes, participants with or without BV provided vaginal tract (VT) and ectocervical (CX) tissue biopsies and peripheral blood mononuclear cells (PBMC). Immunofluorescence analysis of genital mucosal tissues revealed a reduced density of CD3[+]CD4[+]CCR5[+] cells in the VT lamina propria of individuals with compared to those without BV (median 243.8 cells/mm[2] BV- vs 106.9 cells/mm[2] BV+, p=0.043). High-parameter flow cytometry of VT biopsies revealed an increased frequency in individuals with compared to those without BV of dysfunctional CD39[+] conventional CD4[+] T cells (Tconv) (median frequency 15% BV- vs 30% BV+, padj=0.0331) and tissue-resident CD69+CD103[+] Tconv (median frequency 24% BV- vs 38% BV+, padj=0.0061), previously reported to be implicated in HIV acquisition and replication. Our data suggests that BV elicits diverse and complex VT T cell alterations and expands on potential immunological mechanisms that may promote adverse outcomes including HIV susceptibility.}, }
@article {pmid39003390, year = {2024}, author = {Cox, ER and Summers, C and Milano, F and Dahlberg, A and Bleakley, M and Sandmaier, BM and Thakar, MS}, title = {Outcomes of patients undergoing third hematopoietic cell transplantation for hematologic malignancies.}, journal = {Annals of hematology}, volume = {103}, number = {9}, pages = {3737-3743}, pmid = {39003390}, issn = {1432-0584}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation ; Adult ; Middle Aged ; Male ; Female ; Adolescent ; Aged ; *Hematologic Neoplasms/therapy/mortality ; Child ; Young Adult ; Treatment Outcome ; Survival Rate ; Leukemia, Myeloid, Acute/therapy/mortality ; Retrospective Studies ; }, abstract = {With advancements in novel therapeutics, it is unclear whether third hematopoietic cell transplantation (HCT3) has a place in the treatment of recurrent hematopoietic malignancies. We evaluated patients with hematologic malignancies who underwent HCT3 between 2000-2020. Nine patients, with a median age of 18 (9-68) years at HCT3 with acute myelogenous leukemia (n = 5), acute lymphoblastic leukemia (n = 2), myelodysplastic syndrome (n = 1), or undifferentiated acute leukemia (n = 1), were identified. The median time between first HCT and HCT3 was 3.9 (0.7-13.6) years. Indication for HCT3 was relapse (n = 8) or graft failure (n = 1) after second HCT. At HCT3, seven of nine patients were in complete remission by flow cytometry. All experienced robust donor engraftment by one month after HCT3 (≥ 90% CD3) while one died at day + 24 of multi-organ failure and was not evaluable for chimerism. In total, eight patients died from relapse (n = 4), non-relapse, (n = 3) or unknown (n = 1) causes at a median of 0.6 (range, 0.1 - 9.9) years after HCT3. After HCT3, estimated overall survival at 6 months, 1 year, and 5 years was 88%, 63%, and 22%, respectively. In this highly selected group, HCT3 provided a treatment option although long-term survival was still dismal.}, }
@article {pmid39003201, year = {2024}, author = {Plimack, ER and Tangen, C and Plets, M and Kokate, R and Xiu, J and Nabhan, C and Ross, EA and Grundy, E and Choi, W and Dinney, CPN and Lee, IC and Fong, M and Scott Lucia, M and Daneshmand, S and Theodorescu, D and Goldkorn, A and Lerner, SP and Flaig, TW and McConkey, DJ}, title = {Correlative Analysis of ATM, RB1, ERCC2, and FANCC Mutations and Pathologic Complete Response After Neoadjuvant Chemotherapy in Patients with Muscle-invasive Bladder Cancer: Results from the SWOG S1314 Trial.}, journal = {European urology}, volume = {86}, number = {4}, pages = {297-300}, pmid = {39003201}, issn = {1873-7560}, support = {P30 CA006927/CA/NCI NIH HHS/United States ; U10 CA180819/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; U24 CA196175/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Urinary Bladder Neoplasms/genetics/drug therapy/pathology/surgery ; *Neoadjuvant Therapy ; *Mutation ; *Cisplatin/therapeutic use/administration &amp; dosage ; *Xeroderma Pigmentosum Group D Protein/genetics ; *Retinoblastoma Binding Proteins/genetics ; Male ; *Ataxia Telangiectasia Mutated Proteins/genetics ; Female ; *Fanconi Anemia Complementation Group C Protein/genetics ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; *Cystectomy ; Middle Aged ; Ubiquitin-Protein Ligases/genetics ; Aged ; Neoplasm Invasiveness ; Biomarkers, Tumor/genetics ; Treatment Outcome ; Chemotherapy, Adjuvant ; Pathologic Complete Response ; }, abstract = {We previously reported that tumors harboring any one of four gene mutations (ATM, RB1, FANCC, or ERCC2) were likely to respond to neoadjuvant cisplatin-based chemotherapy (NAC), resulting in cancer-free surgical specimens at the time of cystectomy (pT0). Here, we report our validation of this finding. Using the CARIS 592 Gene Panel (Caris Life Sciences, Phoenix, AZ, USA), we analyzed 105 pre-NAC tumor specimens from a large multicenter trial (S1314) of either neoadjuvant gemcitabine and cisplatin (GC), or dose-dense methotrexate, vinblastine, Adriamycin, and cisplatin (DDMVAC). We found that a mutation in any one of these four genes predicted for pT0 at surgery (odds ratio = 5.36; 95% confidence interval [CI] 2.05, 14.02; two-sided p = 0.0006). The biomarker was better at predicting the presence of disease (negative predictive value for pT0 86%; 95% CI 73%, 94%) than the absence of disease (positive predictive value for pT0 48%; 95% CI 35%, 62%). There was no evidence of an interaction between the treatment arm (DDMVAC vs GC) and the genetic variant in terms of pT0. When combined with clinical assessment, these findings help inform patient selection for bladder preservation after cisplatin-based chemotherapy.}, }
@article {pmid39001544, year = {2024}, author = {Foley, GR and Marthick, JR and Lucas, SE and Raspin, K and Banks, A and Stanford, JL and Ostrander, EA and FitzGerald, LM and Dickinson, JL}, title = {Germline Sequencing of DNA Damage Repair Genes in Two Hereditary Prostate Cancer Cohorts Reveals New Disease Risk-Associated Gene Variants.}, journal = {Cancers}, volume = {16}, number = {13}, pages = {}, pmid = {39001544}, issn = {2072-6694}, support = {NA//Cancer Council Tasmania/ ; IPAP20210253//IMPACT Perpetual Trustees/ ; NA//Royal Hobart Hospital Research Foundation/ ; NA//Cancer Australia/ ; NA//The Mazda Foundation/ ; NA//Max Bruce Trust/ ; NA//The Estate of Dr RA Parker/ ; NA//Tasmanian Community Fund/ ; NA//Robert Malcom Familial Prostate Cancer Bequest/ ; P30 CA015704/CA/NCI NIH HHS/United States ; NA//Institute for Prostate Cancer Research of the University of Washington Medicine and Fred Hutchinson Cancer Center/ ; }, abstract = {Rare, inherited variants in DNA damage repair (DDR) genes have a recognised role in prostate cancer (PrCa) susceptibility. In addition, these genes are therapeutically targetable. While rare variants are informing clinical management in other common cancers, defining the rare disease-associated variants in PrCa has been challenging. Here, whole-genome and -exome sequencing data from two independent, high-risk Australian and North American familial PrCa datasets were interrogated for novel DDR risk variants. Rare DDR gene variants (predicted to be damaging and present in two or more family members) were identified and subsequently genotyped in 1963 individuals (700 familial and 459 sporadic PrCa cases, 482 unaffected relatives, and 322 screened controls), and association analyses accounting for relatedness (MQLS) undertaken. In the combined datasets, rare ERCC3 (rs145201970, p = 2.57 × 10[-4]) and BRIP1 (rs4988345, p = 0.025) variants were significantly associated with PrCa risk. A PARP2 (rs200603922, p = 0.028) variant in the Australian dataset and a MUTYH (rs36053993, p = 0.031) variant in the North American dataset were also associated with risk. Evaluation of clinicopathological characteristics provided no evidence for a younger age or higher-grade disease at diagnosis in variant carriers, which should be taken into consideration when determining genetic screening eligibility criteria for targeted, gene-based treatments in the future. This study adds valuable knowledge to our understanding of PrCa-associated DDR genes, which will underpin effective clinical screening and treatment strategies.}, }
@article {pmid39001542, year = {2024}, author = {Alam, R and Fan, X and Hippe, DS and Tachiki, LM and Gong, E and Huynh, E and Nghiem, P and Park, SY}, title = {Lack of Clinically Significant Relationships of Age or Body Mass Index with Merkel Cell Carcinoma Immunotherapy Outcomes.}, journal = {Cancers}, volume = {16}, number = {13}, pages = {}, pmid = {39001542}, issn = {2072-6694}, support = {P01 CA225517/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; Kelsey Dickson Team Science Courage Research Award//Prostate Cancer Foundation/ ; MCC Gift Fund//University of Washington/ ; }, abstract = {Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer with a high risk of metastasis. The development of anti-PD-1/PD-L1 immunotherapy has improved outcomes for advanced MCC, yet about 50% of such patients do not achieve durable responses. This study analyzed the effects of age and body mass index (BMI) on immunotherapy response in 183 advanced MCC patients from a single-center longitudinal database. Using Fine-Gray or Cox regression models, treatment response, progression-free survival (PFS), MCC-specific survival, and overall survival (OS) were evaluated. Age showed a significant non-linear relationship with treatment response (p = 0.04), with patients much older or younger than 70 years less likely to respond. However, age was not significantly associated with PFS (p = 0.21), MCC-specific survival (p = 0.72), or OS (p = 0.36). Similarly, BMI was not significantly correlated with treatment response (p = 0.41), PFS (p = 0.52), MCC-specific survival (p = 0.78), or OS (p = 0.71). Unlike previous studies suggesting that obesity and advanced age improve outcomes in other cancers, these associations were not observed in MCC. These findings suggest that age and BMI should not influence eligibility for immunotherapy in MCC patients, emphasizing the importance of unbiased patient selection for this treatment.}, }
@article {pmid38997299, year = {2024}, author = {Koester, ST and Chow, A and Pepper-Tunick, E and Lee, P and Eckert, M and Brenchley, L and Gardner, P and Song, HJ and Li, N and Schiffenbauer, A and Volochayev, R and Bayat, N and McLean, JS and Rider, LG and Shenoi, S and Stevens, AM and Dey, N}, title = {Familial clustering of dysbiotic oral and fecal microbiomes in juvenile dermatomyositis.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {16158}, pmid = {38997299}, issn = {2045-2322}, support = {HHSN2732016000021/ES/NIEHS NIH HHS/United States ; ZIAES101074/NH/NIH HHS/United States ; DK111941/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; *Feces/microbiology ; *Dermatomyositis/microbiology/genetics ; Female ; Male ; Child ; *Mouth/microbiology ; *RNA, Ribosomal, 16S/genetics ; *Gastrointestinal Microbiome/genetics ; Prospective Studies ; Dysbiosis/microbiology ; Microbiota/genetics ; Child, Preschool ; Adolescent ; Saliva/microbiology ; Adult ; }, abstract = {Juvenile dermatomyositis (JDM) is a rare immune-mediated disease of childhood with putative links to microbial exposures. In this multi-center, prospective, observational cohort study, we evaluated whether JDM is associated with discrete oral and gut microbiome signatures. We generated 16S rRNA sequencing data from fecal, saliva, supragingival, and subgingival plaque samples from JDM probands (n = 28). To control for genetic and environmental determinants of microbiome community structure, we also profiled microbiomes of unaffected family members (n = 27 siblings, n = 26 mothers, and n = 17 fathers). Sample type (oral-vs-fecal) and nuclear family unit were the predominant variables explaining variance in microbiome diversity, more so than having a diagnosis of JDM. The oral and gut microbiomes of JDM probands were more similar to their own unaffected siblings than they were to the microbiomes of other JDM probands. In a sibling-paired within-family analysis, several potentially immunomodulatory bacterial taxa were differentially abundant in the microbiomes of JDM probands compared to their unaffected siblings, including Faecalibacterium (gut) and Streptococcus (oral cavity). While microbiome features of JDM are often shared by unaffected family members, the loss or gain of specific fecal and oral bacteria may play a role in disease pathogenesis or be secondary to immune dysfunction in susceptible individuals.}, }
@article {pmid38996457, year = {2024}, author = {Sokolov, D and Sullivan, LB}, title = {Thrifty tissues prefer recycled purines over new-cleotides.}, journal = {Molecular cell}, volume = {84}, number = {13}, pages = {2407-2409}, doi = {10.1016/j.molcel.2024.06.015}, pmid = {38996457}, issn = {1097-4164}, mesh = {*Purines/metabolism ; Humans ; Animals ; Neoplasms/metabolism/genetics/pathology ; Purine Nucleotides/metabolism ; }, abstract = {In two recent studies appearing in Cell[1] and Cell Metabolism,[2] Tran et al. and Wu et al. describe underappreciated nuance in organismal and cellular purine nucleotide salvage pathways and identify purine salvage as a metabolic limitation for tumor growth.}, }
@article {pmid38996210, year = {2024}, author = {Xie, Z and Komrokji, R and Al Ali, N and Regelson, A and Geyer, S and Patel, A and Saygin, C and Zeidan, AM and Bewersdorf, JP and Mendez, L and Kishtagari, A and Zeidner, JF and Coombs, CC and Madanat, YF and Chung, S and Badar, T and Foran, J and Desai, P and Tsai, C and Griffiths, EA and Al Malki, MM and Amanam, I and Lai, C and Deeg, HJ and Ades, L and Arana Yi, C and Osman, AEG and Dinner, S and Abaza, Y and Taylor, J and Chandhok, N and Soong, D and Brunner, AM and Carraway, HE and Singh, A and Elena, C and Ferrari, J and Gallì, A and Pozzi, S and Padron, E and Patnaik, MM and Malcovati, L and Savona, MR and Al-Kali, A}, title = {Risk prediction for clonal cytopenia: multicenter real-world evidence.}, journal = {Blood}, volume = {144}, number = {19}, pages = {2033-2044}, pmid = {38996210}, issn = {1528-0020}, mesh = {Humans ; Female ; Male ; Aged ; Middle Aged ; *Mutation ; Adult ; Aged, 80 and over ; Prognosis ; Risk Factors ; Risk Assessment/methods ; Clonal Hematopoiesis ; Cytopenia ; }, abstract = {Clonal cytopenia of undetermined significance (CCUS) represents a distinct disease entity characterized by myeloid-related somatic mutations with a variant allele fraction of ≥2% in individuals with unexplained cytopenia(s) but without a myeloid neoplasm (MN). Notably, CCUS carries a risk of progressing to MN, particularly in cases featuring high-risk mutations. Understanding CCUS requires dedicated studies to elucidate its risk factors and natural history. Our analysis of 357 patients with CCUS investigated the interplay between clonality, cytopenia, and prognosis. Multivariate analysis identified 3 key adverse prognostic factors: the presence of splicing mutation(s) (score = 2 points), platelet count of <100 × 109/L (score = 2.5), and ≥2 mutations (score = 3). Variable scores were based on the coefficients from the Cox proportional hazards model. This led to the development of the clonal cytopenia risk score (CCRS), which stratified patients into low- (score of <2.5 points), intermediate- (score of 2.5 to <5), and high-risk (score of ≥5) groups. The CCRS effectively predicted 2-year cumulative incidence of MN for low- (6.4%), intermediate- (14.1%), and high-risk (37.2%) groups, respectively, by the Gray test (P < .0001). We further validated the CCRS by applying it to an independent CCUS cohort of 104 patients, demonstrating a c-index of 0.64 (P = .005) in stratifying the cumulative incidence of MN. Our study underscores the importance of integrating clinical and molecular data to assess the risk of CCUS progression, making the CCRS a valuable tool that is practical and easily calculable. These findings are clinically relevant, shaping the management strategies for CCUS and informing future clinical trial designs.}, }
@article {pmid38992469, year = {2024}, author = {Mehta, RS and Petersdorf, EW and Wang, T and Lee, SJ}, title = {Haploidentical Versus Mismatched Unrelated Donor Hematopoietic Cell Transplantation: HLA Factors and Donor Age Considerations.}, journal = {Transplantation and cellular therapy}, volume = {30}, number = {9}, pages = {909.e1-909.e11}, doi = {10.1016/j.jtct.2024.07.005}, pmid = {38992469}, issn = {2666-6367}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/methods ; *Unrelated Donors ; Adult ; Middle Aged ; Female ; Male ; Adolescent ; Age Factors ; Child, Preschool ; Histocompatibility Testing ; Transplantation, Haploidentical ; Aged ; Child ; Graft vs Host Disease/prevention &amp; control ; Young Adult ; HLA Antigens/immunology ; Infant ; Cyclophosphamide/therapeutic use ; HLA-DRB1 Chains/genetics ; }, abstract = {HLA-mismatched unrelated donors and haploidentical related donors are suitable stem cell sources for hematopoietic cell transplantation (HCT) when patients lack HLA-matched donors. Clinical outcome after mismatched HCT is influenced by HLA factors including the similarity of peptide-binding motifs (PBMs) between the patient and unrelated donor, and of the HLA-B leader in unrelated and haploidentical donors. Whether these factors can aid in the selection between mismatched unrelated and haploidentical donors is not known. To address this question, we investigated outcomes between the two donor types defined by matching for the PBM and leader peptide. We compared PBM-matched (n = 614) and mismatched (n = 958) MMUDs with calcineurin-inhibitor-based prophylaxis to four haploidentical groups that received post-transplant cyclophosphamide (PTCy)-based prophylaxis. The haploidentical groups were B-leader matched/DRB1-mismatched (n = 722), B-leader matched/DRB1-matched (n = 154), B-leader mismatched/DRB1-mismatched (n = 493), and B-leader mismatched/DRB1-matched (n = 63). Multivariate analysis showed that the B-leader matched/DRB1-mismatched haploidentical group had the best overall survival (OS) compared to the PBM-matched MMUD, while other haploidentical groups had comparable OS. The PBM-mismatched MMUD showed the poorest outcomes, similar to the B-leader mismatched/DRB1-matched haploidentical group. Among non-HLA factors, donor age was the most significant predictor of OS. These results suggest that a B-leader matched/DRB1 mismatched haploidentical donor might be the preferred choice among donors of similar age. If such a donor is not available, the youngest donor from either PBM-matched unrelated or other haploidentical groups could be a beneficial choice. These findings need validation with both donor groups receiving PTCy-based graft-versus-host disease prophylaxis.}, }
@article {pmid38991829, year = {2024}, author = {Cicero, KI and Dlamini, X and Mavengere, Y and Justman, J and Nuwagaba-Biribonwoha, H and Dlamini, S and Dlamini, M and Ngwenyama, S and Ngcamphalala, C and Low, A and Philip, NM and El-Sadr, WM and Sahabo, R and Abreha, T and Temesgen, S and Mahlalela, N and Chiuzan, C and Chen, Y and Pan, SS and Lentzsch, S and Neugut, AI}, title = {Prevalence of monoclonal gammopathy of undetermined significance in Eswatini: a population-based study in Africa.}, journal = {JNCI cancer spectrum}, volume = {8}, number = {4}, pages = {}, pmid = {38991829}, issn = {2515-5091}, support = {P30 CA013696/CA/NCI NIH HHS/United States ; 22-40-15-CICE//2022 American Association for Cancer Research &amp; Bristol Myers Squibb Cancer Disparities Fellowship/ ; }, mesh = {Humans ; Female ; Male ; Prevalence ; Middle Aged ; *Monoclonal Gammopathy of Undetermined Significance/epidemiology/blood ; Aged ; Adult ; Aged, 80 and over ; *HIV Infections/epidemiology/complications ; Eswatini/epidemiology ; Minnesota/epidemiology ; Multiple Myeloma/epidemiology ; Incidence ; Odds Ratio ; }, abstract = {BACKGROUND: Although monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma disproportionately affect Black individuals, few epidemiological studies have been conducted on these plasma cell disorders in Africa. Here we describe the prevalence of MGUS in Eswatini and compare our results to the landmark Olmsted County, Minnesota study.<br><br>METHODS: Between 2016 and 2017, 13&#x2009;339 residents of Eswatini participated in the Swaziland HIV Incidence Measurement Survey, from which a nationally representative biorepository was created. Plasma samples were then randomly selected and analyzed for MGUS. MGUS prevalence in Eswatini was compared with that of Olmsted County. In addition, demographic and HIV-related associations with MGUS were assessed.<br><br>RESULTS: Of the 515 samples randomly selected, the median age was 50&#x2009;years (range&#x2009;=&#x2009;35-80 years); 60% were female; and 38.6% were HIV positive, of whom 82.4% were on antiretroviral therapy. We found that 68 participants had evidence of MGUS, for a prevalence of 13.2%. HIV status was not significantly associated with MGUS (odds ratio&#x2009;=&#x2009;1.05, 95% confidence interval&#x2009;=&#x2009;0.62 to 1.77), but among HIV-positive individuals, MGUS was less frequent for patients on antiretroviral therapy (adjusted odds ratio&#x2009;=&#x2009;0.31, 95% confidence interval&#x2009;=&#x2009;0.11 to 0.82). The prevalence of conventional MGUS was similar between Eswatini and Olmsted County (3.4% vs 3.2%-3.4%), whereas the incidence of light-chain MGUS was significantly greater in Eswatini (12.3% vs 0.8%).<br><br>CONCLUSION: Our study suggests that the incidence of MGUS is similar between ethnicities and raises the question of whether the current definition of light-chain MGUS reliably reflects a true monoclonal protein precursor state. Perhaps the current definition of light-chain MGUS may be capturing alternate etiologies, such as untreated HIV infection.}, }
@article {pmid38991631, year = {2024}, author = {Vinayak, S and Cecil, DL and Disis, ML}, title = {Vaccines for breast cancer prevention: Are we there yet?.}, journal = {Molecular aspects of medicine}, volume = {98}, number = {}, pages = {101292}, doi = {10.1016/j.mam.2024.101292}, pmid = {38991631}, issn = {1872-9452}, mesh = {Female ; Humans ; *Breast Neoplasms/prevention &amp; control/immunology ; *Cancer Vaccines/immunology/therapeutic use ; }, }
@article {pmid38991590, year = {2024}, author = {Plender, EG and Prodanov, T and Hsieh, P and Nizamis, E and Harvey, WT and Sulovari, A and Munson, KM and Kaufman, EJ and O'Neal, WK and Valdmanis, PN and Marschall, T and Bloom, JD and Eichler, EE}, title = {Structural and genetic diversity in the secreted mucins MUC5AC and MUC5B.}, journal = {American journal of human genetics}, volume = {111}, number = {8}, pages = {1700-1716}, pmid = {38991590}, issn = {1537-6605}, support = {R00 HG011041/HG/NHGRI NIH HHS/United States ; U41 HG007497/HG/NHGRI NIH HHS/United States ; R01 HG010169/HG/NHGRI NIH HHS/United States ; U24 HG007497/HG/NHGRI NIH HHS/United States ; R01 HG002385/HG/NHGRI NIH HHS/United States ; }, mesh = {Humans ; *Mucin-5B/genetics ; *Haplotypes ; Animals ; *Mucin 5AC/genetics/metabolism ; *Minisatellite Repeats/genetics ; *Genetic Variation ; *Alleles ; *Phylogeny ; DNA Copy Number Variations ; Primates/genetics ; }, abstract = {The secreted mucins MUC5AC and MUC5B are large glycoproteins that play critical defensive roles in pathogen entrapment and mucociliary clearance. Their respective genes contain polymorphic and degenerate protein-coding variable number tandem repeats (VNTRs) that make the loci difficult to investigate with short reads. We characterize the structural diversity of MUC5AC and MUC5B by long-read sequencing and assembly of 206 human and 20 nonhuman primate (NHP) haplotypes. We find that human MUC5B is largely invariant (5,761-5,762 amino acids [aa]); however, seven haplotypes have expanded VNTRs (6,291-7,019 aa). In contrast, 30 allelic variants of MUC5AC encode 16 distinct proteins (5,249-6,325 aa) with cysteine-rich domain and VNTR copy-number variation. We group MUC5AC alleles into three phylogenetic clades: H1 (46%, ∼5,654 aa), H2 (33%, ∼5,742 aa), and H3 (7%, ∼6,325 aa). The two most common human MUC5AC variants are smaller than NHP gene models, suggesting a reduction in protein length during recent human evolution. Linkage disequilibrium and Tajima's D analyses reveal that East Asians carry exceptionally large blocks with an excess of rare variation (p < 0.05) at MUC5AC. To validate this result, we use Locityper for genotyping MUC5AC haplogroups in 2,600 unrelated samples from the 1000 Genomes Project. We observe a signature of positive selection in H1 among East Asians and a depletion of the likely ancestral haplogroup (H3). In Europeans, H3 alleles show an excess of common variation and deviate from Hardy-Weinberg equilibrium (p < 0.05), consistent with heterozygote advantage and balancing selection. This study provides a generalizable strategy to characterize complex protein-coding VNTRs for improved disease associations.}, }
@article {pmid38991198, year = {2024}, author = {Vonhoff, F and Ko'omoa-Lange, DL and Davis, JS and Termini, CM and Martínez-Montemayor, MM}, title = {Maximizing Access to Cell Biology for PEERS: Retracting the term minority in favor of a more inclusive lexicon.}, journal = {Molecular biology of the cell}, volume = {35}, number = {8}, pages = {vo1}, pmid = {38991198}, issn = {1939-4586}, mesh = {Humans ; *Cell Biology ; *Minority Groups ; Societies, Scientific ; United States ; Peer Group ; Terminology as Topic ; }, abstract = {The word minority, when used incorrectly, is a condescending term that segregates, inaccurately represents groups as being smaller or less important, and fuels microaggressions. Scientific societies and other institutions have normalized using the word minority, or the "M word," to refer to members of underrepresented groups in Science, Technology, Engineering, and Mathematics (STEM). The message put forth using the term minority often directly conflicts with the inclusive agenda these societies seek to enact. More inclusive acronyms such as PEER (Persons Excluded because of their Ethnicity or Race) have been created to more accurately reflect the active process of exclusion by institutions. Here, we detail the rationale behind the decision to eradicate the word minority from the name of a prominent committee within the American Society for Cell Biology (ASCB). The ASCB Minority Affairs Committee changed its name to the Maximizing Access to Cell Biology for PEERS Committee. Herein, we emphasize the basis for the name change and highlight the contradictions intrinsic to the word minority in this context. We highlight why swift action is required for this rewording within the context of a committee dedicated to supporting the inclusion of PEERs in the scientific community.}, }
@article {pmid38991033, year = {2024}, author = {Yanagi, KS and Jochim, B and Kunjo, SO and Breen, P and Ruvkun, G and Lehrbach, N}, title = {Mutations in nucleotide metabolism genes bypass proteasome defects in png-1/NGLY1-deficient Caenorhabditis elegans.}, journal = {PLoS biology}, volume = {22}, number = {7}, pages = {e3002720}, pmid = {38991033}, issn = {1545-7885}, support = {P40 OD010440/OD/NIH HHS/United States ; R01 AG016636/AG/NIA NIH HHS/United States ; R35 GM142728/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Caenorhabditis elegans/genetics/metabolism ; *Caenorhabditis elegans Proteins/genetics/metabolism ; Congenital Disorders of Glycosylation/genetics/metabolism ; DNA-Binding Proteins/metabolism/genetics ; Glycosylation ; *Mutation ; Nucleotides/metabolism/genetics ; Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase/metabolism/genetics/deficiency ; *Proteasome Endopeptidase Complex/metabolism/genetics ; Transcription Factors/metabolism/genetics ; }, abstract = {The conserved SKN-1A/Nrf1 transcription factor regulates the expression of proteasome subunit genes and is essential for maintenance of adequate proteasome function in animal development, aging, and stress responses. Unusual among transcription factors, SKN-1A/Nrf1 is a glycoprotein synthesized in the endoplasmic reticulum (ER). N-glycosylated SKN-1A/Nrf1 exits the ER and is deglycosylated in the cytosol by the PNG-1/NGLY1 peptide:N-glycanase. Deglycosylation edits the protein sequence of SKN-1A/Nrf1 by converting N-glycosylated asparagine residues to aspartate, which is necessary for SKN-1A/Nrf1 transcriptional activation of proteasome subunit genes. Homozygous loss-of-function mutations in the peptide:N-glycanase (NGLY1) gene cause NGLY1 deficiency, a congenital disorder of deglycosylation. There are no effective treatments for NGLY1 deficiency. Since SKN-1A/Nrf1 is a major client of NGLY1, the resulting proteasome deficit contributes to NGLY1 disease. We sought to identify targets for mitigation of proteasome dysfunction in NGLY1 deficiency that might indicate new avenues for treatment. We isolated mutations that suppress the sensitivity to proteasome inhibitors caused by inactivation of the NGLY1 ortholog PNG-1 in Caenorhabditis elegans. We identified multiple suppressor mutations affecting 3 conserved genes: rsks-1, tald-1, and ent-4. We show that the suppressors act through a SKN-1/Nrf-independent mechanism and confer proteostasis benefits consistent with amelioration of proteasome dysfunction. ent-4 encodes an intestinal nucleoside/nucleotide transporter, and we show that restriction of nucleotide availability is beneficial, whereas a nucleotide-rich diet exacerbates proteasome dysfunction in PNG-1/NGLY1-deficient C. elegans. Our findings suggest that dietary or pharmacological interventions altering nucleotide availability have the potential to mitigate proteasome insufficiency in NGLY1 deficiency and other diseases associated with proteasome dysfunction.}, }
@article {pmid38990255, year = {2024}, author = {Dickerson, LK and Lipson, TA and Chauhan, SSB and Allen, GI and Young, B and Park, JO and Pillarisetty, VG and O'Connell, KM and Sham, JG}, title = {Evaluating surgeon communication of pancreatic cancer prognosis using the VitalTalk ADAPT framework.}, journal = {Journal of surgical oncology}, volume = {130}, number = {3}, pages = {476-484}, doi = {10.1002/jso.27777}, pmid = {38990255}, issn = {1096-9098}, support = {//The Donald E. Bocek Endowed Research Development Award in Pancreatic Cancer/ ; }, mesh = {Humans ; *Pancreatic Neoplasms/surgery/pathology/psychology ; Prognosis ; *Communication ; Female ; Male ; *Physician-Patient Relations ; *Surgeons/psychology ; Middle Aged ; Aged ; }, abstract = {BACKGROUND AND OBJECTIVES: Few data exist to guide optimal communication practices for surgical oncologists. VitalTalk, an evidence-based communication skills training model for clinicians, offers the five-step ADAPT tool for discussing prognosis. This study aimed to characterize surgeon communication of pancreatic cancer prognosis using VitalTalk's ADAPT framework.<br><br>METHODS: Contemporaneous audio recordings from 12 initial surgeon-patient encounters for borderline resectable pancreatic cancer were transcribed. Directed qualitative content analysis based on ADAPT (Ask, Discover, Anticipate, Provide, and Track) was used to deductively code transcripts.<br><br>RESULTS: All encounters contained at least one ADAPT step while only one (8%) incorporated four or five steps. Surgeons provided prognostic information (Provide) in all but one encounter (92%); most was qualitative and clustered into themes: serious illness, surgical candidacy, prognostic ambiguity, and cancer recurrence. Surgeons elicited understanding (Ask), requested information preferences (Discover), anticipated ambivalence (Anticipate), and responded to emotion (Track) in a minority of encounters (25%-42%); of 15 patient emotional cues, six were not addressed by surgeons.<br><br>CONCLUSIONS: During an initial encounter for pancreatic cancer, surgeons focus heavily on providing information but omit critical prognostic communication steps. Future studies are needed to investigate if surgeon training in palliative care-based communication&#xa0;is feasible and impacts patient-perceived quality of communication.}, }
@article {pmid38988271, year = {2024}, author = {Rashidi, A and Liang, L and Gooley, T and Hujoel, PP and Zevin, A and Rothen, M and Hagstrom, MK and Cutler, C and Lee, SJ and Dean, DR and Sroussi, HY and Treister, NS}, title = {Microbiota signature of oral chronic graft-&lt;I&gt;versus&lt;/I&gt;-host disease 6+ years after transplantation.}, journal = {Haematologica}, volume = {109}, number = {11}, pages = {3800-3805}, pmid = {38988271}, issn = {1592-8721}, support = {R01 DE028336/DE/NIDCR NIH HHS/United States ; }, }
@article {pmid38987855, year = {2024}, author = {Middeldorp, ME and Manson, JE and Aragaki, AK and Clar, A and Sesso, HD and Albert, CM}, title = {Cocoa flavanol supplementation and incident atrial fibrillation in the COSMOS trial.}, journal = {European journal of preventive cardiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/eurjpc/zwae229}, pmid = {38987855}, issn = {2047-4881}, }
@article {pmid38985835, year = {2024}, author = {Jiang, D and Houck, KL and Murdiyarso, L and Higgins, H and Rhoads, N and Romero, SK and Kozar, R and Nascimbene, A and Gernsheimer, TB and Sanchez, ZAC and Ramasubramanian, AK and Adili, R and Dong, JF}, title = {RBCs regulate platelet function and hemostasis under shear conditions through biophysical and biochemical means.}, journal = {Blood}, volume = {144}, number = {14}, pages = {1521-1531}, doi = {10.1182/blood.2024023887}, pmid = {38985835}, issn = {1528-0020}, support = {T32 HL007093/HL/NHLBI NIH HHS/United States ; R01 HL152200/HL/NHLBI NIH HHS/United States ; R01 GM140983/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Hemostasis/physiology ; *Blood Platelets/metabolism ; *Erythrocytes/metabolism/cytology ; Mice ; Adenosine Diphosphate/metabolism ; Platelet Aggregation ; Humans ; Mice, Inbred C57BL ; Thrombocytopenia/pathology/blood ; Erythrocyte Transfusion ; }, abstract = {Red blood cells (RBCs) have been hypothesized to support hemostasis by facilitating platelet margination and releasing platelet-activating factors such as adenosine 5'-diphosphate (ADP). Significant knowledge gaps remain regarding how RBCs influence platelet function, especially in (patho)physiologically relevant hemodynamic conditions. Here, we present results showing how RBCs affect platelet function and hemostasis in conditions of anemia, thrombocytopenia, and pancytopenia and how the biochemical and biophysical properties of RBCs regulate platelet function at the blood and vessel wall interface and in the fluid phase under flow conditions. We found that RBCs promoted platelet deposition to collagen under flow conditions in moderate (50 × 103/μL) but not severe (10 × 103/μL) thrombocytopenia in vitro. Reduction in hematocrit by 45% increased bleeding in mice with hemolytic anemia. In contrast, bleeding diathesis was observed in mice with a 90% but not with a 60% reduction in platelet counts. RBC transfusion improved hemostasis by enhancing fibrin clot formation at the site of vascular injury in mice with severe pancytopenia induced by total body irradiation. Altering membrane deformability changed the ability of RBCs to promote shear-induced platelet aggregation. RBC-derived ADP contributed to platelet activation and aggregation in vitro under pathologically high shear stresses, as observed in patients supported by left ventricular assist devices. These findings demonstrate that RBCs support platelet function and hemostasis through multiple mechanisms, both at the blood and vessel wall interface and in the fluidic phase of circulation.}, }
@article {pmid38985302, year = {2024}, author = {Pophali, PA and Fein, JA and Ahn, KW and Allbee-Johnson, M and Ahmed, N and Awan, FT and Farhan, S and Grover, NS and Hilal, T and Iqbal, M and Maakaron, J and Modi, D and Nasrollahi, E and Schachter, LG and Sauter, C and Hamadani, M and Herrera, A and Shouval, R and Shadman, M}, title = {CD19-directed CART therapy for T-cell/histiocyte-rich large B-cell lymphoma.}, journal = {Blood advances}, volume = {8}, number = {20}, pages = {5290-5296}, pmid = {38985302}, issn = {2473-9537}, support = {K08 CA282987/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; Middle Aged ; Female ; *Antigens, CD19/immunology/therapeutic use ; Adult ; *Lymphoma, Large B-Cell, Diffuse/therapy/drug therapy/mortality ; Aged ; *Immunotherapy, Adoptive/adverse effects/methods ; T-Lymphocytes/immunology/metabolism ; Histiocytes/pathology ; Treatment Outcome ; Receptors, Chimeric Antigen/therapeutic use ; Young Adult ; }, abstract = {T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare histologic variant of LBCL. Limited data regarding CD19-directed chimeric antigen receptor T-cell (CART) therapy in relapsed/refractory (R/R) THRLBCL suggest poor efficacy. We investigated CART outcomes for R/R THRLBCL through the Center for International Blood and Marrow Transplant Research registry. A total of 58 adult patients with R/R THRLBCL who received commercial CD19-CART therapy between 2018 and 2022 were identified. Most patients (67%) had early relapse of disease (45% primary refractory) with a median of 3 (range, 1-7) prior therapies and were treated with axicabtagene ciloleucel (69%). At median follow-up of 23 months after CART therapy, 2-year overall and progression-free survival were 42% (95% confidence interval [CI], 27-57) and 29% (95% CI, 17-43), respectively. In univariable analysis, poor performance status before CART therapy was associated with higher mortality (hazard ratio, 2.35; 95%CI, 1.02-5.5). The 2-year cumulative incidences of relapse/progression and nonrelapse mortality were 69% and 2%, respectively. Grade ≥3 cytokine release syndrome and immune effector cell-associated neurologic syndrome occurred in 7% and 15% of patients, respectively. In this largest analysis of CD19-CART therapy for R/R THRLBCL, ∼30% of patients were alive and progression free 2 years after CART therapy. Despite a high incidence of progression (69% at 2 years), these results suggest a subset of patients with R/R THRLBCL may have durable responses with CARTs.}, }
@article {pmid38984364, year = {2024}, author = {Singh, SN and Wininger, M and Raitt, M and Adabag, S and Moore, H and Rottman, JN and Scrymgeour, A and Zhang, J and Zheng, K and Guarino, P and Kyriakides, TC and ,  and Johnson, G and Williams, A and Beed, A and MacMurdy, K and Saavedra, P}, title = {Efficacy and safety of implantable cardioverter-defibrillator implantation in the elderly-The I-70 Study: A randomized clinical trial.}, journal = {Heart rhythm O2}, volume = {5}, number = {6}, pages = {365-373}, pmid = {38984364}, issn = {2666-5018}, abstract = {BACKGROUND: There is conflicting evidence on the efficacy of primary prevention implantable cardioverter-defibrillator (ICD) implantation in the elderly.<br><br>OBJECTIVE: The purpose of this study was to determine the efficacy and safety of ICD implantation in patients 70 years and older.<br><br>METHODS: Patients (n = 167) aged 70 years or older and eligible for ICD implantation were randomly assigned (1:1) to receive either optimal medical therapy (OMT) (n = 85) or OMT plus ICD (n = 82).<br><br>RESULTS: Of the 167 participants (mean age 76.4 years; 165 men), 144 completed the study protocol according to their assigned treatment. Average participant follow-up was 31.5 months. Mortality was similar between the 2 groups: 27 deaths in OMT vs 26 death in ICD (unadjusted hazard ratio 0.92; 95% confidence interval 0.53-1.57), but there was a trend favoring the ICD over the first 36 months of follow-up. Rates of sudden death (7 vs 5; P = .81) and all-cause hospitalization (2.65 events per participant in OMT vs 3.09 in ICD; P = .31) were not statistically significantly different. Eleven participants randomized to ICD received appropriate therapy. Five participants received an inappropriate therapy that included at least 1 ICD shock.<br><br>CONCLUSION: The study did not recruit to target sample size, and accumulated data did not show benefit of ICD therapy in patients 70 years or older. Future studies similar in design might be feasible but will need to contend with patient treatment preference given the large number of patients who do not want an ICD implanted. Further research is needed to determine whether the ICD is effective in prolonging life among elderly device candidates.}, }
@article {pmid38983599, year = {2024}, author = {Cadiou, G and Beauvais, T and Marotte, L and Lambot, S and Deleine, C and Vignes, C and Gantier, M and Hussong, M and Rulli, S and Jarry, A and Simon, S and Malissen, B and Labarriere, N}, title = {Differential impact of genetic deletion of TIGIT or PD-1 on melanoma-specific T-lymphocytes.}, journal = {Oncoimmunology}, volume = {13}, number = {1}, pages = {2376782}, pmid = {38983599}, issn = {2162-402X}, mesh = {Animals ; Mice ; *Programmed Cell Death 1 Receptor/genetics/metabolism ; *Receptors, Immunologic/genetics/metabolism ; *Melanoma/immunology/genetics/pathology/therapy ; Gene Deletion ; Tumor Microenvironment/immunology ; Mice, Knockout ; Mice, Inbred C57BL ; T-Lymphocytes/immunology/metabolism ; Cell Line, Tumor ; Humans ; Lymphocyte Activation/immunology ; }, abstract = {Immune checkpoint (IC) blockade and adoptive transfer of tumor-specific T-cells (ACT) are two major strategies to treat metastatic melanoma. Their combination can potentiate T-cell activation in the suppressive tumor microenvironment, but the autoimmune adverse effects associated with systemic injection of IC blockers persist with this strategy. ACT of tumor-reactive T-cells defective for IC expression would overcome this issue. For this purpose, PD-1 and TIGIT appear to be relevant candidates, because their co-expression on highly tumor-reactive lymphocytes limits their therapeutic efficacy within the tumor microenvironme,nt. Our study compares the consequences of PDCD1 or TIGIT genetic deletion on anti-tumor properties and T-cell fitness of melanoma-specific T lymphocytes. Transcriptomic analyses revealed down-regulation of cell cycle-related genes in PD-1[KO] T-cells, consistent with biological observations, whereas proliferative pathways were preserved in TIGIT[KO] T-cells. Functional analyses showed that PD-1[KO] and TIGIT[KO] T-cells displayed superior antitumor reactivity than their wild-type counterpart in vitro and in a preclinical melanoma model using immunodeficient mice. Interestingly, it appears that TIGIT[KO] T-cells were more effective at inhibiting tumor cell proliferation in vivo, and persist longer within tumors than PD-1[KO] T-cells, consistent with the absence of impact of TIGIT deletion on T-cell fitness. Taken together, these results suggest that TIGIT deletion, over PD-1 deletion, in melanoma-specific T-cells is a compelling option for future immunotherapeutic strategies.}, }
@article {pmid38982075, year = {2024}, author = {Hurvitz, SA and Bardia, A and Punie, K and Kalinsky, K and Carey, LA and Rugo, HS and Diéras, V and Phan, S and Delaney, R and Zhu, Y and Tolaney, SM}, title = {Author Correction: Subgroup analyses from the phase 3 ASCENT study of sacituzumab govitecan in metastatic triple-negative breast cancer.}, journal = {NPJ breast cancer}, volume = {10}, number = {1}, pages = {55}, doi = {10.1038/s41523-024-00666-y}, pmid = {38982075}, issn = {2374-4677}, }
@article {pmid38981645, year = {2024}, author = {Manyara, AM and Davies, P and Stewart, D and Weir, CJ and Young, AE and Blazeby, J and Butcher, NJ and Bujkiewicz, S and Chan, AW and Dawoud, D and Offringa, M and Ouwens, M and Hróbjartsson, A and Amstutz, A and Bertolaccini, L and Bruno, VD and Devane, D and Faria, CDCM and Gilbert, PB and Harris, R and Lassere, M and Marinelli, L and Markham, S and Powers, JH and Rezaei, Y and Richert, L and Schwendicke, F and Tereshchenko, LG and Thoma, A and Turan, A and Worrall, A and Christensen, R and Collins, GS and Ross, JS and Taylor, RS and Ciani, O}, title = {Reporting of surrogate endpoints in randomised controlled trial reports (CONSORT-Surrogate): extension checklist with explanation and elaboration.}, journal = {BMJ (Clinical research ed.)}, volume = {386}, number = {}, pages = {e078524}, pmid = {38981645}, issn = {1756-1833}, mesh = {*Checklist ; Humans ; *Randomized Controlled Trials as Topic/standards ; *Biomarkers/blood ; Research Design/standards ; }, abstract = {Randomised controlled trials commonly use surrogate endpoints to substitute for a target outcome (outcome of direct interest and relevance to trial participants, clinicians, and other stakeholders—eg, all cause mortality) to improve their efficiency (through shorter trial duration, reduced sample size, and thus lower research costs), or for ethical or practical reasons. But reliance on surrogate endpoints can increase the uncertainty of an intervention’s treatment effect and potential failure to provide adequate information on intervention harms, which has led to calls for improved reporting of trials using surrogate endpoints. This report presents a consensus driven reporting guideline for trials using surrogate endpoints as the primary outcomes—the CONSORT (Consolidated Standards of Reporting Trials) extension checklist: CONSORT-Surrogate. The extension includes nine items modified from the CONSORT 2010 checklist and two new items. Examples and explanations for each item are provided. We recommend that all stakeholders (including trial investigators and sponsors, journal editors and peer reviewers, research ethics reviewers, and funders) use this extension in reporting trial reports using surrogate endpoints. Use of this checklist will improve transparency, interpretation, and usefulness of trial findings, and ultimately reduce research waste.}, }
@article {pmid38981624, year = {2024}, author = {Manyara, AM and Davies, P and Stewart, D and Weir, CJ and Young, AE and Blazeby, J and Butcher, NJ and Bujkiewicz, S and Chan, AW and Dawoud, D and Offringa, M and Ouwens, M and Hróbjartsson, A and Amstutz, A and Bertolaccini, L and Bruno, VD and Devane, D and Faria, CDCM and Gilbert, PB and Harris, R and Lassere, M and Marinelli, L and Markham, S and Powers, JH and Rezaei, Y and Richert, L and Schwendicke, F and Tereshchenko, LG and Thoma, A and Turan, A and Worrall, A and Christensen, R and Collins, GS and Ross, JS and Taylor, RS and Ciani, O}, title = {Reporting of surrogate endpoints in randomised controlled trial protocols (SPIRIT-Surrogate): extension checklist with explanation and elaboration.}, journal = {BMJ (Clinical research ed.)}, volume = {386}, number = {}, pages = {e078525}, pmid = {38981624}, issn = {1756-1833}, mesh = {*Checklist ; Humans ; *Randomized Controlled Trials as Topic/methods/standards ; *Biomarkers/blood ; Research Design/standards ; Clinical Trial Protocols as Topic ; }, abstract = {Randomised controlled trials often use surrogate endpoints to substitute for a target outcome (an outcome of direct interest and relevance to trial participants, clinicians, and other stakeholders—eg, all cause mortality) to improve efficiency (through shortened duration of follow-up, reduced sample size, and lower research costs), and for ethical or practical reasons. However, their use has a fundamental limitation in terms of uncertainty of the intervention effect on the target outcome and limited information on potential intervention harms. There have been increasing calls for improved reporting of trial protocols that use surrogate endpoints. This report presents the SPIRIT-Surrogate, an extension of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist, a consensus driven reporting guideline designed for trial protocols using surrogate endpoints as the primary outcome(s). The SPIRIT-Surrogate extension includes nine items modified from the SPIRIT 2013 checklist. The guideline provides examples and explanations for each item. We recommend that all stakeholders (including trial investigators and sponsors, research ethics reviewers, funders, journal editors, and peer reviewers) use this extension in reporting trial protocols that use surrogate endpoints. Its use will allow for improved design of such trials, improved transparency, and interpretation of findings when trials are completed, and ultimately reduced research waste.}, }
@article {pmid38981590, year = {2024}, author = {Duan, C and Liu, Q and Wang, J and Tong, Q and Bai, F and Han, J and Wang, S and Hippe, DS and Zeng, J and Bowen, SR}, title = {GWO+RuleFit: rule-based explainable machine-learning combined with heuristics to predict mid-treatment FDG PET response to chemoradiation for locally advanced non-small cell lung cancer.}, journal = {Physics in medicine and biology}, volume = {69}, number = {15}, pages = {}, pmid = {38981590}, issn = {1361-6560}, support = {R01 CA204301/CA/NCI NIH HHS/United States ; R01 CA258997/CA/NCI NIH HHS/United States ; }, mesh = {*Carcinoma, Non-Small-Cell Lung/diagnostic imaging/radiotherapy/therapy ; Humans ; *Machine Learning ; *Lung Neoplasms/diagnostic imaging/radiotherapy/therapy ; *Fluorodeoxyglucose F18 ; *Positron-Emission Tomography ; *Chemoradiotherapy ; Heuristics ; Male ; Middle Aged ; Female ; Treatment Outcome ; Aged ; Image Processing, Computer-Assisted/methods ; }, abstract = {Objective.Vital rules learned from fluorodeoxyglucose positron emission tomography (FDG-PET) radiomics of tumor subregional response can provide clinical decision support for precise treatment adaptation. We combined a rule-based machine learning (ML) model (RuleFit) with a heuristic algorithm (gray wolf optimizer, GWO) for mid-chemoradiation FDG-PET response prediction in patients with locally advanced non-small cell lung cancer.Approach.Tumors subregions were identified using K-means clustering. GWO+RuleFit consists of three main parts: (i) a random forest is constructed based on conventional features or radiomic features extracted from tumor regions or subregions in FDG-PET images, from which the initial rules are generated; (ii) GWO is used for iterative rule selection; (iii) the selected rules are fit to a linear model to make predictions about the target variable. Two target variables were considered: a binary response measure (ΔSUVmean ⩾ 20% decline) for classification and a continuous response measure (ΔSUVmean) for regression. GWO+RuleFit was benchmarked against common ML algorithms and RuleFit, with leave-one-out cross-validated performance evaluated by the area under the receiver operating characteristic curve (AUC) in classification and root-mean-square error (RMSE) in regression.Main results.GWO+RuleFit selected 15 rules from the radiomic feature dataset of 23 patients. For treatment response classification, GWO+RuleFit attained numerically better cross-validated performance than RuleFit across tumor regions and sets of features (AUC: 0.58-0.86 vs. 0.52-0.78,p= 0.170-0.925). GWO+Rulefit also had the best or second-best performance numerically compared to all other algorithms for all conditions. For treatment response regression prediction, GWO+RuleFit (RMSE: 0.162-0.192) performed better numerically for low-dimensional models (p= 0.097-0.614) and significantly better for high-dimensional models across all tumor regions except one (RMSE: 0.189-0.219,p< 0.004).Significance. The GWO+RuleFit selected rules were interpretable, highlighting distinct radiomic phenotypes that modulated treatment response. GWO+Rulefit achieved parsimonious models while maintaining utility for treatment response prediction, which can aid clinical decisions for patient risk stratification, treatment selection, and biologically driven adaptation. Clinical trial: NCT02773238.}, }
@article {pmid38981364, year = {2024}, author = {Ng, ZX and Koh, ES and Lee, SF and Tan, CL and Teo, K and Wong, A and Lo, SS and Vellayappan, B}, title = {A systematic review and meta-analysis informing the role of adjuvant radiotherapy (RT) in Grade 2 and 3 oligodendroglioma.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {126}, number = {}, pages = {247-255}, doi = {10.1016/j.jocn.2024.06.020}, pmid = {38981364}, issn = {1532-2653}, mesh = {*Oligodendroglioma/radiotherapy/mortality/therapy ; Humans ; *Brain Neoplasms/radiotherapy/mortality ; Radiotherapy, Adjuvant/methods ; Neoplasm Grading ; }, abstract = {BACKGROUND AND PURPOSE: Evidence and clinical guidelines support the use of adjuvant RT in high-risk low-grade gliomas. However, patients with oligodendroglioma have a more indolent disease course and delaying or avoiding RT is often considered to reduce treatment-related toxicities. As the optimal adjuvant management for oligodendroglioma is unclear, we aimed to assess the effect of adjuvant RT on overall survival (OS) and progression-free survival (PFS).<br><br>METHODS: MEDLINE, EMBASE, CENTRAL and CINAHL were searched from January 1990 to February 2023 for studies comparing adjuvant RT versus no adjuvant RT for patients with oligodendroglioma.<br><br>RESULTS: This review found 17 eligible studies including 14 comparative retrospective studies and 3 randomized controlled trials. Using random-effects model, the results suggested that adjuvant RT improved OS by 28&#xa0;% (HR 0.72, 95&#xa0;% CI (0.56-0.93), I[2]&#xa0;=&#xa0;86&#xa0;%), and PFS by 48&#xa0;% (HR 0.52, (95&#xa0;% CI 0.40-0.66), I[2]&#xa0;=&#xa0;48&#xa0;%) compared to patients without adjuvant RT. Subgroup analysis showed that upfront adjuvant RT improved OS and PFS compared to salvage RT. There were no significant differences in OS and PFS between adjuvant RT versus adjuvant chemotherapy. There was improvement in PFS but not OS for adjuvant chemoradiotherapy versus adjuvant chemotherapy alone. Adjuvant RT improved OS in WHO Grade 3 but not WHO Grade 2 oligodendroglioma.<br><br>CONCLUSION: Overall, adjuvant RT improved OS and PFS in patients with oligodendroglioma. In patients with low-risk features (e.g. Grade 2, gross total resection), alternative approaches and individualization of management such as adjuvant chemotherapy alone may be reasonable considering the lack of survival benefit. Future efforts should prospectively investigate these treatment regimens on molecularly-classified oligodendroglioma patients (defined by presence of IDH mutation and 1p/19q co-deletion), balancing between maximizing survival outcomes and reducing RT-related toxicities.}, }
@article {pmid38981063, year = {2024}, author = {Alberts, NM and Leisenring, W and Whitton, J and Stratton, K and Jibb, L and Flynn, J and Pizzo, A and Brinkman, TM and Birnie, K and Gibson, TM and McDonald, A and Ford, J and Olgin, JE and Nathan, PC and Stinson, JN and Armstrong, GT}, title = {Characterization of chronic pain, pain interference, and daily pain experiences in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.}, journal = {Pain}, volume = {165}, number = {11}, pages = {2530-2543}, pmid = {38981063}, issn = {1872-6623}, support = {U24 CA055727/CA/NCI NIH HHS/United States ; U2CEB021881//National Institutes of Health (NIH)/ ; P30 CA021765/CA/NCI NIH HHS/United States ; N/A//Canada Research Chairs/ ; U2C EB021881/EB/NIBIB NIH HHS/United States ; N/A//Childhood Cancer Survivor Study (CCSS)/ ; CA55727//National Cancer Institute (NCI)/ ; }, mesh = {Humans ; Male ; Female ; *Chronic Pain/psychology/epidemiology ; *Cancer Survivors/psychology ; Adult ; Young Adult ; Middle Aged ; *Neoplasms/complications/psychology/epidemiology ; Pain Measurement/methods ; }, abstract = {Although survivors of childhood cancer are at an increased risk, little is known about the prevalence of chronic pain, associated interference, and daily pain experiences. Survivors (N = 233; mean age = 40.8 years, range 22-64 years; mean time since diagnosis = 32.7 years) from the Childhood Cancer Survivor Study completed pain and psychosocial measures. Survivors with chronic pain completed 2-week, daily measures assessing pain and psychological symptoms using mHealth-based ecological momentary assessment. Multivariable-modified Poisson and linear regression models estimated prevalence ratio estimates (PR) and mean effects with 95% confidence intervals (CI) for associations of key risk factors with chronic pain and pain interference, respectively. Multilevel mixed models examined outcomes of daily pain and pain interference with prior day symptoms. Ninety-six survivors (41%) reported chronic pain, of whom 23 (24%) had severe interference. Chronic pain was associated with previous intravenous methotrexate treatment (PR = 1.6, 95% CI 1.1-2.3), respiratory (PR = 1.8, 95% CI 1.2-2.5), gastrointestinal (PR = 1.6, 95% CI 11.0-2.3), and neurological (PR = 1.5, 95% CI 1.0-2.1) chronic health conditions, unemployment (PR = 1.4, 95% CI 1.0-1.9) and clinically significant depression and anxiety (PR = 2.9, 95% CI 2.0-4.2), as well as a diagnosis of childhood Ewing sarcoma or osteosarcoma (PR = 1.9, 95% CI 1.0-3.5). Higher pain interference was associated with cardiovascular and neurological conditions, unemployment and clinical levels of depression and/or anxiety, and fear of cancer recurrence. For male, but not female survivors, low sleep quality, elevated anxiety, and elevated depression predicted high pain intensity and interference the next day. A substantial proportion of childhood cancer survivors experience chronic pain and significant associated interference. Chronic pain should be routinely evaluated, and interventions are needed.}, }
@article {pmid38980855, year = {2024}, author = {Kazmirak, C and Tollefson, D and Lankowski, A and Sanchez, H and Gonzales, I and Espinoza, D and Duerr, A}, title = {Practices and preferences for HIV testing and treatment services amongst partners of transgender women in Lima, Peru: An exploratory, mixed methods study.}, journal = {PloS one}, volume = {19}, number = {7}, pages = {e0306852}, pmid = {38980855}, issn = {1932-6203}, mesh = {Humans ; *Transgender Persons/psychology ; Female ; Peru/epidemiology ; *HIV Infections/diagnosis/epidemiology/psychology ; Adult ; Male ; Cross-Sectional Studies ; *Sexual Partners/psychology ; *HIV Testing ; Middle Aged ; Young Adult ; Adolescent ; Surveys and Questionnaires ; Patient Preference/statistics &amp; numerical data ; }, abstract = {BACKGROUND: In Peru, one-third of transgender women (TW) are estimated to be living with HIV. While TW are recognized as a priority population, their sexual partners are an at-risk hidden population with unmet needs for HIV services. We conducted a study examining the practices and preferences for HIV services among partners of transgender women (PTW), as compared to TW, to better understand the needs of PTW and inform HIV service delivery for them in Peru.<br><br>METHODS: Between July-October 2022 we conducted a cross-sectional mixed methods study among PTW and TW in Lima, Peru. Using an explanatory sequential design, we administered online surveys to PTW (n = 165) and TW (n = 69), then interviewed a subset of participants (n = 20: 16 PTW, 4 TW). We quantitatively and qualitatively described PTW practices/perspectives on HIV testing and treatment and compared them to TW practices/preferences; we also compared practices/preferences among PTW based on their relationship with TW.<br><br>RESULTS: Overall, PTW and TW shared similar experiences and preferences for HIV testing/treatment, but fewer PTW reported accessing non-traditional HIV testing options and PTW expressed less strong preferences for HIV services. PTW practices/preferences varied by type of relationship with TWs. Surveys and interviews highlighted a need to prioritize efficiency for HIV testing, eliminate gender/sexuality-based discrimination in healthcare settings, increase privacy when delivering HIV services, and increase awareness of pre-exposure prophylaxis.<br><br>CONCLUSION: PTW identified many aspects related to the location, convenience, and privacy of HIV services as important. Next steps could include a discrete choice experiment to further clarify priorities for HIV services for PTW in Peru.}, }
@article {pmid38980676, year = {2024}, author = {Gebrael, G and Jo, Y and Swami, U and Plets, M and Hage Chehade, C and Narang, A and Gupta, S and Myint, ZW and Sayegh, N and Tangen, CM and Hussain, M and Dorff, T and Lara, PN and Lerner, SP and Thompson, I and Agarwal, N}, title = {Bone Pain and Survival Among Patients With Metastatic, Hormone-Sensitive Prostate Cancer: A Secondary Analysis of the SWOG-1216 Trial.}, journal = {JAMA network open}, volume = {7}, number = {7}, pages = {e2419966}, pmid = {38980676}, issn = {2574-3805}, mesh = {Humans ; Male ; Aged ; *Androgen Antagonists/therapeutic use ; Middle Aged ; *Prostatic Neoplasms/mortality/drug therapy/complications/pathology ; *Bone Neoplasms/secondary/mortality/complications/drug therapy ; Nitriles/therapeutic use ; Prospective Studies ; Cancer Pain/drug therapy ; Anilides/therapeutic use ; Tosyl Compounds/therapeutic use/adverse effects ; Androstenes/therapeutic use ; Pain/drug therapy/etiology ; }, abstract = {IMPORTANCE: The presence of bone pain is significantly associated with worse overall survival (OS) in patients with castration-resistant prostate cancer. However, there are few data regarding bone pain and survival outcomes in the context of metastatic, hormone-sensitive prostate cancer (MHSPC).<br><br>OBJECTIVE: To compare survival outcomes among patients with MHSPC by presence or absence of baseline bone pain at diagnosis.<br><br>This post hoc secondary analysis, conducted from September 1 to December 31, 2023, used patient-level data from SWOG-1216, a phase 3, prospective randomized clinical trial that enrolled patients with newly diagnosed MHSPC from 248 academic and community centers across the US from March 1, 2013, to July 15, 2017. All patients in the intention-to-treat population who had available bone pain status were eligible and included in this secondary analysis.<br><br>INTERVENTIONS: In the SWOG-1216 trial, patients were randomized (1:1) to receive either androgen deprivation therapy (ADT) with orteronel, 300 mg orally twice daily (experimental group), or ADT with bicalutamide, 50 mg orally daily (control group), until disease progression, unacceptable toxic effects, or patient withdrawal.<br><br>MAIN OUTCOMES AND MEASURES: Overall survival was the primary end point; progression-free survival (PFS) and prostate-specific antigen (PSA) response were secondary end points. Cox proportional hazards regression models were used for both univariable and multivariable analyses adjusting for age, treatment type, Gleason score, disease volume, Zubrod performance status, and PSA level.<br><br>RESULTS: Of the 1279 male study participants, 301 (23.5%) had baseline bone pain at MHSPC diagnosis and 896 (70.1%) did not. Bone pain status was unavailable in 82 patients (6.4%). The median age of the 1197 patients eligible and included in this secondary analysis was 67.6 years (IQR, 61.8-73.6 years). Compared with patients who did not experience bone pain, those with baseline bone pain were younger (median age, 66.0 [IQR, 60.1-73.4] years vs 68.2 [IQR, 62.4-73.7] years; P&#x2009;=&#x2009;.02) and had a higher incidence of high-volume disease (212 [70.4%] vs 373 [41.6%]; P&#x2009;<&#x2009;.001). After adjustment, bone pain was associated with shorter PFS and OS. At a median follow-up of 4.0 years (IQR, 2.5-5.4 years), patients with bone pain had median PFS of 1.3 years (95% CI, 1.1-1.7 years) vs 3.7 years (95% CI, 3.3-4.2 years) in patients without initial bone pain (adjusted hazard ratio [AHR], 1.46; 95% CI, 1.22-1.74; P&#x2009;<&#x2009;.001) and OS of 3.9 years (95% CI, 3.3-4.8 years) vs not reached (NR) (95% CI, 6.6 years to NR) in patients without initial bone pain (AHR, 1.66; 95% CI, 1.34-2.05; P&#x2009;<&#x2009;.001).<br><br>CONCLUSIONS AND RELEVANCE: In this post hoc secondary analysis of the SWOG-1216 randomized clinical trial, patients with baseline bone pain at MHSPC diagnosis had worse survival outcomes than those without bone pain. These data suggest prioritizing these patients for enrollment in clinical trials, may aid patient counseling, and indicate that the inclusion of bone pain in prognostic models of MHSPC may be warranted.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01809691.}, }
@article {pmid38980027, year = {2024}, author = {Fogel, JM and Piwowar-Manning, E and Moser, A and Hill, T and Ahmed, S and Cummings, V and Mostafa, HH and Wang, Z and Jennings, A and Gallardo-Cartagena, JA and Figueroa, MI and St Clair, M and Rinehart, AR and Adeyeye, A and Rooney, JF and Cohen, MS and Grinsztejn, B and Landovitz, RJ and Eshleman, SH and , }, title = {Evaluation of Xpert point-of-care assays for detection of HIV infection in persons using long-acting cabotegravir for pre-exposure prophylaxis.}, journal = {Microbiology spectrum}, volume = {12}, number = {8}, pages = {e0030724}, pmid = {38980027}, issn = {2165-0497}, support = {UM1 AI068619/AI/NIAID NIH HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; UM1 AI069476/AI/NIAID NIH HHS/United States ; UM1 AI069424/AI/NIAID NIH HHS/United States ; UM1 AI068613/AI/NIAID NIH HHS/United States ; U01 AI069424/AI/NIAID NIH HHS/United States ; }, abstract = {UNLABELLED: Detection of HIV infection may be challenging in persons using long-acting cabotegravir (CAB-LA) pre-exposure prophylaxis (PrEP) due to viral suppression and reduced/delayed antibody production. We evaluated two point-of-care tests for detecting HIV infection in persons who received CAB-LA in the HPTN 083 trial. Samples were obtained from 12 participants who received CAB-LA and had delayed detection of HIV infection using HIV rapid tests and an antigen/antibody test (52 plasma samples; 18 dried blood spot [DBS] samples). Plasma samples were tested with the Xpert HIV-1 Viral Load XC test (Xpert VL-XC); DBS samples were tested with the total nucleic acid Xpert HIV-1 Qual XC test (Xpert Qual-XC). Results from these assays were compared to results from three reference, laboratory-based, plasma RNA assays (Aptima HIV-1 Qualitative assay [Aptima Qual]; Aptima HIV-1 Quant DX Assay [Aptima Quant]; cobas HIV-1/HIV-2 Qualitative Test [cobas]). HIV RNA was detected with all four plasma assays for all samples with viral loads (VLs) ≥ 200 copies/mL; the number of samples with VLs < 200 copies/mL with HIV RNA detected was: Xpert VL-XC: 19/26 (73.1%); Aptima Qual: 17/26 (65.4%); Aptima Quant: 17/26 (65.4%); and cobas: 12/21 (57.1%). The Xpert Qual-XC assay was positive for all DBS samples with VLs ≥ 200 copies/mL and 1/10 DBS with VLs < 200 copies/mL. The performance of the Xpert VL-XC assay was comparable to the reference assays for detecting HIV infection in these cases. The Xpert Qual-XC assay was less sensitive than plasma-based HIV RNA assays for detecting HIV in the setting of CAB-LA PrEP.<br><br>IMPORTANCE: HIV RNA assays can detect HIV infections earlier than HIV rapid tests or Ag/Ab tests in persons using CAB-LA PrEP. Earlier HIV diagnosis could allow for earlier treatment initiation and reduced risk of INSTI resistance. POC tests may help detect HIV infection before CAB-LA administration and may be more accessible than laboratory-based assays in some settings. In this study, the POC Xpert VL-XC assay detected HIV RNA in most samples from individuals who received CAB-LA PrEP and had delayed detection of HIV infection with HIV rapid tests and an Ag/Ab test. The performance of this assay was similar to laboratory-based HIV RNA assays in this cohort. The POC Xpert Qual-XC assay detects both HIV RNA and DNA, with a higher viral load cutoff for RNA detection. This assay was negative for most lower viral load samples and did not offer an advantage for HIV screening in persons using CAB-LA PrEP.}, }
@article {pmid38979380, year = {2024}, author = {Wang, X and Guillem-Marti, J and Kumar, S and Lee, DS and Cabrerizo-Aguado, D and Werther, R and Alamo, KAE and Zhao, YT and Nguyen, A and Kopyeva, I and Huang, B and Li, J and Hao, Y and Li, X and Brizuela-Velasco, A and Murray, A and Gerben, S and Roy, A and DeForest, CA and Springer, T and Ruohola-Baker, H and Cooper, JA and Campbell, MG and Manero, JM and Ginebra, MP and Baker, D}, title = {De Novo Design of Integrin α5β1 Modulating Proteins for Regenerative Medicine.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38979380}, issn = {2692-8205}, support = {R35 GM147414/GM/NIGMS NIH HHS/United States ; R01 GM109463/GM/NIGMS NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 HL131729/HL/NHLBI NIH HHS/United States ; T90 DE021984/DE/NIDCR NIH HHS/United States ; R35 GM138036/GM/NIGMS NIH HHS/United States ; T32 CA080416/CA/NCI NIH HHS/United States ; }, abstract = {Integrin α5β1 is crucial for cell attachment and migration in development and tissue regeneration, and α5β1 binding proteins could have considerable utility in regenerative medicine and next-generation therapeutics. We use computational protein design to create de novo α5β1-specific modulating miniprotein binders, called NeoNectins, that bind to and stabilize the open state of α5β1. When immobilized onto titanium surfaces and throughout 3D hydrogels, the NeoNectins outperform native fibronectin and RGD peptide in enhancing cell attachment and spreading, and NeoNectin-grafted titanium implants outperformed fibronectin and RGD-grafted implants in animal models in promoting tissue integration and bone growth. NeoNectins should be broadly applicable for tissue engineering and biomedicine.}, }
@article {pmid38977707, year = {2024}, author = {Chari, A and Kaufman, JL and Laubach, J and Sborov, DW and Reeves, B and Rodriguez, C and Silbermann, R and Costa, LJ and Anderson, LD and Nathwani, N and Shah, N and Bumma, N and Holstein, SA and Costello, C and Jakubowiak, A and Wildes, TM and Orlowski, RZ and Shain, KH and Cowan, AJ and Pei, H and Cortoos, A and Patel, S and Lin, TS and Voorhees, PM and Usmani, SZ and Richardson, PG}, title = {Daratumumab in transplant-eligible patients with newly diagnosed multiple myeloma: final analysis of clinically relevant subgroups in GRIFFIN.}, journal = {Blood cancer journal}, volume = {14}, number = {1}, pages = {107}, pmid = {38977707}, issn = {2044-5385}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; P30 CA142543/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Antibodies, Monoclonal/therapeutic use/administration &amp; dosage ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Bortezomib/therapeutic use/administration &amp; dosage ; Dexamethasone/administration &amp; dosage/therapeutic use ; Lenalidomide/therapeutic use/administration &amp; dosage ; *Multiple Myeloma/drug therapy/mortality/therapy/diagnosis ; }, abstract = {The randomized, phase 2 GRIFFIN study (NCT02874742) evaluated daratumumab plus lenalidomide/bortezomib/dexamethasone (D-RVd) in transplant-eligible newly diagnosed multiple myeloma (NDMM). We present final post hoc analyses (median follow-up, 49.6 months) of clinically relevant subgroups, including patients with high-risk cytogenetic abnormalities (HRCAs) per revised definition (del[17p], t[4;14], t[14;16], t[14;20], and/or gain/amp[1q21]). Patients received 4 induction cycles (D-RVd/RVd), high-dose therapy/transplant, 2 consolidation cycles (D-RVd/RVd), and lenalidomide±daratumumab maintenance (≤ 2 years). Minimal residual disease-negativity (10[-5]) rates were higher for D-RVd versus RVd in patients ≥ 65 years (67.9% vs 17.9%), with HRCAs (54.8% vs 32.4%), and with gain/amp(1q21) (61.8% vs 28.6%). D-RVd showed a trend toward improved progression-free survival versus RVd (hazard ratio [95% confidence interval]) in patients ≥ 65 years (0.29 [0.06-1.48]), with HRCAs (0.38 [0.14-1.01]), and with gain/amp(1q21) (0.42 [0.14-1.27]). In the functional high-risk subgroup (not MRD negative at the end of consolidation), the hazard ratio was 0.82 (0.35-1.89). Among patients ≥ 65 years, grade 3/4 treatment-emergent adverse event (TEAE) rates were higher for D-RVd versus RVd (88.9% vs 77.8%), as were TEAEs leading to discontinuation of ≥ 1 treatment component (37.0% vs 25.9%). One D-RVd patient died due to an unrelated TEAE. These results support the addition of daratumumab to RVd in transplant-eligible patients with high-risk NDMM. Video Abstract.}, }
@article {pmid38977682, year = {2024}, author = {Shadman, M and Ahn, KW and Kaur, M and Lekakis, L and Beitinjaneh, A and Iqbal, M and Ahmed, N and Hill, B and Hossain, NM and Riedell, P and Gopal, AK and Grover, N and Frigault, M and Brammer, J and Ghosh, N and Merryman, R and Lazaryan, A and Ram, R and Hertzberg, M and Savani, B and Awan, F and Khimani, F and Ahmed, S and Kenkre, VP and Ulrickson, M and Shah, N and Kharfan-Dabaja, MA and Herrera, A and Sauter, C and Hamadani, M}, title = {Autologous transplant vs. CAR-T therapy in patients with DLBCL treated while in complete remission.}, journal = {Blood cancer journal}, volume = {14}, number = {1}, pages = {108}, pmid = {38977682}, issn = {2044-5385}, support = {27305C0011/ES/NIEHS NIH HHS/United States ; 27307C0011/ES/NIEHS NIH HHS/United States ; 27398C0011/ES/NIEHS NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Lymphoma, Large B-Cell, Diffuse/therapy/mortality ; Middle Aged ; Female ; Male ; Adult ; *Transplantation, Autologous ; Retrospective Studies ; Aged ; *Hematopoietic Stem Cell Transplantation/methods ; *Immunotherapy, Adoptive/methods ; Young Adult ; Remission Induction ; Adolescent ; Treatment Outcome ; Pathologic Complete Response ; }, abstract = {In patients with relapsed DLBCL in complete remission (CR), autologous hematopoietic cell transplantation (auto-HCT) and CAR-T therapy are both effective, but it is unknown which modality provides superior outcomes. We compared the efficacy of auto-HCT vs. CAR-T in patients with DLBCL in a CR. A retrospective observational study comparing auto-HCT (2015-2021) vs. CAR-T (2018-2021) using the Center for International Blood &amp; Marrow Transplant Research registry. Median follow-up was 49.7 months for the auto-HCT and 24.7 months for the CAR-T cohort. Patients ages 18 and 75 with a diagnosis of DLBCL were included if they received auto-HCT (n = 281) or commercial CAR-T (n = 79) while in a CR. Patients undergoing auto-HCT with only one prior therapy line and CAR-T patients with a previous history of auto-HCT treatment were excluded. Endpoints included Progression-free survival (PFS), relapse rate, non-relapse mortality (NRM) and overall survival (OS). In univariate analysis, treatment with auto-HCT was associated with a higher rate of 2-year PFS (66.2% vs. 47.8%; p < 0.001), a lower 2-year cumulative incidence of relapse (27.8% vs. 48% ; p < 0.001), and a superior 2-year OS (78.9% vs. 65.6%; p = 0.037). In patients with early (within 12 months) treatment failure, auto-HCT was associated with a superior 2-year PFS (70.9% vs. 48.3% ; p < 0.001), lower 2-year cumulative incidence of relapse (22.8% vs. 45.9% ; p < 0.001) and trend for higher 2-year OS (82.4% vs. 66.1% ; p = 0.076). In the multivariable analysis, treatment with auto-HCT was associated with a superior PFS (hazard ratio 1.83; p = 0.0011) and lower incidence of relapse (hazard ratio 2.18; p < 0.0001) compared to CAR-T. In patients with relapsed LBCL who achieve a CR, treatment with auto-HCT is associated with improved clinical outcomes compared to CAR-T. These data support the consideration of auto-HCT in select patients with LBCL achieving a CR in the relapsed setting.}, }
@article {pmid38976877, year = {2024}, author = {Vedula, RS and Karp, HQ and Koob, J and Lim, F and Garcia, JS and Winer, ES and Luskin, MR and Ghiaur, G and Kim, AS and Beppu, LW and Sala-Torra, O and Radich, J and Gootenberg, J and Abudayyeh, O and Zhang, F and Lindsley, RC}, title = {CRISPR-based rapid molecular diagnostic tests for fusion-driven leukemias.}, journal = {Blood}, volume = {144}, number = {12}, pages = {1290-1299}, doi = {10.1182/blood.2023022908}, pmid = {38976877}, issn = {1528-0020}, mesh = {Humans ; *Oncogene Proteins, Fusion/genetics ; Molecular Diagnostic Techniques/methods ; Leukemia, Promyelocytic, Acute/genetics/diagnosis/therapy ; CRISPR-Cas Systems ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics/diagnosis/therapy ; Leukemia/genetics/diagnosis/therapy ; Clustered Regularly Interspaced Short Palindromic Repeats ; }, abstract = {Fusion oncogenes can be cancer-defining molecular alterations that are essential for diagnosis and therapy selection.1,2 Rapid and accessible molecular diagnostics for fusion-driven leukemias such as acute promyelocytic leukemia (APL), Philadelphia chromosome-positive acute lymphoblastic leukemia, and chronic myeloid leukemia (CML) are unavailable, creating a barrier to timely diagnosis and effective targeted therapy in many health care settings, including community hospitals and low-resource environments. We developed CRISPR-based RNA-fusion transcript detection assays using SHERLOCK (specific high-sensitivity enzymatic reporter unlocking) for the diagnosis of fusion-driven leukemias. We validated these assays using diagnostic samples from patients with APL and CML from academic centers and dried blood spots from low-resource environments, demonstrating 100% sensitivity and specificity. We identified assay optimizations to enable the use of these tests outside of tertiary cancer centers and clinical laboratories, enhancing the potential impact of this technology. Rapid point-of-care diagnostics can improve outcomes for patients with cancer by expanding access to therapies for highly treatable diseases that would otherwise lead to serious adverse outcomes due to delayed or missed diagnoses.}, }
@article {pmid38976697, year = {2024}, author = {Kosmider, E and Wallner, J and Gervassi, A and Bender Ignacio, RA and Pinto-Santini, D and Gornalusse, G and Pandey, U and Hladik, F and Edlefsen, PT and Lama, JR and Duerr, AC and Frenkel, LM}, title = {Observational study of effects of HIV acquisition and antiretroviral treatment on biomarkers of systemic immune activation.}, journal = {PloS one}, volume = {19}, number = {7}, pages = {e0288895}, pmid = {38976697}, issn = {1932-6203}, support = {KL2 TR002317/TR/NCATS NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; R01 DA040532/DA/NIDA NIH HHS/United States ; UM1 AI106716/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *HIV Infections/drug therapy/immunology/blood ; Male ; *Biomarkers/blood ; Female ; Adult ; Retrospective Studies ; Inflammation/blood ; Middle Aged ; Acute-Phase Proteins/metabolism ; C-Reactive Protein/metabolism/analysis ; Anti-HIV Agents/therapeutic use ; Transgender Persons ; Carrier Proteins ; Membrane Glycoproteins ; }, abstract = {To assess whether biomarkers of systemic inflammation are associated with HIV acquisition or with the timing of ART initiation ("immediate", at diagnosis, versus "deferred", at 24 weeks post-diagnosis) in men-who-have-sex-with-men (MSM) and transgender women, we conducted a retrospective study comparing inflammatory biomarkers in participants' specimens collected before infection and after ≥2 years of effective ART. We measured biomarkers in four longitudinally collected plasma, including two specimens collected from each participant before and two after HIV acquisition and confirmed ART-suppression. Biomarkers were quantified by enzyme-linked immuno-assay or Meso Scale Discovery. When evaluating systematic variation in these markers over time, we found that multiple biomarkers consistently varied across participants' two pre-infection or two post-ART-suppression specimens. Additionally, we compared changes in biomarkers after vs before HIV acquisition. Across 47 participants, the levels of C-reactive protein (CRP), monocyte chemo-attractant protein-1, tumor necrosis factor-α and interferon gamma-induced protein-10 significantly increased while leptin and lipopolysaccharide binding protein (LBP) significantly decreased following HIV infection. Randomization to deferred-ART initiation was associated with greater increases in CRP and no decrease in LBP. Acquisition of HIV appeared to induce systemic inflammation, with elevation of biomarkers previously associated with infections and cardiovascular disease. Initiation of ART during the early weeks of infection tempered the increase in pro-inflammatory biomarkers compared to delaying ART for ~24 weeks after HIV diagnosis. These findings provide insight into potential mediators by which immediate-ART initiation improves health outcomes, perhaps because immediate-ART limits the size of the HIV reservoir or limits immune dysregulation that in turn trigger systemic inflammation.}, }
@article {pmid38976321, year = {2024}, author = {McClure, JB and Heffner, JL and Krakauer, C and Mun, S and Catz, SL}, title = {A Novel mHealth App for Smokers Living With HIV Who Are Ambivalent About Quitting Smoking: Formative Research and Randomized Feasibility Study.}, journal = {JMIR formative research}, volume = {8}, number = {}, pages = {e58063}, pmid = {38976321}, issn = {2561-326X}, support = {R21 CA261199/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: More people who smoke and are living with HIV now die from tobacco-related diseases than HIV itself. Most people are ambivalent about quitting smoking and want to quit someday but not yet. Scalable, effective interventions are needed to motivate and support smoking cessation among people ambivalent about quitting smoking (PAQS) who are living with HIV.<br><br>OBJECTIVE: This study aims to develop an app-based intervention for PAQS who are living with HIV and assess its feasibility, acceptability, and potential impact. Results of this study will inform plans for future research and development.<br><br>METHODS: In phase 1, PAQS living with HIV (n=8) participated in user-centered design interviews to inform the final intervention app design and recruitment plan for a subsequent randomized pilot study. In phase 2, PAQS living with HIV were randomized to either a standard care control app or a similar experimental app with additional content tailored for PAQS and those with HIV. Participants were followed for 3 months. Feasibility focused on recruitment, retention, and participants' willingness to install the app. The study was not powered for statistical significance. Indices of acceptability (satisfaction and use) and impact (smoking behavior change and treatment uptake) were assessed via automated data and self-report among those who installed and used the app (n=19).<br><br>RESULTS: Recruitment for both study phases was a challenge, particularly via web-based and social media platforms. Enrollment success was greater among people living with HIV recruited from a health care provider and research registry. Once enrolled, retention for the phase 2 randomized study was good; 74% (14/19) of the participants completed the 3-month follow-up. Phase 1 findings suggested that PAQS living with HIV were receptive to using an app-based intervention to help them decide whether, when, and how to stop smoking, despite not being ready to quit smoking. Phase 2 findings further supported this conclusion based on feedback from people who agreed to use an app, but group differences were observed. Indices of acceptability favored the experimental arm, including a descriptively higher mean number of sessions and utilization badges. Similarly, indices of potential impact were descriptively higher in the experimental arm (proportion reducing smoking, making a quit attempt, or calling free tobacco quitline). No participants in either arm quit smoking at the 3-month follow-up.<br><br>CONCLUSIONS: On the basis of this formative work, PAQS living with HIV may be receptive to using a mobile health-based app intervention to help them decide whether, when, or how to stop using tobacco. Indices of acceptability and impact indicate that additional research and development are warranted.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT05339659; https://clinicaltrials.gov/study/NCT05339659.}, }
@article {pmid38974349, year = {2024}, author = {Liu, Y and Lawler, T and Liu, Z and Thuruthumaly, C and Vajaranant, T and Wallace, R and Tinker, L and Nalbandyan, M and Mares, J}, title = {Low Macular Pigment Optical Density Is Associated with Manifest Primary Open-Angle Glaucoma in Older Women.}, journal = {Current developments in nutrition}, volume = {8}, number = {6}, pages = {103789}, pmid = {38974349}, issn = {2475-2991}, support = {R01 EY025292/EY/NEI NIH HHS/United States ; }, abstract = {BACKGROUND: Lower density of carotenoids lutein and zeaxanthin (L/Z) in the macula (i.e., macular pigment) has been linked to greater risk for age-related eye disease.<br><br>OBJECTIVES: We evaluated whether macular pigment optical density (MPOD) was associated with manifest primary open-angle glaucoma (POAG) among older women in the Carotenoids in Age-Related Eye Disease Study 2 (CAREDS2).<br><br>METHODS: MPOD was measured with customized heterochromatic flicker photometry in women who attended CAREDS2 (2016-2019) and CAREDS1 (2001-2004) study visits. Manifest POAG at CAREDS2 was assessed using visual fields, disc photos, optical coherence tomography, and medical records. Age-adjusted linear and logistic regression models were used to investigate the cross-sectional association between POAG and MPOD at CAREDS2, and MPOD measured 15 years earlier at CAREDS1.<br><br>RESULTS: Among 426 CAREDS2 participants (mean age: 80 y; range: 69-98 y), 26 eyes with manifest POAG from 26 participants were identified. Glaucomatous eyes had 25% lower MPOD compared to nonglaucomatous eyes [mean (SE): 0.40 (0.05) compared with 0.53 (0.01)] optical density units (ODU), respectively (P = 0.01). Compared with MPOD quartile 1, odds for POAG were lower for women in quartiles 2-4 (P-trend = 0.01). After excluding eyes with age-related macular degeneration, associations were similar but not statistically significant (P-trend = 0.16). Results were similar for MPOD measured at CAREDS1.<br><br>CONCLUSIONS: Our results add to growing evidence that low MPOD may be a novel glaucoma risk factor and support further studies to assess the utility of dietary interventions for glaucoma prevention.}, }
@article {pmid38973806, year = {2024}, author = {Sofer, T and Granot-Hershkovitz, E and Tarraf, W and Filigrana, P and Isasi, CR and Suglia, SF and Kaplan, R and Taylor, K and Daviglus, ML and Testai, FD and Zeng, D and Cai, J and Fornage, M and González, HM and DeCarli, C}, title = {Intracranial Volume Is Driven by Both Genetics and Early Life Exposures: The SOL-INCA-MRI Study.}, journal = {Ethnicity &amp; disease}, volume = {34}, number = {2}, pages = {103-112}, pmid = {38973806}, issn = {1945-0826}, support = {N01HC65236/HL/NHLBI NIH HHS/United States ; R01 AG080598/AG/NIA NIH HHS/United States ; N01HC65233/HL/NHLBI NIH HHS/United States ; RF1 AG077639/AG/NIA NIH HHS/United States ; R01 AG075758/AG/NIA NIH HHS/United States ; R01 AG048642/AG/NIA NIH HHS/United States ; RF1 AG061022/AG/NIA NIH HHS/United States ; N01HC65235/HL/NHLBI NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; RF1 AG054548/AG/NIA NIH HHS/United States ; N01HC65234/HL/NHLBI NIH HHS/United States ; N01HC65237/HL/NHLBI NIH HHS/United States ; R21 AG070644/AG/NIA NIH HHS/United States ; R21 AG056952/AG/NIA NIH HHS/United States ; P30 AG072972/AG/NIA NIH HHS/United States ; }, mesh = {Adult ; Aged ; Child ; Female ; Humans ; Male ; Middle Aged ; *Brain/diagnostic imaging ; *Hispanic or Latino ; *Magnetic Resonance Imaging ; Organ Size ; United States ; Adolescent ; Young Adult ; }, abstract = {Intracranial volume (ICV) reflects maximal brain development and is associated with later-life cognitive abilities. We quantified ICV among first- and second-generation Hispanic and Latino adults from the Study of Latinos-Investigation of Cognitive Aging - MRI (SOL-INCA-MRI), estimated ICV heritability, and tested its associations with previously reported genetic variants, both individually and as a genetic risk score (GRS). We also estimated the association of ICV with early life environmental measures: nativity or age of immigration and parental education. The estimated heritability of ICV was 19% (95% CI, 0.1%-56%) in n=1781 unrelated SOL-INCA-MRI individuals. Four of 10 tested genetic variants were associated with ICV and an increase of 1 SD of the ICV-GRS was associated with an increase of 10.37 cm[3] in the ICV (95% CI, 5.29-15.45). Compared to being born in the continental United States, immigrating to the United States at age 11 years or older was associated with 24 cm[3] smaller ICV (95% CI, -39.97 to -8.06). Compared to both parents having less than high-school education, at least 1 parent completing high-school education was associated with 15.4 cm[3] greater ICV (95% CI, 4.46-26.39). These data confirm the importance of early life health on brain development.}, }
@article {pmid38972511, year = {2024}, author = {Iqbal, M and Kumar, A and Dreger, P and Chavez, J and Sauter, CS and Sureda, AM and Bachanova, V and Maziarz, RT and Dreyling, M and Smith, SM and Jacobson, C and Glass, B and Casulo, C and Oluwole, OO and Montoto, S and Advani, R and Cohen, J and Salles, G and Hamad, N and Kuruvilla, J and Kahl, BS and Shadman, M and Kanate, AS and Budde, LE and Kamdar, M and Flowers, C and Hamadani, M and Kharfan-Dabaja, MA}, title = {Clinical Practice Recommendations for Hematopoietic Cell Transplantation and Cellular Therapies in Follicular Lymphoma: A Collaborative Effort on Behalf of the American Society for Transplantation and Cellular Therapy and the European Society for Blood and Marrow Transplantation.}, journal = {Transplantation and cellular therapy}, volume = {30}, number = {9}, pages = {832-843}, doi = {10.1016/j.jtct.2024.06.025}, pmid = {38972511}, issn = {2666-6367}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation ; *Lymphoma, Follicular/therapy ; Europe ; Societies, Medical ; United States ; Immunotherapy, Adoptive/methods ; Cell- and Tissue-Based Therapy/methods ; }, abstract = {Follicular lymphoma (FL) is the most common indolent B-cell non-Hodgkin lymphoma (NHL), accounting for nearly one-third of all NHL. The therapeutic landscape for patients with FL has significantly expanded over the past decade, but the disease continues to be considered incurable. Hematopoietic cell transplantation (HCT) is potentially curative in some cases. Recently, the emergence of chimeric antigen receptor T-cell therapy (CAR-T) for patients with relapsed/refractory (R/R) FL has yielded impressive response rates and long-term remissions, but definitive statement on the curative potential of CAR-T is currently not possible due to limited patient numbers and relatively short follow up. A consensus on the contemporary role, optimal timing, and sequencing of HCT (autologous or allogeneic) and cellular therapies in FL is needed. As a result, the American Society of Transplantation and Cellular Therapy (ASTCT) Committee on Practice Guidelines endorsed this effort to formulate consensus recommendations to address this unmet need. The RAND-modified Delphi method was used to generate 15 consensus statements/recommendations. These clinical practice recommendations will help guide clinicians managing patients with FL. Of note, the use of bispecific antibodies in R/R FL was not in the scope of this project.}, }
@article {pmid38971667, year = {2024}, author = {Chauhan, SSB and Vierra, B and Park, JO and Pillarisetty, VG and Davidson, GH and Sham, JG}, title = {Prophylactic somatostatin analogs for postoperative pancreatic fistulas: a cross-sectional survey of AHPBA surgeons.}, journal = {HPB : the official journal of the International Hepato Pancreato Biliary Association}, volume = {26}, number = {10}, pages = {1229-1236}, doi = {10.1016/j.hpb.2024.06.002}, pmid = {38971667}, issn = {1477-2574}, mesh = {Humans ; *Pancreatic Fistula/prevention &amp; control ; Cross-Sectional Studies ; *Somatostatin/therapeutic use/analogs &amp; derivatives ; *Practice Patterns, Physicians' ; *Surgeons ; *Pancreatectomy/adverse effects ; *Octreotide/therapeutic use ; Health Care Surveys ; Postoperative Complications/prevention &amp; control ; Surveys and Questionnaires ; United States ; Treatment Outcome ; Gastrointestinal Agents/therapeutic use ; Male ; }, abstract = {BACKGROUND: Postoperative pancreatic fistulas lead to substantially increased morbidity, mortality, and healthcare costs after pancreatectomy. Studies have reported conflicting data on the role of prophylactic somatostatin analogs in the reduction of postoperative pancreatic fistula. Current practice patterns, surgeon beliefs, and barriers to using these drugs in the Americas is not known.<br><br>METHODS: An online 26-question cross-sectional survey was distributed via email to the members of the Americas Hepato-Pancreato-Biliary Association in April 2023.<br><br>RESULTS: One hundred and two surgeons responded in spring 2023. 48.0% of respondents reported using prophylactic SSAs during their surgical training, however, only 29.4% do so in their current practice, most commonly when performing Whipple procedures. Octreotide was the most frequently used SSA (34.3%), followed by octreotide LAR (12.7%) and pasireotide (11.8%). Reasons for not prescribing included a lack of high-quality data (62.7%), perception of limited efficacy (34.3%) and high cost (30.4%).<br><br>CONCLUSION: These results highlight key areas for future study including understanding surgeon rationale for patient and drug selection. Variable practice patterns amongst surgeons also underscore the importance of generalizability in the design of future clinical trials in order to maximize impact.}, }
@article {pmid38971327, year = {2024}, author = {Wang, J and Zhang, W and Xu, X and Buglioni, A and Li, P and Chen, X and Liu, Y and Xu, M and Herrick, JL and Horna, P and Zhang, X and Song, J and Jevremovic, D and He, R and Shi, M and Yuan, J}, title = {Clinicopathologic features and outcomes of acute leukemia harboring PICALM::MLLT10 fusion.}, journal = {Human pathology}, volume = {151}, number = {}, pages = {105626}, doi = {10.1016/j.humpath.2024.07.003}, pmid = {38971327}, issn = {1532-8392}, mesh = {Humans ; Male ; Female ; Adult ; Young Adult ; Adolescent ; *Oncogene Proteins, Fusion/genetics ; Child ; Middle Aged ; Child, Preschool ; *Leukemia, Myeloid, Acute/genetics/pathology ; Biomarkers, Tumor/genetics/analysis ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics/pathology/mortality/therapy ; Aged ; Phenotype ; Genetic Predisposition to Disease ; Infant ; Transcription Factors/genetics ; }, abstract = {The PICALM::MLLT10 fusion is a rare but recurrent cytogenetic abnormality in acute leukemia, with limited clinicopathologic and outcome data available. Herein, we analyzed 156 acute leukemia patients with PICALM::MLLT10 fusion, including 12 patients from our institutions and 144 patients from the literature. The PICALM::MLLT10 fusion preferentially manifested in pediatric and young adult patients, with a median age of 24 years. T-lymphoblastic leukemia/lymphoma (T-ALL) constituted 65% of cases, acute myeloid leukemia (AML) 27%, and acute leukemia of ambiguous lineage (ALAL) 8%. About half of T-ALL were classified as an early T-precursor (ETP)-ALL. In our institutions' cohort, mediastinum was the most common extramedullary site of involvement. Eight of 12 patients were diagnosed with T-ALL exhibiting a pro-/pre-T stage phenotype (CD4/CD8-double negative, CD7-positive), and frequent CD79a expression. NGS revealed pathogenic mutations in 5 of 6 tested cases, including NOTCH1, and genes in RAS and JAK-STAT pathways and epigenetic modifiers. Of 138 cases with follow-up, pediatric patients (<18 years) had 5-year overall survival (OS) of 71%, significantly better than adults at 33%. The 5-year OS for AML patients was 25%, notably shorter than T-ALL patients at 54%; this distinction was observed in both pediatric and adult populations. Furthermore, adult but not pediatric ETP-ALL patients demonstrated inferior survival compared to non-ETP-ALL patients. Neither karyotype complexity nor transplant status had a discernible impact on OS. In conclusion, PICALM::MLLT10 fusion is most commonly seen in T-ALL patients, particularly those with an ETP phenotype. AML and adult ETP-ALL patients had adverse prognosis. PICALM::MLTT10 fusion testing should be considered in T-ALL, AML, and ALAL patients.}, }
@article {pmid38969253, year = {2024}, author = {Lee, JM and Ichikawa, LE and Kerlikowske, K and Buist, DSM and Lee, CI and Sprague, BL and Henderson, LM and Onega, T and Wernli, KJ and Lowry, KP and Stout, NK and Tosteson, ANA and Miglioretti, DL}, title = {Relative Timing of Mammography and MRI for Breast Cancer Screening: Impact on Performance Evaluation.}, journal = {Journal of the American College of Radiology : JACR}, volume = {21}, number = {11}, pages = {1722-1732}, doi = {10.1016/j.jacr.2024.06.020}, pmid = {38969253}, issn = {1558-349X}, support = {P01 CA154292/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Breast Neoplasms/diagnostic imaging ; *Mammography ; Female ; *Early Detection of Cancer ; *Magnetic Resonance Imaging/methods ; Middle Aged ; *Sensitivity and Specificity ; Aged ; Time Factors ; United States ; Adult ; Mass Screening ; }, abstract = {OBJECTIVE: Mammography and MRI screening typically occur in combination or in alternating sequence. We compared multimodality screening performance accounting for the relative timing of mammography and MRI and overlapping follow-up periods.<br><br>METHODS: We identified 8,260 screening mammograms performed 2005 to 2017 in the Breast Cancer Surveillance Consortium, paired with screening MRIs within &#xb1;90 days (combined screening) or 91 to 270 days (alternating screening). Performance for combined screening (cancer detection rate [CDR] per 1,000 examinations and sensitivity) was calculated with 1-year follow-up for each modality, and with a single follow-up period treating the two tests as a single test. Alternating screening performance was calculated with 1-year follow-up for each modality and also with follow-up ending at the next screen if within 1 year (truncated follow-up).<br><br>RESULTS: For 3,810 combined screening pairs, CDR per 1,000 screens was 6.8 (95% confidence interval [CI]: 4.6-10.0) for mammography and 12.3 (95% CI: 9.3-16.4) for MRI as separate tests compared with 13.1 (95% CI: 10.0-17.3) as a single combined test. Sensitivity of each test was 48.1% (35.0%-61.5%) for mammography and 79.7% (95% CI: 67.7%-88.0%) for MRI compared with 96.2% (95% CI: 85.9%-99.0%) for combined screening. For 4,450 alternating screening pairs, mammography CDR per 1,000 screens changed from 3.6 (95% CI: 2.2-5.9) to zero with truncated follow-up; sensitivity was incalculable (denominator&#xa0;= 0). MRI CDR per 1,000 screens changed from 12.1 (95% CI 9.3-15.8) to 11.7 (95% CI: 8.9-15.3) with truncated follow-up; sensitivity changed from 75.0% (95% CI 63.8%-83.6%) to 86.7% (95% CI 75.5%-93.2%).<br><br>DISCUSSION: Updating auditing approaches to account for combined and alternating screening sequencing and to address outcome attribution issues arising from overlapping follow-up periods can improve the accuracy of multimodality screening performance evaluation.}, }
@article {pmid38968146, year = {2024}, author = {Fingrut, WB and Troyer, J and Russell, E and Aviles, M and Della-Moretta, S and Dobson, D and Hasanali, Z and Hu, B and Lapite, A and Pillai, PM and Schramm, JW and Villagomez, LM and Vo, P and Wang'ondu, R and Yui, J and Weyand, AC}, title = {The American Society of Hematology Health Equity Compendium: examining health equity across the Blood journals.}, journal = {Blood advances}, volume = {8}, number = {17}, pages = {4616-4624}, pmid = {38968146}, issn = {2473-9537}, mesh = {Humans ; *Health Equity ; *Hematology ; Periodicals as Topic ; United States ; Societies, Medical ; }, }
@article {pmid38968122, year = {2024}, author = {Zaidi, S and Park, J and Chan, JM and Roudier, MP and Zhao, JL and Gopalan, A and Wadosky, KM and Patel, RA and Sayar, E and Karthaus, WR and Kates, DH and Chaudhary, O and Xu, T and Masilionis, I and Mazutis, L and Chaligné, R and Obradovic, A and Linkov, I and Barlas, A and Jungbluth, AA and Rekhtman, N and Silber, J and Manova-Todorova, K and Watson, PA and True, LD and Morrissey, C and Scher, HI and Rathkopf, DE and Morris, MJ and Goodrich, DW and Choi, J and Nelson, PS and Haffner, MC and Sawyers, CL}, title = {Single-cell analysis of treatment-resistant prostate cancer: Implications of cell state changes for cell surface antigen-targeted therapies.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {28}, pages = {e2322203121}, pmid = {38968122}, issn = {1091-6490}, support = {CA155169//HHS | NIH | National Cancer Institute (NCI)/ ; R21 CA277368/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; R01 CA070292/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; R01 CA155169/CA/NCI NIH HHS/United States ; P01 CA265768/CA/NCI NIH HHS/United States ; R37 CA286450/CA/NCI NIH HHS/United States ; U54 CA224079/CA/NCI NIH HHS/United States ; K08 CA282978/CA/NCI NIH HHS/United States ; R01 CA266452/CA/NCI NIH HHS/United States ; R01 CA193837/CA/NCI NIH HHS/United States ; K08 CA259161/CA/NCI NIH HHS/United States ; R01 CA234715/CA/NCI NIH HHS/United States ; P50 CA092629/CA/NCI NIH HHS/United States ; NA//Howard Hughes Medical Institute (HHMI)/ ; R01 CA234162/CA/NCI NIH HHS/United States ; }, mesh = {Male ; Humans ; *Single-Cell Analysis/methods ; Animals ; Mice ; Prostatic Neoplasms/genetics/metabolism/pathology/drug therapy ; Antigens, Surface/metabolism/genetics ; Antigens, Neoplasm/metabolism/genetics/immunology ; Biomarkers, Tumor/metabolism/genetics ; Adenocarcinoma/genetics/pathology/metabolism/drug therapy ; Carcinoma, Neuroendocrine/genetics/pathology/metabolism/drug therapy ; Gene Expression Regulation, Neoplastic ; Prostatic Neoplasms, Castration-Resistant/metabolism/pathology/genetics/drug therapy ; }, abstract = {Targeting cell surface molecules using radioligand and antibody-based therapies has yielded considerable success across cancers. However, it remains unclear how the expression of putative lineage markers, particularly cell surface molecules, varies in the process of lineage plasticity, wherein tumor cells alter their identity and acquire new oncogenic properties. A notable example of lineage plasticity is the transformation of prostate adenocarcinoma (PRAD) to neuroendocrine prostate cancer (NEPC)-a growing resistance mechanism that results in the loss of responsiveness to androgen blockade and portends dismal patient survival. To understand how lineage markers vary across the evolution of lineage plasticity in prostate cancer, we applied single-cell analyses to 21 human prostate tumor biopsies and two genetically engineered mouse models, together with tissue microarray analysis on 131 tumor samples. Not only did we observe a higher degree of phenotypic heterogeneity in castrate-resistant PRAD and NEPC than previously anticipated but also found that the expression of molecules targeted therapeutically, namely PSMA, STEAP1, STEAP2, TROP2, CEACAM5, and DLL3, varied within a subset of gene-regulatory networks (GRNs). We also noted that NEPC and small cell lung cancer subtypes shared a set of GRNs, indicative of conserved biologic pathways that may be exploited therapeutically across tumor types. While this extreme level of transcriptional heterogeneity, particularly in cell surface marker expression, may mitigate the durability of clinical responses to current and future antigen-directed therapies, its delineation may yield signatures for patient selection in clinical trials, potentially across distinct cancer types.}, }
@article {pmid38965267, year = {2024}, author = {Riem, L and DuCharme, O and Cousins, M and Feng, X and Kenney, A and Morris, J and Tapscott, SJ and Tawil, R and Statland, J and Shaw, D and Wang, L and Walker, M and Lewis, L and Jacobs, MA and Leung, DG and Friedman, SD and Blemker, SS}, title = {AI driven analysis of MRI to measure health and disease progression in FSHD.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {15462}, pmid = {38965267}, issn = {2045-2322}, support = {K23 NS091379/NS/NINDS NIH HHS/United States ; P50 AR065139/AR/NIAMS NIH HHS/United States ; 1K23NS091379/GF/NIH HHS/United States ; }, mesh = {Humans ; *Muscular Dystrophy, Facioscapulohumeral/diagnostic imaging/pathology ; *Magnetic Resonance Imaging/methods ; *Disease Progression ; *Artificial Intelligence ; Male ; Female ; Middle Aged ; Adult ; Muscle, Skeletal/diagnostic imaging/pathology ; Image Processing, Computer-Assisted/methods ; }, abstract = {Facioscapulohumeral muscular dystrophy (FSHD) affects roughly 1 in 7500 individuals. While at the population level there is a general pattern of affected muscles, there is substantial heterogeneity in muscle expression across- and within-patients. There can also be substantial variation in the pattern of fat and water signal intensity within a single muscle. While quantifying individual muscles across their full length using magnetic resonance imaging (MRI) represents the optimal approach to follow disease progression and evaluate therapeutic response, the ability to automate this process has been limited. The goal of this work was to develop and optimize an artificial intelligence-based image segmentation approach to comprehensively measure muscle volume, fat fraction, fat fraction distribution, and elevated short-tau inversion recovery signal in the musculature of patients with FSHD. Intra-rater, inter-rater, and scan-rescan analyses demonstrated that the developed methods are robust and precise. Representative cases and derived metrics of volume, cross-sectional area, and 3D pixel-maps demonstrate unique intramuscular patterns of disease. Future work focuses on leveraging these AI methods to include upper body output and aggregating individual muscle data across studies to determine best-fit models for characterizing progression and monitoring therapeutic modulation of MRI biomarkers.}, }
@article {pmid38964333, year = {2024}, author = {Wang, H and Yao, Z and Kang, K and Zhou, L and Xiu, W and Sun, J and Xie, C and Yu, M and Li, Y and Zhang, Y and Zheng, Y and Lin, G and Pan, X and Wu, Y and Luo, R and Wang, L and Tang, M and Liao, S and Zhu, J and Zhou, X and Zhang, X and Xu, Y and Liu, Y and Peng, F and Wang, J and Xiang, L and Yin, L and Deng, L and Huang, M and Gong, Y and Zou, B and Wang, H and Wu, L and Yuan, Z and Bi, N and Fan, M and Xu, Y and Tong, R and Yi, L and Gan, L and Xue, J and Mo, X and Chen, C and Na, F and Lu, Y}, title = {Preclinical study and phase II trial of adapting low-dose radiotherapy to immunotherapy in small cell lung cancer.}, journal = {Med (New York, N.Y.)}, volume = {5}, number = {10}, pages = {1237-1254.e9}, doi = {10.1016/j.medj.2024.06.002}, pmid = {38964333}, issn = {2666-6340}, mesh = {*Small Cell Lung Carcinoma/radiotherapy/immunology/pathology/therapy/mortality ; *Lung Neoplasms/radiotherapy/pathology/immunology/mortality/therapy ; Animals ; Humans ; Mice ; Female ; Male ; Middle Aged ; *Immune Checkpoint Inhibitors/therapeutic use/pharmacology ; Aged ; *Immunotherapy/methods ; Tumor Microenvironment/immunology/drug effects ; Prospective Studies ; Combined Modality Therapy ; Radiotherapy Dosage ; Progression-Free Survival ; }, abstract = {BACKGROUND: Immune checkpoint inhibitors (ICIs) provide modest but unsatisfactory benefits for extensive-stage small cell lung cancer (ES-SCLC). Developing strategies for treating ES-SCLC is critical.<br><br>METHODS: We preliminarily explored the outcomes of salvage low-dose radiotherapy (LDRT) plus ICI on refractory SCLC patients. Next, we evaluated the combinational efficacy in murine SCLC. The tumor immune microenvironment (TIME) was analyzed for mechanistic study. Subsequently, we conducted a multicenter, prospective phase II trial that administered concurrent thoracic LDRT plus chemoimmunotherapy to treatment-naive ES-SCLC patients (MATCH trial, NCT04622228). The primary endpoint was confirmed objective response rate (ORR), and the key secondary endpoints included progression-free survival (PFS) and safety.<br><br>FINDINGS: Fifteen refractory SCLC patients treated with LDRT plus ICI were retrospectively reviewed. The ORR was 73.3% (95% confidence interval [CI], 44.9-92.2). We identified a specific dose of LDRT (15 Gy/5 fractions) that exhibited growth retardation and improved survival in murine SCLC when combined with ICIs. This combination recruited a special T&#xa0;cell population, TCF1[+] PD-1[+] CD8[+] stem-like T&#xa0;cells, from tumor-draining lymph nodes into the TIME. The MATCH trial showed a confirmed ORR of 87.5% (95% CI, 75.9-94.8). The median PFS was 6.9&#xa0;months (95% CI, 5.4-9.3).<br><br>CONCLUSIONS: These findings verified that LDRT plus chemoimmunotherapy was safe, feasible, and effective for ES-SCLC, warranting further investigation.<br><br>FUNDING: This research was funded by West China Hospital (no. ZYJC21003), the National Natural Science Foundation of China (no. 82073336), and the MATCH trial was fully funded by Roche (China) Holding Ltd. (RCHL) and Shanghai Roche Pharmaceuticals Ltd. (SRPL).}, }
@article {pmid38963827, year = {2024}, author = {Goya, S and Wendm, ST and Xie, H and Nguyen, TV and Barnes, S and Shankar, RR and Sereewit, J and Cruz, K and Pérez-Osorio, AC and Mills, MG and Greninger, AL}, title = {Genomic epidemiology and evolution of rhinovirus in western Washington State, 2021-22.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiae347}, pmid = {38963827}, issn = {1537-6613}, abstract = {BACKGROUND: Human rhinoviruses (RV) primarily cause the common cold, but infection outcomes vary from subclinical to severe cases, including asthma exacerbations and fatal pneumonia in immunocompromised individuals. To date, therapeutic strategies have been hindered by the high diversity of serotypes. Global surveillance efforts have traditionally focused on sequencing VP1 or VP2/VP4 genetic regions, leaving gaps in our understanding of RV genomic diversity.<br><br>METHODS: We sequenced 1,078 RV genomes from nasal swabs of symptomatic and asymptomatic individuals to explore viral evolution during two epidemiologically distinct periods in Washington State: when the COVID-19 pandemic affected the circulation of other seasonal respiratory viruses except for RV (February - July 2021), and when the seasonal viruses reemerged with the severe RSV and influenza outbreak (November-December 2022). We constructed maximum likelihood and BEAST-phylodynamic trees to characterize intra-genotype evolution.<br><br>RESULTS: We detected 99 of 168 known genotypes and observed inter-genotypic recombination and genotype cluster swapping from 2021 to 2022. We found a significant association between the presence of symptoms and viral load, but not with RV species or genotype. Phylodynamic trees, polyprotein selection pressure, and Shannon entropy revealed co-circulation of divergent clades within genotypes with high amino acid constraints throughout polyprotein.<br><br>DISCUSSION: Our study underscores the dynamic nature of RV genomic epidemiology within a localized geographic region, as more than 20% of existing genotypes within each RV species co-circulated each studied month. Our findings also emphasize the importance of investigating correlations between rhinovirus genotypes and serotypes to understand long-term immunity and cross-protection.}, }
@article {pmid38963825, year = {2024}, author = {Papini, C and Mirzaei S, S and Xing, M and Tonning Olsson, I and Salloum, R and de Blank, PMK and Lange, KR and King, TZ and Srivastava, D and Leisenring, WM and Howell, RM and Oeffinger, KC and Robison, LL and Armstrong, GT and Krull, KR and Brinkman, TM}, title = {Neurocognitive outcomes and functional independence in adult survivors of childhood medulloblastoma diagnosed over three decades.}, journal = {Neuro-oncology}, volume = {}, number = {}, pages = {}, doi = {10.1093/neuonc/noae119}, pmid = {38963825}, issn = {1523-5866}, support = {P30 CA021765/CA/NCI NIH HHS/United States ; T32 CA250803/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Treatment of childhood medulloblastoma has evolved to reduce neurotoxicity while improving survival. However, the impact of evolving therapies on late neurocognitive outcomes and adult functional independence remains unknown.<br><br>METHODS: Adult survivors of childhood medulloblastoma (n=505; median[minimum-maximum] age, 29[18-46] years) and sibling controls (n=727; 32[18-58] years) from the Childhood Cancer Survivor Study completed surveys assessing neurocognitive problems and chronic health conditions (CHCs). Treatment exposures were categorized as historical (craniospinal irradiation [CSI]&#x2265;30 Gy, no chemotherapy), standard-risk (CSI>0 to <30 Gy +chemotherapy) and high-risk (CSI&#x2265;30 Gy +chemotherapy) therapy. Latent class analysis identified patterns of functional independence using employment, independent living, assistance with routine/personal care needs, driver's license, marital/partner status. Multivariable models estimated risk of neurocognitive impairment in survivors versus siblings and by treatment exposure group, and associations between neurocognitive impairment, CHCs, and functional independence.<br><br>RESULTS: Survivors in each treatment exposure group had 4- to 5-fold elevated risk of impaired memory and task efficiency compared to siblings. Contemporary risk-based therapies did not confer lower risk compared to historical therapy. Survivors treated in the 1990s had higher risk of memory impairment (relative risk [RR] 2.24, 95% confidence interval [CI] 1.39-3.60) compared to survivors treated in the 1970s. Sensorimotor, hearing problems and seizures were associated with 33%-34%, 25-26% and 21%-42% elevated risk of task efficiency and memory impairment, respectively. Treatment-related CHCs and neurocognitive impairment were associated with non-independence.<br><br>CONCLUSIONS: Despite treatment changes, long-term survivors of childhood medulloblastoma remain at risk for neurocognitive impairment, which was associated with CHCs. Neurocognitive surveillance after contemporary regimens is imperative.}, }
@article {pmid38963280, year = {2024}, author = {Lyman, GH and Kuderer, NM}, title = {Artificial Intelligence and Cancer Clinical Research: III Risk Prediction Models for Febrile Neutropenia in Patients Receiving Cancer Chemotherapy.}, journal = {Cancer investigation}, volume = {42}, number = {7}, pages = {539-543}, doi = {10.1080/07357907.2024.2370692}, pmid = {38963280}, issn = {1532-4192}, mesh = {Humans ; *Artificial Intelligence ; *Neoplasms/drug therapy ; Risk Assessment ; Febrile Neutropenia/chemically induced ; Antineoplastic Agents/adverse effects/therapeutic use ; Risk Factors ; }, }
@article {pmid38961298, year = {2024}, author = {Dadonaite, B and Brown, J and McMahon, TE and Farrell, AG and Figgins, MD and Asarnow, D and Stewart, C and Lee, J and Logue, J and Bedford, T and Murrell, B and Chu, HY and Veesler, D and Bloom, JD}, title = {Spike deep mutational scanning helps predict success of SARS-CoV-2 clades.}, journal = {Nature}, volume = {631}, number = {8021}, pages = {617-626}, pmid = {38961298}, issn = {1476-4687}, support = {DP1 AI158186/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; P01 AI167966/AI/NIAID NIH HHS/United States ; 75N93021C00015/AI/NIAID NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; R01 AI141707/AI/NIAID NIH HHS/United States ; 75N93022C00036/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Angiotensin-Converting Enzyme 2/metabolism ; Antibodies, Neutralizing/immunology ; Antibodies, Viral/immunology ; Binding Sites ; COVID-19/immunology/virology ; *DNA Mutational Analysis ; *Evolution, Molecular ; *Genetic Fitness/genetics ; *Immune Evasion/genetics ; *Mutation ; Neutralization Tests ; Protein Binding ; Protein Domains/genetics ; *SARS-CoV-2/genetics/immunology/classification ; *Spike Glycoprotein, Coronavirus/genetics/chemistry/metabolism/immunology ; Virus Internalization ; HEK293 Cells ; }, abstract = {SARS-CoV-2 variants acquire mutations in the spike protein that promote immune evasion[1] and affect other properties that contribute to viral fitness, such as ACE2 receptor binding and cell entry[2,3]. Knowledge of how mutations affect these spike phenotypes can provide insight into the current and potential future evolution of the virus. Here we use pseudovirus deep mutational scanning[4] to measure how more than 9,000 mutations across the full XBB.1.5 and BA.2 spikes affect ACE2 binding, cell entry or escape from human sera. We find that mutations outside the receptor-binding domain (RBD) have meaningfully affected ACE2 binding during SARS-CoV-2 evolution. We also measure how mutations to the XBB.1.5 spike affect neutralization by serum from individuals who recently had SARS-CoV-2 infections. The strongest serum escape mutations are in the RBD at sites 357, 420, 440, 456 and 473; however, the antigenic effects of these mutations vary across individuals. We also identify strong escape mutations outside the RBD; however, many of them decrease ACE2 binding, suggesting they act by modulating RBD conformation. Notably, the growth rates of human SARS-CoV-2 clades can be explained in substantial part by the measured effects of mutations on spike phenotypes, suggesting our data could enable better prediction of viral evolution.}, }
@article {pmid38955177, year = {2024}, author = {Madan, A and Kelly, KP and Bahk, P and Sullivan, CE and Poling, ME and Brent, AE and Alassaf, M and Dubrulle, J and Rajan, A}, title = {Atg8/LC3 controls systemic nutrient surplus signaling in flies and humans.}, journal = {Current biology : CB}, volume = {34}, number = {15}, pages = {3327-3341.e9}, pmid = {38955177}, issn = {1879-0445}, support = {R35 GM124593/GM/NIGMS NIH HHS/United States ; P40 OD018537/OD/NIH HHS/United States ; P40 OD010949/OD/NIH HHS/United States ; R01 GM084947/GM/NIGMS NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P41 GM132087/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Drosophila Proteins/metabolism/genetics ; *Signal Transduction ; *Drosophila melanogaster/metabolism/genetics/physiology ; Adipocytes/metabolism ; Autophagy-Related Protein 8 Family/metabolism/genetics ; Leptin/metabolism/genetics ; Nutrients/metabolism ; Transcription Factors/metabolism/genetics ; Microtubule-Associated Proteins/metabolism/genetics ; Autophagy ; }, abstract = {Organisms experience constant nutritional flux. Mechanisms at the interface of opposing nutritional states-scarcity and surplus-enable organismal energy homeostasis. Contingent on nutritional stores, adipocytes secrete adipokines, such as the fat hormone leptin, to signal nutrient status to the central brain. Increased leptin secretion underlies metabolic dysregulation during common obesity, but the molecular mechanisms regulating leptin secretion from human adipocytes are poorly understood. Here, we report that Atg8/LC3 family proteins, best known for their role in autophagy during nutrient scarcity, play an evolutionarily conserved role during nutrient surplus by promoting adipokine secretion. We show that in a well-fed state, Atg8/LC3 promotes the secretion of the Drosophila functional leptin ortholog unpaired 2 (Upd2) and leptin from human adipocytes. Proteomic analyses reveal that LC3 directs leptin to a secretory pathway in human cells. We identified LC3-dependent extracellular vesicle (EV) loading and secretion (LDELS) as a required step for leptin release, highlighting a unique secretory route adopted by leptin in human adipocytes. In Drosophila, mutations to Upd2's Atg8 interaction motif (AIM) result in constitutive adipokine retention. Atg8-mediated Upd2 retention alters lipid storage and hunger response and rewires the bulk organismal transcriptome in a manner conducive to starvation survival. Thus, Atg8/LC3's bidirectional role in nutrient sensing-conveying nutrient surplus and responding to nutrient deprivation-enables organisms to manage nutrient flux effectively. We posit that decoding how bidirectional molecular switches-such as Atg8/LC3-operate at the nexus of nutritional scarcity and surplus will inform therapeutic strategies to tackle chronic metabolic disorders.}, }
@article {pmid38954235, year = {2024}, author = {Marín-Chollom, AM and Rillamas-Sun, E and Koch, PA and Contento, IR and Gaffney, AO and Ulanday, KT and Hershman, DL and Greenlee, H}, title = {Social Support, Diet, and Physical Activity among Latina/Hispanic Women Breast Cancer Survivors.}, journal = {Journal of immigrant and minority health}, volume = {26}, number = {6}, pages = {1053-1061}, pmid = {38954235}, issn = {1557-1920}, support = {R01 CA186080-01A1/CA/NCI NIH HHS/United States ; UL1TR00040/TR/NCATS NIH HHS/United States ; Avon Pilot Study//Herbert Irving comprehensive cancer center, Columbia University/ ; R01 CA186080-01A1/CA/NCI NIH HHS/United States ; UL1TR00040/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; Female ; *Hispanic or Latino/psychology/statistics &amp; numerical data ; Middle Aged ; *Breast Neoplasms/ethnology ; *Exercise ; *Cancer Survivors/psychology ; *Social Support ; *Diet ; Cross-Sectional Studies ; Adult ; Aged ; Socioeconomic Factors ; Vegetables ; White ; }, abstract = {Diet and physical activity guidelines for cancer survivorship are less likely to be followed by populations of minority cancer survivors, such as Latina/Hispanic women, compared to non-Hispanic White women. It is important to understand psychosocial mechanisms that may increase adherence to healthy lifestyle habits, especially in populations at risk for poorer cancer outcomes. This cross-sectional study examined the relationships between overall social support (SS) and SS from three sources (family, friends, and significant other) with diet (fruit and vegetables, fat, energy density, and diet quality), and moderate-to-vigorous physical activity (MVPA) behaviors in Latina/Hispanic women with a history of breast cancer (n = 85; M age = 55.2; SD = 9.2). Linear regression models and odds ratios were used to examine associations and adjusted for age, income, and acculturation. Family, significant other, and total SS were positively related to total fruit and vegetable intake but SS from friends was not. Higher levels of SS from all sources were each related to a low energy density diet. A higher quality diet was only related to SS from family. SS was not related to fat intake or MVPA. Higher SS from family and a significant other were associated with higher odds of meeting the fruit/vegetable guidelines; (family, OR = 3.72, 95% CI [1.21, 11.39]; significant other, OR = 3.32, 95% CI [1.08, 10.30]). Having more SS from family or a significant other may contribute to Latina/Hispanic women breast cancer survivors meeting national guidelines for a diet high in fruits and vegetables and low in energy density.}, }
@article {pmid38953656, year = {2024}, author = {Rudd, PA and Kher, G and Tame, JRH and Irie, H and Haselhorst, T and von Itzstein, M and Pancera, M and Hansman, GS}, title = {Human milk oligosaccharide 2'-fucosyllactose guards norovirus histo-blood group antigen co-factor binding site.}, journal = {Journal of virology}, volume = {98}, number = {7}, pages = {e0086524}, pmid = {38953656}, issn = {1098-5514}, mesh = {Humans ; *Norovirus/drug effects/metabolism ; *Milk, Human/chemistry ; *Blood Group Antigens/metabolism ; Binding Sites ; Oligosaccharides/metabolism/chemistry ; Trisaccharides/metabolism ; }, }
@article {pmid38953655, year = {2024}, author = {Hansman, GS and Kher, G and Svirina, AD and Tame, JRH and Hartley-Tassell, L and Irie, H and Haselhorst, T and von Itzstein, M and Rudd, PA and Pancera, M}, title = {Development of a broad-spectrum therapeutic Fc-nanobody for human noroviruses.}, journal = {Journal of virology}, volume = {98}, number = {7}, pages = {e0070724}, pmid = {38953655}, issn = {1098-5514}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {*Norovirus/genetics/drug effects/immunology ; Humans ; *Single-Domain Antibodies/immunology/pharmacology/chemistry ; *Capsid Proteins/immunology/metabolism/chemistry/genetics ; *Caliciviridae Infections/immunology/virology/therapy ; Antiviral Agents/pharmacology ; Immunoglobulin Fc Fragments/immunology/chemistry ; Antibodies, Viral/immunology ; Cross Reactions ; Capsid/metabolism/immunology ; Blood Group Antigens/metabolism ; Virus Replication/drug effects ; Gastroenteritis/virology ; Immunoglobulin G/immunology ; Antibodies, Monoclonal/immunology ; Antibodies, Neutralizing/immunology ; }, abstract = {Human norovirus was discovered more than five decades ago and is a widespread cause of outbreaks of acute gastroenteritis. There are no approved vaccines or antivirals currently available. However, norovirus inhibitors, including capsid-specific monoclonal antibodies (Mabs) and nanobodies, have recently shown promising results. Several Mabs and nanobodies were found to inhibit norovirus replication using a human intestinal enteroid (HIE) culture system and/or could block norovirus attachment to histo-blood group antigen (HBGA) co-factors. In our pursuit to develop a single broad-spectrum norovirus therapeutic, we continued our analysis and development of a cross-reactive and HBGA interfering nanobody (NB26). To improve NB26 binding capacity and therapeutic potential, we conjugated NB26 onto a human IgG Fc domain (Fc-NB26). We confirmed that Fc-NB26 cross-reacts with genetically diverse GII genotype capsid protruding (P) domains (GII.8, GII.14, GII.17, GII.24, GII.26, and GII.NA1) using a direct enzyme-linked immunosorbent assay. Furthermore, X-ray crystallography structures of these P domains and structures of other GII genotypes reveal that the NB26 binding site is largely conserved, validating its broad reactivity. We showed that Fc-NB26 has ~100-fold higher affinity toward the norovirus P domain compared to native NB26. We also found that both NB26 and Fc-NB26 neutralize human norovirus replication in the HIE culture system. Furthermore, the mode of inhibition confirmed that like NB26, Fc-NB26 caused norovirus particle disassembly and aggregation. Overall, these new findings demonstrate that structural modifications to nanobodies can improve their therapeutic potential.IMPORTANCEDeveloping vaccines and antivirals against norovirus remains a challenge, mainly due to the constant genetic and antigenic evolution. Moreover, re-infection with genetically related and/or antigenic variants is not uncommon. We further developed our leading norovirus nanobody (NB26) that indirectly interfered with norovirus binding to HBGAs, by converting NB26 into a dimeric Fc-linked Nanobody (Fc-NB26). We found that Fc-NB26 had improved binding affinity and neutralization capacity compared with native NB26. Using X-ray crystallography, we showed this nanobody engaged highly conserved capsid residues among genetically diverse noroviruses. Development of such broadly reactive potent therapeutic nanobodies delivered as a slow-releasing prophylactic could be of exceptional value for norovirus outbreaks, especially for the prevention or treatment of severe acute gastroenteritis in high-risk groups such as the young, elderly, and immunocompromised.}, }
@article {pmid38950184, year = {2024}, author = {Samorodnitsky, S and Campbell, K and Ribas, A and Wu, MC}, title = {A Spatial Omnibus Test (SPOT) for Spatial Proteomic Data.}, journal = {Bioinformatics (Oxford, England)}, volume = {40}, number = {7}, pages = {}, pmid = {38950184}, issn = {1367-4811}, support = {U10 CA180819/CA/NCI NIH HHS/United States ; U10 CA180819/GF/NIH HHS/United States ; }, mesh = {*Proteomics/methods ; Humans ; Software ; Tumor Microenvironment ; Lung Neoplasms/metabolism ; Ovarian Neoplasms/metabolism ; Cluster Analysis ; Female ; Algorithms ; }, abstract = {MOTIVATION: Spatial proteomics can reveal the spatial organization of immune cells in the tumor immune microenvironment. Relating measures of spatial clustering, such as Ripley's K or Besag's L, to patient outcomes may offer important clinical insights. However, these measures require pre-specifying a radius in which to quantify clustering, yet no consensus exists on the optimal radius which may be context-specific.<br><br>RESULTS: We propose a SPatial Omnibus Test (SPOT) which conducts this analysis across a range of candidate radii. At each radius, SPOT evaluates the association between the spatial summary and outcome, adjusting for confounders. SPOT then aggregates results across radii using the Cauchy combination test, yielding an omnibus P-value characterizing the overall degree of association. Using simulations, we verify that the type I error rate is controlled and show SPOT can be more powerful than alternatives. We also apply SPOT to ovarian and lung cancer studies.<br><br>An R package and tutorial are provided at https://github.com/sarahsamorodnitsky/SPOT.}, }
@article {pmid38950175, year = {2024}, author = {Li, M and Hua, X and Li, S and Wu, MC and Zhao, N}, title = {A multi-bin rarefying method for evaluating alpha diversities in TCR sequencing data.}, journal = {Bioinformatics (Oxford, England)}, volume = {40}, number = {7}, pages = {}, pmid = {38950175}, issn = {1367-4811}, support = {U10 CA180819/CA/NCI NIH HHS/United States ; U10CA180819//The Hope Foundation/ ; }, mesh = {*Receptors, Antigen, T-Cell/genetics ; Humans ; High-Throughput Nucleotide Sequencing/methods ; Sequence Analysis, DNA/methods ; Gene Library ; Genetic Variation ; }, abstract = {MOTIVATION: T cell receptors (TCRs) constitute a major component of our adaptive immune system, governing the recognition and response to internal and external antigens. Studying the TCR diversity via sequencing technology is critical for a deeper understanding of immune dynamics. However, library sizes differ substantially across samples, hindering the accurate estimation/comparisons of alpha diversities. To address this, researchers frequently use an overall rarefying approach in which all samples are sub-sampled to an even depth. Despite its pervasive application, its efficacy has never been rigorously assessed.<br><br>RESULTS: In this paper, we develop an innovative "multi-bin" rarefying approach that partitions samples into multiple bins according to their library sizes, conducts rarefying within each bin for alpha diversity calculations, and performs meta-analysis across bins. Extensive simulations using real-world data highlight the inadequacy of the overall rarefying approach in controlling the confounding effect of library size. Our method proves robust in addressing library size confounding, outperforming competing normalization strategies by achieving better-controlled type-I error rates and enhanced statistical power in association tests.<br><br>The code is available at https://github.com/mli171/MultibinAlpha. The datasets are freely available at https://doi.org/10.21417/B7001Z and https://doi.org/10.21417/AR2019NC.}, }
@article {pmid38949847, year = {2024}, author = {Zhao, LP and Papadopoulos, GK and Skyler, JS and Parikh, HM and Kwok, WW and Bondinas, GP and Moustakas, AK and Wang, R and Pyo, CW and Nelson, WC and Geraghty, DE and Lernmark, &#xc5;}, title = {Oral Insulin Delay of Stage 3 Type 1 Diabetes Revisited in HLA DR4-DQ8 Participants in the TrialNet Oral Insulin Prevention Trial (TN07).}, journal = {Diabetes care}, volume = {47}, number = {9}, pages = {1608-1616}, pmid = {38949847}, issn = {1935-5548}, support = {R01 DK132406/DK/NIDDK NIH HHS/United States ; RO1 DK132406//Division of Diabetes, Endocrinology, and Metabolic Diseases/ ; }, mesh = {Humans ; *Diabetes Mellitus, Type 1/drug therapy/immunology ; Female ; *HLA-DQ Antigens/genetics ; *Insulin/therapeutic use/administration &amp; dosage ; Male ; Administration, Oral ; *HLA-DR4 Antigen/genetics ; Child ; Autoantibodies/blood ; Adolescent ; Adult ; }, abstract = {OBJECTIVE: To explore if oral insulin could delay onset of stage 3 type 1 diabetes (T1D) among patients with stage 1/2 who carry HLA DR4-DQ8 and/or have elevated levels of IA-2 autoantibodies (IA-2As).<br><br>RESEARCH AND METHODS: Next-generation targeted sequencing technology was used to genotype eight HLA class II genes (DQA1, DQB1, DRB1, DRB3, DRB4, DRB5, DPA1, and DPB1) in 546 participants in the TrialNet oral insulin preventative trial (TN07). Baseline levels of autoantibodies against insulin (IAA), GAD65 (GADA), and IA-2A were determined prior to treatment assignment. Available clinical and demographic covariables from TN07 were used in this post hoc analysis with the Cox regression model to quantify the preventive efficacy of oral insulin.<br><br>RESULTS: Oral insulin reduced the frequency of T1D onset among participants with elevated IA-2A levels (HR 0.62; P = 0.012) but had no preventive effect among those with low IA-2A levels (HR 1.03; P = 0.91). High IA-2A levels were positively associated with the HLA DR4-DQ8 haplotype (OR 1.63; P = 6.37 &#xd7; 10-6) and negatively associated with the HLA DR7-containing DRB1*07:01-DRB4*01:01-DQA1*02:01-DQB1*02:02 extended haplotype (OR 0.49; P = 0.037). Among DR4-DQ8 carriers, oral insulin delayed the progression toward stage 3 T1D onset (HR 0.59; P = 0.027), especially if participants also had high IA-2A level (HR 0.50; P = 0.028).<br><br>CONCLUSIONS: These results suggest the presence of a T1D endotype characterized by HLA DR4-DQ8 and/or elevated IA-2A levels; for those patients with stage 1/2 disease with such an endotype, oral insulin delays the clinical T1D onset.}, }
@article {pmid38949435, year = {2024}, author = {McClelland, RS and Lokken, EM and Kinuthia, J and Srinivasan, S and Richardson, BA and Jaoko, W and Lannon, S and Pulei, A and Fiedler, TL and Munch, MM and Proll, S and John-Stewart, G and Fredricks, DN}, title = {A prospective cohort study examining the association between the periconceptual vaginal microbiota and first-trimester miscarriage in Kenyan women.}, journal = {Paediatric and perinatal epidemiology}, volume = {38}, number = {7}, pages = {599-611}, pmid = {38949435}, issn = {1365-3016}, support = {T32 AI007140/AI/NIAID NIH HHS/United States ; //United States National Institutes of Health/ ; T32 AI07140/AI/NIAID NIH HHS/United States ; F32 HD100202/HD/NICHD NIH HHS/United States ; R01 HD87346-RSM/HD/NICHD NIH HHS/United States ; UL1 TR002319/TR/NCATS NIH HHS/United States ; R01 HD087346/HD/NICHD NIH HHS/United States ; }, mesh = {Humans ; Female ; Pregnancy ; *Pregnancy Trimester, First ; *Vagina/microbiology ; *Microbiota ; Adult ; Prospective Studies ; *Abortion, Spontaneous/microbiology/epidemiology ; Kenya/epidemiology ; RNA, Ribosomal, 16S/analysis ; Young Adult ; }, abstract = {BACKGROUND: Studies evaluating the association between the vaginal microbiota and miscarriage have produced variable results.<br><br>OBJECTIVE: This study evaluated the association between periconceptual and first-trimester vaginal microbiota and women's risk for miscarriage.<br><br>METHODS: At monthly preconception visits and at 9-12&#x2009;weeks gestation, women collected vaginal swabs for molecular characterisation of the vaginal microbiota. Participants who became pregnant were followed to identify miscarriage versus pregnancy continuing to at least 20&#x2009;weeks gestation.<br><br>RESULTS: Forty-five women experienced miscarriage and 144 had pregnancies continuing to &#x2265;20&#x2009;weeks. A principal component analysis of periconceptual and first-trimester vaginal bacteria identified by 16S rRNA gene PCR with next-generation sequencing did not identify distinct bacterial communities with miscarriage versus continuing pregnancy. Using taxon-directed quantitative PCR assays, increasing concentrations of Megasphaera hutchinsoni, Mageeibacillus indolicus, Mobiluncus mulieris and Sneathia sanguinegens/vaginalis were not associated with miscarriage. In exploratory analyses, these data were examined as a binary exposure to allow for multivariable modelling. Detection of Mobiluncus mulieris in first-trimester samples was associated with miscarriage (adjusted relative risk [aRR] 2.14, 95% confidence interval [CI] 1.08, 4.22). Additional analyses compared women with early first-trimester miscarriage (range 4.7-7.3&#x2009;weeks) to women with continuing pregnancies. Mobiluncus mulieris was detected in all eight (100%) first-trimester samples from women with early first-trimester miscarriage compared to 101/192 (52.6%) samples from women with continuing pregnancy (model did not converge). Detection of Mageeibacillus indolicus in first-trimester samples was also associated with early first-trimester miscarriage (aRR 4.10, 95% CI 1.17, 14.31).<br><br>CONCLUSIONS: The primary analyses in this study demonstrated no association between periconceptual or first-trimester vaginal microbiota and miscarriage. Exploratory analyses showing strong associations between first-trimester detection of Mobiluncus mulieris and Mageeibacillus indolicus and early first-trimester miscarriage suggest the need for future studies to determine if these findings are reproducible.}, }
@article {pmid38947282, year = {2024}, author = {Samorodnitsky, S and Wendt, CH and Lock, EF}, title = {Bayesian Simultaneous Factorization and Prediction Using Multi-Omic Data.}, journal = {Computational statistics &amp; data analysis}, volume = {197}, number = {}, pages = {}, pmid = {38947282}, issn = {0167-9473}, support = {R01 GM130622/GM/NIGMS NIH HHS/United States ; R01 HL140971/HL/NHLBI NIH HHS/United States ; R21 CA231214/CA/NCI NIH HHS/United States ; }, abstract = {Integrative factorization methods for multi-omic data estimate factors explaining biological variation. Factors can be treated as covariates to predict an outcome and the factorization can be used to impute missing values. However, no available methods provide a comprehensive framework for statistical inference and uncertainty quantification for these tasks. A novel framework, Bayesian Simultaneous Factorization (BSF), is proposed to decompose multi-omics variation into joint and individual structures simultaneously within a probabilistic framework. BSF uses conjugate normal priors and the posterior mode of this model can be estimated by solving a structured nuclear norm-penalized objective that also achieves rank selection and motivates the choice of hyperparameters. BSF is then extended to simultaneously predict a continuous or binary phenotype while estimating latent factors, termed Bayesian Simultaneous Factorization and Prediction (BSFP). BSF and BSFP accommodate concurrent imputation, i.e., imputation during the model-fitting process, and full posterior inference for missing data, including "blockwise" missingness. It is shown via simulation that BSFP is competitive in recovering latent variation structure, and demonstrate the importance of accounting for uncertainty in the estimated factorization within the predictive model. The imputation performance of BSF is examined via simulation under missing-at-random and missing-not-at-random assumptions. Finally, BSFP is used to predict lung function based on the bronchoalveolar lavage metabolome and proteome from a study of HIV-associated obstructive lung disease, revealing multi-omic patterns related to lung function decline and a cluster of patients with obstructive lung disease driven by shared metabolomic and proteomic abundance patterns.}, }
@article {pmid38947062, year = {2024}, author = {Scherer, M and Nandi, V and Sobieszczyk, ME and Laeyendecker, O and Karuna, S and Andrasik, M and Janes, HE and Brown, EE and Tieu, HV}, title = {Incidence and prevalence of hepatitis C and B infections among men who have sex with men and transgender women enrolled in a United States HIV vaccine trial.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {38947062}, issn = {2693-5015}, support = {UM1 AI069424/AI/NIAID NIH HHS/United States ; UM1 AI069534/AI/NIAID NIH HHS/United States ; UM1 AI069439/AI/NIAID NIH HHS/United States ; UM1 AI069481/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; P30 AI036211/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; HHSN272200800014C/AI/NIAID NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; UM1 AI069418/AI/NIAID NIH HHS/United States ; UM1 AI069501/AI/NIAID NIH HHS/United States ; P30 AI050409/AI/NIAID NIH HHS/United States ; UM1 AI069554/AI/NIAID NIH HHS/United States ; UL1 TR000154/TR/NCATS NIH HHS/United States ; UM1 AI069412/AI/NIAID NIH HHS/United States ; UM1 AI069470/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UL1 TR000451/TR/NCATS NIH HHS/United States ; UM1 AI069452/AI/NIAID NIH HHS/United States ; UM1 AI069496/AI/NIAID NIH HHS/United States ; UM1 AI069511/AI/NIAID NIH HHS/United States ; P30 AI036219/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: Rising hepatitis C and B virus (HCV and HBV) rates have been reported in men who have sex with men (MSM) and transgender women (TGW). This study characterizes HCV and HBV infections longitudinally among 2,496 MSM/TGW aged 18-50 years and at risk for HIV acquisition enrolled in an HIV-1 vaccine trial in 18 U.S. cities between 2009-2013.<br><br>METHODS: Participants completed behavioral surveys, HIV testing, and blood collection over 24 months. Of the 2,397 participants who consented for future testing, 1,792 (74.8%) had available paired stored blood samples at baseline and a later timepoint (Month 24 [N = 999]; if unavailable, M12 [N = 775] or M15 [N = 18]).<br><br>RESULTS: Among 1,792 participants, 98.1% were MSM, 0.8% were TGW, and the median age was 30 years (IQR 24, 40). Participants reported a median number of 3 male sex partners (IQR 1,5) within the past 3 months. Condomless insertive anal sex was reported by 55.8% and condomless receptive anal sex by 46.7%.1.3% reported injection drug use. During follow-up, 1.4% reported pre-exposure prophylaxis (PrEP) use. At baseline 11/1792 (0.61%) participants had HCV infection (HCV AB positive, RNA detectable), with all having persistent detectable RNA and chronic HCV infection at follow-up. Phylogenetic analysis showed no clusters of HCV infection. 8 participants had HCV AB positive, RNA undetectable at baseline and follow-up, representing past HCV infection with clearance; only 2 acquired HCV, which cleared over 12-24 months. At baseline, 2 participants (2/1792 = 0.11%) had positive HBsAg, indicating chronic HBV infection. Over 12-24 months, 4 (4/1790, 0.22%) developed HBsAg positivity; these participants had HBcAB positivity at baseline, thereby likely representing reactivation. There were no new HBV infections during follow-up.<br><br>CONCLUSION: Among 1,792 men who have sex with men and transgender women aged 18-50 years and at risk for HIV acquisition enrolled in a U.S. HIV-1 vaccine trial, incident hepatitis C infection rates were extremely low, with no cases of incident hepatitis B infection. These rates of incident HCV infection and HBSAg positivity are lower than previously reported among MSM/TGW.}, }
@article {pmid38947011, year = {2024}, author = {Abernethy, NF and McCloskey, K and Trahey, M and Rinn, L and Broder, GB and Andrasik, M and Laborde, R and McGhan, D and Spendolini, S and Marimuthu, S and Kanzmeier, A and Hanes, J and Kublin, J}, title = {Rapid Development of a Registry to Accelerate COVID-19 Vaccine Clinical Trials.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {38947011}, issn = {2693-5015}, support = {UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: The unprecedented scientific response to the SARS-Cov-2 pandemic in 2020 required the rapid development and activation of extensive clinical trial networks to study vaccines and therapeutics. The COVID-19 Prevention Network (CoVPN) coordinated hundreds of sites conducting phase 2 and 3 clinical trials of vaccines and antibody therapeutics. To facilitate these clinical trials, the CoVPN Volunteer Screening Registry (VSR) was created to collect volunteer information at scale, identify volunteers at risk of COVID-19 who met enrollment criteria, distribute candidates across clinical trial sites, and enable monitoring of volunteering and enrollment progress.<br><br>METHODS: We developed a secure database to support three primary web-based interfaces: a national volunteer questionnaire intake form, a clinical trial site portal, and an Administrative Portal. The Site Portal supported filters based on volunteer attributes, visual analytics, enrollment status tracking, geographic search, and clinical risk prediction. The Administrative Portal supported oversight and development with pre-specified reports aggregated by geography, trial, and trial site; charts of volunteer rates over time; volunteer risk score calculation; and dynamic, user-defined reports.<br><br>FINDINGS: Over 650,000 volunteers joined the VSR, and 1094 users were trained to utilize the system. The VSR played a key role in recruitment for the Moderna, Oxford-AstraZeneca, Janssen, and Novavax vaccine clinical trials, provided support to the Pfizer and Sanofi vaccine and prophylactic antibody clinical trials, and enhanced the diversity of trial participants. Clinical trial sites selected 166,729 volunteer records for follow-up screening, and of these 47&#xb7;7% represented groups prioritized for increased enrollment. Despite the unprecedented urgency of its development, the system maintained 99&#xb7;99% uptime.<br><br>INTERPRETATION: The success of the VSR demonstrates that information tools can be rapidly yet safely developed through a public-private partnership and integrated into a distributed and accelerated clinical trial setting. We further summarize the requirements, design, and development of the system, and discuss lessons learned for future pandemic preparedness.}, }
@article {pmid38946649, year = {2024}, author = {Woolston, DW and Lee, ND and Shadman, M and Latorre-Esteves, E and Tee, XR and Fredrickson, J and Kohrn, BF and Ujjani, C and Eckel, A and Till, B and Fang, M and Radich, J and Bozic, I and Risques, RA and Yeung, CCS}, title = {Erratum to: Ultra-deep mutational landscape in chronic lymphocytic leukemia uncovers dynamics of resistance to targeted therapies.}, journal = {Haematologica}, volume = {109}, number = {7}, pages = {2378}, pmid = {38946649}, issn = {1592-8721}, }
@article {pmid38944153, year = {2024}, author = {Cusatis, R and Litovich, C and Feng, Z and Allbee-Johnson, M and Kapfhammer, M and Mattila, D and Akinola, I and Phelan, R and Broglie, L and Auletta, JJ and Steinert, P and Bolon, YT and Akhtar, O and Bloomquist, J and Chen, M and Devine, SM and Bupp, C and Hamadani, M and Hengen, M and Jaglowski, S and Kaur, M and Kuxhausen, M and Lee, SJ and Moskop, A and Page, KM and Pasquini, MC and Rizzo, D and Saber, W and Spellman, SR and Stefanski, HE and Tuschl, E and Yusuf, R and Zhan, K and Flynn, KE and Shaw, BE}, title = {Current Trends and Outcomes in Cellular Therapy Activity in the United States, Including Prospective Patient-Reported Outcomes Data Collection in the Center for International Blood and Marrow Transplant Research Registry.}, journal = {Transplantation and cellular therapy}, volume = {30}, number = {9}, pages = {917.e1-917.e12}, pmid = {38944153}, issn = {2666-6367}, support = {27305C0011/ES/NIEHS NIH HHS/United States ; 27307C0011/ES/NIEHS NIH HHS/United States ; 27398C0011/ES/NIEHS NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Patient Reported Outcome Measures ; *Registries ; United States ; *Hematopoietic Stem Cell Transplantation ; Prospective Studies ; Cell- and Tissue-Based Therapy ; Data Collection ; }, abstract = {The Center for International Blood and Marrow Transplant Research (CIBMTR) prepares an annual set of summary slides to summarize the trends in transplantation and cellular therapies. For the first time in the 2023 summary slides, the CIBMTR incorporated data for patients receiving chimeric antigen receptor T cell (CAR-T) infusions. In addition, data on patient-reported outcomes (PROs) are included. This report aims to update the annual trends in US hematopoietic cell transplantation (HCT) activity and incorporate data on the use of CAR-T therapies. A second aim is to present and describe the development, implementation, and current status of PRO data collection. In August 2020, the CIBMTR launched the Protocol for Collection of Patient-Reported Outcomes Data (CIBMTR PRO Protocol). The CIBMTR PRO Protocol operates under a centralized infrastructure to reduce the burden to centers. Specifically, PRO data are collected from a prospective convenience sample of adult HCT and CAR-T recipients who received treatment at contributing centers and consented for research. Data are merged and stored with the clinical data and used under the governance of the CIBMTR Research Database Protocol. Participants answer a series of surveys developed by the Patient Reported Outcomes Measurement Information System (PROMIS) focusing on physical, social and emotional, and other measures assessing financial well-being, occupational functioning, and social determinants of health. To complement traditionally measured clinical outcomes, the surveys are administered at the same time points at which clinical data are routinely collected. As of September 2023, PRO data have been collected from 993 patients across 25 different centers. With the goal of incorporating these important patient perspectives into standard clinical care, the CIBMTR has added the PRO data to Data Back to Centers (DBtC). Through expanding the data types represented in the registry, the CIBMTR aims to support holistic research accounting for the patients' perspective in improving patient outcomes. CIBMTR PRO data aim to provide a foundation for future large-scale, population-level evaluations to identify areas for improvement, emerging disparities in access and health outcomes (eg, by age, race, and ethnicity), and new therapies that may impact current treatment guidelines. Continuing to collect and grow the PRO data is critical for understanding these changes and identifying methods for improving patients' quality of life.}, }
@article {pmid38943735, year = {2024}, author = {Schöffski, P and Jones, RL and Agulnik, M and Blay, JY and Chalmers, A and Italiano, A and Pink, D and Stacchiotti, S and Valverde, C and Vincenzi, B and Wagner, MJ and Maki, R}, title = {Current unmet needs in locally advanced (unresectable) or metastatic dedifferentiated liposarcoma, the relevance of progression-free survival as clinical endpoint, and expectations for future clinical trial design: an international Delphi consensus report.}, journal = {ESMO open}, volume = {9}, number = {7}, pages = {103487}, pmid = {38943735}, issn = {2059-7029}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Liposarcoma/therapy/mortality/pathology ; *Delphi Technique ; *Progression-Free Survival ; *Consensus ; Clinical Trials as Topic ; Europe ; Research Design ; }, abstract = {BACKGROUND: Locally advanced (unresectable) or metastatic dedifferentiated liposarcoma (DDLPS) is a common presentation of liposarcoma. Despite established diagnostic and treatment guidelines for DDLPS, critical clinical gaps remain driven by diagnostic challenges, symptom burden and the lack of targeted, safe and effective treatments. The objective of this study was to gather expert opinions from Europe and the United States on the management, unmet needs and expectations for clinical trial design as well as the value of progression-free survival (PFS) in this disease. Other aims included raising awareness and educate key stakeholders across healthcare systems.<br><br>MATERIALS AND METHODS: An international panel of 12 sarcoma key opinion leaders (KOLs) was recruited. The study consisted of two rounds of surveys with pre-defined statements. Experts scored each statement on a 9-point Likert scale. Consensus agreement was defined as &#x2265;75% of experts scoring a statement with &#x2265;7. Revised statements were discussed in a consensus meeting.<br><br>RESULTS: Consensus was reached on 43 of 55 pre-defined statements across disease burden, treatment paradigm, unmet needs, value of PFS and its association with overall survival (OS), and cross-over trial design. Twelve statements were deprioritised or merged with other statements. There were no statements where experts disagreed.<br><br>CONCLUSION: This study constitutes the first international Delphi panel on DDLPS. It aimed to explore KOL perception of the disease burden and unmet need in DDLPS, the value of PFS, and its potential translation to OS benefit, as well as the relevance of a cross-over trial design for DDLPS therapies. Results indicate an alignment across Europe and the United States regarding DDLPS management, unmet needs, and expectations for clinical trials. Raising awareness of critical clinical gaps in relation to DDLPS can contribute to improving patient outcomes and supporting the development of innovative treatments.}, }
@article {pmid38942778, year = {2024}, author = {Esmaeili, S and Owens, K and Wagoner, J and Polyak, SJ and White, JM and Schiffer, JT}, title = {A unifying model to explain frequent SARS-CoV-2 rebound after nirmatrelvir treatment and limited prophylactic efficacy.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {5478}, pmid = {38942778}, issn = {2041-1723}, support = {R01 AI177512/AI/NIAID NIH HHS/United States ; R01AI177512//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; R01AI121129//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; R01AI169427//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; }, mesh = {Humans ; *SARS-CoV-2/drug effects ; *Ritonavir/therapeutic use/administration &amp; dosage ; *COVID-19 Drug Treatment ; *COVID-19/prevention &amp; control/virology/immunology ; *Viral Load/drug effects ; *Antiviral Agents/administration &amp; dosage/therapeutic use/pharmacology ; Indazoles/pharmacology ; Models, Theoretical ; Post-Exposure Prophylaxis/methods ; Lactams ; Leucine ; Nitriles ; Proline ; }, abstract = {In a pivotal trial (EPIC-HR), a 5-day course of oral ritonavir-boosted nirmatrelvir, given early during symptomatic SARS-CoV-2 infection (within three days of symptoms onset), decreased hospitalization and death by 89.1% and nasal viral load by 0.87 log relative to placebo in high-risk individuals. Yet, nirmatrelvir/ritonavir failed as post-exposure prophylaxis in a trial, and frequent viral rebound has been observed in subsequent cohorts. We develop a mathematical model capturing viral-immune dynamics and nirmatrelvir pharmacokinetics that recapitulates viral loads from this and another clinical trial (PLATCOV). Our results suggest that nirmatrelvir's in vivo potency is significantly lower than in vitro assays predict. According to our model, a maximally potent agent would reduce the viral load by approximately 3.5 logs relative to placebo at 5 days. The model identifies that earlier initiation and shorter treatment duration are key predictors of post-treatment rebound. Extension of treatment to 10 days for Omicron variant infection in vaccinated individuals, rather than increasing dose or dosing frequency, is predicted to lower the incidence of viral rebound significantly.}, }
@article {pmid38941510, year = {2024}, author = {Reiner, AS and Knight, JA and John, EM and Lynch, CF and Malone, KE and Liang, X and Woods, M and Root, JC and Bernstein, JL}, title = {Agreement of medical record abstraction and self-report of breast cancer treatment with an extended recall window.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.35459}, pmid = {38941510}, issn = {1097-0142}, support = {CA008748/NH/NIH HHS/United States ; CA083178/NH/NIH HHS/United States ; CA097397/NH/NIH HHS/United States ; CA114236/NH/NIH HHS/United States ; CA129639/NH/NIH HHS/United States ; }, abstract = {BACKGROUND: Medical record abstraction (MRA) and self-report questionnaires are two methods frequently used to ascertain cancer treatment information. Prior studies have shown excellent agreement between MRA and self-report, but it is unknown how a recall window longer than 3 years may affect this agreement.<br><br>METHODS: The Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study is a multicenter, population-based case-control study of controls with unilateral breast cancer individually matched to cases with contralateral breast cancer. Participants who were diagnosed with a first primary breast cancer from 1985 to 2008 before the age of 55 years completed a questionnaire that included questions on treatment. First primary breast cancer treatment information was abstracted from the medical record from radiation oncology clinic notes for radiation treatment and from systemic adjuvant treatment reports for hormone therapy and chemotherapy. Agreement between MRA and self-reported treatment was assessed with the kappa statistic and corresponding 95% confidence intervals (CIs).<br><br>RESULTS: A total of 2808 participants with MRA and self-reported chemotherapy treatment information, 2733 participants with MRA and self-reported hormone therapy information, and 2905 participants with MRA and self-reported radiation treatment information were identified. The median recall window was 12.5 years (range, 2.8-22.2 years). MRA and self-reported treatment agreement was excellent across treatment modalities (kappachemo, 98.5; 95% CI, 97.9-99.2; kappahorm, 87.7; 95% CI, 85.9-89.5; kapparad, 97.9; 95% CI, 97.0-98.7). There was no heterogeneity across recall windows (pchemo&#xa0;=&#xa0;.46; phorm&#xa0;=&#xa0;.40; prad&#xa0;=&#xa0;.61).<br><br>CONCLUSIONS: Agreement between self-reported and MRA primary breast cancer treatment modality information was excellent for young women diagnosed with breast cancer and was maintained even among women whose recall window was more than 20 years after diagnosis.}, }
@article {pmid38940271, year = {2024}, author = {Chen, BD and Lee, C and Tapia, AL and Reiner, AP and Tang, H and Kooperberg, C and Manson, JE and Li, Y and Raffield, LM}, title = {Proteome-wide association study using cis and trans variants and applied to blood cell and lipid-related traits in the Women's Health Initiative study.}, journal = {Genetic epidemiology}, volume = {48}, number = {7}, pages = {310-323}, doi = {10.1002/gepi.22578}, pmid = {38940271}, issn = {1098-2272}, support = {/NH/NIH HHS/United States ; /NH/NIH HHS/United States ; }, mesh = {Humans ; *Polymorphism, Single Nucleotide ; Female ; *Genome-Wide Association Study ; *Quantitative Trait Loci ; *Proteome/genetics ; Middle Aged ; Women's Health ; Aged ; Phenotype ; Lipids/blood/genetics ; }, abstract = {In most Proteome-Wide Association Studies (PWAS), variants near the protein-coding gene (±1 Mb), also known as cis single nucleotide polymorphisms (SNPs), are used to predict protein levels, which are then tested for association with phenotypes. However, proteins can be regulated through variants outside of the cis region. An intermediate GWAS step to identify protein quantitative trait loci (pQTL) allows for the inclusion of trans SNPs outside the cis region in protein-level prediction models. Here, we assess the prediction of 540 proteins in 1002 individuals from the Women's Health Initiative (WHI), split equally into a GWAS set, an elastic net training set, and a testing set. We compared the testing r[2] between measured and predicted protein levels using this proposed approach, to the testing r[2] using only cis SNPs. The two methods usually resulted in similar testing r[2], but some proteins showed a significant increase in testing r[2] with our method. For example, for cartilage acidic protein 1, the testing r[2] increased from 0.101 to 0.351. We also demonstrate reproducible findings for predicted protein association with lipid and blood cell traits in WHI participants without proteomics data and in UK Biobank utilizing our PWAS weights.}, }
@article {pmid38939155, year = {2024}, author = {Bradbury, JD and Hodgkinson, T and Thomas, AM and Tanwar, O and La Monica, G and Rogga, VV and Mackay, LJ and Taylor, EK and Gilbert, K and Zhu, Y and Sefton, AY and Edwards, AM and Gray-Hammerton, CJ and Smith, GR and Roberts, PM and Walsh, TR and Lanyon-Hogg, T}, title = {Development of an inhibitor of the mutagenic SOS response that suppresses the evolution of quinolone antibiotic resistance.}, journal = {Chemical science}, volume = {15}, number = {25}, pages = {9620-9629}, pmid = {38939155}, issn = {2041-6520}, abstract = {Antimicrobial resistance (AMR) is a growing threat to health globally, with the potential to render numerous medical procedures so dangerous as to be impractical. There is therefore an urgent need for new molecules that function through novel mechanisms of action to combat AMR. The bacterial DNA-repair and SOS-response pathways promote survival of pathogens in infection settings and also activate hypermutation and resistance mechanisms, making these pathways attractive targets for new therapeutics. Small molecules, such as IMP-1700, potentiate DNA damage and inhibit the SOS response in methicillin-resistant S. aureus; however, understanding of the structure-activity relationship (SAR) of this series is lacking. We report here the first comprehensive SAR study of the IMP-1700 scaffold, identifying key pharmacophoric groups and delivering the most potent analogue reported to date, OXF-077. Furthermore, we demonstrate that as a potent inhibitor of the mutagenic SOS response, OXF-077 suppresses the rate of ciprofloxacin resistance emergence in S. aureus. This work supports SOS-response inhibitors as a novel means to combat AMR, and delivers OXF-077 as a tool molecule for future development.}, }
@article {pmid38937547, year = {2024}, author = {Walter, RB and Gale, RP}, title = {Measurable residual disease in haematological and solid cancers.}, journal = {Leukemia}, volume = {38}, number = {8}, pages = {1647-1648}, pmid = {38937547}, issn = {1476-5551}, mesh = {Humans ; *Neoplasm, Residual ; *Neoplasms/complications ; *Hematologic Neoplasms/pathology/therapy ; }, }
@article {pmid38937187, year = {2024}, author = {Morrissey, S and Vasconcelos, AG and Wang, CL and Wang, S and Cunha, GM}, title = {Pooled Rate of Pseudoprogression, Patterns of Response, and Tumor Burden Analysis in Patients Undergoing Immunotherapy Oncologic Trials for Different Malignancies.}, journal = {Clinical oncology (Royal College of Radiologists (Great Britain))}, volume = {36}, number = {10}, pages = {624-631}, doi = {10.1016/j.clon.2024.06.002}, pmid = {38937187}, issn = {1433-2981}, mesh = {Humans ; *Neoplasms/therapy/pathology/immunology ; *Immunotherapy/methods ; Male ; Female ; *Disease Progression ; *Tumor Burden ; Middle Aged ; Retrospective Studies ; Aged ; Adult ; Clinical Trials as Topic ; }, abstract = {AIMS: Assess rates of true pseudoprogression in unconfirmed progressive disease (iUPD) in a pool of immunotherapy clinical trials for different cancers, analyze tumor characteristics that drive iUPD classification, and investigate potentials predictors of pseudoprogression.<br><br>MATERIALS AND METHODS: Retrospective interpretation of prospectively acquired data. Patients from 18 immunotherapy clinical trials with two arms (RECIST 1.1, iRECIST), of 10 cancer types were selected. Pooled rate of true pseudoprogression among iUPD was estimated using a common effect meta-analysis. Target, Non-target, and new lesions as the trigger of confirmed-vs pseudo-progression were compared using Chi-Square and Fisher exact tests. Conditional logistic regression was used to investigate the association between age, sex, tumor burden at baseline, and number of follow ups and pseudoprogression.<br><br>RESULTS: 60/287 (21%) patients (17 women) were classified as iUPD with at least one subsequent confirmatory timepoint. The overall pooled estimate of pseudoprogression was 15% (95%CI: 8%--26%). Nontarget lesions were significantly more frequent the cause of iUPD than change in Target lesions size (p< 0.001). Most observations of true pseudoprogression occurred in the first follow-up (77%), whereas confirmed progression occurred in later time points during the trial. Pseudoprogression was not significantly associated with age, sex, tumor burden at baseline, or number of timepoints.<br><br>CONCLUSION: In a pool of immunotherapy trials, the rate of true pseudoprogression was 15%, most often in the first timepoint after baseline than later in treatment. iUPD categorization was mostly driven by changes in NT lesions rather than objective changes in measurements of target lesions.}, }
@article {pmid38935372, year = {2024}, author = {Doll, KM and Pike, M and Alson, J and Williams, P and Carey, E and Stürmer, T and Wood, M and Marsh, EE and Katz, R and Robinson, WR}, title = {Endometrial Thickness as Diagnostic Triage for Endometrial Cancer Among Black Individuals.}, journal = {JAMA oncology}, volume = {10}, number = {8}, pages = {1068-1076}, pmid = {38935372}, issn = {2374-2445}, mesh = {Humans ; Female ; *Endometrial Neoplasms/diagnostic imaging/ethnology/pathology ; Middle Aged ; *Endometrium/diagnostic imaging/pathology ; *Triage ; Retrospective Studies ; *Ultrasonography ; Black or African American ; Hysterectomy ; Adult ; Aged ; Risk Factors ; }, abstract = {IMPORTANCE: Poor performance of the transvaginal ultrasonography triage strategy has been suggested as a contributor to racial disparity between Black individuals and White individuals in endometrial cancer (EC) stage at diagnosis in population-level simulation analyses.<br><br>OBJECTIVES: To examine the false-negative probability using ultrasonography-measured endometrial thickness (ET) thresholds as triage for EC diagnosis among Black individuals and assess whether known risk factors of EC modify ET triage performance.<br><br>This retrospective diagnostic study of merged abstracted electronic health record data and secondary administrative data (January 1, 2014, to December 31, 2020) from the Guidelines for Transvaginal Ultrasound in the Detection of Early Endometrial Cancer sample assessed Black individuals who underwent hysterectomy in a 10-hospital academic-affiliated health care system and affiliated outpatient practices. Data analysis was performed from January 31, 2023, to November 30, 2023.<br><br>EXPOSURE: Pelvic ultrasonography within 24 months before hysterectomy.<br><br>MAIN OUTCOME AND MEASURES: Ultrasonography performed before hysterectomy as well as demographic and clinical data on symptom presentation, endometrial characterization, and final EC diagnosis were abstracted. Endometrial thickness thresholds were examined for accuracy in ruling out EC diagnosis by using sensitivity, specificity, and negative predictive value. False-negative probability was defined as 1&#x2009;-&#x2009;sensitivity. Accuracy measures were stratified by risk factors for EC and by factors hypothesized to influence ET measurement quality.<br><br>RESULTS: A total of 1494 individuals with a uterus (median [IQR] age, 46.1 [41.1-54.0] years) comprised the sample, and 210 had EC. Fibroids (1167 [78.1%]), vaginal bleeding (1067 [71.4%]), and pelvic pain (857 [57.4%]) were the most common presenting diagnoses within 30 days of ultrasonography. Applying the less than 5-mm ET threshold, there was an 11.4% probability that someone with EC would be classified as not having EC (n&#x2009;=&#x2009;24). At the 4-mm (cumulative) threshold, the probability was 9.5%, and at 3 mm, it was 3.8%. False-negative probability at the 5-mm threshold was similar among EC risk factor groups: postmenopausal bleeding (12.4%; 95% CI, 7.8%-18.5%), body mass index greater than 40 (9.3%; 95% CI, 3.1%-20.3%); and age 50 years or older (12.8%; 95% CI, 8.4%-18.5%). False-negative probability was also similar among those with fibroids on ultrasonography (11.8%; 95% CI, 6.9%-18.4%) but higher in the setting of reported partial ET visibility (26.1%; 95% CI, 10.2%-48.4%) and pelvic pain (14.5%; 95% CI, 7.7%-23.9%).<br><br>CONCLUSION AND RELEVANCE: These findings suggest that the transvaginal ultrasonography triage strategy is not reliable among Black adults at risk for EC. In the presence of postmenopausal bleeding, tissue sampling is strongly recommended.}, }
@article {pmid38933740, year = {2024}, author = {Lau, J and Huang, J and Kassamali Escobar, Z}, title = {Antipseudomonal Antibiotics in Diabetic Foot Infections: A Practical Perspective From a Community Hospital.}, journal = {Open forum infectious diseases}, volume = {11}, number = {6}, pages = {ofae258}, pmid = {38933740}, issn = {2328-8957}, }
@article {pmid38933492, year = {2024}, author = {Chu, Y and Nayyar, G and Tian, M and Lee, DA and Ozkaynak, MF and Ayala-Cuesta, J and Klose, K and Foley, K and Mendelowitz, AS and Luo, W and Liao, Y and Ayello, J and Behbehani, GK and Riddell, S and Cripe, T and Cairo, MS}, title = {Efficiently targeting neuroblastoma with the combination of anti-ROR1 CAR NK cells and N-803 in vitro and in vivo in NB xenografts.}, journal = {Molecular therapy. Oncology}, volume = {32}, number = {2}, pages = {200820}, pmid = {38933492}, issn = {2950-3299}, abstract = {The prognosis for children with recurrent and/or refractory neuroblastoma (NB) is dismal. The receptor tyrosine kinase-like orphan receptor 1 (ROR1), which is highly expressed on the surface of NB cells, provides a potential target for novel immunotherapeutics. Anti-ROR1 chimeric antigen receptor engineered ex vivo expanded peripheral blood natural killer (anti-ROR1 CAR exPBNK) cells represent this approach. N-803 is an IL-15 superagonist with enhanced biological activity. In this study, we investigated the in vitro and in vivo anti-tumor effects of anti-ROR1 CAR exPBNK cells with or without N-803 against ROR1[+] NB models. Compared to mock exPBNK cells, anti-ROR1 CAR exPBNK cells had significantly enhanced cytotoxicity against ROR1[+] NB cells, and N-803 further increased cytotoxicity. High-dimensional analysis revealed that N-803 enhanced Stat5 phosphorylation and Ki67 levels in both exPBNK and anti-ROR1 CAR exPBNK cells with or without NB cells. In vivo, anti-ROR1 CAR exPBNK plus N-803 significantly (p < 0.05) enhanced survival in human ROR1[+] NB xenografted NSG mice compared to anti-ROR1 CAR exPBNK alone. Our results provide the rationale for further development of anti-ROR1 CAR exPBNK cells plus N-803 as a novel combination immunotherapeutic for patients with recurrent and/or refractory ROR1[+] NB.}, }
@article {pmid38932740, year = {2024}, author = {Reid, TB and Godornes, C and Campbell, VL and Laing, KJ and Tantalo, LC and Gomez, A and Pholsena, TN and Lieberman, NAP and Krause, TM and Cegielski, VI and Culver, LA and Nguyen, N and Tong, DQ and Hawley, KL and Greninger, AL and Giacani, L and Cameron, CE and Dombrowski, JC and Wald, A and Koelle, DM}, title = {Treponema pallidum Periplasmic and Membrane Proteins Are Recognized by Circulating and Skin CD4+ T Cells.}, journal = {The Journal of infectious diseases}, volume = {230}, number = {2}, pages = {281-292}, pmid = {38932740}, issn = {1537-6613}, support = {UL1 TR002319/TR/NCATS NIH HHS/United States ; //National Institute of Allergy and Infectious Diseases/ ; U19AI144133/NH/NIH HHS/United States ; }, mesh = {Humans ; *Treponema pallidum/immunology ; *CD4-Positive T-Lymphocytes/immunology ; *Syphilis/immunology ; *Skin/immunology/microbiology ; Adult ; Male ; Female ; Membrane Proteins/immunology ; Antigens, Bacterial/immunology ; Middle Aged ; Interferon-gamma/metabolism ; Bacterial Proteins/immunology ; Enzyme-Linked Immunospot Assay ; Leukocytes, Mononuclear/immunology ; Young Adult ; }, abstract = {BACKGROUND: Histologic and serologic studies suggest the induction of local and systemic Treponema pallidum-specific CD4+ T-cell responses to T. pallidum infection. We hypothesized that T. pallidum-specific CD4+ T cells are detectable in blood and in the skin rash of secondary syphilis and persist in both compartments after treatment.<br><br>METHODS: Peripheral blood mononuclear cells collected from 67 participants were screened by interferon-&#x3b3; (IFN-&#x3b3;) ELISPOT response to T. pallidum sonicate. T. pallidum-reactive T-cell lines from blood and skin were probed for responses to 89 recombinant T. pallidum antigens. Peptide epitopes and HLA class II restriction were defined for selected antigens.<br><br>RESULTS: We detected CD4+ T-cell responses to T. pallidum sonicate ex vivo. Using T. pallidum-reactive T-cell lines we observed recognition of 14 discrete proteins, 13 of which localize to bacterial membranes or the periplasmic space. After therapy, T. pallidum-specific T cells persisted for at least 6 months in skin and 10 years in blood.<br><br>CONCLUSIONS: T. pallidum infection elicits an antigen-specific CD4+ T-cell response in blood and skin. T. pallidum-specific CD4+ T cells persist as memory in both compartments long after curative therapy. The T. pallidum antigenic targets we identified may be high-priority vaccine candidates.}, }
@article {pmid38932701, year = {2024}, author = {Qian, C and Yang, Q and Rotinen, M and Huang, R and Kim, H and Gallent, B and Yan, Y and Cadaneanu, RM and Zhang, B and Kaochar, S and Freedland, SJ and Posadas, EM and Ellis, L and Di Vizio, D and Morrissey, C and Nelson, PS and Brady, L and Murali, R and Campbell, MJ and Yang, W and Knudsen, BS and Mostaghel, EA and Ye, H and Garraway, IP and You, S and Freeman, MR}, title = {ONECUT2 acts as a lineage plasticity driver in adenocarcinoma as well as neuroendocrine variants of prostate cancer.}, journal = {Nucleic acids research}, volume = {52}, number = {13}, pages = {7740-7760}, pmid = {38932701}, issn = {1362-4962}, support = {R21 CA277368/CA/NCI NIH HHS/United States ; R01 CA220327/CA/NCI NIH HHS/United States ; R01 CA271750/CA/NCI NIH HHS/United States ; P50CA97186//Institute for Prostate Cancer Research/ ; 2P50CA092131//UCLA Prostate Cancer SPORE/ ; T32 CA240172/CA/NCI NIH HHS/United States ; PC180541//Department of Defense/ ; }, mesh = {Male ; Humans ; *Receptors, Androgen/metabolism/genetics ; *Adenocarcinoma/genetics/pathology/metabolism/drug therapy ; *Receptors, Glucocorticoid/metabolism/genetics ; *Prostatic Neoplasms/genetics/pathology/metabolism/drug therapy ; *Drug Resistance, Neoplasm/genetics ; *Benzamides/pharmacology ; Cell Line, Tumor ; *Nitriles/pharmacology ; *Gene Expression Regulation, Neoplastic ; Phenylthiohydantoin/pharmacology/analogs &amp; derivatives ; Nerve Tissue Proteins/genetics/metabolism ; Epigenesis, Genetic ; RNA-Binding Proteins/metabolism/genetics ; Neuroendocrine Tumors/genetics/pathology/metabolism/drug therapy ; Animals ; Cell Lineage/genetics ; Mice ; }, abstract = {Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 gene targets include the glucocorticoid receptor (GR; NR3C1) and the NE splicing factor SRRM4, which are key drivers of lineage plasticity. Thus, OC2, despite its previously described NEPC driver function, can indirectly activate a portion of the AR cistrome through epigenetic activation of GR. Mechanisms by which OC2 regulates gene expression include promoter binding, enhancement of genome-wide chromatin accessibility, and super-enhancer reprogramming. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC and support enhanced efforts to therapeutically target OC2 as a means of suppressing treatment-resistant disease.}, }
@article {pmid38926438, year = {2024}, author = {Edwards, KR and Malhi, H and Schmidt, K and Davis, AR and Homad, LJ and Warner, NL and Chhan, CB and Scharffenberger, SC and Gaffney, K and Hinkley, T and Potchen, NB and Wang, JY and Price, J and McElrath, MJ and Olson, J and King, NP and Lund, JM and Moodie, Z and Erasmus, JH and McGuire, AT}, title = {A gH/gL-encoding replicon vaccine elicits neutralizing antibodies that protect humanized mice against EBV challenge.}, journal = {NPJ vaccines}, volume = {9}, number = {1}, pages = {120}, pmid = {38926438}, issn = {2059-0105}, support = {T32 AI007509/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; 5T32AI007509//Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)/ ; R01 CA285227/CA/NCI NIH HHS/United States ; R01CA285227//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R01 AI147846/AI/NIAID NIH HHS/United States ; R01AI147846//Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)/ ; P30 AI027757/AI/NIAID NIH HHS/United States ; }, abstract = {Epstein-Barr virus (EBV) is associated with several malignancies, neurodegenerative disorders and is the causative agent of infectious mononucleosis. A vaccine that prevents EBV-driven morbidity and mortality remains an unmet need. EBV is orally transmitted, infecting both B cells and epithelial cells. Several virally encoded proteins are involved in entry. The gH/gL glycoprotein complex is essential for infectivity irrespective of cell type, while gp42 is essential for infection of B cells. gp350 promotes viral attachment by binding to CD21 or CD35 and is the most abundant glycoprotein on the virion. gH/gL, gp42 and gp350, are known targets of neutralizing antibodies and therefore relevant immunogens for vaccine development. Here, we developed and optimized the delivery of several alphavirus-derived replicon RNA (repRNA) vaccine candidates encoding gH/gL, gH/gL/gp42 or gp350 delivered by a cationic nanocarrier termed LION™. The lead candidate, encoding full-length gH/gL, elicited high titers of neutralizing antibodies that persisted for at least 8 months and a vaccine-specific CD8[+] T cell response. Transfer of vaccine-elicited IgG protected humanized mice from EBV-driven tumor formation and death following high-dose viral challenge. These data demonstrate that LION/repRNA-gH/gL is an ideal candidate vaccine for preventing EBV infection and/or related malignancies in humans.}, }
@article {pmid38926343, year = {2024}, author = {Veit, EC and Salim, MS and Jung, MJ and Richardson, RB and Boys, IN and Quinlan, M and Barrall, EA and Bednarski, E and Hamilton, RE and Kikawa, C and Elde, NC and García-Sastre, A and Evans, MJ}, title = {Evolution of STAT2 resistance to flavivirus NS5 occurred multiple times despite genetic constraints.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {5426}, pmid = {38926343}, issn = {2041-1723}, support = {T32 AI007647/AI/NIAID NIH HHS/United States ; GM134936//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; T32 AI083203/AI/NIAID NIH HHS/United States ; R35 GM134936/GM/NIGMS NIH HHS/United States ; AI007647//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; AI083203//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; R01 AI175303/AI/NIAID NIH HHS/United States ; }, mesh = {*STAT2 Transcription Factor/metabolism/genetics ; Animals ; *Viral Nonstructural Proteins/genetics/metabolism ; *Evolution, Molecular ; Humans ; Mice ; Dengue Virus/genetics/physiology ; Zika Virus/genetics ; Flavivirus/genetics/physiology ; Phylogeny ; Host-Pathogen Interactions/genetics ; }, abstract = {Zika and dengue virus nonstructural protein 5 antagonism of STAT2, a critical interferon signaling transcription factor, to suppress the host interferon response is required for viremia and pathogenesis in a vertebrate host. This affects viral species tropism, as mouse STAT2 resistance renders only immunocompromised or humanized STAT2 mice infectable. Here, we explore how STAT2 evolution impacts antagonism. By measuring the susceptibility of 38 diverse STAT2 proteins, we demonstrate that resistance arose numerous times in mammalian evolution. In four species, resistance requires distinct sets of multiple amino acid changes that often individually disrupt STAT2 signaling. This reflects an evolutionary ridge where progressive resistance is balanced by the need to maintain STAT2 function. Furthermore, resistance may come with a fitness cost, as resistance that arose early in lemur evolution was subsequently lost in some lemur lineages. These findings underscore that while it is possible to evolve resistance to antagonism, complex evolutionary trajectories are required to avoid detrimental host fitness consequences.}, }
@article {pmid38926066, year = {2024}, author = {Yu, EY and Ferrario, C and Linch, MD and Stoeckle, M and Laguerre, B and Arranz, JA and Todenhöfer, T and Fong, PC and Piulats, JM and Berry, W and Emmenegger, U and Mourey, L and Joshua, AM and Mar, N and Appleman, LJ and Conter, HJ and Gravis, G and Li, XT and Schloss, C and Poehlein, C and de Bono, JS}, title = {Pembrolizumab plus Abiraterone Acetate and Prednisone in Patients with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Results from KEYNOTE-365 Cohort D.}, journal = {European urology oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.euo.2024.05.013}, pmid = {38926066}, issn = {2588-9311}, abstract = {BACKGROUND AND OBJECTIVE: Abiraterone acetate (abiraterone) plus prednisone is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Our aim was to evaluate the efficacy and safety of pembrolizumab plus abiraterone in mCRPC.<br><br>METHODS: In cohort D of the phase 1b/2 KEYNOTE-365 study (NCT02861573), patients were chemotherapy-na&#xef;ve, had disease progression &#x2264;6 mo before screening, and had either not received prior next-generation hormonal agents for mCRPC or had received prior enzalutamide for mCRPC and had disease progression or became intolerant to enzalutamide. Patients received pembrolizumab 200 mg intravenously every 3 wk plus abiraterone 1000 mg orally once daily and prednisone 5 mg orally twice daily. The primary endpoints were safety, prostate-specific antigen (PSA) response rate, and objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by blinded independent central review (BICR). Secondary endpoints included radiographic progression-free survival (rPFS) according to Prostate Cancer Clinical Trials Working Group 3-modified RECIST v1.1 by BICR and overall survival (OS).<br><br>KEY FINDINGS AND LIMITATIONS: For the 103 patients who were treated, median follow-up was 28 mo (interquartile range 26-31). The confirmed PSA response rate was 56% (58/103 patients). The ORR for patients with RECIST v1.1-measurable disease was 16% (6/37 patients). Median rPFS was 15 mo (95% confidence interval 9.2-22) and median OS was 30 mo (95% confidence interval 23-not reached); the estimated 24-mo OS rate was 58%. In total, 91% of patients experienced treatment-related adverse events, and 39% experienced grade 3-5 events. Grade 3/4 elevation of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) was observed in 12% and 6.8% of patients, respectively. One patient died due to treatment-related myasthenic syndrome. Study limitations include the single-arm design.<br><br>CONCLUSIONS: Pembrolizumab plus abiraterone and prednisone demonstrated antitumor activity and acceptable safety in patients with chemotherapy-na&#xef;ve mCRPC. Higher incidence of grade 3/4 elevated ALT/AST occurred than was reported for the individual agents.<br><br>PATIENT SUMMARY: For patients with metastatic castratation-resistant prostate cancer, the drug combination of pembrolizumab plus abiraterone and prednisone showed antitumor activity and acceptable safety.}, }
@article {pmid38925732, year = {2024}, author = {Beyrer, C and Tomaras, GD and Gelderblom, HC and Gray, GE and Janes, HE and Bekker, LG and Millett, G and Pantaleo, G and Buchbinder, S and Corey, L}, title = {Is HIV epidemic control by 2030 realistic?.}, journal = {The lancet. HIV}, volume = {11}, number = {7}, pages = {e489-e494}, pmid = {38925732}, issn = {2352-3018}, support = {UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; T32 AI102623/AI/NIAID NIH HHS/United States ; P30 AI064518/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *HIV Infections/prevention &amp; control/epidemiology ; *Epidemics/prevention &amp; control ; Pre-Exposure Prophylaxis ; Incidence ; Global Health ; }, abstract = {Rates of new HIV acquisition remain unacceptably high in most populations in low-income, middle-income, and high-income settings despite advances in treatment and prevention strategies. Although biomedical advances in primary prevention of new infections exist, systematic scale-up of these interventions has not occurred at the pace required to end AIDS by 2030. Low population coverage, adherence to oral pre-exposure prophylaxis in settings with high rates of HIV acquisition, and the fact that a significant proportion of new HIV infections occurs in populations not identified as high risk and are hence not targeted for prevention approaches impedes current prevention strategies. Although long-acting injectables and monoclonal antibodies are promising approaches to help reduce incidence, high cost and the need for high coverage rates mean that a vaccine or vaccine-like intervention still remains the most likely scenario to produce a population-level impact on HIV incidence, especially in countries with generalised epidemics. Current global efforts are not sufficient to meet 2030 HIV epidemic goals; acknowledgment of this issue is required to ensure persistent advocacy for population-based control of the ongoing HIV pandemic.}, }
@article {pmid38924728, year = {2024}, author = {Zamora, D and Xie, H and Sadowska-Klasa, A and Kampouri, E and Biernacki, MA and Ueda Oshima, M and Duke, E and Green, ML and Kimball, LE and Holmberg, L and Waghmare, A and Greninger, AL and Jerome, KR and Hill, GR and Hill, JA and Leisenring, WM and Boeckh, MJ}, title = {CMV reactivation during pretransplantation evaluation: a novel risk factor for posttransplantation CMV reactivation.}, journal = {Blood advances}, volume = {8}, number = {17}, pages = {4568-4580}, pmid = {38924728}, issn = {2473-9537}, support = {K23 AI163343/AI/NIAID NIH HHS/United States ; T32 AI118690/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; K23 AI097234/AI/NIAID NIH HHS/United States ; K24 HL093294/HL/NHLBI NIH HHS/United States ; R01 AI175535/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Cytomegalovirus Infections/etiology ; *Hematopoietic Stem Cell Transplantation/adverse effects ; *Virus Activation ; Risk Factors ; Male ; *Cytomegalovirus/physiology ; Middle Aged ; Female ; Adult ; Antiviral Agents/therapeutic use ; Aged ; }, abstract = {Cytomegalovirus (CMV) disease occurs occasionally before allogeneic hematopoietic cell transplantation (HCT) and is associated with poor post-HCT outcomes; however, the impact of pre-HCT CMV reactivation is unknown. Pre-HCT CMV reactivation was assessed in HCT candidates from the preemptive antiviral therapy (2007-2017) and letermovir prophylaxis (2018-2021) eras. CMV DNA polymerase chain reaction (PCR) surveillance was routinely performed during the pre-HCT workup period, and antiviral therapy was recommended according to risk of progression to CMV disease. Risk factors for pre-HCT CMV reactivation were characterized, and the associations of pre-HCT CMV reactivation with post-HCT outcomes were examined using logistic regression and Cox proportional hazard models, respectively. A total of 1694 patients were identified, and 11% had pre-HCT CMV reactivation 14 days (median; interquartile range [IQR], 6-23) before HCT. Lymphopenia (≤0.3 × 103/μL) was the strongest risk factor for pre-HCT CMV reactivation at multiple PCR levels. In the preemptive therapy era, patients with pre-HCT CMV reactivation had a significantly increased risk of CMV reactivation by day 100 as well as CMV disease and death by 1 year after HCT. Clearance of pre-HCT CMV reactivation was associated with a lower risk of post-HCT CMV reactivation. Similar associations with post-HCT CMV end points were observed in a cohort of patients receiving letermovir prophylaxis. Pre-HCT CMV reactivation can be routinely detected in high-risk HCT candidates and is a significant risk factor for post-HCT CMV reactivation and disease. Pre-HCT CMV DNA PCR surveillance is recommended in high-risk HCT candidates, and antiviral therapy may be indicated to prevent post-HCT CMV reactivation.}, }
@article {pmid38919390, year = {2024}, author = {Stull, AJ and Cassidy, A and Djousse, L and Johnson, SA and Krikorian, R and Lampe, JW and Mukamal, KJ and Nieman, DC and Porter Starr, KN and Rasmussen, H and Rimm, EB and Stote, KS and Tangney, C}, title = {The state of the science on the health benefits of blueberries: a perspective.}, journal = {Frontiers in nutrition}, volume = {11}, number = {}, pages = {1415737}, pmid = {38919390}, issn = {2296-861X}, abstract = {Mounting evidence indicates that blueberry consumption is associated with a variety of health benefits. It has been suggested that regular consumption of blueberries can support and/or protect against cardiovascular disease and function, pre-diabetes and type 2 diabetes, and brain and cognitive function in individuals with health conditions and age-related decline. Further, mechanistic investigations highlight the role of blueberry anthocyanins in mediating these health benefits, in part through interactions with gut microbiota. Also, nutritional interventions with blueberries have demonstrated the ability to improve recovery following exercise-induced muscle damage, attributable to anti-inflammatory effects. Despite these advancements in blueberry health research, research gaps persist which affects the generalizability of findings from clinical trials. To evaluate the current state of knowledge and research gaps, a blueberry health roundtable with scientific experts convened in Washington, DC (December 6-7, 2022). Discussions centered around five research domains: cardiovascular health, pre-diabetes and diabetes, brain health and cognitive function, gut health, and exercise recovery. This article synthesizes the outcomes of a blueberry research roundtable discussion among researchers in these domains, offering insights into the health benefits of blueberries and delineating research gaps and future research directions.}, }
@article {pmid38918632, year = {2024}, author = {Mei, Z and Wang, F and Bhosle, A and Dong, D and Mehta, R and Ghazi, A and Zhang, Y and Liu, Y and Rinott, E and Ma, S and Rimm, EB and Daviglus, M and Willett, WC and Knight, R and Hu, FB and Qi, Q and Chan, AT and Burk, RD and Stampfer, MJ and Shai, I and Kaplan, RC and Huttenhower, C and Wang, DD}, title = {Strain-specific gut microbial signatures in type 2 diabetes identified in a cross-cohort analysis of 8,117 metagenomes.}, journal = {Nature medicine}, volume = {30}, number = {8}, pages = {2265-2276}, pmid = {38918632}, issn = {1546-170X}, support = {K99 DK119412/DK/NIDDK NIH HHS/United States ; R01NR01999//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01 MD011389/MD/NIMHD NIH HHS/United States ; U01 CA152904/CA/NCI NIH HHS/United States ; N01HC65235/HL/NHLBI NIH HHS/United States ; R01AG077489//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; N01HC65234/HL/NHLBI NIH HHS/United States ; R01 NR019992/NR/NINR NIH HHS/United States ; P30 DK046200/DK/NIDDK NIH HHS/United States ; N01HC65237/HL/NHLBI NIH HHS/United States ; R01 AG077489/AG/NIA NIH HHS/United States ; RF1 AG083764/AG/NIA NIH HHS/United States ; R01 HL035464/HL/NHLBI NIH HHS/United States ; P30DK046200//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R00DK119412//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R24 DK110499/DK/NIDDK NIH HHS/United States ; R00 DK119412/DK/NIDDK NIH HHS/United States ; R24DK110499//U.S. Department of Health &amp; Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes &amp; Digestive &amp; Kidney Diseases)/ ; R01 CA202704/CA/NCI NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; 209933838//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 897161//American Heart Association (American Heart Association, Inc.)/ ; U01 CA176726/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; N01HC65236/HL/NHLBI NIH HHS/United States ; P30 DK111022/DK/NIDDK NIH HHS/United States ; N01HC65233/HL/NHLBI NIH HHS/United States ; R35 CA253185/CA/NCI NIH HHS/United States ; R01 HL060712/HL/NHLBI NIH HHS/United States ; }, mesh = {*Diabetes Mellitus, Type 2/microbiology/genetics ; Humans ; *Gastrointestinal Microbiome/genetics ; *Metagenome/genetics ; *Phylogeny ; Cohort Studies ; Male ; Middle Aged ; Female ; China/epidemiology ; Dysbiosis/microbiology ; United States/epidemiology ; Israel/epidemiology ; Europe/epidemiology ; }, abstract = {The association of gut microbial features with type 2 diabetes (T2D) has been inconsistent due in part to the complexity of this disease and variation in study design. Even in cases in which individual microbial species have been associated with T2D, mechanisms have been unable to be attributed to these associations based on specific microbial strains. We conducted a comprehensive study of the T2D microbiome, analyzing 8,117 shotgun metagenomes from 10 cohorts of individuals with T2D, prediabetes, and normoglycemic status in the United States, Europe, Israel and China. Dysbiosis in 19 phylogenetically diverse species was associated with T2D (false discovery rate < 0.10), for example, enriched Clostridium bolteae and depleted Butyrivibrio crossotus. These microorganisms also contributed to community-level functional changes potentially underlying T2D pathogenesis, for example, perturbations in glucose metabolism. Our study identifies within-species phylogenetic diversity for strains of 27 species that explain inter-individual differences in T2D risk, such as Eubacterium rectale. In some cases, these were explained by strain-specific gene carriage, including loci involved in various mechanisms of horizontal gene transfer and novel biological processes underlying metabolic risk, for example, quorum sensing. In summary, our study provides robust cross-cohort microbial signatures in a strain-resolved manner and offers new mechanistic insights into T2D.}, }
@article {pmid38918394, year = {2024}, author = {Whiteaker, JR and Zhao, L and Schoenherr, RM and Huang, D and Kennedy, JJ and Ivey, RG and Lin, C and Lorentzen, TD and Colantonio, S and Caceres, TW and Roberts, RR and Knotts, JG and Reading, JJ and Perry, CD and Garcia-Buntley, SS and Bocik, W and Hewitt, SM and Paulovich, AG}, title = {Characterization of an expanded set of assays for immunomodulatory proteins using targeted mass spectrometry.}, journal = {Scientific data}, volume = {11}, number = {1}, pages = {682}, pmid = {38918394}, issn = {2052-4463}, support = {R01 CA235575/CA/NCI NIH HHS/United States ; R50 CA211499/CA/NCI NIH HHS/United States ; U01CA271407//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; U01CA214114//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; U01 CA214114/CA/NCI NIH HHS/United States ; R50CA211499//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; U01 CA271407/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R01CA235575//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; }, mesh = {Humans ; *Antibodies, Monoclonal/immunology ; Immunotherapy ; *Mass Spectrometry ; *Neoplasms/immunology ; }, abstract = {Immunotherapies are revolutionizing cancer care, but many patients do not achieve durable responses and immune-related adverse events are difficult to predict. Quantifying the hundreds of proteins involved in cancer immunity has the potential to provide biomarkers to monitor and predict tumor response. We previously developed robust, multiplexed quantitative assays for immunomodulatory proteins using targeted mass spectrometry, providing measurements that can be performed reproducibly and harmonized across laboratories. Here, we expand upon those efforts in presenting data from a multiplexed immuno-oncology (IO)-3 assay panel targeting 43 peptides representing 39 immune- and inflammation-related proteins. A suite of novel monoclonal antibodies was generated as assay reagents, and the fully characterized antibodies are made available as a resource to the community. The publicly available dataset contains complete characterization of the assay performance, as well as the mass spectrometer parameters and reagent information necessary for implementation of the assay. Quantification of the proteins will provide benefit to correlative studies in clinical trials, identification of new biomarkers, and improve understanding of the immune response in cancer.}, }
@article {pmid38916866, year = {2024}, author = {Jain, T and Estrada-Merly, N and Salas, MQ and Kim, S and DeVos, J and Chen, M and Fang, X and Kumar, R and Andrade-Campos, M and Elmariah, H and Agrawal, V and Aljurf, M and Bacher, U and Badar, T and Badawy, SM and Ballen, K and Beitinjaneh, A and Bhatt, VR and Bredeson, C and DeFilipp, Z and Dholaria, B and Farhadfar, N and Farhan, S and Gandhi, AP and Ganguly, S and Gergis, U and Grunwald, MR and Hamad, N and Hamilton, BK and Inamoto, Y and Iqbal, M and Jamy, O and Juckett, M and Kharfan-Dabaja, MA and Krem, MM and Lad, DP and Liesveld, J and Al Malki, MM and Malone, AK and Murthy, HS and Ortí, G and Patel, SS and Pawarode, A and Perales, MA and van der Poel, M and Ringden, O and Rizzieri, DA and Rovó, A and Savani, BN and Savoie, ML and Seo, S and Solh, M and Ustun, C and Verdonck, LF and Wingard, JR and Wirk, B and Bejanyan, N and Jones, RJ and Nishihori, T and Oran, B and Nakamura, R and Scott, B and Saber, W and Gupta, V}, title = {Donor types and outcomes of transplantation in myelofibrosis: a CIBMTR study.}, journal = {Blood advances}, volume = {8}, number = {16}, pages = {4281-4293}, pmid = {38916866}, issn = {2473-9537}, support = {U24 CA076518/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; 27307C0011/ES/NIEHS NIH HHS/United States ; 27398C0011/ES/NIEHS NIH HHS/United States ; 27305C0011/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Primary Myelofibrosis/therapy/mortality ; *Hematopoietic Stem Cell Transplantation/methods ; Male ; Female ; Middle Aged ; Adult ; Treatment Outcome ; Transplantation Conditioning/methods ; Aged ; Graft vs Host Disease/etiology ; Tissue Donors ; Registries ; Unrelated Donors ; }, abstract = {We evaluate the impact of donor types on outcomes of hematopoietic cell transplantation (HCT) in myelofibrosis, using the Center for International Blood and Marrow Transplant Research registry data for HCTs done between 2013 and 2019. In all 1597 patients, the use of haploidentical donors increased from 3% in 2013 to 19% in 2019. In study-eligible 1032 patients who received peripheral blood grafts for chronic-phase myelofibrosis, 38% of recipients of haploidentical HCT were non-White/Caucasian. Matched sibling donor (MSD)-HCTs were associated with superior overall survival (OS) in the first 3 months (haploidentical hazard ratio [HR], 5.80 [95% confidence interval (CI), 2.52-13.35]; matched unrelated (MUD) HR, 4.50 [95% CI, 2.24-9.03]; mismatched unrelated HR, 5.13 [95% CI, 1.44-18.31]; P < .001). This difference in OS aligns with lower graft failure with MSD (haploidentical HR, 6.11 [95% CI, 2.98-12.54]; matched unrelated HR, 2.33 [95% CI, 1.20-4.51]; mismatched unrelated HR, 1.82 [95% CI, 0.58-5.72]). There was no significant difference in OS among haploidentical, MUD, and mismatched unrelated donor HCTs in the first 3 months. Donor type was not associated with differences in OS beyond 3 months after HCT, relapse, disease-free survival, or OS among patients who underwent HCT within 24 months of diagnosis. Patients who experienced graft failure had more advanced disease and commonly used nonmyeloablative conditioning. Although MSD-HCTs were superior, there is no significant difference in HCT outcomes from haploidentical and MUDs. These results establish haploidentical HCT with posttransplantation cyclophosphamide as a viable option in myelofibrosis, especially for ethnic minorities underrepresented in the donor registries.}, }
@article {pmid38916429, year = {2024}, author = {Garrett, N and Dintwe, O and Monaco, CL and Jones, M and Seaton, KE and Church, EC and Grunenberg, N and Hutter, J and deCamp, A and Huang, Y and Lu, H and Mann, P and Robinson, ST and Heptinstall, J and Jensen, RL and Pantaleo, G and Ding, S and Koutsoukos, M and Hosseinipour, MC and Van Der Meeren, O and Gilbert, PB and Ferrari, G and Andersen-Nissen, E and McElrath, MJ and Tomaras, GD and Gray, GE and Corey, L and Kublin, JG and , }, title = {Safety and Immunogenicity of a DNA Vaccine With Subtype C gp120 Protein Adjuvanted With MF59 or AS01B: A Phase 1/2a HIV-1 Vaccine Trial.}, journal = {Journal of acquired immune deficiency syndromes (1999)}, volume = {96}, number = {4}, pages = {350-360}, pmid = {38916429}, issn = {1944-7884}, support = {UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI069469/AI/NIAID NIH HHS/United States ; UM1 AI069481/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *AIDS Vaccines/immunology/administration &amp; dosage/adverse effects ; *Vaccines, DNA/immunology/administration &amp; dosage/adverse effects ; Female ; Male ; Adult ; *Squalene/administration &amp; dosage ; *Polysorbates/administration &amp; dosage ; *HIV Envelope Protein gp120/immunology ; *Adjuvants, Immunologic/administration &amp; dosage ; *HIV-1/immunology ; *HIV Infections/immunology/prevention &amp; control ; *HIV Antibodies/blood ; Double-Blind Method ; Middle Aged ; Young Adult ; Adjuvants, Vaccine/administration &amp; dosage ; South Africa ; Immunogenicity, Vaccine ; Adolescent ; United States ; }, abstract = {BACKGROUND: An effective vaccine is required to end the HIV pandemic. We evaluated the safety and immunogenicity of a DNA (DNA-HIV-PT123) vaccine with low- or high-dose bivalent (TV1.C and 1086.C glycoprotein 120) subtype C envelope protein combinations, adjuvanted with MF59 or AS01B.<br><br>METHODS: HIV Vaccine Trials Network (HVTN)108 was a randomized, placebo-controlled, double-blind, phase 1/2a trial conducted in the United States and South Africa. HIV-negative adults were randomly assigned to 1 of 7 intervention arms or placebo to assess DNA prime with DNA/protein/adjuvant boosts, DNA/protein/adjuvant co-administration, and low-dose protein/adjuvant regimens. HVTN111 trial participants who received an identical regimen were also included. Outcomes included safety and immunogenicity 2 weeks and 6 months after final vaccination.<br><br>RESULTS: From June 2016 to July 2018, 400 participants were enrolled (N = 334 HVTN108, N = 66 HVTN111); 370 received vaccine and 30 received placebo. There were 48 grade 3 and 3 grade 4 reactogenicity events among 39/400 (9.8%) participants, and 32 mild/moderate-related adverse events in 23/400 (5.8%) participants. All intervention groups demonstrated high IgG response rates (>89%) and high magnitudes to HIV-1 Env gp120 and gp140 proteins; response rates for AS01B-adjuvanted groups approached 100%. V1V2 IgG magnitude, Fc-mediated functions, IgG3 Env response rates, and CD4+ T-cell response magnitudes and rates were higher in the AS01B-adjuvanted groups. The AS01B-adjuvanted low-dose protein elicited greater IgG responses than the higher protein dose.<br><br>CONCLUSIONS: The vaccine regimens were generally well tolerated. Co-administration of DNA with AS01B-adjuvanted bivalent Env gp120 elicited the strongest humoral responses; AS01B-adjuvanted regimens elicited stronger CD4+ T-cell responses, justifying further evaluation.ClinicalTrials.gov registration: NCT02915016, registered 26 September 2016.}, }
@article {pmid38915666, year = {2024}, author = {Kelnhofer-Millevolte, LE and Smith, JR and Nguyen, DH and Wilson, LS and Lewis, HC and Arnold, EA and Brinkley, MR and Geballe, AP and Ramachandran, S and Avgousti, DC}, title = {Human cytomegalovirus induces neuronal gene expression for viral maturation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38915666}, issn = {2692-8205}, support = {R35 GM133434/GM/NIGMS NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; T32 AI083203/AI/NIAID NIH HHS/United States ; R01 AI145945/AI/NIAID NIH HHS/United States ; R35 GM133441/GM/NIGMS NIH HHS/United States ; }, abstract = {Viral invasion of the host cell causes some of the most dramatic changes in biology. Human cytomegalovirus (HCMV) extensively remodels host cells, altering nuclear shape and generating a cytoplasmic viral-induced assembly compartment (vIAC). How these striking morphology changes take place in the context of host gene regulation is still emerging. Here, we discovered that histone variant macroH2A1 is essential for producing infectious progeny. Because virion maturation and cellular remodeling are closely linked processes, we investigated structural changes in the host cell upon HCMV infection. We discovered that macroH2A1 is necessary for HCMV-induced reorganization of the host nucleus, cytoskeleton, and endoplasmic reticulum. Furthermore, using RNA-seq we found that while all viral genes were highly expressed in the absence of macroH2A1, many HCMV-induced host genes were not. Remarkably, hundreds of these HCMV-induced macroH2A1-dependent host genes are associated with neuronal synapse formation and vesicle trafficking. Knock-down of these HCMV-induced neuronal genes during infection resulted in malformed vIACs and smaller plaques, establishing their importance to HCMV infection. Together, our findings demonstrate that HCMV manipulates host gene expression by hijacking a dormant neuronal secretory pathway for efficient virion maturation.}, }
@article {pmid38915597, year = {2024}, author = {Maurice, NJ and Erickson, JR and DeJong, CS and Mair, F and Taber, AK and Frutoso, M and Islas, LV and Vigil, AB and Lawler, RL and McElrath, MJ and Newell, EW and Sullivan, LB and Shree, R and McCartney, SA}, title = {Converging cytokine and metabolite networks shape asymmetric T cell fate at the term human maternal-fetal interface.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38915597}, issn = {2692-8205}, support = {K12 HD000849/HD/NICHD NIH HHS/United States ; R21 AI144677/AI/NIAID NIH HHS/United States ; F31 HD098769/HD/NICHD NIH HHS/United States ; R01 CA264646/CA/NCI NIH HHS/United States ; F99 CA245735/CA/NCI NIH HHS/United States ; TL1 TR002318/TR/NCATS NIH HHS/United States ; }, abstract = {Placentation presents immune conflict between mother and fetus, yet in normal pregnancy maternal immunity against infection is maintained without expense to fetal tolerance. This is believed to result from adaptations at the maternal-fetal interface (MFI) which affect T cell programming, but the identities (i.e., memory subsets and antigenic specificities) of T cells and the signals that mediate T cell fates and functions at the MFI remain poorly understood. We found intact recruitment programs as well as pro-inflammatory cytokine networks that can act on maternal T cells in an antigen-independent manner. These inflammatory signals elicit T cell expression of co-stimulatory receptors necessary for tissue retention, which can be engaged by local macrophages. Although pro-inflammatory molecules elicit T cell effector functions, we show that additional cytokine (TGF-β1) and metabolite (kynurenine) networks may converge to tune T cell function to those of sentinels. Together, we demonstrate an additional facet of fetal tolerance, wherein T cells are broadly recruited and restrained in an antigen-independent, cytokine/metabolite-dependent manner. These mechanisms provide insight into antigen-nonspecific T cell regulation, especially in tissue microenvironments where they are enriched.}, }
@article {pmid38914826, year = {2024}, author = {Quinn-Bohmann, N and Wilmanski, T and Sarmiento, KR and Levy, L and Lampe, JW and Gurry, T and Rappaport, N and Ostrem, EM and Venturelli, OS and Diener, C and Gibbons, SM}, title = {Microbial community-scale metabolic modelling predicts personalized short-chain fatty acid production profiles in the human gut.}, journal = {Nature microbiology}, volume = {9}, number = {7}, pages = {1700-1712}, pmid = {38914826}, issn = {2058-5276}, support = {R01DK133468//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; P30CA015704//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; U19AG023122//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; }, mesh = {Humans ; *Fatty Acids, Volatile/metabolism ; *Gastrointestinal Microbiome ; Prebiotics ; Probiotics/metabolism/administration &amp; dosage ; Models, Biological ; Diet ; Bacteria/metabolism/genetics ; Cohort Studies ; Gastrointestinal Tract/microbiology/metabolism ; Adult ; }, abstract = {Microbially derived short-chain fatty acids (SCFAs) in the human gut are tightly coupled to host metabolism, immune regulation and integrity of the intestinal epithelium. However, the production of SCFAs can vary widely between individuals consuming the same diet, with lower levels often associated with disease. A systems-scale mechanistic understanding of this heterogeneity is lacking. Here we use a microbial community-scale metabolic modelling (MCMM) approach to predict individual-specific SCFA production profiles to assess the impact of different dietary, prebiotic and probiotic inputs. We evaluate the quantitative accuracy of our MCMMs using in vitro and ex vivo data, plus published human cohort data. We find that MCMM SCFA predictions are significantly associated with blood-derived clinical chemistries, including cardiometabolic and immunological health markers, across a large human cohort. Finally, we demonstrate how MCMMs can be leveraged to design personalized dietary, prebiotic and probiotic interventions aimed at optimizing SCFA production in the gut. Our model represents an approach to direct gut microbiome engineering for precision health and nutrition.}, }
@article {pmid38914309, year = {2024}, author = {Pennington, KP and Schlumbrecht, M and McGregor, BA and Goodheart, MJ and Heron, L and Zimmerman, B and Telles, R and Zia, S and Penedo, FJ and Lutgendorf, SK}, title = {Living Well: Protocol for a web-based program to improve quality of life in rural and urban ovarian cancer survivors.}, journal = {Contemporary clinical trials}, volume = {144}, number = {}, pages = {107612}, pmid = {38914309}, issn = {1559-2030}, support = {P30 CA086862/CA/NCI NIH HHS/United States ; R01 CA246540/CA/NCI NIH HHS/United States ; T32 GM108540/GM/NIGMS NIH HHS/United States ; T32 GM149386/GM/NIGMS NIH HHS/United States ; UM1 TR004403/TR/NCATS NIH HHS/United States ; }, mesh = {Female ; Humans ; Middle Aged ; Adaptation, Psychological ; Anxiety/therapy/psychology ; *Cancer Survivors/psychology ; *Depression/therapy/epidemiology/psychology ; *Fatigue/therapy/psychology ; Healthy Lifestyle ; *Internet-Based Intervention ; Mindfulness/methods ; *Ovarian Neoplasms/psychology/therapy ; *Quality of Life ; *Rural Population ; Stress, Psychological/therapy/psychology ; Urban Population ; Randomized Controlled Trials as Topic ; Multicenter Studies as Topic ; Clinical Trials, Phase II as Topic ; }, abstract = {BACKGROUND: Ovarian cancer (OC) survivors commonly experience chronic symptoms including anxiety, depression, sleep disturbances, fatigue, physical symptoms, poor health-related quality of life (HRQOL), and a generally poor prognosis. Additionally, factors such as social isolation, stress, and depression are associated with key biological processes promoting tumor progression and poorer survival. Accessible psychosocial interventions to improve HRQOL and clinical outcomes are needed. This need is particularly true in rural settings where survivors may have less access to clinic-based support systems.<br><br>METHODS: The Living Well Study, a cluster-randomized Phase II multi-site clinical trial, is designed to evaluate the efficacy of a group-based, web-delivered psychosocial intervention (Mindful Living) verses a Health Promotion active control (Healthy Lifestyles) in increasing HRQOL and decreasing perceived stress (primary outcomes), depressive mood, anxiety, and fatigue (secondary outcomes) for 256 OC survivors who are <5&#xa0;years post-primary therapy. Mindful Living targets key concerns of OC survivors and teaches stress reduction skills and coping strategies utilizing cognitive behavioral, mindfulness, and acceptance and commitment therapies. Healthy Lifestyles provides lifestyle information including exercise, nutrition, sleep, and other survivorship topics. Interventions consist of 11 consecutive weekly group sessions lasting 1.5-2&#xa0;h led by trained facilitators and two booster sessions. Participants complete psychosocial questionnaires at baseline, post-intervention, at 6-months, and at 12-months. A subset completes bloodspots for analysis of inflammatory biology.<br><br>CONCLUSION: Easily accessible psychosocial interventions addressing key concerns of OC survivors are an unmet need. The Mindful Living intervention has the potential to substantially enhance HRQOL and decrease distress in OC survivors. Trial registrationclinicaltrials.gov Identifier: NCT04533763.}, }
@article {pmid38914227, year = {2024}, author = {Rodríguez-Arbolí, E and Othus, M and Orvain, C and Ali, N and Milano, F and Davis, C and Basom, R and Baccon, D and Sandmaier, BM and Appelbaum, FR and Walter, RB}, title = {Second Allogeneic Hematopoietic Cell Transplantation for Relapsed Adult Acute Myeloid Leukemia: Outcomes and Prognostic Factors.}, journal = {Transplantation and cellular therapy}, volume = {30}, number = {9}, pages = {905.e1-905.e14}, pmid = {38914227}, issn = {2666-6367}, support = {P01 CA018029/CA/NCI NIH HHS/United States ; P01 CA078902/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation ; *Leukemia, Myeloid, Acute/therapy/mortality ; Middle Aged ; Female ; Male ; Adult ; Prognosis ; Aged ; *Transplantation, Homologous ; Recurrence ; Young Adult ; Treatment Outcome ; Retrospective Studies ; Adolescent ; }, abstract = {Second allogeneic hematopoietic cell transplantation (HCT2) is potentially curative for adults with acute myeloid leukemia (AML) or myelodysplastic neoplasm (MDS)/AML experiencing relapse after a first allograft (HCT1), but prognostic factors for outcomes are poorly characterized. To provide a detailed analysis of HCT2 outcomes and associated prognostic factors in a large single-center cohort, with a focus on identifying predictors of relapse and nonrelapse mortality (NRM), we studied adults ≥18 years who underwent HCT2 at a single institution between April 2006 and June 2022 for relapsed AML (n = 73) or MDS/AML (n = 8). With a median follow-up among survivors of 74.0 (range: 10.4 to 187.3) months, there were 30 relapses and 57 deaths, of which 29 were NRM events, contributing to the estimates for relapse, overall survival (OS), relapse-free survival (RFS), and NRM. Three-year estimates for relapse, RFS, and OS were 37% (95% confidence interval: 27% to 48%), 32% (23% to 44%), and 35% (26% to 47%). The rate of NRM at 100 days and 18 months was 20% (12% to 29%) and 28% (19% to 39%). Outcomes differed markedly across patient subsets and were substantially worse for patients who underwent HCT2 with active disease (ie, morphologic evidence of bone marrow and/or extramedullary disease), for patients who relapsed ≤6 months after HCT1, and for patients with higher HCT-specific Comorbidity Index (HCT-CI) or treatment-related mortality (TRM) scores. After multivariable adjustment, active disease was associated with a higher risk of relapse (hazard ratio [HR] = 3.19, P = .006) and shorter RFS (HR = 2.41, P = .008) as well as OS (HR = 2.17, P = .027) compared to transplant in morphologic remission without multiparameter flow cytometric evidence of measurable residual disease. Similarly, a relapse-free interval ≤6 months after the first allograft was associated with higher risk of relapse (HR = 5.86, P < .001) and shorter RFS (HR = 2.86; P = .001) and OS (HR = 2.45, P = .003). Additionally, a high HCT-CI score was associated with increased NRM (HR = 4.30, P = .035), and shorter RFS (HR = 3.87, P = .003) and OS (HR = 3.74, P = .006). Likewise, higher TRM scores were associated with increased risk of relapse (HR = 2.27; P = .024) and NRM (HR = 2.01, P = .001), and inferior RFS (HR = 1.90 P = .001) and OS (HR = 1.88, P = .001). A significant subset of patients with AML or MDS/AML relapse after HCT1 are alive and leukemia-free 3 years after undergoing HCT2. Our study identifies active leukemia at the time of HCT2 and early relapse after HCT1 as major adverse prognostic factors, highlighting patient subsets in particular need of novel therapeutic approaches, and supports the use of the HCT-CI and TRM scores for outcome prognostication.}, }
@article {pmid38913882, year = {2024}, author = {Bricker, JB and Sullivan, B and Mull, K and Santiago-Torres, M and Lavista Ferres, JM}, title = {Conversational Chatbot for Cigarette Smoking Cessation: Results From the 11-Step User-Centered Design Development Process and Randomized Controlled Trial.}, journal = {JMIR mHealth and uHealth}, volume = {12}, number = {}, pages = {e57318}, pmid = {38913882}, issn = {2291-5222}, mesh = {Humans ; *Smoking Cessation/methods/psychology ; Male ; Adult ; Female ; Middle Aged ; *User-Centered Design ; }, abstract = {BACKGROUND: Conversational chatbots are an emerging digital intervention for smoking cessation. No studies have reported on the entire development process of a cessation chatbot.<br><br>OBJECTIVE: We aim to report results of the user-centered design development process and randomized controlled trial for a novel and comprehensive quit smoking conversational chatbot called QuitBot.<br><br>METHODS: The 4 years of formative research for developing QuitBot followed an 11-step process: (1) specifying a conceptual model; (2) conducting content analysis of existing interventions (63 hours of intervention transcripts); (3) assessing user needs; (4) developing the chat's persona ("personality"); (5) prototyping content and persona; (6) developing full functionality; (7) programming the QuitBot; (8) conducting a diary study; (9) conducting a pilot randomized controlled trial (RCT); (10) reviewing results of the RCT; and (11) adding a free-form question and answer (QnA) function, based on user feedback from pilot RCT results. The process of adding a QnA function itself involved a three-step process: (1) generating QnA pairs, (2) fine-tuning large language models (LLMs) on QnA pairs, and (3) evaluating the LLM outputs.<br><br>RESULTS: We developed a quit smoking program spanning 42 days of 2- to 3-minute conversations covering topics ranging from motivations to quit, setting a quit date, choosing Food and Drug Administration-approved cessation medications, coping with triggers, and recovering from lapses and relapses. In a pilot RCT with 96% three-month outcome data retention, QuitBot demonstrated high user engagement and promising cessation rates compared to the National Cancer Institute's SmokefreeTXT text messaging program, particularly among those who viewed all 42 days of program content: 30-day, complete-case, point prevalence abstinence rates at 3-month follow-up were 63% (39/62) for QuitBot versus 38.5% (45/117) for SmokefreeTXT (odds ratio 2.58, 95% CI 1.34-4.99; P=.005). However, Facebook Messenger intermittently blocked participants' access to QuitBot, so we transitioned from Facebook Messenger to a stand-alone smartphone app as the communication channel. Participants' frustration with QuitBot's inability to answer their open-ended questions led to us develop a core conversational feature, enabling users to ask open-ended questions about quitting cigarette smoking and for the QuitBot to respond with accurate and professional answers. To support this functionality, we developed a library of 11,000 QnA pairs on topics associated with quitting cigarette smoking. Model testing results showed that Microsoft's Azure-based QnA maker effectively handled questions that matched our library of 11,000 QnA pairs. A fine-tuned, contextualized GPT-3.5 (OpenAI) responds to questions that are not within our library of QnA pairs.<br><br>CONCLUSIONS: The development process yielded the first LLM-based quit smoking program delivered as a conversational chatbot. Iterative testing led to significant enhancements, including improvements to the delivery channel. A pivotal addition was the inclusion of a core LLM-supported conversational feature allowing users to ask open-ended questions.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT03585231; https://clinicaltrials.gov/study/NCT03585231.}, }
@article {pmid38913710, year = {2024}, author = {Walsh, SR and Gay, CL and Karuna, ST and Hyrien, O and Skalland, T and Mayer, KH and Sobieszczyk, ME and Baden, LR and Goepfert, PA and Del Rio, C and Pantaleo, G and Andrew, P and Karg, C and He, Z and Lu, H and Paez, CA and Baumblatt, JAG and Polakowski, LL and Chege, W and Anderson, MA and Janto, S and Han, X and Huang, Y and Dumond, J and Ackerman, ME and McDermott, AB and Flach, B and Piwowar-Manning, E and Seaton, K and Tomaras, GD and Montefiori, DC and Gama, L and Mascola, JR and , }, title = {Safety and pharmacokinetics of VRC07-523LS administered via different routes and doses (HVTN 127/HPTN 087): A Phase I randomized clinical trial.}, journal = {PLoS medicine}, volume = {21}, number = {6}, pages = {e1004329}, pmid = {38913710}, issn = {1549-1676}, support = {UM1 AI069423/AI/NIAID NIH HHS/United States ; U01 AI069470/AI/NIAID NIH HHS/United States ; UM1 TR004406/TR/NCATS NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI068619/AI/NIAID NIH HHS/United States ; UM1 AI069412/AI/NIAID NIH HHS/United States ; UM1 AI069470/AI/NIAID NIH HHS/United States ; UM1 AI068613/AI/NIAID NIH HHS/United States ; UL1 RR025758/RR/NCRR NIH HHS/United States ; U01 AI068614/AI/NIAID NIH HHS/United States ; P30 AI050410/AI/NIAID NIH HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; Adult ; *Antibodies, Neutralizing/blood ; *HIV Antibodies/blood ; Middle Aged ; HIV Infections/drug therapy/immunology ; HIV-1/immunology ; Young Adult ; Broadly Neutralizing Antibodies/administration &amp; dosage/adverse effects ; Adolescent ; Injections, Intramuscular ; }, abstract = {BACKGROUND: Broadly neutralizing antibodies (bnAbs) are a promising approach for HIV-1 prevention. In the Antibody Mediated Prevention (AMP) trials, a CD4-binding site targeting bnAb, VRC01, administered intravenously (IV), demonstrated 75% prevention efficacy against highly neutralization-sensitive viruses but was ineffective against less sensitive viruses. VRC07-523LS is a next-generation bnAb targeting the CD4-binding site and was engineered for increased neutralization breadth and half-life. We conducted a multicenter, randomized, partially blinded Phase I clinical trial to evaluate the safety and serum concentrations of VRC07-523LS, administered in multiple doses and routes to healthy adults without HIV.<br><br>METHODS AND FINDINGS: Participants were recruited between 2 February 2018 and 9 October 2018. A total of 124 participants were randomized to receive 5 VRC07-523LS administrations via IV (T1: 2.5 mg/kg, T2: 5 mg/kg, T3: 20 mg/kg), subcutaneous (SC) (T4: 2.5 mg/kg, T5: 5 mg/kg), or intramuscular (IM) (T6: 2.5 mg/kg or P6: placebo) routes at 4-month intervals. Participants and site staff were blinded to VRC07-523LS versus placebo for the IM group, while all other doses and routes were open-label. Safety data were collected for 144 weeks following the first administration. VRC07-523LS serum concentrations were measured by ELISA through Day 112 in all participants and by binding antibody multiplex assay (BAMA) thereafter in 60 participants (10 per treatment group) through Day 784. Compartmental population pharmacokinetic (PK) analyses were conducted to evaluate the VRC07-523LS serum PK. Neutralization activity was measured in a TZM-bl assay and antidrug antibodies (ADAs) were assayed using a tiered bridging assay testing strategy. Injections and infusions were well tolerated, with mild pain or tenderness reported commonly in the SC and IM groups, and mild to moderate erythema or induration reported commonly in the SC groups. Infusion reactions were reported in 3 of 20 participants in the 20 mg/kg IV group. Peak geometric mean (GM) concentrations (95% confidence intervals [95% CIs]) following the first administration were 29.0 &#x3bc;g/mL (25.2, 33.4), 58.5 &#x3bc;g/mL (49.4, 69.3), and 257.2 &#x3bc;g/mL (127.5, 518.9) in T1-T3 with IV dosing; 10.8 &#x3bc;g/mL (8.8, 13.3) and 22.8 &#x3bc;g/mL (20.1, 25.9) in T4-T5 with SC dosing; and 16.4 &#x3bc;g/mL (14.7, 18.2) in T6 with IM dosing. Trough GM (95% CIs) concentrations immediately prior to the second administration were 3.4 &#x3bc;g/mL (2.5, 4.6), 6.5 &#x3bc;g/mL (5.6, 7.5), and 27.2 &#x3bc;g/mL (23.9, 31.0) with IV dosing; 0.97 &#x3bc;g/mL (0.65, 1.4) and 3.1 &#x3bc;g/mL (2.2, 4.3) with SC dosing, and 2.6 &#x3bc;g/mL (2.05, 3.31) with IM dosing. Peak VRC07-523LS serum concentrations increased linearly with the administered dose. At a given dose, peak and trough concentrations, as well as serum neutralization titers, were highest in the IV groups, reflecting the lower bioavailability following SC and IM administration. A single participant was found to have low titer ADA at a lone time point. VRC07-523LS has an estimated mean half-life of 42 days across all doses and routes (95% CI: 40.5, 43.5), over twice as long as VRC01 (15 days).<br><br>CONCLUSIONS: VRC07-523LS was safe and well tolerated across a range of doses and routes and is a promising long-acting bnAb for inclusion in HIV-1 prevention regimens.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov/ NCT03387150 (posted on 21 December 2017).}, }
@article {pmid38912739, year = {2024}, author = {Hagen, MW and Setiawan, NJ and Woodruff, KA and Termini, CM}, title = {Syndecans in hematopoietic cells and their niches.}, journal = {American journal of physiology. Cell physiology}, volume = {327}, number = {2}, pages = {C372-C378}, pmid = {38912739}, issn = {1522-1563}, support = {K01 DK126989/DK/NIDDK NIH HHS/United States ; 23CDA1039196//American Heart Association (AHA)/ ; FY23-DR-01//Andy Hill Cancer Research Endowment Fund/ ; 5K01DK126989//HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)/ ; }, mesh = {Humans ; *Hematopoietic Stem Cells/metabolism ; Animals ; *Stem Cell Niche ; *Syndecans/metabolism/genetics ; Signal Transduction ; Hematologic Neoplasms/metabolism/pathology ; Hematopoiesis/physiology ; }, abstract = {Heparan sulfate proteoglycans are a family of glycoproteins that modulate cell signaling by binding growth factors and changing their bioavailability. Syndecans are a specific family of transmembrane heparan sulfate proteoglycans that regulate cell adhesion, migration, and signaling. In this review, we will summarize emerging evidence for the functions of syndecans in the normal and malignant blood systems and their microenvironments. More specifically, we detail the known functions of syndecans within normal hematopoietic stem cells. Furthermore, we discuss the functions of syndecans in hematological malignancies, including myeloid malignancies, lymphomas, and bleeding disorders. As normal and malignant hematopoietic cells require cues from their microenvironments to function, we also summarize the roles of syndecans in cells of the stromal, endothelial, and osteolineage compartments. Syndecan biology is a rapidly evolving field; a comprehensive understanding of these molecules and their place in the hematopoietic system promises to improve our grasp on disease processes and better predict the efficacies of growth factor-targeting therapies.}, }
@article {pmid38908745, year = {2024}, author = {Turchetta, A and Moodie, EEM and Stephens, DA and Savy, N and Moodie, Z}, title = {The time-dependent Poisson-gamma model in practice: Recruitment forecasting in HIV trials.}, journal = {Contemporary clinical trials}, volume = {144}, number = {}, pages = {107607}, doi = {10.1016/j.cct.2024.107607}, pmid = {38908745}, issn = {1559-2030}, mesh = {Humans ; *HIV Infections ; *Patient Selection ; *AIDS Vaccines/therapeutic use ; *Models, Statistical ; Poisson Distribution ; Multicenter Studies as Topic/methods ; Randomized Controlled Trials as Topic/methods ; Time Factors ; Forecasting ; Africa South of the Sahara ; }, abstract = {Despite a growing body of literature in the area of recruitment modeling for multicenter studies, in practice, statistical models to predict enrollments are rarely used and when they are, they often rely on unrealistic assumptions. The time-dependent Poisson-Gamma model (tPG) is a recently developed flexible methodology which allows analysts to predict recruitments in an ongoing multicenter trial, and its performance has been validated on data from a cohort study. In this article, we illustrate and further validate the tPG model on recruitment data from randomized controlled trials. Additionally, in the appendix, we provide a practical and easy to follow guide to its implementation via the tPG R package. To validate the model, we show the predictive performance of the proposed methodology in forecasting the recruitment process of two HIV vaccine trials conducted by the HIV Vaccine Trials Network in multiple Sub-Saharan countries.}, }
@article {pmid38908483, year = {2024}, author = {Graham, JB and Swarts, JL and Koehne, AL and Watson, CE and Lund, JM}, title = {Regulatory T cells restrict immunity and pathology in distal tissue sites following a localized infection.}, journal = {Mucosal immunology}, volume = {17}, number = {5}, pages = {923-938}, pmid = {38908483}, issn = {1935-3456}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 AI141435/AI/NIAID NIH HHS/United States ; U19 AI100625/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; *T-Lymphocytes, Regulatory/immunology ; Mice ; *Zika Virus Infection/immunology ; Female ; *Zika Virus/immunology ; *CD8-Positive T-Lymphocytes/immunology ; *Vagina/immunology/pathology/virology ; Cytokines/metabolism ; Disease Models, Animal ; Mice, Knockout ; Central Nervous System/immunology/pathology ; Humans ; Mice, Inbred C57BL ; }, abstract = {Regulatory T cells (Tregs) are well-known to mediate peripheral tolerance at homeostasis, and there is a growing appreciation for their role in modulating infectious disease immunity. Following acute and chronic infections, Tregs can restrict pathogen-specific T cell responses to limit immunopathology. However, it is unclear if Tregs mediate control of pathology and immunity in distal tissue sites during localized infections. We investigated the role of Tregs in immunity and disease in various tissue compartments in the context of "mild" vaginal Zika virus infection. We found that Tregs are critical to generating robust virus-specific CD8 T cell responses in the initial infection site. Further, Tregs limit inflammatory cytokines and immunopathology during localized infection; a dysregulated immune response in Treg-depleted mice leads to increased T cell infiltrates and immunopathology in both the vagina and the central nervous system (CNS). Importantly, these CNS infiltrates are not present at the same magnitude during infection of Treg-sufficient mice, in which there is no CNS immunopathology. Our data suggest that Tregs are necessary to generate a robust virus-specific response at the mucosal site of infection, while Treg-mediated restriction of bystander inflammation limits immunopathology both at the site of infection as well as distal tissue sites.}, }
@article {pmid38907026, year = {2024}, author = {Sureda, A and Carpenter, PA and Bacigalupo, A and Bhatt, VR and de la Fuente, J and Ho, A and Kean, L and Lee, JW and Sánchez-Ortega, I and Savani, BN and Schetelig, J and Stadtmauer, EA and Takahashi, Y and Atsuta, Y and Koreth, J and Kröger, N and Ljungman, P and Okamoto, S and Popat, U and Soiffer, R and Stefanski, HE and Kharfan-Dabaja, MA}, title = {Correction: Harmonizing definitions for hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism in allogeneic hematopoietic cell transplantation: a report on behalf of the EBMT, ASTCT, CIBMTR, and APBMT.}, journal = {Bone marrow transplantation}, volume = {59}, number = {9}, pages = {1335}, doi = {10.1038/s41409-024-02336-w}, pmid = {38907026}, issn = {1476-5365}, }
@article {pmid38906514, year = {2024}, author = {Daher, R and Ruplin, A and Gupta, S and Spiess, PE and Kamat, AM and Cigliola, A and Tateo, V and Mercinelli, C and Grivas, P and Necchi, A}, title = {The spectrum of cutaneous toxicities related to novel genitourinary cancer therapies.}, journal = {Critical reviews in oncology/hematology}, volume = {200}, number = {}, pages = {104420}, doi = {10.1016/j.critrevonc.2024.104420}, pmid = {38906514}, issn = {1879-0461}, mesh = {Humans ; *Urogenital Neoplasms/drug therapy ; Immune Checkpoint Inhibitors/adverse effects ; Antineoplastic Agents/adverse effects/therapeutic use ; Angiogenesis Inhibitors/adverse effects/therapeutic use ; Risk Factors ; Drug Eruptions/etiology/therapy/epidemiology/diagnosis ; Skin Diseases/chemically induced/etiology/epidemiology ; Androgen Receptor Antagonists/adverse effects/therapeutic use ; Antibodies, Monoclonal ; }, abstract = {CONTEXT: Genitourinary cancers (GUCs) encompass malignancies affecting the urinary and reproductive systems, including renal cell carcinoma (RCC), urothelial carcinoma (UC), and prostate cancer (PC). With the rapidly evolving therapeutic domain of these cancers, cutaneous adverse events (AEs) remain among the most observed toxicities.<br><br>OBJECTIVE: To explore the dermatologic AEs linked to novel GUC treatments, their underlying pathophysiology, clinical presentations, and risk factors.<br><br>EVIDENCE ACQUISITION: A narrative review of the literature from PubMed and Embase databases was conducted. The search strategy included dermatologic/cutaneous adverse events, risk factors, and pathophysiology in conjunction with the following classes of therapies; immune checkpoint inhibitors (ICIs), antiangiogenic therapies, enfortumab vedotin (EV), erdafitinib, and androgen receptor antagonists (ARAs).<br><br>EVIDENCE SYNTHESIS: Maculopapular rash, pruritus, and alopecia are present among the five classes of therapies. ICIs demonstrate the highest incidence of severe drug AEs including Steven Johnson syndrome/toxic epidermal necrolysis. Unique cutaneous AEs present with specific therapies including hand-foot skin reaction and subungual splinter hemorrhage with antiangiogenic drugs, stomatitis/mucositis and onycholysis with erdafitinib. Incidence and type of cutaneous AE also differed within therapies in the same class as seen with apalutamide displaying the highest risk of cutaneous AEs within ARAs. Risk factors for development of cutaneous AEs can be general to therapies, or specific, and include age, immune status, BMI, and gender.<br><br>CONCLUSIONS: Dermatologic AEs may impact patients' quality of life and increase the tendency to dose reduce, hold or discontinue life-saving therapies, underscoring the need for vigilant monitoring, early recognition, and collaborative management between medical oncologists, pharmacists, dermatologists and other specialists.}, }
@article {pmid38906271, year = {2024}, author = {Buxton, C and Schmeusser, BN and Holt, SK and Patil, D and Phuong, A and Chahine, S and Marquardt, JP and O'Malley, R and Laidlaw, G and Schade, GR and Lin, DW and Schweizer, MT and Yezefski, T and Yu, EY and Montgomery, B and Fintelmann, FJ and Master, VA and Psutka, SP}, title = {A Multicenter Evaluation of Treatment-associated Changes in Body Composition in Men With Germ Cell Tumors of the Testis: Implications for Adverse Events and Complications.}, journal = {Urology}, volume = {192}, number = {}, pages = {74-82}, doi = {10.1016/j.urology.2024.06.030}, pmid = {38906271}, issn = {1527-9995}, mesh = {Humans ; Male ; *Testicular Neoplasms/drug therapy/surgery ; Retrospective Studies ; *Neoplasms, Germ Cell and Embryonal/drug therapy ; *Body Composition ; Adult ; Lymph Node Excision/adverse effects ; Cisplatin/adverse effects/administration &amp; dosage ; Postoperative Complications/epidemiology/etiology ; Young Adult ; Middle Aged ; Antineoplastic Agents/adverse effects ; }, abstract = {OBJECTIVE: To characterize changes in body composition following cytotoxic chemotherapy for germ cell carcinoma of the testis (GCT) and quantify associations between body composition metrics and chemotherapy-associated adverse events (AEs) and post-retroperitoneal lymph node dissection (RPLND) complications.<br><br>MATERIALS AND METHODS: This retrospective multi-center study included 216 men with GCT treated with cytotoxic chemotherapy and/or RPLND (2005-2020). We measured body composition including skeletal muscle (SMI), visceral adipose (VAI,), subcutaneous adipose (SAI), and fat mass (FMI) indices on computed tomography. We quantified chemotherapy-associated changes in body composition and evaluated associations between body composition and incidence of grade 3&#xa0;+&#xa0;AEs and post-RPLND complications on multivariable logistic regression analyses.<br><br>RESULTS: One hundred and eighty-two men received a median of 3 cycles of cisplatin-based chemotherapy. Following chemotherapy, median change in SMI was -6% (P&#xa0;=&#xa0;<.0001), while VAI, SAI, and FMI increased by +13% (P&#xa0;=&#xa0;<.0001), +11% (P&#xa0;=&#xa0;<.0001), and +6% (P&#xa0;=&#xa0;<.0001), respectively. Seventy-nine patients (43%) experienced at least one grade 3&#xa0;+&#xa0;AE. A decrease in SMI following chemotherapy was associated with increased risk of grade 3&#xa0;+&#xa0;AEs (P&#xa0;=&#xa0;.047). One hundred and 3&#xa0;men with a median age of 28.5 years (IQR 23-35.5) underwent RPLND of whom 22 (21.3%) experienced at least 1 grade 3&#xa0;+&#xa0;post-RPLND complication. No baseline body composition metrics were associated with post-RPLND complications.<br><br>CONCLUSION: In men with GCT of the testis, chemotherapy was associated with 6% loss of lean muscle mass and gains in adiposity. Lower skeletal muscle was associated with a higher incidence of chemotherapy-associated AEs. Body composition was not associated with the incidence of post-RPLND complications.}, }
@article {pmid38905473, year = {2024}, author = {Peters, BA and Hanna, DB and Xue, X and Weber, K and Appleton, AA and Kassaye, SG and Topper, E and Tracy, RP and Guillemette, C and Caron, P and Tien, PC and Qi, Q and Burk, RD and Sharma, A and Anastos, K and Kaplan, RC}, title = {Menopause and Estrogen Associations With Gut Barrier, Microbial Translocation, and Immune Activation Biomarkers in Women With and Without HIV.}, journal = {Journal of acquired immune deficiency syndromes (1999)}, volume = {96}, number = {3}, pages = {214-222}, pmid = {38905473}, issn = {1944-7884}, support = {R01HL140976/HL/NHLBI NIH HHS/United States ; K01HL160146/HL/NHLBI NIH HHS/United States ; KL2 TR001432/TR/NCATS NIH HHS/United States ; U01 HL146192/HL/NHLBI NIH HHS/United States ; TL1 TR001431/TR/NCATS NIH HHS/United States ; R01 HL148094/HL/NHLBI NIH HHS/United States ; U01 HL146194/HL/NHLBI NIH HHS/United States ; U01 HL146241/HL/NHLBI NIH HHS/United States ; P30 AI027767/AI/NIAID NIH HHS/United States ; P30 AI050409/AI/NIAID NIH HHS/United States ; U01 HL146333/HL/NHLBI NIH HHS/United States ; U01HL146204/HL/NHLBI NIH HHS/United States ; U01 HL146245/HL/NHLBI NIH HHS/United States ; K24 AI108516/AI/NIAID NIH HHS/United States ; U01 HL146205/HL/NHLBI NIH HHS/United States ; P30 MH116867/MH/NIMH NIH HHS/United States ; U01 HL146208/HL/NHLBI NIH HHS/United States ; K24AI108516//National Institute of Allergy and Infectious Diseases/ ; UL1 TR001409/TR/NCATS NIH HHS/United States ; K01 HL160146/HL/NHLBI NIH HHS/United States ; R01HL148094/HL/NHLBI NIH HHS/United States ; U01 HL146242/HL/NHLBI NIH HHS/United States ; P30 AI073961/AI/NIAID NIH HHS/United States ; U01 HL146201/HL/NHLBI NIH HHS/United States ; U01 HL146193/HL/NHLBI NIH HHS/United States ; R01 HL140976/HL/NHLBI NIH HHS/United States ; U01 HL146204/HL/NHLBI NIH HHS/United States ; U01 HL146202/HL/NHLBI NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; UL1 TR000004/TR/NCATS NIH HHS/United States ; U01 HL146240/HL/NHLBI NIH HHS/United States ; U01 HL146203/HL/NHLBI NIH HHS/United States ; UL1 TR003098/TR/NCATS NIH HHS/United States ; P30 AI050410/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Female ; *HIV Infections/immunology/blood ; Adult ; Cross-Sectional Studies ; *Lipopolysaccharide Receptors/blood ; *Menopause/blood ; *Biomarkers/blood ; Middle Aged ; Longitudinal Studies ; *Estrogens/blood ; *Bacterial Translocation ; *Fatty Acid-Binding Proteins/blood ; Membrane Glycoproteins/blood ; Acute-Phase Proteins ; Carrier Proteins ; }, abstract = {OBJECTIVES: Estrogens may protect the gut barrier and reduce microbial translocation and immune activation, which are prevalent in HIV infection. We investigated relationships of the menopausal transition and estrogens with gut barrier, microbial translocation, and immune activation biomarkers in women with and without HIV.<br><br>DESIGN: Longitudinal and cross-sectional studies nested in the Women's Interagency HIV Study.<br><br>METHODS: Intestinal fatty acid binding protein, lipopolysaccharide binding protein, and soluble CD14 (sCD14) levels were measured in serum from 77 women (43 with HIV) before, during, and after the menopausal transition (&#x223c;6 measures per woman over &#x223c;13 years). A separate cross-sectional analysis was conducted among 72 postmenopausal women with HIV with these biomarkers and serum estrogens.<br><br>RESULTS: Women in the longitudinal analysis were a median age of 43 years at baseline. In piecewise, linear, mixed-effects models with cutpoints 2 years before and after the final menstrual period to delineate the menopausal transition, sCD14 levels increased over time during the menopausal transition (Beta [95% CI]: 38 [12 to 64] ng/mL/yr, P = 0.004), followed by a decrease posttransition (-46 [-75 to -18], P = 0.001), with the piecewise model providing a better fit than a linear model (P = 0.0006). In stratified analyses, these results were only apparent in women with HIV. In cross-sectional analyses, among women with HIV, free estradiol inversely correlated with sCD14 levels (r = -0.26, P = 0.03). Lipopolysaccharide binding protein and intestinal fatty acid binding protein levels did not appear related to the menopausal transition and estrogen levels.<br><br>CONCLUSIONS: Women with HIV may experience heightened innate immune activation during menopause, possibly related to the depletion of estrogens.}, }
@article {pmid38903517, year = {2024}, author = {Mosmann, TR and Rebhahn, JA and De Rosa, SC and Keefer, MC and McElrath, MJ and Rouphael, NG and Pantaleo, G and Gilbert, PB and Corey, L and Kobie, JJ and Thakar, J}, title = {SWIFT clustering analysis of intracellular cytokine staining flow cytometry data of the HVTN 105 vaccine trial reveals high frequencies of HIV-specific CD4+ T cell responses and associations with humoral responses.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1347926}, pmid = {38903517}, issn = {1664-3224}, support = {UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI069481/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *AIDS Vaccines/immunology ; *CD4-Positive T-Lymphocytes/immunology ; Cluster Analysis ; *Cytokines/metabolism/immunology ; Flow Cytometry ; HIV Antibodies/immunology/blood ; *HIV Infections/immunology/virology ; HIV-1/immunology ; Immunity, Humoral ; Interleukins/immunology ; Vaccines, DNA/immunology ; }, abstract = {INTRODUCTION: The HVTN 105 vaccine clinical trial tested four combinations of two immunogens - the DNA vaccine DNA-HIV-PT123, and the protein vaccine AIDSVAX B/E. All combinations induced substantial antibody and CD4+ T cell responses in many participants. We have now re-examined the intracellular cytokine staining flow cytometry data using the high-resolution SWIFT clustering algorithm, which is very effective for enumerating rare populations such as antigen-responsive T cells, and also determined correlations between the antibody and T cell responses.<br><br>METHODS: Flow cytometry samples across all the analysis batches were registered using the swiftReg registration tool, which reduces batch variation without compromising biological variation. Registered data were clustered using the SWIFT algorithm, and cluster template competition was used to identify clusters of antigen-responsive T cells and to separate these from constitutive cytokine producing cell clusters.<br><br>RESULTS: Registration strongly reduced batch variation among batches analyzed across several months. This in-depth clustering analysis identified a greater proportion of responders than the original analysis. A subset of antigen-responsive clusters producing IL-21 was identified. The cytokine patterns in each vaccine group were related to the type of vaccine - protein antigens tended to induce more cells producing IL-2 but not IFN-&#x3b3;, whereas DNA vaccines tended to induce more IL-2+ IFN-&#x3b3;+ CD4 T cells. Several significant correlations were identified between specific antibody responses and antigen-responsive T cell clusters. The best correlations were not necessarily observed with the strongest antibody or T cell responses.<br><br>CONCLUSION: In the complex HVTN105 dataset, alternative analysis methods increased sensitivity of the detection of antigen-specific T cells; increased the number of identified vaccine responders; identified a small IL-21-producing T cell population; and demonstrated significant correlations between specific T cell populations and serum antibody responses. Multiple analysis strategies may be valuable for extracting the most information from large, complex studies.}, }
@article {pmid38900845, year = {2024}, author = {Hsieh, YP and Sun, W and Young, JM and Cheung, R and Hogan, DA and Dandekar, AA and Malik, HS}, title = {Widespread fungal-bacterial competition for magnesium lowers bacterial susceptibility to polymyxin antibiotics.}, journal = {PLoS biology}, volume = {22}, number = {6}, pages = {e3002694}, pmid = {38900845}, issn = {1545-7885}, support = {R01 AI127548/AI/NIAID NIH HHS/United States ; R01 GM125714/GM/NIGMS NIH HHS/United States ; R35 GM152107/GM/NIGMS NIH HHS/United States ; }, mesh = {*Magnesium/pharmacology/metabolism ; *Pseudomonas aeruginosa/drug effects ; *Anti-Bacterial Agents/pharmacology ; *Candida albicans/drug effects/metabolism ; *Colistin/pharmacology ; Microbial Sensitivity Tests ; Polymyxins/pharmacology ; Drug Resistance, Bacterial/drug effects ; Microbial Interactions/drug effects ; }, abstract = {Fungi and bacteria coexist in many polymicrobial communities, yet the molecular basis of their interactions remains poorly understood. Here, we show that the fungus Candida albicans sequesters essential magnesium ions from the bacterium Pseudomonas aeruginosa. To counteract fungal Mg2+ sequestration, P. aeruginosa expresses the Mg2+ transporter MgtA when Mg2+ levels are low. Thus, loss of MgtA specifically impairs P. aeruginosa in co-culture with C. albicans, but fitness can be restored by supplementing Mg2+. Using a panel of fungi and bacteria, we show that Mg2+ sequestration is a general mechanism of fungal antagonism against gram-negative bacteria. Mg2+ limitation enhances bacterial resistance to polymyxin antibiotics like colistin, which target gram-negative bacterial membranes. Indeed, experimental evolution reveals that P. aeruginosa evolves C. albicans-dependent colistin resistance via non-canonical means; antifungal treatment renders resistant bacteria colistin-sensitive. Our work suggests that fungal-bacterial competition could profoundly impact polymicrobial infection treatment with antibiotics of last resort.}, }
@article {pmid38900510, year = {2024}, author = {Brasky, TM and Jager, LR and Newton, AM and Li, X and Loomans-Kropp, HA and Hays, JL and Margolis, KL and Luo, J}, title = {Use of Nonsteroidal Anti-Inflammatory Drugs and Pancreatic Cancer Risk in the Women's Health Initiative.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {33}, number = {9}, pages = {1203-1210}, pmid = {38900510}, issn = {1538-7755}, support = {75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Anti-Inflammatory Agents, Non-Steroidal/therapeutic use/adverse effects ; *Pancreatic Neoplasms/epidemiology/chemically induced/prevention &amp; control ; Middle Aged ; Aged ; *Women's Health ; Risk Factors ; Prospective Studies ; United States/epidemiology ; Incidence ; Postmenopause ; }, abstract = {BACKGROUND: Pancreatic cancer is among the most fatal human cancers and the fourth leading cause of cancer death in the United States. Evidence suggests that chronic inflammation may play a role in pancreatic carcinogenesis and its inhibition through nonsteroidal anti-inflammatory drugs (NSAID) may reduce pancreatic cancer incidence.<br><br>METHODS: We examined associations of total and individual NSAIDs with pancreatic cancer risk among postmenopausal women participating in the Women's Health Initiative observational study and clinical trial cohorts. Among 117,452 women, aged 55 to 79 years, 727 incident pancreatic cancer cases were reported over 18 years of follow-up. Cox regression was used to estimate hazard ratio (HR) and 95% confidence interval (CI) for associations between NSAIDs and pancreatic cancer risk.<br><br>RESULTS: Relative to non-use, consistent use of any NSAID was inversely associated with pancreatic cancer risk (HR 0.71, 95% CI, 0.59-0.87), primarily driven by strong associations for aspirin use (HR 0.67, 95% CI, 0.52-0.86). Use of total or individual non-aspirin NSAIDs was not associated with pancreatic cancer. Upon stratified analysis, we observed stronger associations for NSAIDs among participants with prevalent diabetes (HR 0.28, 95% CI, 0.10-0.75) relative to those without (HR 0.75, 95% CI, 0.61-0.92; P-interaction = 0.03).<br><br>CONCLUSIONS: Additional large prospective studies with careful measurement of NSAID type, dose, and frequency are needed to further investigate the possibility of added benefit among individuals diagnosed with diabetes.<br><br>IMPACT: This study adds to existing evidence from prospective studies and clinical trials suggesting that use of aspirin may provide moderate benefit for pancreatic cancer prevention.}, }
@article {pmid38900319, year = {2024}, author = {Swensen, S and Liao, JJ and Chen, JJ and Kim, K and Ma, TM and Weg, ES}, title = {The expanding role of radiation oncology across the prostate cancer continuum.}, journal = {Abdominal radiology (New York)}, volume = {49}, number = {8}, pages = {2693-2705}, pmid = {38900319}, issn = {2366-0058}, mesh = {Humans ; *Prostatic Neoplasms/radiotherapy/diagnostic imaging/pathology ; Male ; *Radiation Oncology ; Neoplasm Recurrence, Local/diagnostic imaging ; Neoplasm Metastasis ; Radiotherapy Planning, Computer-Assisted/methods ; }, abstract = {Radiotherapy is used in the treatment of prostate cancer in a variety of disease states with significant reliance on imaging to guide clinical decision-making and radiation delivery. In the definitive setting, the choice of radiotherapy treatment modality, dose, and fractionation for localized prostate cancer is determined by the patient's initial risk stratification and other clinical considerations. Radiation is also an option as salvage therapy in patients with locoregionally recurrent disease after prior definitive radiation or surgery. In recent years, the role of radiation has expanded for patients with metastatic disease, including prostate-directed radiotherapy in de novo low volume metastatic disease, metastasis-directed therapy for oligorecurrent disease, and palliative management of symptomatic metastases in the advanced setting. Here we review the expanding role of radiation in the treatment of prostate cancer in the definitive, locoregionally recurrent, and metastatic settings, as well as highlight the role of imaging in clinical reasoning, radiation planning, and treatment delivery.}, }
@article {pmid38899711, year = {2024}, author = {Chung, DC and Raymond, VM and Grady, WM}, title = {Stool and Blood DNA Tests for Colorectal Cancer Screening. Reply.}, journal = {The New England journal of medicine}, volume = {390}, number = {23}, pages = {2224-2225}, doi = {10.1056/NEJMc2404924}, pmid = {38899711}, issn = {1533-4406}, mesh = {Humans ; *Colorectal Neoplasms/blood/diagnosis/genetics ; *DNA, Neoplasm/blood/analysis ; *Early Detection of Cancer/methods ; *Feces/chemistry ; Occult Blood ; High-Throughput Nucleotide Sequencing ; Sensitivity and Specificity ; }, }
@article {pmid38898090, year = {2024}, author = {Zismanov, S and Shalem, B and Margolin-Miller, Y and Rosin-Grunewald, D and Adar, R and Keren-Naus, A and Amichay, D and Ben-Dor, A and Shemer-Avni, Y and Porgador, A and Shental, N and Hertz, T}, title = {High capacity clinical SARS-CoV-2 molecular testing using combinatorial pooling.}, journal = {Communications medicine}, volume = {4}, number = {1}, pages = {121}, pmid = {38898090}, issn = {2730-664X}, support = {SARS-CoV-2 pilot funding//Ben-Gurion University of the Negev (Ben-Gurion University)/ ; }, abstract = {BACKGROUND: The SARS-CoV-2 pandemic led to unprecedented testing demands, causing major testing delays globally. One strategy used for increasing testing capacity was pooled-testing, using a two-stage technique first introduced during WWII. However, such traditional pooled testing was used in practice only when positivity rates were below 2%.<br><br>METHODS: Here we report the development, validation and clinical application of P-BEST - a single-stage pooled-testing strategy that was approved for clinical use in Israel.<br><br>RESULTS: P-BEST is clinically validated using 3636 side-by-side tests and is able to correctly detect all positive samples and accurately estimate their Ct value. Following regulatory approval by the Israeli Ministry of Health, P-BEST was used in 2021 to clinically test 837,138 samples using 270,095 PCR tests - a 3.1fold reduction in the number of tests. This period includes the Alpha and Delta waves, when positivity rates exceeded 10%, rendering traditional pooling non-practical. We also describe a tablet-based solution that allows performing manual single-stage pooling in settings where liquid dispensing robots are not available.<br><br>CONCLUSIONS: Our data provides a proof-of-concept for large-scale clinical implementation of single-stage pooled-testing for continuous surveillance of multiple pathogens with reduced test costs, and as an important tool for increasing testing efficiency during pandemic outbreaks.}, }
@article {pmid38895348, year = {2024}, author = {Shasha, C and Glass, DR and Moelhman, E and Islas, L and Tian, Y and Szeto, GL and Peng, T and Song, X and Wurscher, M and Bumol, TF and Torgerson, TR and Greenberg, PD and Green, DJ and Newell, EW}, title = {Hallmarks of tumor-experienced T cells are absent in multiple myeloma patients from diagnosis through maintenance therapy.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38895348}, issn = {2692-8205}, support = {P01 CA018029/CA/NCI NIH HHS/United States ; UL1 TR002319/TR/NCATS NIH HHS/United States ; }, abstract = {Dysregulation of the bone marrow (BM) niche in multiple myeloma (MM) alters the composition and state of resident immune cells, potentially impeding anti-tumor immunity. One common mechanism of immune inhibition in solid tumors is the induction of exhaustion in tumor-specific T cells. However, the extent of T cell tumor recognition and exhaustion is not well-characterized in MM. As the specific mechanisms of immune evasion are critical for devising effective therapeutic strategies, we deeply profiled the CD8[+] T cell compartment of newly-diagnosed MM (NDMM) patients for evidence of tumor reactivity and T cell exhaustion. We applied single-cell multi-omic sequencing and antigen-specific mass cytometry to longitudinal BM and peripheral blood (PB) samples taken from timepoints spanning from diagnosis through induction therapy, autologous stem cell transplant (ASCT), and maintenance therapy. We identified an exhausted-like population that lacked several canonical exhaustion markers, was not significantly enriched in NDMM patients, and consisted of small, nonpersistent clones. We also observed an activated population with increased frequency in the PB of NDMM patients exhibiting phenotypic and clonal features consistent with homeostatic, antigen-nonspecific activation. However, there was no evidence of "tumor-experienced" T cells displaying hallmarks of terminal exhaustion and/or tumor-specific activation/expansion in NDMM patients at any timepoint.}, }
@article {pmid38895105, year = {2024}, author = {Vargas, AM and DeBiasse, MB and Dykes, LL and Edgar, A and Hayes, TD and Groso, DJ and Babonis, LS and Martindale, MQ and Ryan, JF}, title = {Morphological and dietary changes encoded in the genome of Beroe ovata, a ctenophore-eating ctenophore.}, journal = {NAR genomics and bioinformatics}, volume = {6}, number = {2}, pages = {lqae072}, pmid = {38895105}, issn = {2631-9268}, abstract = {As the sister group to all other animals, ctenophores (comb jellies) are important for understanding the emergence and diversification of numerous animal traits. Efforts to explore the evolutionary processes that promoted diversification within Ctenophora are hindered by undersampling genomic diversity within this clade. To address this gap, we present the sequence, assembly and initial annotation of the genome of Beroe ovata. Beroe possess unique morphology, behavior, ecology and development. Unlike their generalist carnivorous kin, beroid ctenophores feed exclusively on other ctenophores. Accordingly, our analyses revealed a loss of chitinase, an enzyme critical for the digestion of most non-ctenophore prey, but superfluous for ctenophorivores. Broadly, our genomic analysis revealed that extensive gene loss and changes in gene regulation have shaped the unique biology of B. ovata. Despite the gene losses in B. ovata, our phylogenetic analyses on photosensitive opsins and several early developmental regulatory genes show that these genes are conserved in B. ovata. This additional sampling contributes to a more complete reconstruction of the ctenophore ancestor and points to the need for extensive comparisons within this ancient and diverse clade of animals. To promote further exploration of these data, we present BovaDB (http://ryanlab.whitney.ufl.edu/bovadb/), a portal for the B. ovata genome.}, }
@article {pmid38892379, year = {2024}, author = {Lin, CH and Tariq, MJ and Ullah, F and Sannareddy, A and Khalid, F and Abbas, H and Bader, A and Samaras, C and Valent, J and Khouri, J and Anwer, F and Raza, S and Dima, D}, title = {Current Novel Targeted Therapeutic Strategies in Multiple Myeloma.}, journal = {International journal of molecular sciences}, volume = {25}, number = {11}, pages = {}, pmid = {38892379}, issn = {1422-0067}, mesh = {Humans ; *Multiple Myeloma/drug therapy/metabolism ; *Molecular Targeted Therapy/methods ; Antineoplastic Agents/therapeutic use ; Animals ; }, abstract = {Multiple myeloma (MM) is a hematologic malignancy caused by the clonal expansion of immunoglobulin-producing plasma cells in the bone marrow and/or extramedullary sites. Common manifestations of MM include anemia, renal dysfunction, infection, bone pain, hypercalcemia, and fatigue. Despite numerous recent advancements in the MM treatment paradigm, current therapies demonstrate limited long-term effectiveness and eventual disease relapse remains exceedingly common. Myeloma cells often develop drug resistance through clonal evolution and alterations of cellular signaling pathways. Therefore, continued research of new targets in MM is crucial to circumvent cumulative drug resistance, overcome treatment-limiting toxicities, and improve outcomes in this incurable disease. This article provides a comprehensive overview of the landscape of novel treatments and emerging therapies for MM grouped by molecular target. Molecular targets outlined include BCMA, GPRC5D, FcRH5, CD38, SLAMF7, BCL-2, kinesin spindle protein, protein disulfide isomerase 1, peptidylprolyl isomerase A, Sec61 translocon, and cyclin-dependent kinase 6. Immunomodulatory drugs, NK cell therapy, and proteolysis-targeting chimera are described as well.}, }
@article {pmid38890744, year = {2024}, author = {Lagat, HK and Pintye, J and Harrington, E and Houck, S and Kwena, Z and Lenn, M and Mogaka, F and Momanyi, V and Mugambi, M and Nyerere, B and Odoyo, J and Omollo, V and Ortblad, KF and Rota, G and Sharma, M and Bukusi, EA}, title = {Enhancing HIV pre-exposure prophylaxis outcomes among Kenyan adolescent girls and young women with a novel pharmacy-based PrEP delivery platform: protocol for a cluster-randomized controlled trial.}, journal = {Trials}, volume = {25}, number = {1}, pages = {394}, pmid = {38890744}, issn = {1745-6215}, support = {K01MH122326/MH/NIMH NIH HHS/United States ; R01HD108041//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; R00MH121166/MH/NIMH NIH HHS/United States ; R01 HD100201/HD/NICHD NIH HHS/United States ; K01 MH122326/MH/NIMH NIH HHS/United States ; R01 NR019220/NR/NINR NIH HHS/United States ; R01HD100201//National Institute of Child Health and Human Development/ ; NICHD//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P30 AI027757/AI/NIAID NIH HHS/United States ; R01NR019220/NR/NINR NIH HHS/United States ; R01 HD108041/HD/NICHD NIH HHS/United States ; }, mesh = {Humans ; Female ; Adolescent ; *HIV Infections/prevention &amp; control ; *Pre-Exposure Prophylaxis/methods ; Kenya ; Young Adult ; *Anti-HIV Agents/administration &amp; dosage ; *Randomized Controlled Trials as Topic ; Medication Adherence ; Treatment Outcome ; Time Factors ; Multicenter Studies as Topic ; Community Pharmacy Services ; }, abstract = {BACKGROUND: In Kenya, 65% of sexually active unmarried women use modern contraceptives, a population at increased risk of HIV acquisition compared to other populations. Anchoring HIV prevention services, including pre-exposure prophylaxis (PrEP), to trusted contraceptive delivery settings offers opportunities to efficiently reach this important population. In Kenya, almost half (40%) of women accessing contraception services do so outside traditional healthcare facilities, such as retail pharmacies. Thus, integrating PrEP services into retail pharmacies may increase options for reaching adolescent girls and young women (AGYW) who could benefit from PrEP. Efforts are underway to define care pathways for pharmacy-delivered PrEP services in Kenya, including unsupported and supported models with nurse navigators.<br><br>METHODS: The AGYW Pharmacy PrEP study is an unblinded 2-arm cluster-randomized controlled trial in Kisumu, Kenya. The objective is to determine the effect that unsupported versus supported pharmacy-delivered PrEP services has on PrEP initiation, persistence, and adherence among AGYW seeking contraception. Twenty retail pharmacies offering pharmacy provider-led PrEP delivery will be randomized 1:1 to either receive or not receive a nurse navigator to support PrEP delivery. Eligible AGYW (n&#x2009;=&#x2009;1900 total, n&#x2009;=&#x2009;950/arm) will be&#x2009;&#x2265;&#x2009;15&#xa0;years old, purchasing a method of contraception at the pharmacy. Trained pharmacy provider will offer eligible AGYW either daily oral PrEP or the monthly DPV vaginal ring. The primary trial outcomes are PrEP initiation (use of PrEP at 1&#xa0;month), persistence (use of PrEP at 10&#xa0;months), and adherence (quantified by levels of TFV or DPV in hair samples). Additionally, several secondary (STI incidence, PrEP method selection, predictors of PrEP adherence) and exploratory outcomes (HIV incidence, quality of care, contraceptive method mix) will be explored.<br><br>DISCUSSION: We hypothesize pharmacy-delivered PrEP services supported with nurse navigator, versus delivered by pharmacy providers alone, will improve PrEP outcomes among AGYW seeking contraception. Our results will help policy makers better understand how to potentially implement this novel differentiated service model for PrEP and prime pharmacies for the delivery of new PrEP agents in the pipeline (e.g., long-acting injectables and multi-purpose technologies). The study was initiated on May 13, 2023, and is expected to be completed by February 2025.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov (NCT05467306), with registration on July 20, 2022.}, }
@article {pmid38890426, year = {2024}, author = {Otto, DJ and Jordan, C and Dury, B and Dien, C and Setty, M}, title = {Quantifying cell-state densities in single-cell phenotypic landscapes using Mellon.}, journal = {Nature methods}, volume = {21}, number = {7}, pages = {1185-1195}, pmid = {38890426}, issn = {1548-7105}, support = {R35 GM147125/GM/NIGMS NIH HHS/United States ; R35 GM147125/GM/NIGMS NIH HHS/United States ; }, mesh = {*Single-Cell Analysis/methods ; *Algorithms ; *Cell Differentiation ; *Phenotype ; Animals ; Humans ; Cell Count ; Mice ; }, abstract = {Cell-state density characterizes the distribution of cells along phenotypic landscapes and is crucial for unraveling the mechanisms that drive diverse biological processes. Here, we present Mellon, an algorithm for estimation of cell-state densities from high-dimensional representations of single-cell data. We demonstrate Mellon's efficacy by dissecting the density landscape of differentiating systems, revealing a consistent pattern of high-density regions corresponding to major cell types intertwined with low-density, rare transitory states. We present evidence implicating enhancer priming and the activation of master regulators in emergence of these transitory states. Mellon offers the flexibility to perform temporal interpolation of time-series data, providing a detailed view of cell-state dynamics during developmental processes. Mellon facilitates density estimation across various single-cell data modalities, scaling linearly with the number of cells. Our work underscores the importance of cell-state density in understanding the differentiation processes, and the potential of Mellon to provide insights into mechanisms guiding biological trajectories.}, }
@article {pmid38890283, year = {2024}, author = {Dintwe, OB and Ballweber Fleming, L and Voillet, V and McNevin, J and Seese, A and Naidoo, A and Omarjee, S and Bekker, LG and Kublin, JG and De Rosa, SC and Newell, EW and Fiore-Gartland, A and Andersen-Nissen, E and McElrath, MJ}, title = {Adolescent BCG revaccination induces a phenotypic shift in CD4[+] T cell responses to Mycobacterium tuberculosis.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {5191}, pmid = {38890283}, issn = {2041-1723}, support = {UM1AI068635//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; U01 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; U01 AI068618/AI/NIAID NIH HHS/United States ; UM1AI068618//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; UM1 AI068618/AI/NIAID NIH HHS/United States ; }, mesh = {*Mycobacterium tuberculosis/immunology ; Humans ; Adolescent ; *CD4-Positive T-Lymphocytes/immunology ; *BCG Vaccine/immunology ; Immunization, Secondary ; Tuberculosis/immunology/prevention &amp; control/microbiology ; Female ; Male ; Phenotype ; Single-Cell Analysis ; Th1 Cells/immunology ; Immunologic Memory/immunology ; }, abstract = {A recent clinical trial demonstrated that Bacille Calmette-Guérin (BCG) revaccination of adolescents reduced the risk of sustained infection with Mycobacterium tuberculosis (M.tb). In a companion phase 1b trial, HVTN 602/Aeras A-042, we characterize in-depth the cellular responses to BCG revaccination or to a H4:IC31 vaccine boost to identify T cell subsets that could be responsible for the protection observed. High-dimensional clustering analysis of cells profiled using a 26-color flow cytometric panel show marked increases in five effector memory CD4[+] T cell subpopulations (TEM) after BCG revaccination, two of which are highly polyfunctional. CITE-Seq single-cell analysis shows that the activated subsets include an abundant cluster of Th1 cells with migratory potential. Additionally, a small cluster of Th17 TEM cells induced by BCG revaccination expresses high levels of CD103; these may represent recirculating tissue-resident memory cells that could provide pulmonary immune protection. Together, these results identify unique populations of CD4[+] T cells with potential to be immune correlates of protection conferred by BCG revaccination.}, }
@article {pmid38890069, year = {2024}, author = {Raychaudhuri, R and DeJong, M and Rettig, M and Yu, EY and Gulati, R and Schweizer, MT and Nelson, PS and Pritchard, CC and Montgomery, B and Cheng, HH}, title = {Docetaxel and Carboplatin for the Treatment of Patients with Metastatic Castration-resistant Prostate Cancer and Biallelic Inactivation of Genes in the Homologous Recombination DNA Repair Pathway: The ABCD Trial.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2024.05.025}, pmid = {38890069}, issn = {1873-7560}, }
@article {pmid38889373, year = {2024}, author = {Cortés, J and Hurvitz, SA and O'Shaughnessy, J and Delaloge, S and Iwata, H and Rugo, HS and Neven, P and Kanagavel, D and Cohen, P and Paux, G and Cartot-Cotton, S and Stefanova-Urena, M and Deyme, L and Aouni, J and Sebastien, B and Bardia, A}, title = {Randomized Phase III Study of Amcenestrant Plus Palbociclib Versus Letrozole Plus Palbociclib in Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Primary Results From AMEERA-5.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {42}, number = {22}, pages = {2680-2690}, doi = {10.1200/JCO.23.02036}, pmid = {38889373}, issn = {1527-7755}, mesh = {Humans ; Female ; *Letrozole/administration &amp; dosage/therapeutic use ; *Breast Neoplasms/drug therapy/pathology ; Middle Aged ; *Pyridines/therapeutic use/administration &amp; dosage/adverse effects ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; *Receptor, ErbB-2/metabolism/analysis ; *Receptors, Estrogen/metabolism/analysis ; Aged ; *Piperazines/therapeutic use/administration &amp; dosage/adverse effects ; Double-Blind Method ; Adult ; Male ; Breast Neoplasms, Male/drug therapy/pathology/metabolism ; Aged, 80 and over ; }, abstract = {PURPOSE: AMEERA-5 investigated amcenestrant (oral selective estrogen receptor [ER] degrader) plus palbociclib versus letrozole plus palbociclib as first-line treatment for ER-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced/metastatic breast cancer (aBC).<br><br>MATERIALS AND METHODS: In AMEERA-5 (ClinicalTrials.gov identifier: NCT04478266), a double-blind, double-dummy, international phase III trial, adult pre-/post-menopausal women and men without previous systemic therapy for ER+/HER2- aBC were randomly assigned 1:1 to amcenestrant 200 mg once daily + standard palbociclib dosage (125 mg once daily, 21 days on/7 days off) or letrozole 2.5 mg once daily + standard palbociclib dosage, stratified by de novo metastatic disease, postmenopausal women, and visceral metastasis. The primary end point was progression-free survival (PFS), compared using a stratified log-rank test with one-sided type I error rate of 2.5%. Secondary end points included overall survival (key secondary), pharmacokinetics, and safety.<br><br>RESULTS: Between October 14, 2020, and December 2, 2021, 1,068 patients were randomly assigned to amcenestrant + palbociclib (N = 534) or letrozole + palbociclib (N = 534). At the interim analysis (median follow-up 8.4 months), the stratified hazard ratio for PFS was 1.209 (95% CI, 0.939 to 1.557; one-sided P value = .9304); therefore, the study was stopped for futility. The 6-month PFS rate was 82.7% (95% CI, 79.0 to 85.8) with amcenestrant + palbociclib versus 86.9% (95% CI, 83.5 to 89.6) with letrozole + palbociclib. In the amcenestrant + palbociclib versus letrozole + palbociclib groups, treatment-emergent adverse events (any grade) occurred in 85.6% versus 85.4% of patients and grade &#x2265;3 events in 46.3% versus 60.8%, respectively.<br><br>CONCLUSION: The AMEERA-5 study was discontinued on the basis of the recommendation of the data monitoring committee at the interim futility analysis. No new safety signals were identified.}, }
@article {pmid38887957, year = {2024}, author = {Jiang, L and Shen, J and Darst, BF and Haiman, CA and Mancuso, N and Conti, DV}, title = {Hierarchical joint analysis of marginal summary statistics-Part II: High-dimensional instrumental analysis of omics data.}, journal = {Genetic epidemiology}, volume = {48}, number = {7}, pages = {291-309}, doi = {10.1002/gepi.22577}, pmid = {38887957}, issn = {1098-2272}, support = {P01CA196569/BC/NCI NIH HHS/United States ; U01CA261339/BC/NCI NIH HHS/United States ; P30CA014089/BC/NCI NIH HHS/United States ; U01CA257328/BC/NCI NIH HHS/United States ; U19CA214253/BC/NCI NIH HHS/United States ; U01CA164973/BC/NCI NIH HHS/United States ; R01HG010297/HG/NHGRI NIH HHS/United States ; }, mesh = {Humans ; *Polymorphism, Single Nucleotide ; *Prostatic Neoplasms/genetics ; Male ; Genome-Wide Association Study/methods ; Models, Statistical ; Mendelian Randomization Analysis ; ROC Curve ; Computer Simulation ; }, abstract = {Instrumental variable (IV) analysis has been widely applied in epidemiology to infer causal relationships using observational data. Genetic variants can also be viewed as valid IVs in Mendelian randomization and transcriptome-wide association studies. However, most multivariate IV approaches cannot scale to high-throughput experimental data. Here, we leverage the flexibility of our previous work, a hierarchical model that jointly analyzes marginal summary statistics (hJAM), to a scalable framework (SHA-JAM) that can be applied to a large number of intermediates and a large number of correlated genetic variants-situations often encountered in modern experiments leveraging omic technologies. SHA-JAM aims to estimate the conditional effect for high-dimensional risk factors on an outcome by incorporating estimates from association analyses of single-nucleotide polymorphism (SNP)-intermediate or SNP-gene expression as prior information in a hierarchical model. Results from extensive simulation studies demonstrate that SHA-JAM yields a higher area under the receiver operating characteristics curve (AUC), a lower mean-squared error of the estimates, and a much faster computation speed, compared to an existing approach for similar analyses. In two applied examples for prostate cancer, we investigated metabolite and transcriptome associations, respectively, using summary statistics from a GWAS for prostate cancer with more than 140,000 men and high dimensional publicly available summary data for metabolites and transcriptomes.}, }
@article {pmid38886574, year = {2024}, author = {Zemek, RM and Anagnostou, V and Pires da Silva, I and Long, GV and Lesterhuis, WJ}, title = {Exploiting temporal aspects of cancer immunotherapy.}, journal = {Nature reviews. Cancer}, volume = {24}, number = {7}, pages = {480-497}, pmid = {38886574}, issn = {1474-1768}, mesh = {Humans ; *Neoplasms/therapy/immunology ; *Immunotherapy/methods ; *Tumor Microenvironment/immunology ; Immune Checkpoint Inhibitors/therapeutic use ; Time Factors ; Combined Modality Therapy ; Animals ; }, abstract = {Many mechanisms underlying an effective immunotherapy-induced antitumour response are transient and critically time dependent. This is equally true for several immunological events in the tumour microenvironment induced by other cancer treatments. Immune checkpoint therapy (ICT) has proven to be very effective in the treatment of some cancers, but unfortunately, with many cancer types, most patients do not experience a benefit. To improve outcomes, a multitude of clinical trials are testing combinations of ICT with various other treatment modalities. Ideally, those combination treatments should take time-dependent immunological events into account. Recent studies have started to map the dynamic cellular and molecular changes that occur during treatment with ICT, in the tumour and systemically. Here, we overlay the dynamic ICT response with the therapeutic response following surgery, radiotherapy, chemotherapy and targeted therapies. We propose that by combining treatments in a time-conscious manner, we may optimally exploit the interactions between the individual therapies.}, }
@article {pmid38885948, year = {2024}, author = {Balay-Dustrude, E and Weiss, NS and Sutton, A and Shenoi, S}, title = {Predictors of Disease Activity in Patients With Juvenile Idiopathic Arthritis at 12 and 24 Months After Diagnosis.}, journal = {ACR open rheumatology}, volume = {6}, number = {8}, pages = {489-496}, pmid = {38885948}, issn = {2578-5745}, support = {T32 AR007108/AR/NIAMS NIH HHS/United States ; 5T32AR7108-42/NH/NIH HHS/United States ; }, abstract = {OBJECTIVE: Identification of characteristics associated with active disease in juvenile idiopathic arthritis (JIA) could inform early disease treatment strategies. This study evaluated characteristics associated with active disease at 12 and 24 months after JIA diagnosis in the era in which biologic disease-modifying antirheumatic drugs (DMARDs) became available for JIA.<br><br>METHODS: This single-center retrospective study from 2004 through 2018 assessed characteristics associated with active nonsystemic categories of JIA at 12 and 24 months after diagnosis. Relative prevalence (RP) of disease activity was evaluated in relation to prespecified characteristics. Using RP, the effect of increasing biologic DMARD availability on these predictors was assessed at 12 months.<br><br>RESULTS: A total of 1,151 patients with JIA were included. At 12 months, a 40% to 45% higher point prevalence of active disease was noted in older children (>5 years). Patients with active disease at 3 months had a greater prevalence of active disease at 12 months (RP 1.5, 95% confidence interval [CI] 1.2-1.8) and 24 months (RP 1.3, 95% CI 1-1.6). Compared to oligoarticular JIA, polyarticular RF-negative, psoriatic, and enthesitis-related JIA had a greater prevalence of active disease at 12 and 24 months. At 24 months, a greater prevalence of active disease was observed in children &#x2265;10 years. RP of active disease was 25% lower in the late cohort (2013-2018) than in the earliest cohort (2004-2008; RP 0.75, 95% CI 0.62-0.92) when more biologic medications were available, but disease activity predictors were broadly similar over time.<br><br>CONCLUSION: Patients with JIA with active disease at 12 and 24 months were older at diagnosis, categorized as polyarticular RF-negative, psoriatic, or enthesitis-related JIA. Active disease at 3 months after diagnosis was associated with worse outcomes at 12 and 24 months.}, }
@article {pmid38885484, year = {2024}, author = {Pidala, JA and Onstad, L and Baumrin, E and Carpenter, PA and Cutler, C and Arai, S and Kitko, CL and Chen, GL and Lee, SJ}, title = {Comparison of treatment response measures in cutaneous sclerosis after allogeneic hematopoietic cell transplantation.}, journal = {Blood advances}, volume = {8}, number = {17}, pages = {4651-4657}, pmid = {38885484}, issn = {2473-9537}, support = {U54 CA163438/CA/NCI NIH HHS/United States ; R01 CA118953/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects ; *Graft vs Host Disease/etiology/diagnosis ; Female ; Male ; Middle Aged ; Adult ; Transplantation, Homologous ; Treatment Outcome ; Sclerosis ; }, abstract = {Cutaneous sclerosis, a highly morbid subtype of chronic graft-versus-host disease (GVHD), demonstrates limited treatment response under current National Institutes of Health (NIH) response measures. We explored novel sclerosis-specific response measures using Chronic GVHD Consortium data. A training cohort included patients with cutaneous sclerosis from a randomized trial of imatinib vs rituximab and a consortium observational study. The validation cohort was a different consortium observational study. Clinician-reported measures (baseline and baseline to 6-month change) were examined for association with 6-month clinician-reported response. Patient-reported measures (baseline and baseline to 6-month change) were studied for association with 6-month patient-reported response. A total of 347 patients were included (training 183 and validation 164). Although multiple skin and joint measures were associated with clinician-reported response on univariate analysis, patient range of motion (PROM) total score, PROM total score change, and NIH 0 to 3 skin change were retained in the final multivariate model (area under the receiver operating characteristic curve [AUC], 0.83 training and 0.75 validation). Similarly, many patient-reported measures were associated, but final multivariate analysis retained the human activity profile adjusted activity score (AAS), 36 item short form health survey (SF36) vitality change, Lee symptom scale (LSS) skin, and LSS skin change in the model (AUC, 0.86 training and 0.75 validation). We identified which sclerosis measures have the greatest association with 6-month clinician- and patient-reported treatment responses, a previously unstudied area. However, given the observed performance in the validation cohorts, we conclude that further work is needed. Novel response measures may be needed to optimally assess treatment response in cutaneous sclerosis.}, }
@article {pmid38885448, year = {2024}, author = {Cranmer, LD and Konnick, EQ and Yoshida, JR and Jacobson, AL and Malik, BA and Mogal, H and Sullivan, LB and Handfrod, CL and Pritchard, CC and Dubard-Gault, ME}, title = {Combined Germline and Mosaic SDHA Mutation Is Associated With a Multicancer Syndrome Including Neuroblastoma, Renal Cancer, and Multifocal GI Tumor.}, journal = {JCO precision oncology}, volume = {8}, number = {}, pages = {e2300455}, pmid = {38885448}, issn = {2473-4284}, mesh = {Humans ; *Kidney Neoplasms/genetics/pathology ; *Neuroblastoma/genetics ; *Germ-Line Mutation ; Gastrointestinal Neoplasms/genetics/pathology ; Male ; Electron Transport Complex II/genetics ; Mosaicism ; Female ; Neoplasms, Multiple Primary/genetics/pathology ; }, abstract = {Highlighting here a patient case with neuroblastoma, renal cancer &amp; GIST from germline SDHA.}, }
@article {pmid38885329, year = {2024}, author = {Simpson, J and Starke, CE and Ortiz, AM and Ransier, A and Darko, S and Llewellyn-Lacey, S and Fennessey, CM and Keele, BF and Douek, DC and Price, DA and Brenchley, JM}, title = {Immunotoxin-mediated depletion of Gag-specific CD8+ T cells undermines natural control of SIV.}, journal = {JCI insight}, volume = {9}, number = {14}, pages = {}, pmid = {38885329}, issn = {2379-3708}, support = {/WT_/Wellcome Trust/United Kingdom ; 75N91019D00024/CA/NCI NIH HHS/United States ; ZIA AI001029/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Animals ; *CD8-Positive T-Lymphocytes/immunology ; *Simian Immunodeficiency Virus/immunology ; *Simian Acquired Immunodeficiency Syndrome/immunology ; *Macaca mulatta ; *Immunotoxins/immunology/pharmacology ; Gene Products, gag/immunology ; Virus Replication/immunology/drug effects ; Lymphocyte Depletion/methods ; }, abstract = {Antibody-mediated depletion studies have demonstrated that CD8+ T cells are required for effective immune control of SIV. However, this approach is potentially confounded by several factors, including reactive CD4+ T cell proliferation, and provides no information on epitope specificity, a likely determinant of CD8+ T cell efficacy. We circumvented these limitations by selectively depleting CD8+ T cells specific for the Gag epitope CTPYDINQM (CM9) via the administration of immunotoxin-conjugated tetrameric complexes of CM9/Mamu-A*01. Immunotoxin administration effectively depleted circulating but not tissue-localized CM9-specific CD8+ T cells, akin to the bulk depletion pattern observed with antibodies directed against CD8. However, we found no evidence to indicate that circulating CM9-specific CD8+ T cells suppressed viral replication in Mamu-A*01+ rhesus macaques during acute or chronic progressive infection with a pathogenic strain of SIV. This observation extended to macaques with established infection during and after continuous antiretroviral therapy. In contrast, natural controller macaques experienced dramatic increases in plasma viremia after immunotoxin administration, highlighting the importance of CD8+ T cell-mediated immunity against CM9. Collectively, these data showed that CM9-specific CD8+ T cells were necessary but not sufficient for robust immune control of SIV in a nonhuman primate model and, more generally, validated an approach that could inform the design of next-generation vaccines against HIV-1.}, }
@article {pmid38884660, year = {2024}, author = {Wu, Y and Huang, JY and Conlon, MT and Shenoy, MK and Chao, JL and Chooi, MY and Koch, MA and Gerner, MY}, title = {Distal Immunization and Systemic Cytokines Establish a Transient Immune Alert State in the Intestine.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {213}, number = {3}, pages = {373-383}, pmid = {38884660}, issn = {1550-6606}, support = {//Fred Hutchinson Cancer Center (FHCRC)/ ; //Rita Allen Foundation (RAF)/ ; A173128/GF/NIH HHS/United States ; //Pew Charitable Trusts (PCT)/ ; R01 AI134713/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Lymph Nodes/immunology ; *Immunization/methods ; Mice, Inbred C57BL ; Cytokines/immunology/metabolism ; Intestine, Small/immunology ; Dendritic Cells/immunology ; Inflammation/immunology ; Tumor Necrosis Factor-alpha/immunology/metabolism ; T-Lymphocytes/immunology ; Intestinal Mucosa/immunology ; }, abstract = {Conventionally, immune responses are studied in the context of inflamed tissues and their corresponding draining lymph nodes (LNs). However, little is known about the effects of systemic inflammatory signals generated during local inflammation on distal tissues and nondraining LNs. Using a mouse model of cutaneous immunization, we found that systemic inflammatory stimuli triggered a rapid and selective distal response in the small intestine and the mesenteric LN (mesLN). This consisted of increased permeability of intestinal blood vessels and lymphatic drainage of bloodborne solutes into the mesLN, enhanced activation and migration of intestinal dendritic cells, as well as amplified T cell responses in the mesLNs to systemic but not orally derived Ags. Mechanistically, we found that the small intestine endothelial cells preferentially expressed molecules involved in TNF-α signaling and that TNF-α blockade markedly diminished distal intestinal responses to cutaneous immunization. Together, these findings reveal that the intestinal immune system is rapidly and selectively activated in response to inflammatory cues regardless of their origin, thus identifying an additional layer of defense and enhanced surveillance of a key barrier organ at constant risk of pathogen encounter.}, }
@article {pmid38883789, year = {2024}, author = {Demedis, J and Reedy, J and Miller, K and Hu, J and Klosky, JL and Holliman, BD and Peterson, PN and Chow, EJ and Studts, C}, title = {Testing effectiveness and implementation of a standardized approach to sexual dysfunction screening among adolescent and young adult-aged survivors of childhood cancer: A type I hybrid, mixed methods trial protocol: Effectiveness of sexual dysfunction screening among AYA cancer survivors: a study protocol.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {38883789}, support = {K08 CA263192/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Approximately 20-50% of adolescent and young adult-aged childhood cancer survivors (AYA-CCS) experience sexual dysfunction (SD), although this healthcare need is widely underrecognized. Previous research from both AYA-CCS patients and their providers report that SD needs are unaddressed despite patient desires for SD discussions to be incorporated as part of their care. Patients and providers agree that standardized use of a patient-reported outcome measure may facilitate SD discussions; an SD screening approach was developed with patient and provider input. This study will measure the effectiveness of a standardized SD screening intervention and assess implementation outcomes and multilevel barriers and facilitators to guide future research.<br><br>METHODS: This multi-site, mixed methods, type 1 effectiveness-implementation hybrid trial will be evaluated using a pre-post design (NCT05524610). The trial will enroll 86 AYA-CCS (ages 15-39) from two cancer centers in the United States. The SD intervention consists of core fundamental functions with a "menu" of intervention options to allow for flexibility in delivery and tailoring in variable contexts. Effectiveness of the intervention on facilitating SD communication will be measured through patient surveys and clinical data; multivariable logistic regression will be used for the binary outcome of self-reported SD screening, controlling for patient-level predictors. Implementation outcomes will be assessed using mixed methods (electronic health record abstraction, patient and provider surveys, and provider interviews. Quantitative and qualitative findings will be merged using a joint display to understand factors affecting intervention success.<br><br>IMPLICATIONS: Identification and treatment of SD in AYA-CCS is an important and challenging quality of life concern. The type 1 hybrid design will facilitate rapid translation from research to practice by testing the effects of the intervention while simultaneously identifying multilevel barriers and facilitators to real-world implementation. This approach will inform future testing and dissemination of the SD screening intervention.}, }
@article {pmid38881823, year = {2024}, author = {Waters, AR and Meehan, K and Atkins, DL and Ittes, AH and Ferrari, RM and Rohweder, CL and Wangen, M and Ceballos, RM and Issaka, RB and Reuland, DS and Wheeler, SB and Brenner, AT and Shah, PD}, title = {How pharmacists would design and implement a community pharmacy-based colorectal cancer screening program.}, journal = {Preventive oncology &amp; epidemiology}, volume = {2}, number = {1}, pages = {}, pmid = {38881823}, issn = {2832-2134}, support = {T32 CA116339/CA/NCI NIH HHS/United States ; U48 DP006400/DP/NCCDPHP CDC HHS/United States ; U48DP006400/ACL/ACL HHS/United States ; }, abstract = {BACKGROUND: Distributing CRC screening through pharmacies, a highly accessible health service, may create opportunities for more equitable access to CRC screening. However, providing CRC screening in a new context introduces a substantial implementation challenge.<br><br>METHODS: We conducted 23 semi-structured interviews with community pharmacists practicing in Washington state and North Carolina about distributing fecal immunochemical tests (FIT) to patients in the pharmacy. The Consolidated Framework for Implementation Research (CFIR) was used to guide analysis.<br><br>RESULTS: Pharmacists believed that delivering FITs was highly compatible with their environment, workflow, and scope of practice. While knowledge about FIT eligibility criteria varied, pharmacists felt comfortable screening patients. They identified standardized eligibility criteria, patient-facing educational materials, and continuing education as essential design features. Pharmacists proposed adapting existing pharmacy electronic health record systems for patient reminders/prompts to facilitate FIT completion. While pharmacists felt confident that they could discuss test results with patients, they also expressed a need for stronger communication and care coordination with primary care providers.<br><br>DISCUSSION: When designing a pharmacy-based CRC screening program, pharmacists desired programmatic procedures to fit their current knowledge and context. Findings indicate that if proper attention is given to multi-level factors, FIT delivery can be extended to pharmacies.}, }
@article {pmid38880291, year = {2024}, author = {Pishgar, F and Lee, CI}, title = {Improving Patient Understanding of Prostate Cancer Risks Associated With Prostate Imaging Reporting and Data System Lexicon.}, journal = {Journal of the American College of Radiology : JACR}, volume = {21}, number = {10}, pages = {1643-1644}, doi = {10.1016/j.jacr.2024.06.002}, pmid = {38880291}, issn = {1558-349X}, }
@article {pmid38879611, year = {2024}, author = {Sala-Torra, O and Beppu, L and Wu, Q and Welch, E and Berthier, E and Radich, JP and Oehler, VG}, title = {Point-of-care BCR::ABL1 transcript monitoring using capillary dried blood in chronic myeloid leukemia patients.}, journal = {Leukemia}, volume = {38}, number = {8}, pages = {1822-1824}, pmid = {38879611}, issn = {1476-5551}, mesh = {Humans ; *Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics/blood/drug therapy ; *Fusion Proteins, bcr-abl/genetics ; Point-of-Care Systems ; Male ; Female ; Dried Blood Spot Testing/methods ; Middle Aged ; Aged ; Adult ; }, }
@article {pmid38876107, year = {2024}, author = {Hart, TM and Sonnert, ND and Tang, X and Chaurasia, R and Allen, PE and Hunt, JR and Read, CB and Johnson, EE and Arora, G and Dai, Y and Cui, Y and Chuang, YM and Yu, Q and Rahman, MS and Mendes, MT and Rolandelli, A and Singh, P and Tripathi, AK and Ben Mamoun, C and Caimano, MJ and Radolf, JD and Lin, YP and Fingerle, V and Margos, G and Pal, U and Johnson, RM and Pedra, JHF and Azad, AF and Salje, J and Dimopoulos, G and Vinetz, JM and Carlyon, JA and Palm, NW and Fikrig, E and Ring, AM}, title = {An atlas of human vector-borne microbe interactions reveals pathogenicity mechanisms.}, journal = {Cell}, volume = {187}, number = {15}, pages = {4113-4127.e13}, doi = {10.1016/j.cell.2024.05.023}, pmid = {38876107}, issn = {1097-4172}, support = {F32 AI174656/AI/NIAID NIH HHS/United States ; R01 AI017828/AI/NIAID NIH HHS/United States ; R01 AI126853/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Host-Pathogen Interactions ; Animals ; Lyme Disease/microbiology ; Vector Borne Diseases ; Host Microbial Interactions ; Borrelia burgdorferi/pathogenicity/metabolism ; }, abstract = {Vector-borne diseases are a leading cause of death worldwide and pose a substantial unmet medical need. Pathogens binding to host extracellular proteins (the "exoproteome") represents a crucial interface in the etiology of vector-borne disease. Here, we used bacterial selection to elucidate host-microbe interactions in high throughput (BASEHIT)-a technique enabling interrogation of microbial interactions with 3,324 human exoproteins-to profile the interactomes of 82 human-pathogen samples, including 30 strains of arthropod-borne pathogens and 8 strains of related non-vector-borne pathogens. The resulting atlas revealed 1,303 putative interactions, including hundreds of pairings with potential roles in pathogenesis, including cell invasion, tissue colonization, immune evasion, and host sensing. Subsequent functional investigations uncovered that Lyme disease spirochetes recognize epidermal growth factor as an environmental cue of transcriptional regulation and that conserved interactions between intracellular pathogens and thioredoxins facilitate cell invasion. In summary, this interactome atlas provides molecular-level insights into microbial pathogenesis and reveals potential host-directed targets for next-generation therapeutics.}, }
@article {pmid38876098, year = {2024}, author = {Yeh, AC and Koyama, M and Waltner, OG and Minnie, SA and Boiko, JR and Shabaneh, TB and Takahashi, S and Zhang, P and Ensbey, KS and Schmidt, CR and Legg, SRW and Sekiguchi, T and Nelson, E and Bhise, SS and Stevens, AR and Goodpaster, T and Chakka, S and Furlan, SN and Markey, KA and Bleakley, ME and Elson, CO and Bradley, PH and Hill, GR}, title = {Microbiota dictate T cell clonal selection to augment graft-versus-host disease after stem cell transplantation.}, journal = {Immunity}, volume = {57}, number = {7}, pages = {1648-1664.e9}, pmid = {38876098}, issn = {1097-4180}, support = {K08 HL167161/HL/NHLBI NIH HHS/United States ; K12 CA076930/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; KL2 TR002317/TR/NCATS NIH HHS/United States ; R01 HL148164/HL/NHLBI NIH HHS/United States ; }, mesh = {*Graft vs Host Disease/immunology/microbiology ; Animals ; Mice ; Mice, Inbred C57BL ; CD4-Positive T-Lymphocytes/immunology ; Receptors, Antigen, T-Cell/immunology/genetics/metabolism ; Microbiota/immunology ; Clonal Selection, Antigen-Mediated ; Transplantation, Homologous ; Bayes Theorem ; Stem Cell Transplantation/adverse effects ; Mice, Inbred BALB C ; Gastrointestinal Microbiome/immunology ; Hematopoietic Stem Cell Transplantation/adverse effects ; }, abstract = {Allogeneic T cell expansion is the primary determinant of graft-versus-host disease (GVHD), and current dogma dictates that this is driven by histocompatibility antigen disparities between donor and recipient. This paradigm represents a closed genetic system within which donor T cells interact with peptide-major histocompatibility complexes (MHCs), though clonal interrogation remains challenging due to the sparseness of the T cell repertoire. We developed a Bayesian model using donor and recipient T cell receptor (TCR) frequencies in murine stem cell transplant systems to define limited common expansion of T cell clones across genetically identical donor-recipient pairs. A subset of donor CD4[+] T cell clonotypes differentially expanded in identical recipients and were microbiota dependent. Microbiota-specific T cells augmented GVHD lethality and could target microbial antigens presented by gastrointestinal epithelium during an alloreactive response. The microbiota serves as a source of cognate antigens that contribute to clonotypic T cell expansion and the induction of GVHD independent of donor-recipient genetics.}, }
@article {pmid38875510, year = {2024}, author = {Halabi, S and Guo, S and Roy, A and Rydzewska, LE and Godolphin, P and Hussain, M and Tangen, C and Thompson, I and Xie, W and Carducci, MA and Morris, MJ and Smith, MR and Gravis, G and Dearnaley, DP and Verhagen, PJ and Goto, TJ and James, ND and Buyse, ME and Tierney, JF and Sweeney, CJ}, title = {Reply to J.A. Garcia et al.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {42}, number = {24}, pages = {2940-2941}, pmid = {38875510}, issn = {1527-7755}, support = {R01 CA249279/CA/NCI NIH HHS/United States ; R01 CA256157/CA/NCI NIH HHS/United States ; R21 CA263950/CA/NCI NIH HHS/United States ; U01 FD007857/FD/FDA HHS/United States ; }, }
@article {pmid38874345, year = {2024}, author = {Nakamura, M and Parkhurst, SM}, title = {Calcium influx rapidly establishes distinct spatial recruitments of Annexins to cell wounds.}, journal = {Genetics}, volume = {227}, number = {4}, pages = {}, pmid = {38874345}, issn = {1943-2631}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; GM111635/GF/NIH HHS/United States ; P40 OD018537/OD/NIH HHS/United States ; P40 OD010949/OD/NIH HHS/United States ; R24 OD030002/OD/NIH HHS/United States ; R01 GM111635/GM/NIGMS NIH HHS/United States ; //Mark Groudine Chair for Outstanding Achievements in Science and Service/ ; }, mesh = {*Annexins/metabolism/genetics ; Animals ; *Calcium/metabolism ; *Wound Healing ; *Drosophila Proteins/metabolism/genetics ; Actomyosin/metabolism ; Drosophila melanogaster/metabolism/genetics ; Actins/metabolism/genetics ; }, abstract = {To survive daily damage, the formation of actomyosin ring at the wound edge is required to rapidly close cell wounds. Calcium influx is one of the start signals for these cell wound repair events. Here, we find that the rapid recruitment of all 3 Drosophila calcium-responding and phospholipid-binding Annexin proteins (AnxB9, AnxB10, and AnxB11) to distinct regions around the wound is regulated by the quantity of calcium influx rather than their binding to specific phospholipids. The distinct recruitment patterns of these Annexins regulate the subsequent recruitment of RhoGEF2 and RhoGEF3 through actin stabilization to form a robust actomyosin ring. Surprisingly, while the wound does not close in the absence of calcium influx, we find that reduced calcium influx can still initiate repair processes, albeit leading to severe repair phenotypes. Thus, our results suggest that, in addition to initiating repair events, the quantity of calcium influx is important for precise Annexin spatiotemporal protein recruitment to cell wounds and efficient wound repair.}, }
@article {pmid38872845, year = {2024}, author = {Yanagi, KS and Lehrbach, N}, title = {Streamlined single shot safe harbor transgene integration in C. elegans using unc-119 rescue.}, journal = {microPublication biology}, volume = {2024}, number = {}, pages = {}, pmid = {38872845}, issn = {2578-9430}, abstract = {Transgenic animals are an invaluable tool in model organism genetics. The ease of modifying the C. elegans genome through high-copy integration of transgenes facilitates the investigation of diverse and fundamental biological processes. However, generation of new multicopy integrated transgenes is limited by the time and labor cost. Further, many transgenes are integrated using non-specific DNA damaging agents. These DNA damaging agents cause unwanted mutations during the integration process and may have deleterious effects. A recently described method for CRISPR/Cas9-based integration of multicopy transgenes at safe harbor loci using Fluorescent Landmark Interference (FLInt) greatly increases the efficiency of multicopy transgene integration and mitigates issues related to off-target mutagenesis during integration. unc-119 rescue is a simple and widely used phenotypic marker in C. elegans transgenesis and genome engineering. To streamline generation of multicopy transgenes via FLInt, we have generated a set of strains suitable for FLInt-mediated integration of transgenes using rescue of the unc-119 mutant phenotype to select transgenic animals. We demonstrate the utility of this approach and outline a protocol that uses unc-119 rescue as a selection marker for streamlined integration of multicopy transgenes at safe harbor loci.}, }
@article {pmid38872511, year = {2024}, author = {Dima, D and Goel, U and Sannareddy, A and Ibeh, N and Ullah, F and Afrough, A and Mazzoni, S and Mehdi, A and Rudoni, J and Raza, S and De Simone, N and Williams, L and Khan, A and Rashid, A and Rice, M and Ricci, K and Samaras, C and Valent, J and Anderson, LD and Anwer, F and Kaur, G and Khouri, J}, title = {Outcomes of therapeutic plasma exchange for the treatment of patients with multiple myeloma cast nephropathy.}, journal = {Hematological oncology}, volume = {42}, number = {4}, pages = {e3293}, doi = {10.1002/hon.3293}, pmid = {38872511}, issn = {1099-1069}, mesh = {Humans ; *Multiple Myeloma/therapy/mortality ; Male ; Female ; *Plasma Exchange/methods ; Middle Aged ; Aged ; Retrospective Studies ; Treatment Outcome ; Adult ; Aged, 80 and over ; Kidney Diseases/therapy/etiology ; }, abstract = {Current treatment guidelines of myeloma cast nephropathy (MCN) recommend the institution of plasma cell-directed therapy and consideration of therapeutic plasma exchange (TPE), with the goal of rapid reduction of the serum free light chain (sFLC). However, the role of TPE continues to remain a subject of debate. The goal of this retrospective bi-institutional study was to evaluate the clinical outcomes of TPE in combination with systemic therapy. Eighty patients were included in this analysis, of whom 72.5% had ≥50% drop in their initial involved sFLC. At 3 months from TPE initiation, the overall hematologic response rate (ORR) was 67.5% with a very good partial response or better (≥VGPR) rate of 40%. At 6 months, ORR was 57.5%, with ≥VGPR rate of 49%. The renal response rate at 3 and 6 months was 47.5% and 43.75%, respectively; the overall renal response rate was 48.75%. On multivariable analysis, every one unit increase in baseline creatinine (odds ratio [OR] 0.76, p = 0.006), and achievement of ≥VGPR (OR 21.7 p < 0.0001) were significantly associated with renal response. Also, a ≥50% drop in sFLC was favorably associated with renal response (OR 3.39, p = 0.09). With a median follow-up of 36.4 months, the median overall survival (OS) was 11 months. On multivariable analysis, achievement of renal response (hazard ratio [HR] 0.3, p < 0.0001) and newly diagnosed disease (NDMM; HR 0.43, p = 0.0055) were associated with improved OS. Among NDMM patients, those treated with daratumumab-based regimens had a trend for better OS (p = 0.15), compared to other regimens, but the difference was not significant. At the end of follow-up, an estimated 40.4% of patients who were on dialysis were able to become dialysis independent. In conclusion, our study highlights the poor survival of patients with MCN. Achievement of early renal response is crucial for prolonged OS, with daratumumab-based therapies showing promise.}, }
@article {pmid38872307, year = {2024}, author = {Zhu, Q and Yuan, C and Wang, D and Tu, B and Chen, W and Dong, X and Wu, K and Tao, L and Ding, Y and Xiao, W and Hu, L and Gong, W and Li, Z and Lu, G}, title = {The TRIM28/miR133a/CD47 axis acts as a potential therapeutic target in pancreatic necrosis by impairing efferocytosis.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {32}, number = {9}, pages = {3025-3041}, pmid = {38872307}, issn = {1525-0024}, mesh = {*CD47 Antigen/metabolism/genetics ; *MicroRNAs/genetics ; Animals ; Mice ; Humans ; *Phagocytosis ; *Tripartite Motif-Containing Protein 28/metabolism/genetics ; Macrophages/metabolism ; Pancreas/metabolism/pathology ; Apoptosis/genetics ; Disease Models, Animal ; Pancreatitis, Acute Necrotizing/metabolism/genetics/pathology ; Necrosis ; Gene Expression Regulation ; Signal Transduction ; Male ; Efferocytosis ; }, abstract = {Efferocytosis, the clearance of apoptotic cells by macrophages, plays a crucial role in inflammatory responses and effectively prevents secondary necrosis. However, the mechanisms underlying efferocytosis in acute pancreatitis (AP) remain unclear. In this study, we demonstrated the presence of efferocytosis in injured human and mouse pancreatic tissues. We also observed significant upregulation of CD47, an efferocytosis-related the "do not eat me" molecule in injured acinar cells. Subsequently, we used CRISPR-Cas9 gene editing, anti-adeno-associated virus (AAV) gene modification, and anti-CD47 antibody to investigate the potential therapeutic role of AP. CD47 expression was negatively regulated by upstream miR133a, which is controlled by the transcription factor TRIM28. To further investigate the regulation of efferocytosis and reduction of pancreatic necrosis in AP, we used miR-133a-agomir and pancreas-specific AAV-shTRIM28 to modulate CD47 expression. Our findings confirmed that CD47-mediated efferocytosis is critical for preventing pancreatic necrosis and suggest that targeting the TRIM28-miR133a-CD47 axis is clinically relevant for the treatment of AP.}, }
@article {pmid38871437, year = {2024}, author = {Fleurence, RL and Kent, S and Adamson, B and Tcheng, J and Balicer, R and Ross, JS and Haynes, K and Muller, P and Campbell, J and Bouée-Benhamiche, E and García Martí, S and Ramsey, S}, title = {Assessing Real-World Data From Electronic Health Records for Health Technology Assessment: The SUITABILITY Checklist: A Good Practices Report of an ISPOR Task Force.}, journal = {Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research}, volume = {27}, number = {6}, pages = {692-701}, pmid = {38871437}, issn = {1524-4733}, support = {Z99 OD999999/ImNIH/Intramural NIH HHS/United States ; }, mesh = {*Electronic Health Records/standards ; *Technology Assessment, Biomedical ; *Checklist ; Humans ; Reproducibility of Results ; Advisory Committees ; Decision Making ; }, abstract = {This ISPOR Good Practices report provides a framework for assessing the suitability of electronic health records data for use in health technology assessments (HTAs). Although electronic health record (EHR) data can fill evidence gaps and improve decisions, several important limitations can affect its validity and relevance. The ISPOR framework includes 2 components: data delineation and data fitness for purpose. Data delineation provides a complete understanding of the data and an assessment of its trustworthiness by describing (1) data characteristics; (2) data provenance; and (3) data governance. Fitness for purpose comprises (1) data reliability items, ie, how accurate and complete the estimates are for answering the question at hand and (2) data relevance items, which assess how well the data are suited to answer the particular question from a decision-making perspective. The report includes a checklist specific to EHR data reporting: the ISPOR SUITABILITY Checklist. It also provides recommendations for HTA agencies and policy makers to improve the use of EHR-derived data over time. The report concludes with a discussion of limitations and future directions in the field, including the potential impact from the substantial and rapid advances in the diffusion and capabilities of large language models and generative artificial intelligence. The report's immediate audiences are HTA evidence developers and users. We anticipate that it will also be useful to other stakeholders, particularly regulators and manufacturers, in the future.}, }
@article {pmid38871054, year = {2024}, author = {Bolon, YT and Atshan, R and Allbee-Johnson, M and Estrada-Merly, N and Auletta, JJ and Broglie, L and Cusatis, R and Page, KM and Phelan, R and Sajulga, R and Shaw, BE and Spahn, A and Steinert, P and Stewart, V and Vierra-Green, C and Lee, SJ and Spellman, SR}, title = {Leveraging Hematopoietic Cell Transplant Data and Biorepository Resources at the Center for International Blood and Marrow Transplant Research to Improve Patient Outcomes.}, journal = {Transplantation and cellular therapy}, volume = {30}, number = {9}, pages = {921.e1-921.e22}, doi = {10.1016/j.jtct.2024.06.010}, pmid = {38871054}, issn = {2666-6367}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation ; Biological Specimen Banks ; Treatment Outcome ; }, abstract = {Hematopoietic cell transplantation (HCT) has undergone many advances over the decades. Trends in HCT utilization have been impacted by research based on the data and samples collected by the Center for International Blood and Marrow Transplant Research (CIBMTR). Here, we provide a summary report of the CIBMTR Biorepository resource and describe the biospecimen inventory along with collection and request procedures. The diversity captured in this inventory reflects transplant activity, and these samples can be leveraged for secondary analyses to generate more data and insights to advance the field. We describe how our resources have already impacted HCT practice and elaborate on possibilities for further collaboration and utilization to maximize capabilities and research opportunities. Hematopoietic cell transplant data and biorepository resources at the CIBMTR have been and continue to be leveraged to improve patient outcomes.}, }
@article {pmid38870441, year = {2024}, author = {Wahid, KA and Sahin, O and Kundu, S and Lin, D and Alanis, A and Tehami, S and Kamel, S and Duke, S and Sherer, MV and Rasmussen, M and Korreman, S and Fuentes, D and Cislo, M and Nelms, BE and Christodouleas, JP and Murphy, JD and Mohamed, ASR and He, R and Naser, MA and Gillespie, EF and Fuller, CD}, title = {Associations Between Radiation Oncologist Demographic Factors and Segmentation Similarity Benchmarks: Insights From a Crowd-Sourced Challenge Using Bayesian Estimation.}, journal = {JCO clinical cancer informatics}, volume = {8}, number = {}, pages = {e2300174}, pmid = {38870441}, issn = {2473-4276}, support = {T32 CA261856/CA/NCI NIH HHS/United States ; P30 CA016672/CA/NCI NIH HHS/United States ; K08 CA252640/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; R01 CA257814/CA/NCI NIH HHS/United States ; R01 DE028290/DE/NIDCR NIH HHS/United States ; R01 DE025248/DE/NIDCR NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R21 DE031082/DE/NIDCR NIH HHS/United States ; R25 EB025787/EB/NIBIB NIH HHS/United States ; }, mesh = {Humans ; *Bayes Theorem ; *Benchmarking/methods ; *Radiation Oncologists ; Female ; Radiotherapy Planning, Computer-Assisted/methods ; Neoplasms/epidemiology/radiotherapy ; Organs at Risk ; Male ; Radiation Oncology/standards/methods ; Demography ; Observer Variation ; }, abstract = {PURPOSE: The quality of radiotherapy auto-segmentation training data, primarily derived from clinician observers, is of utmost importance. However, the factors influencing the quality of clinician-derived segmentations are poorly understood; our study aims to quantify these factors.<br><br>METHODS: Organ at risk (OAR) and tumor-related segmentations provided by radiation oncologists from the Contouring Collaborative for Consensus in Radiation Oncology data set were used. Segmentations were derived from five disease sites: breast, sarcoma, head and neck (H&amp;N), gynecologic (GYN), and GI. Segmentation quality was determined on a structure-by-structure basis by comparing the observer segmentations with an expert-derived consensus, which served as a reference standard benchmark. The Dice similarity coefficient (DSC) was primarily used as a metric for the comparisons. DSC was stratified into binary groups on the basis of structure-specific expert-derived interobserver variability (IOV) cutoffs. Generalized linear mixed-effects models using Bayesian estimation were used to investigate the association between demographic variables and the binarized DSC for each disease site. Variables with a highest density interval excluding zero were considered to substantially affect the outcome measure.<br><br>RESULTS: Five hundred seventy-four, 110, 452, 112, and 48 segmentations were used for the breast, sarcoma, H&amp;N, GYN, and GI cases, respectively. The median percentage of segmentations that crossed the expert DSC IOV cutoff when stratified by structure type was 55% and 31% for OARs and tumors, respectively. Regression analysis revealed that the structure being tumor-related had a substantial negative impact on binarized DSC for the breast, sarcoma, H&amp;N, and GI cases. There were no recurring relationships between segmentation quality and demographic variables across the cases, with most variables demonstrating large standard deviations.<br><br>CONCLUSION: Our study highlights substantial uncertainty surrounding conventionally presumed factors influencing segmentation quality relative to benchmarks.}, }
@article {pmid38869932, year = {2024}, author = {Steinman, L and Chadwick, K and Chavez Santos, E and Sravanam, S and Johnson, SS and Rensema, E and Mayotte, C and Denison, P and Lorig, K}, title = {Remote Evidence-Based Programs for Health Promotion to Support Older Adults During the COVID-19 Pandemic and Beyond: Mixed Methods Outcome Evaluation.}, journal = {JMIR aging}, volume = {7}, number = {}, pages = {e52069}, pmid = {38869932}, issn = {2561-7605}, support = {UL1 TR002319/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Health Promotion/methods ; *COVID-19/epidemiology/prevention &amp; control ; Aged ; Female ; Male ; Telemedicine ; Evidence-Based Practice ; Program Evaluation ; Pandemics ; Outcome Assessment, Health Care ; Aged, 80 and over ; Chronic Disease ; }, abstract = {BACKGROUND: Evidence-based programs (EBPs) for health promotion were developed to reach older adults where they live, work, pray, and play. When the COVID-19 pandemic placed a disproportionate burden on older adults living with chronic conditions and the community-based organizations that support them, these in-person programs shifted to remote delivery. While EBPs have demonstrated effectiveness when delivered in person, less is known about outcomes when delivered remotely.<br><br>OBJECTIVE: This study evaluated changes in remote EBP participants' health and well-being in a national mixed methods outcome evaluation in January 1, 2021, to March 31, 2022.<br><br>METHODS: We used the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) for equity framework to guide the evaluation. We purposively sampled for diverse remote EBP delivery modes and delivery organizations, staff, and traditionally underserved older adults, including people of color and rural dwellers. We included 5 EBPs for self-management, falls prevention, and physical activity: videoconferencing (Chronic Disease Self-Management Program, Diabetes Self-Management Program, and EnhanceFitness), telephone plus mailed materials (Chronic Pain Self-Management Program), and enhanced self-directed mailed materials (Walk With Ease). Participant and provider data included validated surveys, in-depth interviews, and open-ended survey questions. We used descriptive statistics to characterize the sample and the magnitude of change and paired t tests (2-tailed) and the Fisher exact test to test for change in outcomes between enrollment and 6-month follow-up. Thematic analysis was used to identify similarities and differences in outcomes within and across programs. Joint display tables facilitated the integration of quantitative and qualitative findings.<br><br>RESULTS: A total of 586 older adults, 198 providers, and 37 organizations providing EBPs participated in the evaluation. Of the 586 older adults, 289 (49.3%) provided follow-up outcome data. The mean age of the EBP participants was 65.4 (SD 12.0) years. Of the 289 EBP participants, 241 (83.4%) were female, 108 (37.3%) were people of color, 113 (39.1%) lived alone, and 99 (34.3%) were experiencing financial hardship. In addition, the participants reported a mean of 2.5 (SD 1.7) chronic conditions. Overall, the remote EBP participants showed statistically significant improvements in health, energy, sleep quality, loneliness, depressive symptoms, and technology anxiety. Qualitatively, participants shared improvements in knowledge, attitudes, and skills for healthier living; reduced their social isolation and loneliness; and gained better access to programs. Three-fourths of the providers (149/198, 75.2%) felt that effectiveness was maintained when switching from in-person to remote delivery.<br><br>CONCLUSIONS: The findings suggest that participating in remote EBPs can improve health, social, and technological outcomes of interest for older adults and providers, with benefits extending to policy makers. Future policy and practice can better support remote EBP delivery as one model for health promotion, improving access for all older adults.}, }
@article {pmid38869494, year = {2024}, author = {Ni, Z and Kundu, P and McKean, DF and Wheeler, W and Albanes, D and Andreotti, G and Antwi, SO and Arslan, AA and Bamlet, WR and Beane-Freeman, LE and Berndt, SI and Bracci, PM and Brennan, P and Buring, JE and Chanock, SJ and Gallinger, S and Gaziano, JM and Giles, GG and Giovannucci, EL and Goggins, MG and Goodman, PJ and Haiman, CA and Hassan, MM and Holly, EA and Hung, RJ and Katzke, V and Kooperberg, C and Kraft, P and LeMarchand, L and Li, D and McCullough, ML and Milne, RL and Moore, SC and Neale, RE and Oberg, AL and Patel, AV and Peters, U and Rabe, KG and Risch, HA and Shu, XO and Smith-Byrne, K and Visvanathan, K and Wactawski-Wende, J and White, E and Wolpin, BM and Yu, H and Zeleniuch-Jacquotte, A and Zheng, W and Zhong, J and Amundadottir, LT and Stolzenberg-Solomon, RZ and Klein, AP}, title = {Genome-Wide Analysis to Assess if Heavy Alcohol Consumption Modifies the Association between SNPs and Pancreatic Cancer Risk.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {33}, number = {9}, pages = {1229-1239}, doi = {10.1158/1055-9965.EPI-24-0096}, pmid = {38869494}, issn = {1538-7755}, support = {MC_UU_00006/1/MRC_/Medical Research Council/United Kingdom ; R01 CA154823/CA/NCI NIH HHS/United States ; 001/WHO_/World Health Organization/International ; U01 CA247283/CA/NCI NIH HHS/United States ; P50 CA062924/CA/NCI NIH HHS/United States ; U01CA247283//National Cancer Institute (NCI)/ ; }, mesh = {Humans ; *Pancreatic Neoplasms/genetics/epidemiology/etiology ; *Polymorphism, Single Nucleotide ; *Genome-Wide Association Study ; Case-Control Studies ; *Alcohol Drinking/adverse effects/genetics/epidemiology ; Risk Factors ; Genetic Predisposition to Disease ; Male ; Female ; Middle Aged ; }, abstract = {BACKGROUND: Pancreatic cancer is a leading cause of cancer-related death globally. Risk factors for pancreatic cancer include common genetic variants and potentially heavy alcohol consumption. We assessed if genetic variants modify the association between heavy alcohol consumption and pancreatic cancer risk.<br><br>METHODS: We conducted a genome-wide interaction analysis of single-nucleotide polymorphisms (SNP) by heavy alcohol consumption (more than three drinks per day) for pancreatic cancer in European ancestry populations from genome-wide association studies. Our analysis included 3,707 cases and 4,167 controls from case-control studies and 1,098 cases and 1,162 controls from cohort studies. Fixed-effect meta-analyses were conducted.<br><br>RESULTS: A potential novel region of association on 10p11.22, lead SNP rs7898449 (interaction P value (Pinteraction) = 5.1 &#xd7; 10-8 in the meta-analysis; Pinteraction = 2.1 &#xd7; 10-9 in the case-control studies; Pinteraction = 0.91 in the cohort studies), was identified. An SNP correlated with this lead SNP is an expression quantitative trait locus for the neuropilin 1 gene. Of the 17 genomic regions with genome-wide significant evidence of association with pancreatic cancer in prior studies, we observed suggestive evidence that heavy alcohol consumption modified the association for one SNP near LINC00673, rs11655237 on 17q25.1 (Pinteraction = 0.004).<br><br>CONCLUSIONS: We identified a novel genomic region that may be associated with pancreatic cancer risk in conjunction with heavy alcohol consumption located near an expression quantitative trait locus for neuropilin 1, a protein that plays an important role in the development and progression of pancreatic cancer.<br><br>IMPACT: This work can provide insights into the etiology of pancreatic cancer, particularly in heavy drinkers.}, }
@article {pmid38868534, year = {2024}, author = {Smith, MA and Cheng, G and Phelan, R and Brazauskas, R and Strom, J and Ahn, KW and Hamilton, BK and Peterson, A and Savani, B and Schoemans, H and Schoettler, ML and Sorror, M and Keller, RL and Higham, CS and Dvorak, CC and Fineman, JR and Zinter, MS}, title = {Pulmonary hypertension in the intensive care unit after pediatric allogeneic hematopoietic stem cell transplant: incidence, risk factors, and outcomes.}, journal = {Frontiers in oncology}, volume = {14}, number = {}, pages = {1415984}, pmid = {38868534}, issn = {2234-943X}, support = {T32 CA128583/CA/NCI NIH HHS/United States ; }, abstract = {OBJECTIVE: To determine the incidence, risk factors, and outcomes of pulmonary hypertension (PH) in the pediatric intensive care unit (PICU) after pediatric hematopoietic stem cell transplant (HCT).<br><br>METHODS: This was a retrospective study of pediatric patients who underwent allogeneic HCT between January 2008-December 2014 at a center contributing to the Center for International Blood and Marrow Transplant Research data registry. Incidence of PH was assessed from PICU diagnostic codes from records merged from the Virtual Pediatric Systems database. Regression and survival analyses identified factors associated with post-HCT PH. Additional post-HCT morbidities and survival after PH were also assessed.<br><br>RESULTS: Among 6,995 HCT recipients, there were 29 cases of PH, a cumulative incidence of 0.42% (95% CI 0.27%-0.57%) at 60 months post-HCT. In the sub-cohort of 1,067 patients requiring intensive care after HCT, this accounted for a PH prevalence of 2.72% (95% CI 1.74-3.69%). There was an increased risk of developing PH associated with Black/African American race, metabolic disorders, partially HLA-matched or cord blood allografts, graft-versus-host prophylaxis regimen, and lower pre-HCT functional status. Patients who developed PH had significant PICU comorbidities including heart failure, pulmonary hemorrhage, respiratory failure, renal failure, and infections. Survival at 6 months after diagnosis of post-HCT PH was 51.7% (95% CI 32.5%-67.9%).<br><br>CONCLUSIONS: PH is a rare but serious complication in the pediatric post-HCT population. A significant burden of additional comorbidities, procedural interventions, and risk of mortality is associated with its development. Close monitoring and prompt intervention for this severe complication are necessary in this vulnerable population.}, }
@article {pmid38867431, year = {2024}, author = {Tordoff, DM and Restar, A and Minalga, B and Fernandez, A and Dimitrov, D and Duerr, A and , }, title = {Including transgender populations in mathematical models for HIV treatment and prevention: current barriers and policy implications.}, journal = {Journal of the International AIDS Society}, volume = {27}, number = {6}, pages = {e26304}, pmid = {38867431}, issn = {1758-2652}, support = {//University of Washington's School of Public Health/ ; UM1AI068617//National Institutes of Allergy and Infectious Disease/ ; //American Sexually Transmitted Diseases Association/ ; F31AI152542//National Institute of Allergy and Infectious Diseases/ ; UM1 AI068617/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *HIV Infections/prevention &amp; control/transmission/epidemiology/drug therapy ; *Transgender Persons ; *Models, Theoretical ; Male ; *Health Policy ; Female ; United States/epidemiology ; Disease Transmission, Infectious/prevention &amp; control ; }, abstract = {INTRODUCTION: Mathematical models of HIV have been uniquely important in directing and evaluating HIV policy. Transgender and nonbinary people are disproportionately impacted by HIV; however, few mathematical models of HIV transmission have been published that are inclusive of transgender and nonbinary populations. This commentary discusses current structural challenges to developing robust and accurate trans-inclusive models and identifies opportunities for future research and policy, with a focus on examples from the United States.<br><br>DISCUSSION: As of April 2024, only seven published mathematical models of HIV transmission include transgender people. Existing models have several notable limitations and biases that limit their utility for informing public health intervention. Notably, no models include transgender men or nonbinary individuals, despite these populations being disproportionately impacted by HIV relative to cisgender populations. In addition, existing mathematical models of HIV transmission do not accurately represent the sexual network of transgender people. Data availability and quality remain a significant barrier to the development of accurate trans-inclusive mathematical models of HIV. Using a community-engaged approach, we developed a modelling framework that addresses the limitations of existing model and to highlight how data availability and quality limit the utility of mathematical models for transgender populations.<br><br>CONCLUSIONS: Modelling is an important tool for HIV prevention planning and a key step towards informing public health interventions, programming and policies for transgender populations. Our modelling framework underscores the importance of accurate trans-inclusive data collection methodologies, since the relevance of these analyses for informing public health decision-making is strongly dependent on the validity of the model parameterization and calibration targets. Adopting gender-inclusive and gender-specific approaches starting from the development and data collection stages of research can provide insights into how interventions, programming and policies can distinguish unique health needs across all gender groups. Moreover, in light of the data structure limitations, designing longitudinal surveillance data systems and probability samples will be critical to fill key research gaps, highlight progress and provide additional rigour to the current evidence. Investments and initiatives like Ending the HIV Epidemic in the United States can be further expanded and are highly needed to prioritize and value transgender populations across funding structures, goals and outcome measures.}, }
@article {pmid38865671, year = {2024}, author = {Satyal, U and Valentine, H and Liu, D and Slifker, M and Lallas, CD and Trabulsi, EJ and Bukavina, L and Szeto, L and Hoffman-Censits, JH and Mouw, KW and Faltas, BM and Grivas, P and Ibragimova, I and Porten, SP and Van Allen, EM and Geynisman, DM and Parker, DC and O'Neill, JP and Drevik, J and Christianson, SS and Ginzburg, S and Correa, AF and Uzzo, RG and Ross, EA and Zibelman, MR and Ghatalia, P and Plimack, ER and Kutikov, A and Abbosh, PH}, title = {Urine Biopsy as Dynamic Biomarker to Enhance Clinical Staging of Bladder Cancer in Radical Cystectomy Candidates.}, journal = {JCO precision oncology}, volume = {8}, number = {}, pages = {e2300362}, doi = {10.1200/PO.23.00362}, pmid = {38865671}, issn = {2473-4284}, mesh = {Humans ; *Urinary Bladder Neoplasms/pathology/urine/surgery/drug therapy/genetics ; *Cystectomy ; *Neoplasm Staging ; Female ; Male ; Middle Aged ; Aged ; *Biomarkers, Tumor/urine ; Biopsy ; Retrospective Studies ; Neoadjuvant Therapy ; }, abstract = {PURPOSE: There is significant interest in identifying complete responders to neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) to potentially avoid removal of a pathologically benign bladder. However, clinical restaging after NAC is highly inaccurate. The objective of this study was to develop a next-generation sequencing-based molecular assay using urine to enhance clinical staging of patients with bladder cancer.<br><br>METHODS: Urine samples from 20 and 44 patients with bladder cancer undergoing RC were prospectively collected for retrospective analysis for molecular correlate analysis from two clinical trials, respectively. The first cohort was used to benchmark the assay, and the second was used to determine the performance characteristics of the test as it correlates to responder status as measured by pathologic examination.<br><br>RESULTS: First, to benchmark the assay, known mutations identified in the tissue (MT) of patients from the Accelerated Methotrexate, Vinblastine, Doxorubicin, Cisplatin trial (ClinicalTrials.gov identifier: NCT01611662, n = 16) and a cohort from University of California-San Francisco (n = 4) were cross referenced against mutation profiles from urine (MU). We then determined the correlation between MU persistence and residual disease in pre-RC urine samples from a second prospective clinical trial (The pT0 trial; ClinicalTrials.gov identifier: NCT02968732). Residual MU status correlated strongly with residual disease status (pT0 trial; n = 44; P = .0092) when MU from urine supernatant and urine pellet were assessed separately and analyzed in tandem. The sensitivity, specificity, PPV, and NPV were 91%, 50%, 86%, and 63% respectively, with an overall accuracy of 82% for this second cohort.<br><br>CONCLUSION: MU are representative of MT and thus can be used to enhance clinical staging of urothelial carcinoma. Urine biopsy may be used as a reliable tool that can be further developed to identify complete response to NAC in anticipation of safe RC avoidance.}, }
@article {pmid38862012, year = {2024}, author = {Amonoo, HL and Daskalakis, E and Wolfe, ED and Guo, M and Celano, CM and Healy, BC and Cutler, CS and Antin, JH and Pirl, WF and Park, ER and Jim, HSL and Lee, SJ and LeBlanc, TW and El-Jawahri, A and Huffman, JC}, title = {A Positive Psychology Intervention in Allogeneic Hematopoietic Stem Cell Transplantation Survivors (PATH): A Pilot Randomized Clinical Trial.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {2 D}, pages = {}, doi = {10.6004/jnccn.2023.7117}, pmid = {38862012}, issn = {1540-1413}, support = {R01 HL113272/HL/NHLBI NIH HHS/United States ; K08 CA251654/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/psychology/methods/adverse effects ; Female ; Male ; Middle Aged ; Pilot Projects ; Adult ; *Psychology, Positive/methods ; *Quality of Life ; Transplantation, Homologous ; Hematologic Neoplasms/therapy/psychology ; Aged ; Survivors/psychology ; Cancer Survivors/psychology ; }, abstract = {BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) survivors experience significant psychological distress and low levels of positive psychological well-being, which can undermine patient-reported outcomes (PROs), such as quality of life (QoL). Hence, we conducted a pilot randomized clinical trial to assess the feasibility and preliminary efficacy of a telephone-delivered positive psychology intervention (Positive Affect for the Transplantation of Hematopoietic stem cells intervention [PATH]) for improving well-being in HSCT survivors.<br><br>METHODS: HSCT survivors who were 100 days post-HSCT for hematologic malignancy at an academic institution were randomly assigned to either PATH or usual care. PATH, delivered by a behavioral health expert, entailed 9 weekly phone sessions on gratitude, personal strengths, and meaning. We defined feasibility a priori as >60% of eligible participants enrolling in the study and >75% of PATH participants completing &#x2265;6 of 9 sessions. At baseline and 9 and 18 weeks, patients self-reported gratitude, positive affect, life satisfaction, optimism, anxiety, depression, posttraumatic stress disorder (PTSD), QoL, physical function, and fatigue. We used repeated measures regression models and estimates of effect size (Cohen's d) to explore the preliminary effects of PATH on outcomes.<br><br>RESULTS: We enrolled 68.6% (72/105) of eligible patients (mean age, 57 years; 50% female). Of those randomized to PATH, 91% completed all sessions and reported positive psychology exercises as easy to complete and subjectively useful. Compared with usual care, PATH participants reported greater improvements in gratitude (&#x3b2; = 1.38; d = 0.32), anxiety (&#x3b2; = -1.43; d = -0.40), and physical function (&#x3b2; = 2.15; d = 0.23) at 9 weeks and gratitude (&#x3b2; = 0.97; d = 0.22), positive affect (&#x3b2; = 2.02; d = 0.27), life satisfaction (&#x3b2; = 1.82; d = 0.24), optimism (&#x3b2; = 2.70; d = 0.49), anxiety (&#x3b2; = -1.62; d = -0.46), depression (&#x3b2; = -1.04; d = -0.33), PTSD (&#x3b2; = -2.50; d = -0.29), QoL (&#x3b2; = 7.70; d = 0.41), physical function (&#x3b2; = 5.21; d = 0.56), and fatigue (&#x3b2; = -2.54; d = -0.33) at 18 weeks.<br><br>CONCLUSIONS: PATH is feasible, with promising signals for improving psychological well-being, QoL, physical function, and fatigue in HSCT survivors. Future multisite trials that investigate PATH's efficacy are needed to establish its effects on PROs in this population.}, }
@article {pmid38862008, year = {2024}, author = {Benson, AB and Venook, AP and Adam, M and Chang, G and Chen, YJ and Ciombor, KK and Cohen, SA and Cooper, HS and Deming, D and Garrido-Laguna, I and Grem, JL and Haste, P and Hecht, JR and Hoffe, S and Hunt, S and Hussan, H and Johung, KL and Joseph, N and Kirilcuk, N and Krishnamurthi, S and Malla, M and Maratt, JK and Messersmith, WA and Meyerhardt, J and Miller, ED and Mulcahy, MF and Nurkin, S and Overman, MJ and Parikh, A and Patel, H and Pedersen, K and Saltz, L and Schneider, C and Shibata, D and Shogan, B and Skibber, JM and Sofocleous, CT and Tavakkoli, A and Willett, CG and Wu, C and Gurski, LA and Snedeker, J and Jones, F}, title = {Colon Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {2 D}, pages = {}, doi = {10.6004/jnccn.2024.0029}, pmid = {38862008}, issn = {1540-1413}, mesh = {Humans ; *Colonic Neoplasms/diagnosis/therapy/pathology/drug therapy ; Medical Oncology/standards/methods ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; United States ; }, abstract = {Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. Management of disseminated metastatic CRC involves various active drugs, either in combination or as single agents. The choice of therapy is based on consideration of the goals of therapy, the type and timing of prior therapy, the mutational profile of the tumor, and the differing toxicity profiles of the constituent drugs. This manuscript summarizes the data supporting the systemic therapy options recommended for metastatic CRC in the NCCN Guidelines for Colon Cancer.}, }
@article {pmid38861668, year = {2024}, author = {Nicolai, CJ and Parker, MH and Qin, J and Tang, W and Ulrich-Lewis, JT and Gottschalk, RJ and Cooper, SE and Hernandez Lopez, SA and Parrilla, D and Mangio, RS and Ericson, NG and Brandes, AH and Umuhoza, S and Michels, KR and McDonnell, MM and Park, LY and Shin, S and Leung, WH and Scharenberg, AM and Kiem, HP and Larson, RP and Beitz, LO and Ryu, BY}, title = {In vivo CAR T-cell generation in nonhuman primates using lentiviral vectors displaying a multidomain fusion ligand.}, journal = {Blood}, volume = {144}, number = {9}, pages = {977-987}, pmid = {38861668}, issn = {1528-0020}, mesh = {Animals ; *Lentivirus/genetics ; *Genetic Vectors ; *Receptors, Chimeric Antigen/immunology/genetics ; *T-Lymphocytes/immunology/metabolism ; Humans ; *Immunotherapy, Adoptive/methods ; Ligands ; Recombinant Fusion Proteins/genetics/immunology ; Transduction, Genetic ; Antigens, CD20/immunology/genetics ; Lymphocyte Activation ; }, abstract = {Chimeric antigen receptor (CAR) T-cell therapies have demonstrated transformative efficacy in treating B-cell malignancies. However, high costs and manufacturing complexities hinder their widespread use. To overcome these hurdles, we have developed the VivoVec platform, a lentiviral vector capable of generating CAR T cells in vivo. Here, we describe the incorporation of T-cell activation and costimulatory signals onto the surface of VivoVec particles (VVPs) in the form of a multidomain fusion protein and show enhanced in vivo transduction and improved CAR T-cell antitumor functionality. Furthermore, in the absence of lymphodepleting chemotherapy, administration of VVPs into nonhuman primates resulted in the robust generation of anti-CD20 CAR T cells and the complete depletion of B cells for >10 weeks. These data validate the VivoVec platform in a translationally relevant model and support its transition into human clinical testing, offering a paradigm shift in the field of CAR T-cell therapies.}, }
@article {pmid38860025, year = {2024}, author = {Wu, L and Saina, M and Brown, C and Chege, D and Donnell, D and Glidden, DV and Ngure, K and Mugo, NR and Akelo, N and Schaafsma, T and Anderson, PL and Mugwanya, KK}, title = {Establishing adherence-concentration-efficacy thresholds of TDF-FTC pre-exposure prophylaxis for HIV prevention in African women: a protocol for the Women TDF-FTC Benchmark Study.}, journal = {Frontiers in reproductive health}, volume = {6}, number = {}, pages = {1325257}, pmid = {38860025}, issn = {2673-3153}, abstract = {BACKGROUND: Oral pre-exposure prophylaxis (PrEP) using co-formulated emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) is a potent HIV prevention method for men and women, with its efficacy highly dependent on adherence. A pivotal HIV efficacy study combined with a directly observed pharmacological study defined the thresholds for HIV protection in men who have sex with men (MSM), which are the keys to PrEP promotion and development of new PrEP agents. For African women at risk for HIV and belonging to a priority group considered due to disproportionately high incident HIV infections, the variable adherence in PrEP clinical trials and the limited pharmacologic data have resulted in a lack of clarity about the PrEP adherence required for HIV protection. We propose a study to quantify the adherence-concentration-efficacy thresholds of TDF/FTC PrEP among African cisgender women to inform decisions about optimal PrEP dosing and adherence for HIV protection.<br><br>METHODS: We randomized 45 low-risk HIV-uninfected African women, aged 18-30 years old, to directly observe the TDF/FTC PrEP of two, four, or seven doses per week for 8 weeks. A complementary age-matched pregnant women cohort at high risk of HIV, who will receive seven doses per week, was recruited (N&#x2009;=&#x2009;15) with the primary aim of establishing benchmark concentrations in dried blood spots and peripheral blood mononuclear cells. Plasma, whole blood (WB), urine, hair, vaginal fluid, and vaginal tissue (non-pregnant women only) were archived for future testing. Drug concentrations were measured using methods validated for each biological matrix. Pharmacokinetic models were fitted to drug concentrations to quantify concentration-adherence thresholds. To define the drug concentrations associated with HIV protection, we applied the newly defined thresholds from the primary pharmacologic trial to the subset of women randomized to TDF/FTC or TDF in the Partners PrEP Study with the drug concentration assessed in plasma and WB samples. Multiple imputation was used to construct a data set with drug concentrations at each visit when an HIV test was performed for the entire cohort, replicating the work for MSM.<br><br>DISCUSSION: The proposed study generated the first African women-specific TDF-PrEP adherence-concentration-efficacy thresholds essential for guiding the accurate interpretation of TDF/FTC PrEP programs and clinical trials of novel HIV prevention products using TDF/FTC as an active control.<br><br>CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier (NCT05057858).}, }
@article {pmid38858832, year = {2024}, author = {Pineda-Antunez, C and Seguin, C and van Duuren, LA and Knudsen, AB and Davidi, B and Nascimento de Lima, P and Rutter, C and Kuntz, KM and Lansdorp-Vogelaar, I and Collier, N and Ozik, J and Alarid-Escudero, F}, title = {Emulator-Based Bayesian Calibration of the CISNET Colorectal Cancer Models.}, journal = {Medical decision making : an international journal of the Society for Medical Decision Making}, volume = {44}, number = {5}, pages = {543-553}, pmid = {38858832}, issn = {1552-681X}, support = {U01 CA253913/CA/NCI NIH HHS/United States ; DE-AC0206CH11357//US Department of Energy/ ; }, mesh = {*Bayes Theorem ; *Colorectal Neoplasms ; Humans ; *Algorithms ; *Neural Networks, Computer ; Calibration ; Monte Carlo Method ; Computer Simulation ; }, abstract = {PURPOSE: To calibrate Cancer Intervention and Surveillance Modeling Network (CISNET)'s SimCRC, MISCAN-Colon, and CRC-SPIN simulation models of the natural history colorectal cancer (CRC) with an emulator-based Bayesian algorithm and internally validate the model-predicted outcomes to calibration targets.<br><br>METHODS: We used Latin hypercube sampling to sample up to 50,000 parameter sets for each CISNET-CRC model and generated the corresponding outputs. We trained multilayer perceptron artificial neural networks (ANNs) as emulators using the input and output samples for each CISNET-CRC model. We selected ANN structures with corresponding hyperparameters (i.e., number of hidden layers, nodes, activation functions, epochs, and optimizer) that minimize the predicted mean square error on the validation sample. We implemented the ANN emulators in a probabilistic programming language and calibrated the input parameters with Hamiltonian Monte Carlo-based algorithms to obtain the joint posterior distributions of the CISNET-CRC models' parameters. We internally validated each calibrated emulator by comparing the model-predicted posterior outputs against the calibration targets.<br><br>RESULTS: The optimal ANN for SimCRC had 4 hidden layers and 360 hidden nodes, MISCAN-Colon had 4 hidden layers and 114 hidden nodes, and CRC-SPIN had 1 hidden layer and 140 hidden nodes. The total time for training and calibrating the emulators was 7.3, 4.0, and 0.66&#x2009;h for SimCRC, MISCAN-Colon, and CRC-SPIN, respectively. The mean of the model-predicted outputs fell within the 95% confidence intervals of the calibration targets in 98 of 110 for SimCRC, 65 of 93 for MISCAN, and 31 of 41 targets for CRC-SPIN.<br><br>CONCLUSIONS: Using ANN emulators is a practical solution to reduce the computational burden and complexity for Bayesian calibration of individual-level simulation models used for policy analysis, such as the CISNET CRC models. In this work, we present a step-by-step guide to constructing emulators for calibrating 3 realistic CRC individual-level models using a Bayesian approach.<br><br>HIGHLIGHTS: We use artificial neural networks (ANNs) to build emulators that surrogate complex individual-based models to reduce the computational burden in the Bayesian calibration process.ANNs showed good performance in emulating the CISNET-CRC microsimulation models, despite having many input parameters and outputs.Using ANN emulators is a practical solution to reduce the computational burden and complexity for Bayesian calibration of individual-level simulation models used for policy analysis.This work aims to support health decision scientists who want to quantify the uncertainty of calibrated parameters of computationally intensive simulation models under a Bayesian framework.}, }
@article {pmid38856693, year = {2024}, author = {Sarchi, M and Clough, CA and Crosse, EI and Kim, J and Baquero Galvis, LD and Aydinyan, N and Wellington, R and Yang, F and Gallì, A and Creamer, JP and Stewart, S and Bradley, RK and Malcovati, L and Doulatov, S}, title = {Mis-splicing of Mitotic Regulators Sensitizes SF3B1-Mutated Human HSCs to CHK1 Inhibition.}, journal = {Blood cancer discovery}, volume = {5}, number = {5}, pages = {353-370}, pmid = {38856693}, issn = {2643-3249}, support = {RC2 DK127989/DK/NIDDK NIH HHS/United States ; R01 HL169156/HL/NHLBI NIH HHS/United States ; DP2 HL147126/HL/NHLBI NIH HHS/United States ; 20125//Associazione Italiana per la Ricerca sul Cancro/ ; P30CA015704//National Cancer Institute (NCI)/ ; R01 HL128239/HL/NHLBI NIH HHS/United States ; R01HL128239//National Heart, Lung, and Blood Institute (NHLBI)/ ; R01 CA251138/CA/NCI NIH HHS/United States ; DP2HL147126//Common Fund (NIH Common Fund)/ ; R01CA251138//National Cancer Institute (NCI)/ ; //Mark Foundation For Cancer Research (The Mark Foundation for Cancer Research)/ ; C355/A26819//Cancer Research UK (CRUK)/ ; 28390//AIRC Postdoctoral Fellowship/ ; Scholar Award 1391-24//Leukemia and Lymphoma Society (LLS)/ ; P30 CA015704/CA/NCI NIH HHS/United States ; Discovery Research Grant//Edward P. Evans Foundation/ ; R01HL151651//National Heart, Lung, and Blood Institute (NHLBI)/ ; Discovery Grant//Kuni Foundation/ ; //Damon Runyon Cancer Research Foundation (DRCRF)/ ; RC2DK127989//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)/ ; R01 HL151651/HL/NHLBI NIH HHS/United States ; Blood Cancer Discoveries Grant//Leukemia and Lymphoma Society (LLS)/ ; R01HL169156//National Heart, Lung, and Blood Institute (NHLBI)/ ; }, mesh = {Humans ; *Checkpoint Kinase 1/genetics/metabolism/antagonists &amp; inhibitors ; *RNA Splicing Factors/genetics/metabolism ; *Mutation ; *Hematopoietic Stem Cells/drug effects/metabolism ; *Mitosis/drug effects/genetics ; Phosphoproteins/genetics/metabolism ; Mice ; Animals ; Protein Kinase Inhibitors/pharmacology ; }, abstract = {Splicing factor SF3B1 mutations are frequent somatic lesions in myeloid neoplasms that transform hematopoietic stem cells (HSCs) by inducing mis-splicing of target genes. However, the molecular and functional consequences of SF3B1 mutations in human HSCs and progenitors (HSPCs) remain unclear. Here, we identify the mis-splicing program in human HSPCs as a targetable vulnerability by precise gene editing of SF3B1 K700E mutations in primary CD34+ cells. Mutant SF3B1 induced pervasive mis-splicing and reduced expression of genes regulating mitosis and genome maintenance leading to altered differentiation, delayed G2/M progression, and profound sensitivity to CHK1 inhibition (CHK1i). Mis-splicing or reduced expression of mitotic regulators BUBR1 and CDC27 delayed G2/M transit and promoted CHK1i sensitivity. Clinical CHK1i prexasertib selectively targeted SF3B1-mutant immunophenotypic HSCs and abrogated engraftment in vivo. These findings identify mis-splicing of mitotic regulators in SF3B1-mutant HSPCs as a targetable vulnerability engaged by pharmacological CHK1 inhibition. Significance: In this study, we engineer precise SF3B1 mutations in human HSPCs and identify CHK1 inhibition as a selective vulnerability promoted by mis-splicing of mitotic regulators. These findings uncover the mis-splicing program induced by mutant SF3B1 in human HSPCs and show that it can be therapeutically targeted by clinical CHK1 inhibitors.}, }
@article {pmid38855456, year = {2024}, author = {Barnett, DJ and Sundermeir, SM and Reznar, MM and Lightner, A and Poirier, L and Rosenblum, AJ and Oladimeji, AT and Igusa, T and Neff, R and Ruggiero, CF and Lewis, EC and Jager, L and Moses, L and Velez-Burgess, V and Gagnon, B and Attar, N and Gittelsohn, J}, title = {Protocol for the Support Application for Food PAntrieS trial: design, implementation, and evaluation plan for a digital application to promote healthy food access and support food pantry operations.}, journal = {Frontiers in public health}, volume = {12}, number = {}, pages = {1340707}, pmid = {38855456}, issn = {2296-2565}, support = {R34 HL161566/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Food Assistance ; *Mobile Applications ; *COVID-19/prevention &amp; control ; Baltimore ; Food Supply ; Food Insecurity ; Food Security ; SARS-CoV-2 ; Diet, Healthy ; }, abstract = {INTRODUCTION: Food-insecure households commonly rely on food pantries to supplement their nutritional needs, a challenge that was underscored during the COVID-19 pandemic. Food pantries, and the food banks that supply them, face common challenges in meeting variable client volume and dietary needs under normal and emergency (e.g., pandemic, natural disaster) conditions. A scalable digital strategy that has the capacity to streamline the emergency food distribution system, while promoting healthy food options, managing volunteer recruitment and training, and connecting to emergency management systems in times of need, is urgently required. To address this gap, we are developing a working mobile application (app) called the Support Application for Food PAntrieS (SAFPAS) and will evaluate its feasibility and impact on food pantry staff preparedness, stocking, and client uptake of healthful foods and beverages in two urban United States settings.<br><br>METHODS: This paper describes the protocol for a randomized controlled trial of the SAFPAS mobile application. We will conduct formative research in Baltimore, Maryland and Detroit, Michigan to develop and refine the SAFPAS app and increase scalability potential to other urban settings. Then we will test the app in 20 food pantries in Baltimore randomized to intervention or comparison. The impact of the app will be evaluated at several levels of the emergency food system, including food pantry clients (n&#x2009;=&#x2009;360), food pantry staff and volunteers (n&#x2009;=&#x2009;100), food pantry stock, and city agencies such as the local food bank and Office of Emergency Management. The primary outcome of the SAFPAS trial is to improve the healthfulness of the foods received by food pantry clients, measured using the Food Assessment Scoring Tool (FAST). Post-trial, we will conduct additional formative research in Detroit to prepare the app for scale-up.<br><br>DISCUSSION: We anticipate that SAFPAS will improve alignment in the supply and demand for healthy foods among food pantry clients, food pantries, and city agencies which supply food in Baltimore. Real-time, bidirectional communication between entities across the system allows for increased situational awareness at all levels during normal and emergency operations. By conducting formative research in Detroit, we hope to increase the scalability of the SAFPAS app to additional settings nationwide.<br><br>CLINICAL TRIAL REGISTRATION: NCT87654321. https://classic.clinicaltrials.gov/ct2/show/NCT05880004.}, }
@article {pmid38854397, year = {2024}, author = {Kelly, SP and McEwen, LM and Isaksson, M and Murphy, S and White, S and Levy, ME and McCrone, JT and Levan, G and Santhanam, S and Baniecki, ML and Bramson, C and Rubino, H and Hendrick, V and Soares, H and Hammond, J and Luo, S}, title = {Viral SARS-CoV-2 Rebound Rates in Linked Commercial Pharmacy-Based Testing and Health Care Claims.}, journal = {Open forum infectious diseases}, volume = {11}, number = {6}, pages = {ofae243}, pmid = {38854397}, issn = {2328-8957}, abstract = {BACKGROUND: Viral SARS-CoV-2 rebound (viral RNA rebound) is challenging to characterize in large cohorts due to the logistics of collecting frequent and regular diagnostic test results. Pharmacy-based testing data provide an opportunity to study the phenomenon in a large population, also enabling subgroup analyses. The current real-world evidence approach complements approaches focused on smaller, prospective study designs.<br><br>METHODS: We linked real-time reverse transcription quantitative polymerase chain reaction test data from national pharmacy-based testing to health care claims data via tokenization to calculate the cumulative incidence of viral RNA rebound within 28 days following positive test results in nirmatrelvir/ritonavir (NMV-r)-treated and untreated individuals during the Omicron era (December 2021-November 2022) and prior to the Omicron era (October 2020-November 2021).<br><br>RESULTS: Among 30 646 patients, the rate of viral RNA rebound was 3.5% (95% CI, 2.0%-5.7%) in NMV-r-treated infections as compared with 1.5% (95% CI, 1.3%-1.7%) in untreated infections during the Omicron era and 1.9% (95% CI, 1.7%-2.1%) prior to the Omicron era. Viral RNA rebound in patients who were vaccinated (n = 8151), high risk (n = 4411), or older (&#x2265;65 years, n = 4411) occurred at comparable rates to the overall cohort (range, 1.1%-4.8%). Viral rebounds to high RNA levels in NMV-r-treated infections occurred in 8% of viral rebounds as compared with 5% to 11% in untreated infections. Rates of hospitalization were comparable between patients with NMV-r-treated infections with viral RNA rebound (0%) and untreated patients with viral RNA rebound (0%-1.2%).<br><br>CONCLUSIONS: Our findings suggest viral RNA rebound is rare (< 5%), with rates that were consistent with those from the EPIC-HR trial (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients). Most occurrences of viral RNA rebound were associated with low viral RNA levels, and viral RNA rebound progression to severe disease was not observed.}, }
@article {pmid38854109, year = {2024}, author = {Parrish, AG and Arora, S and Thirimanne, HN and Rudoy, D and Schmid, S and Sievers, P and Sahm, F and Holland, EC and Szulzewsky, F}, title = {Aggressive high-grade NF2 mutant meningiomas downregulate oncogenic YAP signaling via the upregulation of VGLL4 and FAT3/4.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38854109}, issn = {2692-8205}, support = {R35 CA253119/CA/NCI NIH HHS/United States ; U54 CA243125/CA/NCI NIH HHS/United States ; }, abstract = {Meningiomas are the most common primary brain tumors in adults. Although generally benign, a subset of meningiomas is of higher grade, shows aggressive growth behavior and recurs even after multiple surgeries. Around half of all meningiomas harbor inactivating mutations in NF2. While benign low-grade NF2 mutant meningiomas exhibit few genetic events in addition to NF2 inactivation, aggressive high-grade NF2 mutant meningiomas frequently harbor a highly aberrant genome. We and others have previously shown that NF2 inactivation leads to YAP1 activation and that YAP1 acts as the pivotal oncogenic driver in benign NF2 mutant meningiomas. Using bulk and single-cell RNA-Seq data from a large cohort of human meningiomas, we show that aggressive NF2 mutant meningiomas harbor decreased levels YAP1 activity compared to their benign counterparts. Decreased expression levels of YAP target genes are significantly associated with an increased risk of recurrence. We then identify the increased expression of the YAP1 competitor VGLL4 as well as the YAP1 upstream regulators FAT3/4 as a potential mechanism for the downregulation of YAP activity in aggressive NF2 mutant meningiomas. High expression of these genes is significantly associated with an increased risk of recurrence. In vitro, overexpression of VGLL4 resulted in the downregulation of YAP activity in benign NF2 mutant meningioma cells, confirming the direct link between VGLL4 expression and decreased levels of YAP activity observed in aggressive NF2 mutant meningiomas. Our results shed new insight on the biology of benign and aggressive NF2 mutant meningiomas and may have important implications for the efficacy of therapies targeting oncogenic YAP1 activity in NF2 mutant meningiomas.}, }
@article {pmid38853970, year = {2024}, author = {Yeung, CC and Eacker, SM and Sala-Torra, O and Beppu, L and Woolston, DW and Liachko, I and Malig, M and Stirewalt, D and Fang, M and Radich, J}, title = {Evaluation of Acute Myeloid Leukemia Genomes using Genomic Proximity Mapping.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {38853970}, support = {R01 CA175008/CA/NCI NIH HHS/United States ; R44 CA278140/CA/NCI NIH HHS/United States ; UG1 CA233338/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Cytogenetic analysis encompasses a suite of standard-of-care diagnostic testing methods that is routinely applied in cases of acute myeloid leukemia (AML) to assess chromosomal changes that are clinically relevant for risk classification and treatment decisions.<br><br>OBJECTIVE: In this study, we assess the use of Genomic Proximity Mapping (GPM) for cytogenomic analysis of AML diagnostic specimens for detection of cytogenetic risk variants included in the European Leukemia Network (ELN) risk stratification guidelines.<br><br>METHODS: Archival patient samples (N=48) from the Fred Hutchinson Cancer Center leukemia bank with historical clinical cytogenetic data were processed for GPM and analyzed with the CytoTerra[&#xae;] cloud-based analysis platform.<br><br>RESULTS: GPM showed 100% concordance for all specific variants that have associated impacts on risk stratification as defined by ELN 2022 criteria, and a 72% concordance rate when considering all variants reported by the FH cytogenetic lab. GPM identified 39 additional variants, including variants of known clinical impact, not observed by cytogenetics.<br><br>CONCLUSIONS: GPM is an effective solution for the evaluation of known AML-associated risk variants and a source for biomarker discovery.}, }
@article {pmid38853160, year = {2024}, author = {Park, C and Azhideh, A and Pooyan, A and Alipour, E and Haseli, S and Satwah, I and Chalian, M}, title = {Diagnostic performance and inter-reader reliability of bone reporting and data system (Bone-RADS) on computed tomography.}, journal = {Skeletal radiology}, volume = {}, number = {}, pages = {}, pmid = {38853160}, issn = {1432-2161}, support = {HI19C1085//Korea Health Industry Development Institute/Republic of Korea ; }, abstract = {OBJECTIVE: To evaluate the diagnostic performance and inter-reader reliability of the Bone Reporting and Data System (Bone-RADS) for solitary bone lesions on CT.<br><br>MATERIALS AND METHODS: This retrospective analysis included 179 patients (mean age, 56&#x2009;&#xb1;&#x2009;18&#xa0;years; 94 men) who underwent bone biopsies between March 2005 and September 2021. Patients with solitary bone lesions on CT and sufficient histopathology results were included. Two radiologists categorized the bone lesions using the Bone-RADS (1, benign; 4, malignant). The diagnostic performance of the Bone-RADS was calculated using histopathology results as a standard reference. Inter-reader reliability was calculated.<br><br>RESULTS: Bone lesions were categorized into two groups: 103 lucent (pathology: 34 benign, 12 intermediate, 54 malignant, and 3 osteomyelitis) and 76 sclerotic/mixed (pathology: 46 benign, 2 intermediate, 26 malignant, and 2 osteomyelitis) lesions. The Bone-RADS for lucent lesions had sensitivities of 95% and 82%, specificities of 11% and 11%, and accuracies of 57% and 50% for readers 1 and 2, respectively. The Bone-RADS for sclerotic/mixed lesions had sensitivities of 75% and 68%, specificities of 27% and 27%, and accuracies of 45% and 42% for readers 1 and 2, respectively. Inter-reader reliability was moderate to very good (&#x3ba;&#x2009;=&#x2009;0.744, overall; 0.565, lucent lesions; and 0.851, sclerotic/mixed lesions).<br><br>CONCLUSION: Bone-RADS has a high sensitivity for evaluating malignancy in lucent bone lesions and good inter-reader reliability. However, it has poor specificity and accuracy for both lucent and sclerotic/mixed lesions. A possible explanation is that proposed algorithms heavily depend on clinical features such as pain and history of malignancy.}, }
@article {pmid38848737, year = {2024}, author = {Duerr, A and Beyrer, C}, title = {Reducing HIV transmission in British Columbia, Canada.}, journal = {The lancet. HIV}, volume = {11}, number = {7}, pages = {e430-e431}, doi = {10.1016/S2352-3018(24)00117-6}, pmid = {38848737}, issn = {2352-3018}, mesh = {Humans ; British Columbia/epidemiology ; *HIV Infections/prevention &amp; control/transmission/epidemiology ; }, }
@article {pmid38847854, year = {2024}, author = {Hyrien, O and Yanev, NM}, title = {A branching stochastic evolutionary model of the B-cell repertoire.}, journal = {Journal of mathematical biology}, volume = {89}, number = {1}, pages = {10}, pmid = {38847854}, issn = {1432-1416}, support = {AI12951/GF/NIH HHS/United States ; OPP1151646//Bill and Melinda Gates Foundation/ ; }, mesh = {*B-Lymphocytes/immunology ; *Stochastic Processes ; Humans ; *Models, Immunological ; *Germinal Center/immunology/cytology ; Animals ; Somatic Hypermutation, Immunoglobulin/genetics ; Mathematical Concepts ; Receptors, Antigen, B-Cell/genetics/immunology ; }, abstract = {We propose a stochastic framework to describe the evolution of the B-cell repertoire during germinal center (GC) reactions. Our model is formulated as a multitype age-dependent branching process with time-varying immigration. The immigration process captures the mechanism by which founder B cells initiate clones by gradually seeding GC over time, while the branching process describes the temporal evolution of the composition of these clones. The model assigns a type to each cell to represent attributes of interest. Examples of attributes include the binding affinity class of the B cells, their clonal family, or the nucleotide sequence of the heavy and light chains of their receptors. The process is generally non-Markovian. We present its properties, including as t → ∞ when the process is supercritical, the most relevant case to study expansion of GC B cells. We introduce temporal alpha and beta diversity indices for multitype branching processes. We focus on the dynamics of clonal dominance, highlighting its non-stationarity, and the accumulation of somatic hypermutations in the context of sequential immunization. We evaluate the impact of the ongoing seeding of GC by founder B cells on the dynamics of the B-cell repertoire, and quantify the effect of precursor frequency and antigen availability on the timing of GC entry. An application of the model illustrates how it may help with interpretation of BCR sequencing data.}, }
@article {pmid38846336, year = {2024}, author = {Stone, D and Wang, X and Abou-El-Enein, M}, title = {Biomanufacturing in gene and cell therapy.}, journal = {Molecular therapy. Methods &amp; clinical development}, volume = {32}, number = {2}, pages = {101261}, pmid = {38846336}, issn = {2329-0501}, }
@article {pmid38845464, year = {2024}, author = {Heffner, JL and Serfozo, E and Baker, K and Gasser, M and Watson, N and Daughters, SB and Becoňa, E and McClure, JB}, title = {Behavioral Activation mHealth Application for Smoking Cessation: A Randomized Controlled Pilot Trial.}, journal = {Nicotine &amp; tobacco research : official journal of the Society for Research on Nicotine and Tobacco}, volume = {}, number = {}, pages = {}, doi = {10.1093/ntr/ntae137}, pmid = {38845464}, issn = {1469-994X}, abstract = {BACKGROUND: Behavioral activation (BA) is an effective intervention for both depression and substance use disorders. Combining BA with a standard smoking cessation intervention may improve quit rates by addressing depressive symptoms, a key barrier to quitting. This study preliminarily evaluated the acceptability and efficacy of the BA-based Actify! mobile health application (mHealth app) for smoking cessation.<br><br>METHODS: We conducted a pilot randomized controlled trial (n=242) comparing Actify! with the National Cancer Institute's (NCI) app for smoking cessation (QuitGuide) on acceptability (user satisfaction, app openings), smoking abstinence, and mechanisms of change (behavioral activation and depressive symptoms) at 8 weeks and 6 months post-randomization. Participants were US adults recruited online who smoked daily.<br><br>RESULTS: Treatment satisfaction was uniformly higher in the Actify! arm. Number of app openings was similar across arms (M=34.3 openings over 8 weeks in both arms). Self-reported 30-day point prevalence abstinence (PPA) at 8 weeks was 12.6% for Actify! vs. 7.3% for QuitGuide. Differences in 30-day PPA continued through 6 months (18.5% for Actify! vs. 12.2% for QuitGuide). Changes between baseline and 8 weeks in depressive symptoms and behavioral activation favored Actify!. Planned subgroup analyses suggested greater benefit of Actify! among participants with pre-treatment mild to moderate depression symptom severity compared to those with no depression symptoms.<br><br>CONCLUSIONS: Actify! showed considerable promise as a novel mHealth treatment, as evidenced by high usage and higher user satisfaction and quit rates than QuitGuide at both short- and long-term follow-up. The next step is to evaluate Actify! in a fully-powered efficacy trial.<br><br>IMPLICATIONS: Study findings demonstrate the promise of a behavioral activation (BA)-based mobile health app (Actify!) for smoking cessation as a population-level intervention that can effectively address depressive symptoms as a risk factor for worse smoking treatment outcomes. The Actify! app is the first standalone BA-based app to demonstrate potential for improved acceptability and efficacy relative to a standard care comparison app, with user satisfaction and smoking quit rates descriptively exceeding those of the National Cancer Institute's QuitGuide app.}, }
@article {pmid38845072, year = {2024}, author = {Nascimento de Lima, P and van den Puttelaar, R and Knudsen, AB and Hahn, AI and Kuntz, KM and Ozik, J and Collier, N and Alarid-Escudero, F and Zauber, AG and Inadomi, JM and Lansdorp-Vogelaar, I and Rutter, CM}, title = {Characteristics of a cost-effective blood test for colorectal cancer screening.}, journal = {Journal of the National Cancer Institute}, volume = {116}, number = {10}, pages = {1612-1620}, pmid = {38845072}, issn = {1460-2105}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; U01 CA253913/CA/NCI NIH HHS/United States ; U01-CA253913/CA/NCI NIH HHS/United States ; //Cancer Intervention and Surveillance Modeling Network/ ; /NH/NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Colorectal Neoplasms/diagnosis ; *Cost-Benefit Analysis ; *Early Detection of Cancer/economics/methods ; Middle Aged ; *Occult Blood ; United States ; *Quality-Adjusted Life Years ; *Colonoscopy/economics ; Female ; Male ; Biomarkers, Tumor/blood/analysis ; Sensitivity and Specificity ; Hematologic Tests/economics ; Mass Screening/economics/methods ; Adenoma/diagnosis ; Aged ; }, abstract = {BACKGROUND: Blood-based biomarker tests can potentially change the landscape of colorectal cancer (CRC) screening. We characterize the conditions under which blood test screening would be as effective and cost-effective as annual fecal immunochemical testing or decennial colonoscopy.<br><br>METHODS: We used the 3 Cancer Information and Surveillance Modeling Network-Colon models to compare scenarios of no screening, annual fecal immunochemical testing, decennial colonoscopy, and a blood test meeting Centers for Medicare &amp; Medicaid (CMS) coverage criteria (74% CRC sensitivity and 90% specificity). We varied the sensitivity to detect CRC (74%-92%), advanced adenomas (10%-50%), screening interval (1-3&#x2009;years), and test cost ($25-$500). Primary outcomes included quality-adjusted life-years (QALY) gained from screening and costs for a US average-risk cohort of individuals aged 45 years.<br><br>RESULTS: Annual fecal immunochemical testing yielded 125-163 QALY gained per 1000 at a cost of $3811-$5384 per person, whereas colonoscopy yielded 132-177 QALY gained at a cost of $5375-$7031 per person. A blood test with 92% CRC sensitivity and 50% advanced adenoma sensitivity yielded 117-162 QALY gained if used every 3 years and 133-173 QALY gained if used every year but would not be cost-effective if priced above $125 per test. If used every 3 years, a $500 blood test only meeting CMS coverage criteria yielded 83-116 QALY gained at a cost of $8559-$9413 per person.<br><br>CONCLUSION: Blood tests that only meet CMS coverage requirements should not be recommended to patients who would otherwise undergo screening by colonoscopy or fecal immunochemical testing because of lower benefit. Blood tests need higher advanced adenoma sensitivity (above 40%) and lower costs (below $125) to be cost-effective.}, }
@article {pmid38843488, year = {2024}, author = {Camidge, DR and Bar, J and Horinouchi, H and Goldman, J and Moiseenko, F and Filippova, E and Cicin, I and Ciuleanu, T and Daaboul, N and Liu, C and Bradbury, P and Moskovitz, M and Katgi, N and Tomasini, P and Zer, A and Girard, N and Cuppens, K and Han, JY and Wu, SY and Baijal, S and Mansfield, AS and Kuo, CH and Nishino, K and Lee, SH and Planchard, D and Baik, C and Li, M and Ansell, P and Xia, S and Bolotin, E and Looman, J and Ratajczak, C and Lu, S}, title = {Telisotuzumab Vedotin Monotherapy in Patients With Previously Treated c-Met Protein-Overexpressing Advanced Nonsquamous EGFR-Wildtype Non-Small Cell Lung Cancer in the Phase II LUMINOSITY Trial.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {42}, number = {25}, pages = {3000-3011}, pmid = {38843488}, issn = {1527-7755}, mesh = {Humans ; *Proto-Oncogene Proteins c-met/genetics/metabolism ; *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics/pathology ; Female ; Male ; *Lung Neoplasms/drug therapy/genetics/pathology ; Aged ; Middle Aged ; *ErbB Receptors/genetics ; *Immunoconjugates/therapeutic use/adverse effects ; Adult ; Aged, 80 and over ; Antibodies, Monoclonal/therapeutic use ; Oligopeptides/therapeutic use ; }, abstract = {PURPOSE: Telisotuzumab vedotin (Teliso-V) is a c-Met-directed antibody-drug conjugate with a monomethyl auristatin E cytotoxic payload. The phase II LUMINOSITY trial (ClinicalTrials.gov identifier: NCT03539536) aimed to identify the optimal c-Met protein-overexpressing non-small cell lung cancer (NSCLC) population for treatment with Teliso-V (stage I) and expand the selected group for efficacy evaluation (stage II). Stage II enrolled patients with nonsquamous epidermal growth factor receptor (EGFR)-wildtype NSCLC.<br><br>METHODS: Eligible patients had locally advanced/metastatic c-Met protein-overexpressing NSCLC and &#x2264;2 previous lines of therapy (including &#x2264;1 line of systemic chemotherapy). c-Met protein overexpression in nonsquamous EGFR-wildtype NSCLC was defined as &#x2265;25% tumor cells with 3+ staining (high [&#x2265;50% 3+]; intermediate [&#x2265;25%-<50%]). Teliso-V was administered at 1.9 mg/kg once every 2 weeks. The primary end point was overall response rate (ORR) by independent central review.<br><br>RESULTS: In total, 172 patients with nonsquamous EGFR-wildtype NSCLC received Teliso-V in stages I and II. ORR was 28.6% (95% CI, 21.7 to 36.2; c-Met high, 34.6% [95% CI, 24.2 to 46.2]; c-Met intermediate, 22.9% [95% CI, 14.4 to 33.4]). The median duration of response was 8.3 months (95% CI, 5.6 to 11.3; c-Met high, 9.0 [95% CI, 4.2 to 13.0]; c-Met intermediate: 7.2 [95% CI, 5.3 to 11.5]). The median overall survival was 14.5 months (95% CI, 9.9 to 16.6; c-Met high, 14.6 [95% CI, 9.2 to 25.6]; c-Met intermediate, 14.2 [95% CI, 9.6 to 16.6]). The median progression-free survival was 5.7 months (95% CI, 4.6 to 6.9; c-Met high, 5.5 [95% CI, 4.1 to 8.3]; c-Met intermediate: 6.0 [95% CI, 4.5 to 8.1]). Most common any-grade treatment-related adverse events (AEs) were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%); the most common grade &#x2265;3 AE was peripheral sensory neuropathy (7%).<br><br>CONCLUSION: Teliso-V was associated with durable responses in c-Met protein-overexpressing nonsquamous EGFR-wildtype NSCLC, especially in those with high c-Met. AEs were generally manageable.}, }
@article {pmid38843380, year = {2024}, author = {Li, C and Anderson, AK and Ruminski, P and Rettig, M and Karpova, D and Kiem, HP and DiPersio, JF and Lieber, A}, title = {A simplified G-CSF-free procedure allows for in vivo HSC gene therapy of sickle cell disease in a mouse model.}, journal = {Blood advances}, volume = {8}, number = {15}, pages = {4089-4101}, pmid = {38843380}, issn = {2473-9537}, support = {R01 HL141781/HL/NHLBI NIH HHS/United States ; R35 CA210084/CA/NCI NIH HHS/United States ; R50 CA211466/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Anemia, Sickle Cell/therapy/genetics ; Benzylamines ; Cyclams/pharmacology/therapeutic use ; Disease Models, Animal ; Gene Editing ; *Genetic Therapy/methods ; *Granulocyte Colony-Stimulating Factor/pharmacology ; *Hematopoietic Stem Cell Mobilization/methods ; Hematopoietic Stem Cell Transplantation/methods ; Hematopoietic Stem Cells/metabolism ; Heterocyclic Compounds/pharmacology/therapeutic use ; }, abstract = {We have reported the direct repair of the sickle cell mutation in vivo in a disease model using vectorized prime editors after hematopoietic stem cell (HSC) mobilization with granulocyte colony-stimulating factor (G-CSF)/AMD3100. The use of G-CSF for HSC mobilization is a hurdle for the clinical translation of this approach. Here, we tested a G-CSF-free mobilization regimen using WU-106, an inhibitor of integrin α4β1, plus AMD3100 for in vivo HSC prime editing in sickle cell disease (SCD) mice. Mobilization with WU-106 + AMD3100 in SCD mice was rapid and efficient. In contrast to the G-CSF/AMD3100 approach, mobilization of activated granulocytes and elevation of the key proinflammatory cytokine interleukin-6 in the serum were minimal. The combination of WU-106 + AMD3100 mobilization and IV injection of the prime editing vector together with in vivo selection resulted in ∼23% correction of the SCD mutation in the bone marrow and peripheral blood cells of SCD mice. The treated mice demonstrated phenotypic correction, as reflected by normalized blood parameters and spleen size. Editing frequencies were significantly increased (29%) in secondary recipients, indicating the preferential mobilization/transduction of long-term repopulating HSCs. Using this approach, we found <1% undesired insertions/deletions and no detectable off-target editing at the top-scored potential sites. Our study shows that in vivo transduction to treat SCD can now be done within 2 hours involving only simple IV injections with a good safety profile. The same-day mobilization regimen makes in vivo HSC gene therapy more attractive for resource-poor settings, where SCD does the most damage.}, }
@article {pmid38843256, year = {2024}, author = {Pullarkat, S and Black, G and Bleakley, M and Buenrostro, D and Chapuis, AG and Hirayama, AV and Jaeger-Ruckstuhl, CA and Kimble, EL and Lee, BM and Maloney, DG and Radich, J and Seaton, BW and Specht, JM and Turtle, CJ and Woolston, DW and Wright, JH and Yeung, CCS}, title = {qPCR assay for detection of Woodchuck Hepatitis Virus Post-Transcriptional Regulatory Elements from CAR-T and TCR-T cells in fresh and formalin-fixed tissue.}, journal = {PloS one}, volume = {19}, number = {6}, pages = {e0303057}, pmid = {38843256}, issn = {1932-6203}, mesh = {Humans ; *Formaldehyde ; *Hepatitis B Virus, Woodchuck/genetics ; *Receptors, Antigen, T-Cell/genetics/metabolism/immunology ; Receptors, Chimeric Antigen/genetics/metabolism/immunology ; T-Lymphocytes/immunology/metabolism ; Tissue Fixation/methods ; Immunotherapy, Adoptive/methods ; Real-Time Polymerase Chain Reaction/methods ; }, abstract = {As adoptive cellular therapies become more commonplace in cancer care, there is a growing need to monitor site-specific localization of engineered cells-such as chimeric antigen receptor T (CAR-T) cells and T-cell receptor T (TCR-T) cells-in patients' tissues to understand treatment effectiveness as well as associated adverse events. Manufacturing CAR-T and TCR-T cells involves transduction with viral vectors commonly containing the WPRE gene sequence to enhance gene expression, providing a viable assay target unique to these engineered cells. Quantitative PCR (qPCR) is currently used clinically in fresh patient tissue samples and blood with target sequences specific to each immunotherapy product. Herein, we developed a WPRE-targeted qPCR assay that is broadly applicable for detection of engineered cell products in both fresh and archival formalin-fixed paraffin embedded (FFPE) tissues. Using both traditional PCR and SYBR Green PCR protocols, we demonstrate the use of this WPRE-targeted assay to successfully detect two CAR-T cell and two TCR-T cell products in FFPE tissue. Standard curve analysis reported a reproducible limit of detection at 100 WPRE copies per 20μL PCR reaction. This novel and inexpensive technique could provide better understanding of tissue abundance of engineered therapeutic T cells in both tumor and second-site toxicity tissues and provide quantitative assessment of immune effector cell trafficking in archival tissue.}, }
@article {pmid38842811, year = {2024}, author = {Alver, SK and Pan, S and Mossavar-Rahmani, Y and Sotres-Alvarez, D and Evenson, KR and Floyd, JS and Xanthakis, V and Lin, J and Cuthbertson, C and Gallo, LC and Cai, J and Penedo, FJ and Llabre, MM and Matsushita, K and Talavera, GA and Pirzada, A and Spartano, N and Daviglus, ML and Vasan, RS and Kaplan, RC}, title = {Physical Activity, Cardiovascular Status, Mortality, and Prediabetes in Hispanic and Non-Hispanic Adults.}, journal = {JAMA network open}, volume = {7}, number = {6}, pages = {e2415094}, pmid = {38842811}, issn = {2574-3805}, mesh = {Humans ; *Prediabetic State/ethnology ; Female ; Male ; *Exercise ; *Hispanic or Latino/statistics &amp; numerical data ; Middle Aged ; Adult ; *Cardiovascular Diseases/mortality/ethnology ; Cohort Studies ; Aged ; United States/epidemiology ; Accelerometry ; }, abstract = {IMPORTANCE: Data are limited on the association of physical activity (PA) with incident cardiovascular disease (CVD) and mortality in prediabetes, especially in racial and ethnic minority groups, including Hispanic and Latino populations.<br><br>OBJECTIVE: To determine the association of PA with incident CVD and mortality by prediabetes status among Hispanic or Latino and non-Hispanic adults.<br><br>This cohort study included data from 2 cohorts of adults with prediabetes or normoglycemia who were free of CVD at baseline visit: the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) from baseline examination through 2017, with median (IQR) follow-up of 7.8 (7.2-8.5) years, and the Framingham Heart Study (FHS) with non-Hispanic participants from index examination through 2019, with median (IQR) follow-up of 9.6 (8.1-10.7) years. Analyses were conducted between September 1, 2022, and January 10, 2024.<br><br>EXPOSURE: The primary exposure was baseline accelerometry-measured moderate to vigorous PA, insufficient vs sufficient to meet 2018 Physical Activity Guidelines for Americans (PAG) in both cohorts; additional accelerometer-measured exposures in HCHS/SOL were steps per day, sedentary behavior, and counts per min.<br><br>MAIN OUTCOMES AND MEASURES: The outcome was a composite of incident CVD or all-cause mortality, whichever came first.<br><br>RESULTS: This cohort study included 13&#x202f;223 participants: from HCHS/SOL, there were 9456 adults (all self-identified Hispanic or Latino ethnicity; survey-adjusted mean [SD] age, 38.3 [13.9] years, unweighted counts 5673 (60.0%) female; 4882 [51.6%] with normoglycemia; 4574 [48.4%] with prediabetes), and from FHS there were 3767 adults (3623 [96.2%] non-Hispanic and 140 [3.7%] Hispanic or Latino ethnicity, with 4 [0.1%] participants missing ethnicity; mean [SD] age, 54.2 [13.6] years; 2128 (56.5%) female; 2739 [72.7%] with normoglycemia; 1028 [27.3%] with prediabetes). Not meeting PAG was associated with higher risk of the composite outcome among participants with normoglycemia (vs PAG met; hazard ratio [HR], 1.85 [95% CI, 1.12-3.06]), but not among participants with prediabetes (HR, 1.07 [95% CI, 0.72-1.58]). For HCHS/SOL, no statistically significant association was found between the composite outcome and other PA metrics, although estimated HRs tended to be higher for lower activity in the normoglycemia group but not for the prediabetes group (eg, for steps less than vs at least 7000 per day, the HR was 1.58 [95% CI, 0.85-2.93] for normoglycemia vs 1.08 [95% CI 0.67-1.74] for prediabetes). While there was also no association in HCHS/SOL between the composite outcome and sedentary behavior, results were similar in the prediabetes group (HR per 30 minutes per day of sedentary behavior, 1.05 [95% CI 0.99-1.12]) and in the normoglycemia group (HR, 1.07 [95% CI 0.98-1.16]).<br><br>CONCLUSIONS AND RELEVANCE: In this cohort study of US Hispanic or Latino and non-Hispanic adults, lower moderate to vigorous PA levels were associated with CVD or mortality among participants with normoglycemia but not participants with prediabetes. Adults with prediabetes may benefit from reducing sedentary behavior and improving multiple lifestyle factors beyond improving moderate to vigorous PA alone.}, }
@article {pmid38842806, year = {2024}, author = {Yanez Hernandez, M and Kuo, EF and Henriquez Taveras, Y and Lee, A and Ramos, A and Ringel, J and Andreae, S and Tsui, E and Safford, MM and Avgar, AC and Shen, MJ and Dell, N and Shalev, D and Riffin, C and Wiggins, F and Kozlov, E and Moise, N and Sterling, MR}, title = {Mental Health and Well-Being Among Home Health Aides.}, journal = {JAMA network open}, volume = {7}, number = {6}, pages = {e2415234}, pmid = {38842806}, issn = {2574-3805}, mesh = {Humans ; Female ; *COVID-19/psychology/epidemiology ; Male ; *Mental Health ; Adult ; Middle Aged ; *Focus Groups ; *Qualitative Research ; *SARS-CoV-2 ; *Home Health Aides/psychology ; Pandemics ; Stress, Psychological/psychology ; United States ; Depression/psychology ; }, abstract = {IMPORTANCE: Home health aides and attendants (HHAs) provide essential care to older adults and those with chronic conditions in the home. However, some HHAs struggle with poor mood and stress, which may have been exacerbated by the COVID-19 pandemic.<br><br>OBJECTIVE: To elicit HHAs' perspectives toward mental health and well-being, including how their job influences both and how to better support the workforce in the future.<br><br>For this qualitative study, focus groups and interviews with HHAs were facilitated in English and Spanish from August 17, 2022, to February 9, 2023, in partnership with the 1199SEIU Training and Employment Fund, a benefit fund of the 1199SEIU United Healthcare Workers East and the largest health care union in the US. Included were HHAs at risk for poor mental health and well-being, which were defined as having at least mild or more symptoms on either the 8-item Personal Health Questionnaire depression scale, the 4-item Cohen Perceived Stress Scale, or the University of California, Los Angeles Loneliness Scale.<br><br>EXPOSURE: Mental health and well-being of HHAs.<br><br>MAIN OUTCOMES AND MEASURES: Focus groups and interviews were audio recorded, professionally transcribed, and translated. A thematic analysis was performed that was informed by Pender's Health Promotion Model and the National Institute for Occupational Safety and Health's Total Worker Health model.<br><br>RESULTS: A total of 28 HHAs from 14 different agencies participated (mean [SD] age, 54.3 [10.8] years; 26 female [93%]). Seventeen participants (61%) spoke Spanish at home. Five key themes emerged: (1) HHAs' attitudes toward mental health and well-being were influenced by a variety of personal and cultural factors; (2) HHAs' relationships with their patients impacted their mood in both positive and negative ways; (3) structural and organizational aspects of the job, alongside the COVID-19 pandemic, impacted HHAs' mood and stress levels; (4) HHAs used a variety of strategies to cope with their emotions; and (5) HHAs were eager for interventions that can improve their mood, particularly those that bring them closer to their colleagues.<br><br>CONCLUSIONS AND RELEVANCE: These findings suggest that HHAs' mental health and well-being may be influenced by both personal and occupational factors. Interventions and policies to better support their emotional well-being on the job are warranted.}, }
@article {pmid38842605, year = {2024}, author = {Gottschalk, Z and Cohen, SA}, title = {Use of Circulating Tumor DNA to Guide Decision-making in Adjuvant Colon Cancer.}, journal = {Current oncology reports}, volume = {26}, number = {8}, pages = {959-966}, pmid = {38842605}, issn = {1534-6269}, mesh = {Humans ; *Circulating Tumor DNA/blood/genetics ; *Colonic Neoplasms/blood/genetics/drug therapy/pathology ; Chemotherapy, Adjuvant ; *Biomarkers, Tumor/blood/genetics ; *Clinical Decision-Making ; *Neoplasm, Residual ; }, abstract = {PURPOSE OF REVIEW: The use of circulating tumor DNA (ctDNA) assays to guide clinical decision-making in early-stage colon cancer is an area of rapidly advancing active research. With assays clinically available, clinicians must be informed how to best use this novel tool to treat patients.<br><br>RECENT FINDINGS: Recent observational and prospective studies have suggested that ctDNA has potential to guide clinical decision-making in early-stage colon cancer by detecting minimal residual disease (MRD) and predicting recurrence risks. MRD-negative patients may be able to de-escalate or forgo adjuvant chemotherapy (ACT) without compromising disease-free survival or overall survival, while MRD-positive patients may benefit significantly from ACT. Recent and ongoing studies have given reason for optimism about the future of ctDNA as a useful biomarker for clinicians treating early-stage colon cancer. Data thus far are mostly limited to observational studies; inconsistent results highlight the need for caution. As more evidence emerges, ctDNA may become standard of care for colon cancer patients.}, }
@article {pmid38838218, year = {2024}, author = {Files, MA and Gentles, L and Kehoe, L and Adler, A and Lacombe, K and Dickerson, JA and Greninger, A and Waghmare, A and Fairlie, T and Pringle, K and Midgley, CM and Hagen, MB and Englund, JA and Seshadri, C}, title = {Kinetics and Durability of Antibody and T-Cell Responses to SARS-CoV-2 in Children.}, journal = {The Journal of infectious diseases}, volume = {230}, number = {4}, pages = {889-900}, pmid = {38838218}, issn = {1537-6613}, support = {R01 AI142670/AI/NIAID NIH HHS/United States ; /CC/CDC HHS/United States ; //Children's Hospital Foundation/ ; /NH/NIH HHS/United States ; }, mesh = {Humans ; Child ; *COVID-19/immunology ; *SARS-CoV-2/immunology ; Child, Preschool ; *Antibodies, Viral/blood/immunology ; Adolescent ; Infant ; *Spike Glycoprotein, Coronavirus/immunology ; Female ; Male ; *CD4-Positive T-Lymphocytes/immunology ; Young Adult ; T-Lymphocytes/immunology ; Coronavirus Nucleocapsid Proteins/immunology ; Kinetics ; Antibodies, Neutralizing/blood/immunology ; Phosphoproteins/immunology ; }, abstract = {BACKGROUND: The kinetics and durability of T-cell responses to SARS-CoV-2 in children are not well characterized. We studied a cohort of children aged 6 months to 20 years with COVID-19 in whom peripheral blood mononuclear cells and sera were archived at approximately 1, 6, and 12 months after symptom onset.<br><br>METHODS: We compared antibody responses (n = 85) and T-cell responses (n = 30) to nucleocapsid (N) and spike (S) glycoprotein over time across 4 age strata: 6 months to 5 years and 5-9, 10-14, and 15-20 years.<br><br>RESULTS: N-specific antibody responses declined over time, becoming undetectable in 26 (81%) of 32 children by approximately 1 year postinfection. Functional breadth of anti-N CD4+ T-cell responses also declined over time and were positively correlated with N-antibody responses (Pearson r = .31, P = .008). CD4+ T-cell responses to S displayed greater functional breadth than N in unvaccinated children and, with neutralization titers, were stable over time and similar across age strata. Functional profiles of CD4+ T-cell responses against S were not significantly modulated by vaccination.<br><br>CONCLUSIONS: Our data reveal durable age-independent T-cell immunity to SARS-CoV-2 structural proteins in children over time following COVID-19 infection as well as S-antibody responses in comparison with declining antibody responses to N.}, }
@article {pmid38838028, year = {2024}, author = {Achilles, SL and Kelly, CW and Hoesley, CJ and Blithe, DL and Brown, J and Richardson, BA and Devlin, B and Hendrix, CW and Poloyac, SM and Marzinke, MA and Gundacker, H and Singh, D and Piper, JM and Johnson, S and Steytler, J and Chen, BA and , }, title = {Phase 1 randomized trials to assess safety, pharmacokinetics, and vaginal bleeding associated with use of extended duration dapivirine and levonorgestrel vaginal rings.}, journal = {PloS one}, volume = {19}, number = {6}, pages = {e0304552}, pmid = {38838028}, issn = {1932-6203}, support = {UM1 AI068615/AI/NIAID NIH HHS/United States ; UM1 AI106707/AI/NIAID NIH HHS/United States ; HHSN275201200002C/HD/NICHD NIH HHS/United States ; HHSN275201200002I/HD/NICHD NIH HHS/United States ; UM1 AI068633/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Female ; *Levonorgestrel/pharmacokinetics/administration &amp; dosage/adverse effects ; Adult ; *Pyrimidines/pharmacokinetics/adverse effects/administration &amp; dosage ; *Contraceptive Devices, Female/adverse effects ; *Uterine Hemorrhage ; Anti-HIV Agents/pharmacokinetics/adverse effects/administration &amp; dosage ; Young Adult ; Middle Aged ; HIV Infections/drug therapy ; }, abstract = {BACKGROUND: Vaginal rings formulated to deliver two drugs simultaneously have potential as user-controlled, long-acting methods for dual prevention of HIV and pregnancy.<br><br>METHODS: Two phase 1 randomized trials (MTN-030/IPM 041 and MTN-044/IPM 053/CCN019) respectively enrolled 24 and 25 healthy, HIV-negative participants to evaluate safety, pharmacokinetics, and vaginal bleeding associated with use of a vaginal ring containing 200mg dapivirine (DPV) and 320mg levonorgestrel (LNG) designed for 90-day use. MTN-030/IPM 041 compared the DPV/LNG ring to a DPV-only ring (200mg) over 14 days of use. MTN-044/IPM 053/CCN019 compared continuous or cyclic use of the DPV/LNG ring over 90 days of use. Safety was assessed by recording adverse events (AEs). DPV and LNG concentrations were quantified in plasma, cervicovaginal fluid, and cervical tissue. Vaginal bleeding was self-reported.<br><br>RESULTS: There were no differences in the proportion of participants with grade &#x2265;2 genitourinary AEs or grade &#x2265;3 AEs with DPV/LNG ring vs. DPV ring use (p = .22), or with DPV/LNG ring continuous vs. cyclic use (p = .67). Higher plasma DPV concentrations were observed in users of DPV/LNG compared to DPV-only rings (Cmax p = 0.049; AUC p = 0.091). Plasma DPV and LNG concentrations were comparable with continuous and cyclic use (Cmax p = 0.74; AUC p = 0.25). With cyclic use, median nadir plasma DPV concentration was approximately 300 pg/mL two days after removal and median t1/2 for cervicovaginal fluid DPV concentration was 5.76 hours (n = 3). Overall bleeding experiences did not differ between continuous and cyclic users (p = 0.12).<br><br>CONCLUSIONS: The extended duration DPV/ LNG rings were well tolerated and the observed DPV concentrations in plasma and cervicovaginal fluid when used continuously exceeded concentrations observed in previous DPV ring efficacy studies. LNG concentrations in plasma were comparable with other efficacious LNG-based contraceptives. Genital DPV concentrations had a short half-life and were thus not well sustained following ring removal.}, }
@article {pmid38838026, year = {2024}, author = {Gupta, V and Yacoub, A and Mesa, RA and Harrison, CN and Vannucchi, AM and Kiladjian, JJ and Deeg, HJ and Fazal, S and Foltz, L and Mattison, RJ and Miller, CB and Parameswaran, V and Brown, P and Hernandez, C and Wang, J and Talpaz, M}, title = {Safety and efficacy of fedratinib in patients with myelofibrosis previously treated with ruxolitinib: primary analysis of FREEDOM trial.}, journal = {Leukemia &amp; lymphoma}, volume = {65}, number = {9}, pages = {1314-1324}, doi = {10.1080/10428194.2024.2346733}, pmid = {38838026}, issn = {1029-2403}, mesh = {Humans ; *Primary Myelofibrosis/drug therapy/diagnosis ; *Pyrazoles/therapeutic use/adverse effects/administration &amp; dosage ; *Pyrimidines/therapeutic use/adverse effects/administration &amp; dosage ; Male ; Female ; Aged ; Middle Aged ; *Nitriles ; *Pyrrolidines/therapeutic use ; Treatment Outcome ; Sulfonamides/therapeutic use/adverse effects/administration &amp; dosage ; COVID-19/epidemiology ; Aged, 80 and over ; SARS-CoV-2 ; Spleen/pathology/drug effects ; Adult ; Protein Kinase Inhibitors/therapeutic use/adverse effects/administration &amp; dosage ; Benzenesulfonamides ; }, abstract = {The phase 3b FREEDOM trial (ClinicalTrials.gov: NCT03755518) evaluates efficacy/safety of fedratinib in intermediate- or high-risk myelofibrosis patients with platelet count ≥50 × 10[9]/L, previously treated with ruxolitinib. The trial design included protocol specified strategies to mitigate the risk for gastrointestinal (GI) adverse events (AEs), thiamine supplementation, and encephalopathy surveillance. Due to COVID-19, accrual was cut short with 38 patients enrolled. In the efficacy evaluable population (n = 35), nine (25.7%; 95% confidence interval 12.5-43.3) patients achieved primary endpoint of ≥35% spleen volume reduction (SVR) at end of cycle (EOC) 6; and 22 (62.9%) patients showed best overall response of ≥35% SVR up to end of treatment. Sixteen (44.4%) patients showed ≥50% reduction in total symptom score at EOC6 (n = 36). Compared to previously reported JAKARTA-2 trial, rates of GI AEs were lower, and no patient developed encephalopathy. Overall, FREEDOM study showed clinically relevant spleen and symptom responses with fedratinib, and effective mitigation of GI AEs.}, }
@article {pmid38837893, year = {2024}, author = {Saner, FAM and Takahashi, K and Budden, T and Pandey, A and Ariyaratne, D and Zwimpfer, TA and Meagher, NS and Fereday, S and Twomey, L and Pishas, KI and Hoang, T and Bolithon, A and Traficante, N and ,  and Alsop, K and Christie, EL and Kang, EY and Nelson, GS and Ghatage, P and Lee, CH and Riggan, MJ and Alsop, J and Beckmann, MW and Boros, J and Brand, AH and Brooks-Wilson, A and Carney, ME and Coulson, P and Courtney-Brooks, M and Cushing-Haugen, KL and Cybulski, C and El-Bahrawy, MA and Elishaev, E and Erber, R and Gayther, SA and Gentry-Maharaj, A and Gilks, CB and Harnett, PR and Harris, HR and Hartmann, A and Hein, A and Hendley, J and Hernandez, BY and Jakubowska, A and Jimenez-Linan, M and Jones, ME and Kaufmann, SH and Kennedy, CJ and Kluz, T and Koziak, JM and Kristjansdottir, B and Le, ND and Lener, M and Lester, J and Lubiński, J and Mateoiu, C and Orsulic, S and Ruebner, M and Schoemaker, MJ and Shah, M and Sharma, R and Sherman, ME and Shvetsov, YB and Soong, TR and Steed, H and Sukumvanich, P and Talhouk, A and Taylor, SE and Vierkant, RA and Wang, C and Widschwendter, M and Wilkens, LR and Winham, SJ and Anglesio, MS and Berchuck, A and Brenton, JD and Campbell, I and Cook, LS and Doherty, JA and Fasching, PA and Fortner, RT and Goodman, MT and Gronwald, J and Huntsman, DG and Karlan, BY and Kelemen, LE and Menon, U and Modugno, F and Pharoah, PDP and Schildkraut, JM and Sundfeldt, K and Swerdlow, AJ and Goode, EL and DeFazio, A and Köbel, M and Ramus, SJ and Bowtell, DDL and Garsed, DW}, title = {Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {30}, number = {16}, pages = {3481-3498}, pmid = {38837893}, issn = {1557-3265}, support = {P2BEP3-172246//Schweizerischer Nationalfonds zur F&#xf6;rderung der Wissenschaftlichen Forschung (SNF)/ ; //Swedish Cancer Foundation/ ; MCRF22018//Victorian Cancer Agency (VCA)/ ; //Foundation for Clinical-Experimental Cancer Research/ ; R01CA172404//National Cancer Institute (NCI)/ ; UL1 TR000124/TR/NCATS NIH HHS/United States ; 742432//HORIZON EUROPE European Research Council (ERC)/ ; 1186505//National Health and Medical Research Council (NHMRC)/ ; 2009840//National Health and Medical Research Council (NHMRC)/ ; 18274//Michael Smith Health Research BC (MSFHR)/ ; P30 CA015083/CA/NCI NIH HHS/United States ; W81XWH-16-2-0010//U.S. Army Medical Research and Development Command (MRDC)/ ; UL1 TR001881/TR/NCATS NIH HHS/United States ; P50 CA136393/CA/NCI NIH HHS/United States ; BIL KFS-3942-08-2016//Krebsliga Schweiz (Swiss Cancer League)/ ; MCRF21004//Victorian Cancer Agency (VCA)/ ; APP1111032//National Health and Medical Research Council (NHMRC)/ ; R01 CA172404/CA/NCI NIH HHS/United States ; 1092856//National Health and Medical Research Council (NHMRC)/ ; //Janet D. Cottrelle Foundation (JDCF)/ ; W81XWH-21-1-0401//U.S. Army Medical Research and Development Command (MRDC)/ ; R01 CA248288/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Ovarian Neoplasms/genetics/mortality/immunology/pathology ; *BRCA2 Protein/genetics/deficiency ; *BRCA1 Protein/genetics/deficiency ; *Cystadenocarcinoma, Serous/genetics/pathology/mortality/immunology ; *Retinoblastoma Binding Proteins/genetics ; Prognosis ; Ubiquitin-Protein Ligases/genetics ; Neoplasm Grading ; Lymphocytes, Tumor-Infiltrating/immunology/metabolism ; Middle Aged ; Germ-Line Mutation ; Gene Expression Regulation, Neoplastic ; Aged ; Biomarkers, Tumor/genetics ; CD8-Positive T-Lymphocytes/immunology/metabolism ; }, abstract = {PURPOSE: The purpose of this study was to evaluate RB1 expression and survival across ovarian carcinoma histotypes and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC).<br><br>EXPERIMENTAL DESIGN: RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7,436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1,134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes, and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 patients with primary HGSC to characterize tumors with concurrent BRCA deficiency and RB1 loss.<br><br>RESULTS: RB1 loss was associated with longer OS in HGSC but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared with patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA deficiency correlated with transcriptional markers of enhanced IFN response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1.<br><br>CONCLUSIONS: Co-occurrence of RB1 loss and BRCA deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.}, }
@article {pmid38837431, year = {2024}, author = {Voldal, EC and Kenny, A and Xia, F and Heagerty, P and Hughes, JP}, title = {Robust analysis of stepped wedge trials using composite likelihood models.}, journal = {Statistics in medicine}, volume = {43}, number = {17}, pages = {3326-3352}, pmid = {38837431}, issn = {1097-0258}, support = {P30AR072572/AR/NIAMS NIH HHS/United States ; R37 AI029168/AI/NIAID NIH HHS/United States ; R01 AI029168/AI/NIAID NIH HHS/United States ; P30 AR072572/AR/NIAMS NIH HHS/United States ; U24 AT009676/AT/NCCIH NIH HHS/United States ; U24 AT010961/AT/NCCIH NIH HHS/United States ; AI029168/NH/NIH HHS/United States ; }, mesh = {Humans ; Likelihood Functions ; *Randomized Controlled Trials as Topic/methods/statistics &amp; numerical data ; Cluster Analysis ; Computer Simulation ; Models, Statistical ; COVID-19 ; Research Design ; }, abstract = {Stepped wedge trials (SWTs) are a type of cluster randomized trial that involve repeated measures on clusters and design-induced confounding between time and treatment. Although mixed models are commonly used to analyze SWTs, they are susceptible to misspecification particularly for cluster-longitudinal designs such as SWTs. Mixed model estimation leverages both "horizontal" or within-cluster information and "vertical" or between-cluster information. To use horizontal information in a mixed model, both the mean model and correlation structure must be correctly specified or accounted for, since time is confounded with treatment and measurements are likely correlated within clusters. Alternative non-parametric methods have been proposed that use only vertical information; these are more robust because between-cluster comparisons in a SWT preserve randomization, but these non-parametric methods are not very efficient. We propose a composite likelihood method that focuses on vertical information, but has the flexibility to recover efficiency by using additional horizontal information. We compare the properties and performance of various methods, using simulations based on COVID-19 data and a demonstration of application to the LIRE trial. We found that a vertical composite likelihood model that leverages baseline data is more robust than traditional methods, and more efficient than methods that use only vertical information. We hope that these results demonstrate the potential value of model-based vertical methods for SWTs with a large number of clusters, and that these new tools are useful to researchers who are concerned about misspecification of traditional models.}, }
@article {pmid38836649, year = {2024}, author = {Shenoy, ES and Banach, DB and Batshon, LJ and Branch-Elliman, W and Dumyati, G and Haessler, S and Hsu, VP and Jump, RLP and Malani, AN and Mathew, TA and Murthy, RK and Pergam, SA and Seeger, MW and Weber, DJ}, title = {SHEA position statement on pandemic preparedness for policymakers: the role of healthcare epidemiologists in communicating during infectious diseases outbreaks.}, journal = {Infection control and hospital epidemiology}, volume = {45}, number = {7}, pages = {808-812}, doi = {10.1017/ice.2024.63}, pmid = {38836649}, issn = {1559-6834}, mesh = {Humans ; *Epidemiologists ; *Pandemics/prevention &amp; control ; Disease Outbreaks/prevention &amp; control ; Communication ; Pandemic Preparedness ; }, }
@article {pmid38835721, year = {2023}, author = {Zou, J and Lin, T and Di, C and Bellettiere, J and Jankowska, MM and Hartman, SJ and Sears, DD and LaCroix, AZ and Rock, CL and Natarajan, L}, title = {A RIEMANN MANIFOLD MODEL FRAMEWORK FOR LONGITUDINAL CHANGES IN PHYSICAL ACTIVITY PATTERNS.}, journal = {The annals of applied statistics}, volume = {17}, number = {4}, pages = {3216-3240}, pmid = {38835721}, issn = {1932-6157}, support = {P01 AG052352/AG/NIA NIH HHS/United States ; R01 DK114945/DK/NIDDK NIH HHS/United States ; U54 CA155435/CA/NCI NIH HHS/United States ; }, abstract = {Physical activity (PA) is significantly associated with many health outcomes. The wide usage of wearable accelerometer-based activity trackers in recent years has provided a unique opportunity for in-depth research on PA and its relations with health outcomes and interventions. Past analysis of activity tracker data relies heavily on aggregating minute-level PA records into day-level summary statistics in which important information of PA temporal/diurnal patterns is lost. In this paper we propose a novel functional data analysis approach based on Riemann manifolds for modeling PA and its longitudinal changes. We model smoothed minute-level PA of a day as one-dimensional Riemann manifolds and longitudinal changes in PA in different visits as deformations between manifolds. The variability in changes of PA among a cohort of subjects is characterized via variability in the deformation. Functional principal component analysis is further adopted to model the deformations, and PC scores are used as a proxy in modeling the relation between changes in PA and health outcomes and/or interventions. We conduct comprehensive analyses on data from two clinical trials: Reach for Health (RfH) and Metabolism, Exercise and Nutrition at UCSD (MENU), focusing on the effect of interventions on longitudinal changes in PA patterns and how different modes of changes in PA influence weight loss, respectively. The proposed approach reveals unique modes of changes, including overall enhanced PA, boosted morning PA, and shifts of active hours specific to each study cohort. The results bring new insights into the study of longitudinal changes in PA and health and have the potential to facilitate designing of effective health interventions and guidelines.}, }
@article {pmid38835350, year = {2024}, author = {Perrone, G and Rigacci, L and Roviello, G and Landini, I and Fabbri, A and Iovino, L and Puccini, B and Cencini, E and Orciuolo, E and Bocchia, M and Bosi, A and Mini, E and Nobili, S}, title = {Validation of single nucleotide polymorphisms potentially related to R-CHOP resistance in diffuse large B-cell lymphoma patients.}, journal = {Cancer drug resistance (Alhambra, Calif.)}, volume = {7}, number = {}, pages = {21}, pmid = {38835350}, issn = {2578-532X}, abstract = {Aim: Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell non-Hodgkin lymphoma (NHL). Despite the availability of clinical and molecular algorithms applied for the prediction of prognosis, in up to 30%-40% of patients, intrinsic or acquired drug resistance occurs. Constitutional genetics may help to predict R-CHOP resistance. This study aimed to validate previously identified single nucleotide polymorphisms (SNPs) in the literature as potential predictors of R-CHOP resistance in DLBCL patients, SNPs. Methods: Twenty SNPs, involved in R-CHOP pharmacokinetics/pharmacodynamics or other pathobiological processes, were investigated in 185 stage I-IV DLBCL patients included in a multi-institution pharmacogenetic study to validate their previously identified correlations with resistance to R-CHOP. Results: Correlations between rs2010963 (VEGFA gene) and sex (P = 0.046), and rs1625895 (TP53 gene) and stage (P = 0.003) were shown. After multivariate analyses, a concordant effect (i.e., increased risk of disease progression and death) was observed for rs1883112 (NCF4 gene) and rs1800871 (IL10 gene). When patients were grouped according to the revised International Prognostic Index (R-IPI), both these SNPs further discriminated progression-free survival (PFS) and overall survival (OS) of the R-IPI-1-2 subgroup. Overall, patients harboring the rare allele showed shorter PFS and OS compared with wild-type patients. Conclusions: Two out of the 20 study SNPs were validated. Thus, these results support the role of previously identified rs1883112 and rs1800871 in predicting DLBCL resistance to R-CHOP and highlight their ability to further discriminate the prognosis of R-IPI-1-2 patients. These data point to the need to also focus on host genetics for a more comprehensive assessment of DLBCL patient outcomes in future prospective trials.}, }
@article {pmid38835230, year = {2024}, author = {Branch-Elliman, W and Banach, DB and Batshon, LJ and Dumyati, G and Haessler, S and Hsu, VP and Jump, RLP and Malani, AN and Mathew, TA and Murthy, RK and Pergam, SA and Shenoy, ES and Weber, DJ}, title = {SHEA position statement on pandemic preparedness for policymakers: pandemic data collection, maintenance, and release.}, journal = {Infection control and hospital epidemiology}, volume = {45}, number = {7}, pages = {821-825}, doi = {10.1017/ice.2024.65}, pmid = {38835230}, issn = {1559-6834}, mesh = {Humans ; *Pandemics/prevention &amp; control ; *Data Collection/methods/standards ; United States ; COVID-19/prevention &amp; control/epidemiology ; Societies, Medical ; Information Dissemination/methods ; Pandemic Preparedness ; }, abstract = {The Society for Healthcare Epidemiology in America (SHEA) strongly supports modernization of data collection processes and the creation of publicly available data repositories that include a wide variety of data elements and mechanisms for securely storing both cleaned and uncleaned data sets that can be curated as clinical and research needs arise. These elements can be used for clinical research and quality monitoring and to evaluate the impacts of different policies on different outcomes. Achieving these goals will require dedicated, sustained and long-term funding to support data science teams and the creation of central data repositories that include data sets that can be "linked" via a variety of different mechanisms and also data sets that include institutional and state and local policies and procedures. A team-based approach to data science is strongly encouraged and supported to achieve the goal of a sustainable, adaptable national shared data resource.}, }
@article {pmid38835229, year = {2024}, author = {Weber, DJ and Malani, AN and Shenoy, ES and Banach, DB and Batshon, LJ and Branch-Elliman, W and Dumyati, G and Haessler, S and Hsu, VP and Jump, RLP and Mathew, TA and Murthy, RK and Pergam, SA}, title = {Society for Healthcare Epidemiology of America position statement on pandemic preparedness for policymakers: mitigating supply shortages.}, journal = {Infection control and hospital epidemiology}, volume = {45}, number = {7}, pages = {813-817}, doi = {10.1017/ice.2024.67}, pmid = {38835229}, issn = {1559-6834}, mesh = {Humans ; *COVID-19/prevention &amp; control/epidemiology ; United States ; *Personal Protective Equipment/supply &amp; distribution ; Pandemics/prevention &amp; control ; Infection Control/methods/organization &amp; administration ; SARS-CoV-2 ; Strategic Stockpile ; Pandemic Preparedness ; }, abstract = {The COVID-19 has had major direct (e.g., deaths) and indirect (e.g., social inequities) effects in the United States. While the public health response to the epidemic featured some important successes (e.g., universal masking ,and rapid development and approval of vaccines and therapeutics), there were systemic failures (e.g., inadequate public health infrastructure) that overshadowed these successes. Key deficiency in the U.S. response were shortages of personal protective equipment (PPE) and supply chain deficiencies. Recommendations are provided for mitigating supply shortages and supply chain failures in healthcare settings in future pandemics. Some key recommendations for preventing shortages of essential components of infection control and prevention include increasing the stockpile of PPE in the U.S. National Strategic Stockpile, increased transparency of the Stockpile, invoking the Defense Production Act at an early stage, and rapid review and authorization by FDA/EPA/OSHA of non-U.S. approved products. Recommendations are also provided for mitigating shortages of diagnostic testing, medications and medical equipment.}, }
@article {pmid38835227, year = {2024}, author = {Banach, DB and Mathew, TA and Batshon, LJ and Branch-Elliman, W and Dumyati, G and Haessler, S and Hsu, VP and Jump, RLP and Malani, AN and Murthy, RK and Pergam, SA and Shenoy, ES and Weber, DJ}, title = {SHEA position statement on pandemic preparedness for policymakers: building a strong and resilient healthcare workforce.}, journal = {Infection control and hospital epidemiology}, volume = {45}, number = {7}, pages = {804-807}, pmid = {38835227}, issn = {1559-6834}, mesh = {Humans ; *COVID-19/prevention &amp; control/epidemiology ; United States/epidemiology ; *Health Workforce ; *Health Personnel ; Pandemics/prevention &amp; control ; SARS-CoV-2 ; Infection Control/methods/organization &amp; administration ; Pandemic Preparedness ; }, abstract = {Throughout the COVID-19 pandemic, many areas in the United States experienced healthcare personnel (HCP) shortages tied to a variety of factors. Infection prevention programs, in particular, faced increasing workload demands with little opportunity to delegate tasks to others without specific infectious diseases or infection control expertise. Shortages of clinicians providing inpatient care to critically ill patients during the early phase of the pandemic were multifactorial, largely attributed to increasing demands on hospitals to provide care to patients hospitalized with COVID-19 and furloughs.[1] HCP shortages and challenges during later surges, including the Omicron variant-associated surges, were largely attributed to HCP infections and associated work restrictions during isolation periods and the need to care for family members, particularly children, with COVID-19. Additionally, the detrimental physical and mental health impact of COVID-19 on HCP has led to attrition, which further exacerbates shortages.[2] Demands increased in post-acute and long-term care (PALTC) settings, which already faced critical staffing challenges difficulty with recruitment, and high rates of turnover. Although individual healthcare organizations and state and federal governments have taken actions to mitigate recurring shortages, additional work and innovation are needed to develop longer-term solutions to improve healthcare workforce resiliency. The critical role of those with specialized training in infection prevention, including healthcare epidemiologists, was well-demonstrated in pandemic preparedness and response. The COVID-19 pandemic underscored the need to support growth in these fields.[3] This commentary outlines the need to develop the US healthcare workforce in preparation for future pandemics.}, }
@article {pmid38835222, year = {2024}, author = {Hsu, VP and Haessler, S and Banach, DB and Batshon, LJ and Branch-Elliman, W and Dumyati, G and Jump, RLP and Malani, AN and Mathew, TA and Murthy, RK and Pergam, SA and Shenoy, ES and Weber, DJ}, title = {SHEA position statement on pandemic preparedness for policymakers: introduction and overview.}, journal = {Infection control and hospital epidemiology}, volume = {45}, number = {7}, pages = {801-803}, pmid = {38835222}, issn = {1559-6834}, mesh = {Humans ; *COVID-19/epidemiology/prevention &amp; control ; *Pandemics/prevention &amp; control ; SARS-CoV-2 ; United States/epidemiology ; Health Policy ; Pandemic Preparedness ; }, abstract = {Throughout history, pandemics and their aftereffects have spurred society to make substantial improvements in healthcare. After the Black Death in 14[th] century Europe, changes were made to elevate standards of care and nutrition that resulted in improved life expectancy.[1] The 1918 influenza pandemic spurred a movement that emphasized public health surveillance and detection of future outbreaks and eventually led to the creation of the World Health Organization Global Influenza Surveillance Network.[2] In the present, the COVID-19 pandemic exposed many of the pre-existing problems within the US healthcare system, which included (1) a lack of capacity to manage a large influx of contagious patients while simultaneously maintaining routine and emergency care to non-COVID patients; (2) a "just in time" supply network that led to shortages and competition among hospitals, nursing homes, and other care sites for essential supplies; and (3) longstanding inequities in the distribution of healthcare and the healthcare workforce. The decades-long shift from domestic manufacturing to a reliance on global supply chains has compounded ongoing gaps in preparedness for supplies such as personal protective equipment and ventilators. Inequities in racial and socioeconomic outcomes highlighted during the pandemic have accelerated the call to focus on diversity, equity, and inclusion (DEI) within our communities. The pandemic accelerated cooperation between government entities and the healthcare system, resulting in swift implementation of mitigation measures, new therapies and vaccinations at unprecedented speeds, despite our fragmented healthcare delivery system and political divisions. Still, widespread misinformation or disinformation and political divisions contributed to eroded trust in the public health system and prevented an even uptake of mitigation measures, vaccines and therapeutics, impeding our ability to contain the spread of the virus in this country.[3] Ultimately, the lessons of COVID-19 illustrate the need to better prepare for the next pandemic. Rising microbial resistance, emerging and re-emerging pathogens, increased globalization, an aging population, and climate change are all factors that increase the likelihood of another pandemic.[4].}, }
@article {pmid38834882, year = {2024}, author = {Mack, TM and Raddatz, MA and Pershad, Y and Nachun, DC and Taylor, KD and Guo, X and Shuldiner, AR and O'Connell, JR and Kenny, EE and Loos, RJF and Redline, S and Cade, BE and Psaty, BM and Bis, JC and Brody, JA and Silverman, EK and Yun, JH and Cho, MH and DeMeo, DL and Levy, D and Johnson, AD and Mathias, RA and Yanek, LR and Heckbert, SR and Smith, NL and Wiggins, KL and Raffield, LM and Carson, AP and Rotter, JI and Rich, SS and Manichaikul, AW and Gu, CC and Chen, YI and Lee, WJ and Shoemaker, MB and Roden, DM and Kooperberg, C and Auer, PL and Desai, P and Blackwell, TW and Smith, AV and Reiner, AP and Jaiswal, S and Weinstock, JS and Bick, AG}, title = {Epigenetic and proteomic signatures associate with clonal hematopoiesis expansion rate.}, journal = {Nature aging}, volume = {4}, number = {8}, pages = {1043-1052}, pmid = {38834882}, issn = {2662-8465}, mesh = {*Clonal Hematopoiesis/genetics ; Humans ; *Epigenesis, Genetic ; *Proteomics ; DNA Methylation ; Female ; Male ; Hematopoietic Stem Cells/metabolism ; Middle Aged ; Proteome/metabolism/genetics ; Tissue Inhibitor of Metalloproteinase-1/genetics ; Aged ; }, abstract = {Clonal hematopoiesis of indeterminate potential (CHIP), whereby somatic mutations in hematopoietic stem cells confer a selective advantage and drive clonal expansion, not only correlates with age but also confers increased risk of morbidity and mortality. Here, we leverage genetically predicted traits to identify factors that determine CHIP clonal expansion rate. We used the passenger-approximated clonal expansion rate method to quantify the clonal expansion rate for 4,370 individuals in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) cohort and calculated polygenic risk scores for DNA methylation aging, inflammation-related measures and circulating protein levels. Clonal expansion rate was significantly associated with both genetically predicted and measured epigenetic clocks. No associations were identified with inflammation-related lab values or diseases and CHIP expansion rate overall. A proteome-wide search identified predicted circulating levels of myeloid zinc finger 1 and anti-Müllerian hormone as associated with an increased CHIP clonal expansion rate and tissue inhibitor of metalloproteinase 1 and glycine N-methyltransferase as associated with decreased CHIP clonal expansion rate. Together, our findings identify epigenetic and proteomic patterns associated with the rate of hematopoietic clonal expansion.}, }
@article {pmid38834593, year = {2024}, author = {Hall, E and Davis, K and Ohrnberger, J and Pickles, M and Gregson, S and Thomas, R and Hargreaves, JR and Pliakas, T and Bwalya, J and Dunbar, R and Mainga, T and Shanaube, K and Hoddinott, G and Bond, V and Bock, P and Ayles, H and Stangl, AL and Donnell, D and Hayes, R and Fidler, S and Hauck, K and , }, title = {Associations between HIV stigma and health-related quality-of-life among people living with HIV: cross-sectional analysis of data from HPTN 071 (PopART).}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {12835}, pmid = {38834593}, issn = {2045-2322}, support = {MR/R015600/1//Medical Research Council (MRC) and the UK Foreign, Commonwealth &amp; Development Office (FCDO)/ ; UM1-AI068619//National Institute of Allergy and Infectious Diseases/ ; UM1-AI068617//National Institute of Allergy and Infectious Diseases/ ; NIHR200908//National Institute for Health and Care Research (NIHR) Health Protection Research Unit in Modelling and Health Economics/ ; 220098/Z/20/Z/WT_/Wellcome Trust/United Kingdom ; UM1 AI068619/AI/NIAID NIH HHS/United States ; UM1 AI069521/AI/NIAID NIH HHS/United States ; UM1 AI068613/AI/NIAID NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; UM1-AI068613//National Institute of Allergy and Infectious Diseases/ ; UM1 AI068617/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *HIV Infections/psychology/epidemiology ; *Quality of Life ; *Social Stigma ; Male ; Female ; Adult ; Cross-Sectional Studies ; Adolescent ; Young Adult ; Zambia/epidemiology ; South Africa/epidemiology ; Surveys and Questionnaires ; }, abstract = {People living with HIV (PLHIV) report lower health-related quality-of-life (HRQoL) than HIV-negative people. HIV stigma may contribute to this. We explored the association between HIV stigma and HRQoL among PLHIV. We used cross-sectional data from 3991 randomly selected PLHIV who were surveyed in 2017-2018 for HPTN 071 (PopART), a cluster randomised trial in Zambia and South Africa. Participants were 18-44 years, had laboratory-confirmed HIV infection, and knew their status. HRQoL was measured using the EuroQol-5-dimensions-5-levels (EQ-5D-5L) questionnaire. Stigma outcomes included: internalised stigma, stigma experienced in the community, and stigma experienced in healthcare settings. Associations were examined using logistic regression. Participants who had experienced community stigma (n = 693/3991) had higher odds of reporting problems in at least one HRQoL domain, compared to those who had not (adjusted odds ratio, aOR: 1.51, 95% confidence interval, 95% Cl: 1.16-1.98, p = 0.002). Having experienced internalised stigma was also associated with reporting problems in at least one HRQoL domain (n = 552/3991, aOR: 1.98, 95% CI: 1.54-2.54, p < 0.001). However, having experienced stigma in a healthcare setting was less common (n = 158/3991) and not associated with HRQoL (aOR: 1.04, 95% CI: 0.68-1.58, p = 0.850). A stronger focus on interventions for internalised stigma and stigma experienced in the community is required.}, }
@article {pmid38833622, year = {2024}, author = {Nimgaonkar, I and Flaherty, PW and Oshima, MU and Hill, JA}, title = {Acute Endothelial Complications Post-Allogeneic Hematopoietic Cell Transplant in Patients with Pre-Cellular Therapy SARS-CoV-2 Infection.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciae310}, pmid = {38833622}, issn = {1537-6591}, }
@article {pmid38833307, year = {2024}, author = {Joy, J and Gervassi, A and Chen, L and Kirshenbaum, B and Styrchak, S and Ko, D and McLaughlin, S and Shao, D and Kosmider, E and Edlefsen, PT and Maenza, J and Collier, AC and Mullins, JI and Horton, H and Frenkel, LM}, title = {Antigen specificities and proviral integration sites differ in HIV-infected cells by timing of antiretroviral treatment initiation.}, journal = {The Journal of clinical investigation}, volume = {134}, number = {14}, pages = {}, pmid = {38833307}, issn = {1558-8238}, support = {R01 AI134419/AI/NIAID NIH HHS/United States ; P01 AI057005/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; R01 AI111806/AI/NIAID NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; UM1 AI106701/AI/NIAID NIH HHS/United States ; R01 AI125026/AI/NIAID NIH HHS/United States ; UM1 AI106716/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *HIV Infections/drug therapy/genetics/virology/immunology ; *Proviruses/genetics ; *CD4-Positive T-Lymphocytes/immunology/virology ; *Virus Integration ; *HIV-1/genetics ; Male ; Female ; Adult ; Enhancer of Zeste Homolog 2 Protein/genetics/metabolism ; DNA, Viral/genetics ; Anti-Retroviral Agents/administration &amp; dosage/therapeutic use ; }, abstract = {Despite effective antiretroviral therapy (ART), persons living with HIV harbor reservoirs of persistently infected CD4+ cells, which constitute a barrier to cure. Initiation of ART during acute infection reduces the size of the HIV reservoir, and we hypothesized that in addition, it would favor integration of proviruses in HIV-specific CD4+ T cells, while initiation of ART during chronic HIV infection would favor relatively more proviruses in herpesvirus-specific cells. We further hypothesized that proviruses in acute ART initiators would be integrated into antiviral genes, whereas integration sites (ISs) in chronic ART initiators would favor genes associated with cell proliferation and exhaustion. We found that the HIV DNA distribution across HIV-specific versus herpesvirus-specific CD4+ T cells was as hypothesized. HIV ISs in acute ART initiators were significantly enriched in gene sets controlling lipid metabolism and HIF-1α-mediated hypoxia, both metabolic pathways active in early HIV infection. Persistence of these infected cells during prolonged ART suggests a survival advantage. ISs in chronic ART initiators were enriched in a gene set controlling EZH2 histone methylation, and methylation has been associated with diminished long terminal repeat transcription. These differences that we found in antigen specificities and IS distributions within HIV-infected cells might be leveraged in designing cure strategies tailored to the timing of ART initiation.}, }
@article {pmid38833145, year = {2024}, author = {Baik, C and Cheng, ML and Dietrich, M and Gray, JE and Karim, NA}, title = {Correction to: A Practical Review of Encorafenib and Binimetinib Therapy Management in Patients with BRAF V600EMutant Metastatic Non-Small Cell Lung Cancer.}, journal = {Advances in therapy}, volume = {41}, number = {7}, pages = {3016}, doi = {10.1007/s12325-024-02907-9}, pmid = {38833145}, issn = {1865-8652}, }
@article {pmid38832928, year = {2024}, author = {Sun, X and Verma, SP and Jia, G and Wang, X and Ping, J and Guo, X and Shu, XO and Chen, J and Derkach, A and Cai, Q and Liang, X and Long, J and Offit, K and Oh, JH and Reiner, AS and Watt, GP and Woods, M and Yang, Y and Ambrosone, CB and Ambs, S and Chen, Y and Concannon, P and Garcia-Closas, M and Gu, J and Haiman, CA and Hu, JJ and Huo, D and John, EM and Knight, JA and Li, CI and Lynch, CF and Mellemkjær, L and Nathanson, KL and Nemesure, B and Olopade, OI and Olshan, AF and Pal, T and Palmer, JR and Press, MF and Sanderson, M and Sandler, DP and Troester, MA and Zheng, W and Bernstein, JL and Buas, MF and Shu, X}, title = {Case-Case Genome-Wide Analyses Identify Subtype-Informative Variants That Confer Risk for Breast Cancer.}, journal = {Cancer research}, volume = {84}, number = {15}, pages = {2533-2548}, pmid = {38832928}, issn = {1538-7445}, support = {R01DK128615//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)/ ; P30 ES010126/ES/NIEHS NIH HHS/United States ; R21 CA234752/CA/NCI NIH HHS/United States ; R01 CA097397/CA/NCI NIH HHS/United States ; R00CA230205//National Cancer Institute (NCI)/ ; P30 CA008748/CA/NCI NIH HHS/United States ; U01CA083178//National Cancer Institute (NCI))/ ; U01 CA083178/CA/NCI NIH HHS/United States ; R01CA202981//National Cancer Institute (NCI)/ ; R01 CA129639/CA/NCI NIH HHS/United States ; R01CA235553//National Cancer Institute (NCI)/ ; R00 CA230205/CA/NCI NIH HHS/United States ; R01 CA235553/CA/NCI NIH HHS/United States ; P30CA008748//National Cancer Institute (NCI)/ ; R21CA234752//National Cancer Institute (NCI)/ ; R01 CA202981/CA/NCI NIH HHS/United States ; R01 DK128615/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; *Genome-Wide Association Study ; Female ; *Genetic Predisposition to Disease ; *Polymorphism, Single Nucleotide ; *Breast Neoplasms/genetics/pathology ; Triple Negative Breast Neoplasms/genetics/pathology ; Case-Control Studies ; Risk Factors ; }, abstract = {Breast cancer includes several subtypes with distinct characteristic biological, pathologic, and clinical features. Elucidating subtype-specific genetic etiology could provide insights into the heterogeneity of breast cancer to facilitate the development of improved prevention and treatment approaches. In this study, we conducted pairwise case-case comparisons among five breast cancer subtypes by applying a case-case genome-wide association study (CC-GWAS) approach to summary statistics data of the Breast Cancer Association Consortium. The approach identified 13 statistically significant loci and eight suggestive loci, the majority of which were identified from comparisons between triple-negative breast cancer (TNBC) and luminal A breast cancer. Associations of lead variants in 12 loci remained statistically significant after accounting for previously reported breast cancer susceptibility variants, among which, two were genome-wide significant. Fine mapping implicated putative functional/causal variants and risk genes at several loci, e.g., 3q26.31/TNFSF10, 8q22.3/NACAP1/GRHL2, and 8q23.3/LINC00536/TRPS1, for TNBC as compared with luminal cancer. Functional investigation further identified rs16867605 at 8q22.3 as a SNP that modulates the enhancer activity of GRHL2. Subtype-informative polygenic risk scores (PRS) were derived, and patients with a high subtype-informative PRS had an up to two-fold increased risk of being diagnosed with TNBC instead of luminal cancers. The CC-GWAS PRS remained statistically significant after adjusting for TNBC PRS derived from traditional case-control GWAS in The Cancer Genome Atlas and the African Ancestry Breast Cancer Genetic Consortium. The CC-GWAS PRS was also associated with overall survival and disease-specific survival among patients with breast cancer. Overall, these findings have advanced our understanding of the genetic etiology of breast cancer subtypes, particularly for TNBC. Significance: The discovery of subtype-informative genetic risk variants for breast cancer advances our understanding of the etiologic heterogeneity of breast cancer, which could accelerate the identification of targets and personalized strategies for prevention and treatment.}, }
@article {pmid38831036, year = {2024}, author = {Ennist, NM and Wang, S and Kennedy, MA and Curti, M and Sutherland, GA and Vasilev, C and Redler, RL and Maffeis, V and Shareef, S and Sica, AV and Hua, AS and Deshmukh, AP and Moyer, AP and Hicks, DR and Swartz, AZ and Cacho, RA and Novy, N and Bera, AK and Kang, A and Sankaran, B and Johnson, MP and Phadkule, A and Reppert, M and Ekiert, D and Bhabha, G and Stewart, L and Caram, JR and Stoddard, BL and Romero, E and Hunter, CN and Baker, D}, title = {De novo design of proteins housing excitonically coupled chlorophyll special pairs.}, journal = {Nature chemical biology}, volume = {20}, number = {7}, pages = {906-915}, pmid = {38831036}, issn = {1552-4469}, support = {2459-1671//DOE | Advanced Research Projects Agency - Energy (Advanced Research Projects Agency - Energy - U.S. Department of Energy)/ ; P30 GM124169/GM/NIGMS NIH HHS/United States ; S10 OD018483/OD/NIH HHS/United States ; R35 GM148166/GM/NIGMS NIH HHS/United States ; R35 GM128777/GM/NIGMS NIH HHS/United States ; DE-SC0022884//DOE | SC | Basic Energy Sciences (BES)/ ; 805524//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; 754510//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 Marie Sklodowska-Curie Actions (H2020 Excellent Science - Marie Sklodowska-Curie Actions)/ ; Career Award No. 1945572//National Science Foundation (NSF)/ ; 5U19AG065156-02//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19 AG065156/AG/NIA NIH HHS/United States ; R01 GM105691/GM/NIGMS NIH HHS/United States ; 801474//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 Marie Sklodowska-Curie Actions (H2020 Excellent Science - Marie Sklodowska-Curie Actions)/ ; BB/V006630/1//RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; P41 GM103310/GM/NIGMS NIH HHS/United States ; S10 OD028581/OD/NIH HHS/United States ; S10 RR029300/RR/NCRR NIH HHS/United States ; R01 GM139752/GM/NIGMS NIH HHS/United States ; DE-SC0018940 MOD03//DOE | Office of Science (SC)/ ; 854126//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; S10 OD019994/OD/NIH HHS/United States ; DGE1762114//National Science Foundation (NSF)/ ; }, mesh = {*Chlorophyll/chemistry/metabolism ; Crystallography, X-Ray ; Models, Molecular ; Photosynthesis ; Energy Transfer ; Cryoelectron Microscopy ; Protein Conformation ; Light-Harvesting Protein Complexes/chemistry/metabolism ; }, abstract = {Natural photosystems couple light harvesting to charge separation using a 'special pair' of chlorophyll molecules that accepts excitation energy from the antenna and initiates an electron-transfer cascade. To investigate the photophysics of special pairs independently of the complexities of native photosynthetic proteins, and as a first step toward creating synthetic photosystems for new energy conversion technologies, we designed C2-symmetric proteins that hold two chlorophyll molecules in closely juxtaposed arrangements. X-ray crystallography confirmed that one designed protein binds two chlorophylls in the same orientation as native special pairs, whereas a second designed protein positions them in a previously unseen geometry. Spectroscopy revealed that the chlorophylls are excitonically coupled, and fluorescence lifetime imaging demonstrated energy transfer. The cryo-electron microscopy structure of a designed 24-chlorophyll octahedral nanocage with a special pair on each edge closely matched the design model. The results suggest that the de novo design of artificial photosynthetic systems is within reach of current computational methods.}, }
@article {pmid38830960, year = {2024}, author = {Zhang, MY and Othus, M and McMillen, K and Erba, HP and Garcia-Manero, G and Pagel, JM and Sorror, ML and Percival, MM}, title = {Association between class III obesity and overall survival in previously untreated younger patients with acute myeloid leukemia enrolled on SWOG S1203.}, journal = {Leukemia}, volume = {38}, number = {7}, pages = {1488-1493}, pmid = {38830960}, issn = {1476-5551}, support = {U10CA180888//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; U10CA180819//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P30 CA015704/CA/NCI NIH HHS/United States ; CA015704//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Leukemia, Myeloid, Acute/mortality/complications ; Female ; Male ; Adult ; *Obesity/complications/mortality ; Middle Aged ; *Body Mass Index ; Young Adult ; Hematopoietic Stem Cell Transplantation ; Adolescent ; Prognosis ; Survival Rate ; }, abstract = {There has been ongoing debate on the association between obesity and outcomes in acute myeloid leukemia (AML). Currently few studies have stratified outcomes by class I obesity, class II obesity, and class III obesity, and a more nuanced understanding is becoming increasingly important with the rising prevalence of obesity. We examined the association between body mass index (BMI) and outcomes in previously untreated AML in younger patients (age ≤60) enrolled in SWOG S1203 (n = 729). Class III obesity was associated with an increased rate of early death (p = 0.004) and worse overall survival (OS) in multivariate analysis (hazard ratio (HR) 2.48, 95% confidence interval (CI) 1.62-3.80 versus normal weight). Class III obesity was also associated with worse OS after allogeneic hematopoietic cell transplant (HR 2.37, 95% CI 1.24-4.54 versus normal weight). These findings highlight the unique risk of class III obesity in AML, and the importance of further investigation to better characterize this patient population.}, }
@article {pmid38830256, year = {2024}, author = {Loacker, DE and Shannon-Dorcy, K and Rajotte, EJ and Bartell, J}, title = {Closing the Gaps: Addressing the Unmet Needs of Cancer Survivors.}, journal = {Clinical journal of oncology nursing}, volume = {28}, number = {3}, pages = {241-246}, doi = {10.1188/24.CJON.241-246}, pmid = {38830256}, issn = {1538-067X}, mesh = {Humans ; *Cancer Survivors/psychology ; *Neoplasms/nursing ; Female ; Male ; Health Services Needs and Demand ; Middle Aged ; Patient Education as Topic ; Caregivers/psychology/education ; }, abstract = {Moving Beyond Cancer to Wellness is a patient- and caregiver-focused educational outreach event with an inspirational message and lectures that address common concerns among cancer survivors. This event is open to the communi.}, }
@article {pmid38830219, year = {2024}, author = {Gulati, R and Jiao, B and Al-Faouri, R and Sharma, V and Kaul, S and Fleishman, A and Wymer, K and Boorjian, SA and Olumi, AF and Etzioni, R and Gershman, B}, title = {Lifetime Health and Economic Outcomes of Biparametric Magnetic Resonance Imaging as First-Line Screening for Prostate Cancer : A Decision Model Analysis.}, journal = {Annals of internal medicine}, volume = {177}, number = {7}, pages = {871-881}, pmid = {38830219}, issn = {1539-3704}, support = {R50 CA221836/CA/NCI NIH HHS/United States ; U01 CA253915/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; U01 CA199338/CA/NCI NIH HHS/United States ; R35 CA274442/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms/diagnostic imaging/economics/diagnosis ; *Prostate-Specific Antigen/blood ; Middle Aged ; *Cost-Benefit Analysis ; *Decision Support Techniques ; Aged ; *Early Detection of Cancer/economics/methods ; *Multiparametric Magnetic Resonance Imaging ; *Quality-Adjusted Life Years ; Mass Screening/economics/methods ; United States ; Magnetic Resonance Imaging/economics ; Biopsy/economics ; }, abstract = {BACKGROUND: Contemporary prostate cancer (PCa) screening uses first-line prostate-specific antigen (PSA) testing, possibly followed by multiparametric magnetic resonance imaging (mpMRI) for men with elevated PSA levels. First-line biparametric MRI (bpMRI) screening has been proposed as an alternative.<br><br>OBJECTIVE: To evaluate the comparative effectiveness and cost-effectiveness of first-line bpMRI versus PSA-based screening.<br><br>DESIGN: Decision analysis using a microsimulation model.<br><br>DATA SOURCES: Surveillance, Epidemiology, and End Results database; randomized trials.<br><br>TARGET POPULATION: U.S. men aged 55 years with no prior screening or PCa diagnosis.<br><br>TIME HORIZON: Lifetime.<br><br>PERSPECTIVE: U.S. health care system.<br><br>INTERVENTION: Biennial screening to age 69 years using first-line PSA testing (test-positive threshold, 4 &#xb5;g/L) with or without second-line mpMRI or first-line bpMRI (test-positive threshold, PI-RADS [Prostate Imaging Reporting and Data System] 3 to 5 or 4 to 5), followed by biopsy guided by MRI or MRI plus transrectal ultrasonography.<br><br>OUTCOME MEASURES: Screening tests, biopsies, diagnoses, overdiagnoses, treatments, PCa deaths, quality-adjusted and unadjusted life-years saved, and costs.<br><br>RESULTS OF BASE-CASE ANALYSIS: For 1000 men, first-line bpMRI versus first-line PSA testing prevented 2 to 3 PCa deaths and added 10 to 30 life-years (4 to 11 days per person) but increased the number of biopsies by 1506 to 4174 and the number of overdiagnoses by 38 to 124 depending on the biopsy imaging scheme. At conventional cost-effectiveness thresholds, first-line PSA testing with mpMRI followed by either biopsy approach for PI-RADS 4 to 5 produced the greatest net monetary benefits.<br><br>First-line PSA testing remained more cost-effective even if bpMRI was free, all men with low-risk PCa underwent surveillance, or screening was quadrennial.<br><br>LIMITATION: Performance of first-line bpMRI was based on second-line mpMRI data.<br><br>CONCLUSION: Decision analysis suggests that comparative effectiveness and cost-effectiveness of PCa screening are driven by false-positive results and overdiagnoses, favoring first-line PSA testing with mpMRI over first-line bpMRI.<br><br>PRIMARY FUNDING SOURCE: National Cancer Institute.}, }
@article {pmid38829686, year = {2024}, author = {Pineda, JMB and Bradley, RK}, title = {DUX4 is a common driver of immune evasion and immunotherapy failure in metastatic cancers.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, pmid = {38829686}, issn = {2050-084X}, support = {R01 CA251138/CA/NCI NIH HHS/United States ; R01 HL128239/HL/NHLBI NIH HHS/United States ; R01 HL151651/HL/NHLBI NIH HHS/United States ; 1344-18/LLS/LLS/United States ; }, mesh = {Humans ; *Homeodomain Proteins/metabolism/genetics ; *Immunotherapy/methods ; *Immune Evasion ; *Neoplasms/therapy/immunology ; Male ; Female ; Neoplasm Metastasis ; Immune Checkpoint Inhibitors/therapeutic use/pharmacology ; Gene Expression Regulation, Neoplastic ; }, abstract = {Cancer immune evasion contributes to checkpoint immunotherapy failure in many patients with metastatic cancers. The embryonic transcription factor DUX4 was recently characterized as a suppressor of interferon-γ signaling and antigen presentation that is aberrantly expressed in a small subset of primary tumors. Here, we report that DUX4 expression is a common feature of metastatic tumors, with ~10-50% of advanced bladder, breast, kidney, prostate, and skin cancers expressing DUX4. DUX4 expression is significantly associated with immune cell exclusion and decreased objective response to PD-L1 blockade in a large cohort of urothelial carcinoma patients. DUX4 expression is a significant predictor of survival even after accounting for tumor mutational burden and other molecular and clinical features in this cohort, with DUX4 expression associated with a median reduction in survival of over 1 year. Our data motivate future attempts to develop DUX4 as a biomarker and therapeutic target for checkpoint immunotherapy resistance.}, }
@article {pmid38828727, year = {2024}, author = {Wang, Y and Ullah, MA and Waltner, OG and Bhise, SS and Ensbey, KS and Schmidt, CR and Legg, SR and Sekiguchi, T and Nelson, EL and Kuns, RD and Nemychenkov, NS and Atilla, E and Yeh, AC and Takahashi, S and Boiko, JR and Varelias, A and Blazar, BR and Koyama, M and Minnie, SA and Clouston, AD and Furlan, SN and Zhang, P and Hill, GR}, title = {Calcineurin inhibition rescues alloantigen-specific central memory T cell subsets that promote chronic GVHD.}, journal = {The Journal of clinical investigation}, volume = {134}, number = {11}, pages = {}, pmid = {38828727}, issn = {1558-8238}, support = {KL2 TR002317/TR/NCATS NIH HHS/United States ; P01 CA018029/CA/NCI NIH HHS/United States ; R01 HL148164/HL/NHLBI NIH HHS/United States ; }, mesh = {*Graft vs Host Disease/immunology/prevention &amp; control/pathology ; Animals ; Mice ; *Isoantigens/immunology ; *Calcineurin Inhibitors/pharmacology ; Chronic Disease ; *Memory T Cells/immunology ; Tacrolimus/pharmacology ; CD4-Positive T-Lymphocytes/immunology ; Cyclosporine/pharmacology ; Female ; CD8-Positive T-Lymphocytes/immunology ; T-Lymphocyte Subsets/immunology ; }, abstract = {Calcineurin inhibitors (CNIs) constitute the backbone of modern acute graft-versus-host disease (aGVHD) prophylaxis regimens but have limited efficacy in the prevention and treatment of chronic GVHD (cGVHD). We investigated the effect of CNIs on immune tolerance after stem cell transplantation with discovery-based single-cell gene expression and T cell receptor (TCR) assays of clonal immunity in tandem with traditional protein-based approaches and preclinical modeling. While cyclosporin and tacrolimus suppressed the clonal expansion of CD8+ T cells during GVHD, alloreactive CD4+ T cell clusters were preferentially expanded. Moreover, CNIs mediated reversible dose-dependent suppression of T cell activation and all stages of donor T cell exhaustion. Critically, CNIs promoted the expansion of both polyclonal and TCR-specific alloreactive central memory CD4+ T cells (TCM) with high self-renewal capacity that mediated cGVHD following drug withdrawal. In contrast to posttransplant cyclophosphamide (PT-Cy), CSA was ineffective in eliminating IL-17A-secreting alloreactive T cell clones that play an important role in the pathogenesis of cGVHD. Collectively, we have shown that, although CNIs attenuate aGVHD, they paradoxically rescue alloantigen-specific TCM, especially within the CD4+ compartment in lymphoid and GVHD target tissues, thus predisposing patients to cGVHD. These data provide further evidence to caution against CNI-based immune suppression without concurrent approaches that eliminate alloreactive T cell clones.}, }
@article {pmid38828674, year = {2024}, author = {Nguyen, JK and Harik, LR and Klein, EA and Li, J and Corrigan, D and Liu, S and Chan, E and Hawley, S and Auman, H and Newcomb, LF and Carroll, PR and Cooperberg, MR and Filson, CP and Simko, JP and Nelson, PS and Tretiakova, MS and Troyer, D and True, LD and Vakar-Lopez, F and Weight, CJ and Lin, DW and Brooks, JD and McKenney, JK}, title = {Proposal for an optimised definition of adverse pathology (unfavourable histology) that predicts metastatic risk in prostatic adenocarcinoma independent of grade group and pathological stage.}, journal = {Histopathology}, volume = {85}, number = {4}, pages = {598-613}, pmid = {38828674}, issn = {1365-2559}, support = {P50 CA097186/CA/NCI NIH HHS/United States ; U01 CA224255/CA/NCI NIH HHS/United States ; CA097186//PNW Prostate Cancer SPORE/ ; UO1 CA22425//National Institute of Health/ ; //Roswell Country Club Prostate Cancer Research Award/ ; //Winship Cancer Institute of Emory University/ ; //Canary Foundation/ ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms/pathology/surgery ; *Neoplasm Grading ; Middle Aged ; Aged ; *Adenocarcinoma/pathology ; *Prostatectomy ; Prognosis ; Kaplan-Meier Estimate ; Neoplasm Staging ; Proportional Hazards Models ; Neoplasm Metastasis/pathology ; Nomograms ; Cohort Studies ; }, abstract = {AIMS: Histological grading of prostate cancer is a powerful prognostic tool, but current criteria for grade assignment are not fully optimised. Our goal was to develop and test a simplified histological grading model, based heavily on large cribriform/intraductal carcinoma, with optimised sensitivity for predicting metastatic potential.<br><br>METHODS AND RESULTS: Two separate non-overlapping cohorts were identified: a 419-patient post-radical prostatectomy cohort with long term clinical follow-up and a 209-patient post-radical prostatectomy cohort in which all patients had pathologically confirmed metastatic disease. All prostatectomies were re-reviewed for high-risk histological patterns of carcinoma termed 'unfavourable histology'. Unfavourable histology is defined by any classic Gleason pattern 5 component, any large cribriform morphology (>&#x2009;0.25&#x2009;mm) or intraductal carcinoma, complex intraluminal papillary architecture, grade 3 stromogenic carcinoma and complex anastomosing cord-like growth. For the outcome cohort, Kaplan-Meier analysis compared biochemical recurrence, metastasis and death between subjects with favourable and unfavourable histology, stratified by pathological stage and grade group. Multivariable Cox proportional hazards models evaluated adding unfavourable histology to the Memorial Sloan Kettering Cancer Center (MSKCC) post-prostatectomy nomogram and stratification by percentage of unfavourable histology. At 15&#x2009;years unfavourable histology predicted biochemical recurrence, with sensitivity of 93% and specificity of 88%, metastatic disease at 100 and 48% and death at 100 and 46%. Grade group 2 prostate cancers with unfavourable histology were associated with metastasis independent of pathological stage, while those without had no risk. Histological models for prediction of metastasis based on only large cribriform/intraductal carcinoma or increasing diameter of cribriform size improved specificity, but with lower sensitivity. Multivariable Cox proportional hazards models demonstrated that unfavourable histology significantly improved discriminatory power of the MSKCC post-prostatectomy nomogram for biochemical failure (likelihood ratio test P&#x2009;<&#x2009;0.001). In the retrospective review of a separate RP cohort in which all patients had confirmed metastatic disease, none had unequivocal favourable histology.<br><br>CONCLUSIONS: Unfavourable histology at radical prostatectomy is associated with metastatic risk, predicted adverse outcomes better than current grading and staging systems and improved the MSKCC post-prostatectomy nomogram. Most importantly, unfavourable histology stratified grade group 2 prostate cancers into those with and without metastatic potential, independent of stage. While unfavourable histology is driven predominantly by large cribriform/intraductal carcinoma, the recognition and inclusion of other specific architectural patterns add to the sensitivity for predicting metastatic disease. Moreover, a simplified dichotomous model improves communication and could increase implementation.}, }
@article {pmid38827796, year = {2024}, author = {Jones, SM and Yi, J and Henrikson, NB and Panattoni, L and Shankaran, V}, title = {Financial hardship after cancer: revision of a conceptual model and development of patient-reported outcome measures.}, journal = {Future science OA}, volume = {10}, number = {1}, pages = {FSO983}, pmid = {38827796}, issn = {2056-5623}, abstract = {Aim: This qualitative study refined a conceptual model of financial hardship and developed measures corresponding to model constructs. Methods: Eighteen women with breast cancer recruited through a comprehensive cancer center completed interviews. A qualitative framework analysis was conducted of the interviews. Results: Participants experienced varying levels of financial hardship. Protective factors included good health insurance, work accommodations and social support. Participants worried about cancer care costs and employment. Programs for alleviating financial hardship had high administrative burdens. Four preliminary financial hardship measures were developed: coping, impacts, depression and worry. Conclusion: Reducing administrative barriers to benefits could reduce financial hardship after cancer. More research is needed on the effects of out-of-network/formulary care and denials of coverage and to validate the measures.}, }
@article {pmid38826243, year = {2024}, author = {Tran-Kiem, C and Paredes, MI and Perofsky, AC and Frisbie, LA and Xie, H and Kong, K and Weixler, A and Greninger, AL and Roychoudhury, P and Peterson, JM and Delgado, A and Halstead, H and MacKellar, D and Dykema, P and Gamboa, L and Frazar, CD and Ryke, E and Stone, J and Reinhart, D and Starita, L and Thibodeau, A and Yun, C and Aragona, F and Black, A and Viboud, C and Bedford, T}, title = {Fine-scale spatial and social patterns of SARS-CoV-2 transmission from identical pathogen sequences.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {38826243}, support = {R35 GM119774/GM/NIGMS NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; U01 CK000630/CK/NCEZID CDC HHS/United States ; }, abstract = {Pathogen genomics can provide insights into underlying infectious disease transmission patterns, but new methods are needed to handle modern large-scale pathogen genome datasets and realize this full potential. In particular, genetically proximal viruses should be highly informative about transmission events as genetic proximity indicates epidemiological linkage. Here, we leverage pairs of identical sequences to characterise fine-scale transmission patterns using 114,298 SARS-CoV-2 genomes collected through Washington State (USA) genomic sentinel surveillance with associated age and residence location information between March 2021 and December 2022. This corresponds to 59,660 sequences with another identical sequence in the dataset. We find that the location of pairs of identical sequences is highly consistent with expectations from mobility and social contact data. Outliers in the relationship between genetic and mobility data can be explained by SARS-CoV-2 transmission between postal codes with male prisons, consistent with transmission between prison facilities. We find that transmission patterns between age groups vary across spatial scales. Finally, we use the timing of sequence collection to understand the age groups driving transmission. Overall, this work improves our ability to leverage large pathogen genome datasets to understand the determinants of infectious disease spread.}, }
@article {pmid38826197, year = {2024}, author = {Salisbury, NJH and Amonkar, S and Vinueza, JL and Carter, JJ and Roman, A and Galloway, DA}, title = {Polyomavirus ALTOs, but not MTs, downregulate viral early gene expression by activating the NF-κB pathway.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38826197}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R35 CA209979/CA/NCI NIH HHS/United States ; }, abstract = {Polyomaviruses are small, circular dsDNA viruses that can cause cancer. Alternative splicing of polyomavirus early transcripts generates large and small tumor antigens (LT, ST) that play essential roles in viral replication and tumorigenesis. Some polyomaviruses also express middle tumor antigens (MTs) or Alternate LT ORFs (ALTOs), which are evolutionarily related but have distinct gene structures. MTs are a splice variant of the early transcript whereas ALTOs are overprinted on the second exon of the LT transcript in an alternate reading frame and are translated via an alternative start codon. Merkel cell polyomavirus (MCPyV), the only human polyomavirus that causes cancer, encodes an ALTO but its role in the viral lifecycle and tumorigenesis has remained elusive. Here, we show MCPyV ALTO acts as a tumor suppressor and is silenced in Merkel cell carcinoma (MCC). Rescuing ALTO in MCC cells induces growth arrest and activates NF-κB signaling. ALTO activates NF-κB by binding SQSTM1 and TRAF2&amp;3 via two N-Terminal Activating Regions (NTAR1+2), resembling Epstein-Barr virus (EBV) Latent Membrane Protein 1 (LMP1).. Following activation, NF-κB dimers bind the MCPyV non-coding control region (NCCR) and downregulate early transcription. Beyond MCPyV, NTAR motifs are conserved in other polyomavirus ALTOs, which activate NF-κB signaling, but are lacking in MTs that do not. Furthermore, polyomavirus ALTOs downregulate their respective viral early transcription in an NF-κB and NTAR dependent manner. Our findings suggest that ALTOs evolved to suppress viral replication and promote viral latency and that MCPyV ALTO must be silenced for MCC to develop.}, }
@article {pmid38826171, year = {2024}, author = {Lowndes, JS and Holder, AM and Markowitz, EH and Clatterbuck, C and Bradford, AL and Doering, K and Stevens, MH and Butland, S and Burke, D and Kross, S and Hollister, JW and Stawitz, C and Siple, MC and Rios, A and Welch, JN and Li, B and Nojavan, F and Davis, A and Steiner, E and London, JM and Fenwick, I and Hunzinger, A and Verstaen, J and Holmes, E and Virdi, M and Barrett, AP and Robinson, E}, title = {Shifting institutional culture to develop climate solutions with Open Science.}, journal = {Ecology and evolution}, volume = {14}, number = {6}, pages = {e11341}, pmid = {38826171}, issn = {2045-7758}, abstract = {To address our climate emergency, "we must rapidly, radically reshape society"-Johnson &amp; Wilkinson, All We Can Save. In science, reshaping requires formidable technical (cloud, coding, reproducibility) and cultural shifts (mindsets, hybrid collaboration, inclusion). We are a group of cross-government and academic scientists that are exploring better ways of working and not being too entrenched in our bureaucracies to do better science, support colleagues, and change the culture at our organizations. We share much-needed success stories and action for what we can all do to reshape science as part of the Open Science movement and 2023 Year of Open Science.}, }
@article {pmid38825968, year = {2024}, author = {Vilcot, M and Faure, N and Andrews, KR and Bowen, BW and Leprieur, F and Manel, S}, title = {Neutral processes and taxonomic scale drive beta species-genetic diversity correlations in a submesophotic tropical reef fish.}, journal = {Molecular ecology}, volume = {33}, number = {13}, pages = {e17423}, doi = {10.1111/mec.17423}, pmid = {38825968}, issn = {1365-294X}, support = {ANR-18-CE02-0016//Agence Nationale de la Recherche/ ; }, mesh = {Animals ; *Genetic Variation ; *Fishes/genetics/classification ; *Coral Reefs ; Pacific Ocean ; *Polymorphism, Single Nucleotide/genetics ; Indian Ocean ; Biodiversity ; Genetics, Population ; }, abstract = {If similar evolutionary forces maintain intra- and interspecific diversity, patterns of diversity at both levels of biological organization can be expected to covary across space. Although this prediction of a positive species-genetic diversity correlation (SGDC) has been tested for several taxa in natural landscapes, no study has yet evaluated the influence of the community delineation on these SGDCs. In this study, we focused on tropical fishes of the Indo-Pacific Ocean, using range-wide single nucleotide polymorphism data for a deep-sea fish (Etelis coruscans) and species presence data of 4878 Teleostei species. We investigated whether a diversity continuum occurred, for different community delineations (subfamily, family, order and class) and spatial extents, and which processes explained these diversity patterns. We found no association between genetic diversity and species richness (α-SGDC), regardless of the community and spatial extent. In contrast, we evidenced a positive relationship between genetic and species dissimilarities (β-SGDC) when the community was defined at the subfamily or family level of the species of interest, and when the Western Indian Ocean was excluded. This relationship was related to the imprint of dispersal processes across levels of biological organization in Lutjanidae. However, this positive β-SGDC was lost when considering higher taxonomic communities and at the scale of the entire Indo-Pacific, suggesting different responses of populations and communities to evolutionary processes at these scales. This study provides evidence that the taxonomic scale at which communities are defined and the spatial extent are pivotal to better understand the processes shaping diversity across levels of biological organization.}, }
@article {pmid38825885, year = {2024}, author = {Boeckh, M and Pergam, SA and Limaye, AP and Englund, J and Corey, L and Hill, JA}, title = {How Immunocompromised Hosts Were Left Behind in the Quest to Control the COVID-19 Pandemic.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {79}, number = {4}, pages = {1018-1023}, pmid = {38825885}, issn = {1537-6591}, support = {UM1 AI068614/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Immunocompromised Host ; *COVID-19/prevention &amp; control/immunology/epidemiology ; *SARS-CoV-2/immunology ; Antiviral Agents/therapeutic use ; Clinical Trials as Topic ; Pandemics/prevention &amp; control ; COVID-19 Vaccines/immunology ; }, abstract = {The immunocompromised population was disproportionately affected by the severe acute respiratory syndrome coronavirus 2 pandemic. However, these individuals were largely excluded from clinical trials of vaccines, monoclonal antibodies, and small molecule antivirals. Although the community of scientists, clinical researchers, and funding agencies have proven that these therapeutics can be made and tested in record time, extending this progress to vulnerable and medically complex individuals from the start has been a missed opportunity. Here, we advocate that it is paramount to plan for future pandemics by investing in specific clinical trial infrastructure for the immunocompromised population to be prepared when the need arises.}, }
@article {pmid38825627, year = {2024}, author = {Cortés, J and Hurvitz, SA and Im, SA and Iwata, H and Curigliano, G and Kim, SB and Chiu, JWY and Pedrini, JL and Li, W and Yonemori, K and Bianchini, G and Loi, S and Borges, GS and Wang, X and Bachelot, T and Nakatani, S and Ashfaque, S and Liang, Z and Egorov, A and Hamilton, E}, title = {Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer: long-term survival analysis of the DESTINY-Breast03 trial.}, journal = {Nature medicine}, volume = {30}, number = {8}, pages = {2208-2215}, pmid = {38825627}, issn = {1546-170X}, mesh = {Humans ; *Breast Neoplasms/drug therapy/pathology/genetics/mortality ; Female ; *Trastuzumab/therapeutic use/adverse effects ; *Receptor, ErbB-2/metabolism/genetics ; *Ado-Trastuzumab Emtansine/therapeutic use/adverse effects ; Middle Aged ; Adult ; Aged ; Camptothecin/analogs &amp; derivatives/therapeutic use/adverse effects ; Neoplasm Metastasis ; Immunoconjugates/therapeutic use/adverse effects ; Progression-Free Survival ; Survival Analysis ; Antineoplastic Agents, Immunological/therapeutic use/adverse effects ; Maytansine/analogs &amp; derivatives/therapeutic use/adverse effects ; }, abstract = {Trastuzumab deruxtecan (T-DXd) demonstrated significantly improved efficacy over trastuzumab emtansine (T-DM1) in DESTINY-Breast03 (median follow-up, 28 months). We report updated efficacy and safety analyses, including secondary and exploratory efficacy endpoints (median follow-up, 41 months) of DESTINY-Breast03. Patients with advanced HER2-positive metastatic breast cancer previously treated with taxane and trastuzumab were randomized to T-DXd (5.4 mg per kg (261 patients)) or T-DM1 (3.6 mg per kg (263 patients)). The primary endpoint was progression-free survival (PFS) by blinded independent central review and was previously reported. The key secondary endpoint was overall survival (OS). Other secondary endpoints included objective response rate, duration of response and PFS (all by investigator assessment) and safety. At data cutoff, 20 November 2023, median PFS by investigator assessment was 29.0 versus 7.2 months (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.24-0.38), the 36-month PFS rate was 45.7% versus 12.4% and median OS was 52.6 versus 42.7 months (HR, 0.73; 95% CI, 0.56-0.94) with T-DXd versus T-DM1, respectively. Treatment-emergent adverse events were consistent with the previous analyses. No new instances of grade ≥3 interstitial lung disease or pneumonitis occurred (all grade rate, 16.7% (T-DXd) versus 3.4% (T-DM1)). With longer follow-up, T-DXd continued to demonstrate superior efficacy over T-DM1 with a manageable safety profile. ClinicalTrials.gov registration: NCT03529110 .}, }
@article {pmid38825445, year = {2024}, author = {Mehta, RS}, title = {SOHO State of the Art Updates and Next Questions | Current Status and Future Directions of Donor Selection.}, journal = {Clinical lymphoma, myeloma &amp; leukemia}, volume = {24}, number = {12}, pages = {821-826}, doi = {10.1016/j.clml.2024.05.011}, pmid = {38825445}, issn = {2152-2669}, mesh = {Humans ; *Donor Selection/methods/standards ; *Hematopoietic Stem Cell Transplantation/methods ; *Histocompatibility Testing/methods ; HLA Antigens/immunology/genetics ; Tissue Donors ; Histocompatibility ; }, abstract = {The landscape of HLA matching in hematopoietic cell transplantation (HCT) is continuously advancing, introducing more nuanced criteria beyond traditional 10/10 HLA-A, -B, -C, and -DRB1 allele matching. For 10/10 matched donors, prioritizing a donor with a "core" permissive HLA-DPB1 mismatch is recommended over "noncore" permissive mismatches, with nonpermissive mismatches being the least prefered. In the one-antigen mismatched setting (7/8 HLA-matched), HLA-C matching, particularly avoiding high-expression mismatches at residues 116 or 77/80, is preferred over HLA-A or HLA-B mismatches. HLA B-leader matching is beneficial in both one-antigen mismatched and haploidentical HCT. Additionally, specific HLA mismatches in haploidentical HCT, such as DRB1 mismatches with DQB1 matches and DPB1 nonpermissive mismatches are linked to better outcomes. Among non-HLA factors, evidence consistently underscores the pivotal impact of donor age on overall survival. For HLA-mismatched transplants, including haploidentical HCT, avoidance of donors against whom the recipient has preformed donor-specific antibodies is paramount. Selecting a cytomegalovirus (CMV) seronegative donor is important particularly for CMV-negative recipients; however, more research is needed in the letermovir prophylaxis era. The impact of ABO-matching on transplant outcomes is debatable. Other unanswered questions include defining "younger" donors and establishing hierarchy in donor selection based on factors like CMV status, ABO compatibility, or sex-mismatch, to name a few. Future research addressing these issues will refine donor selection algorithms and improve transplant success. In conclusion, selecting a donor for HCT requires multifaceted considerations, integrating evolving HLA-matching criteria and non-HLA factors, to optimize HCT outcomes in this rapidly advancing field.}, }
@article {pmid38825423, year = {2024}, author = {Neefjes, J and Gurova, K and Sarthy, J and Szabó, G and Henikoff, S}, title = {Chromatin as an old and new anticancer target.}, journal = {Trends in cancer}, volume = {10}, number = {8}, pages = {696-707}, pmid = {38825423}, issn = {2405-8025}, support = {/HHMI/Howard Hughes Medical Institute/United States ; K08 CA256167/CA/NCI NIH HHS/United States ; R01 CA266216/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Chromatin/metabolism/drug effects ; *Neoplasms/drug therapy/genetics/pathology ; *DNA Damage/drug effects ; *Antineoplastic Agents/pharmacology/therapeutic use ; Molecular Targeted Therapy/methods ; Anthracyclines/therapeutic use/pharmacology ; Animals ; }, abstract = {Recent genome-wide analyses identified chromatin modifiers as one of the most frequently mutated classes of genes across all cancers. However, chemotherapies developed for cancers involving DNA damage remain the standard of care for chromatin-deranged malignancies. In this review we address this conundrum by establishing the concept of 'chromatin damage': the non-genetic damage to protein-DNA interactions induced by certain small molecules. We highlight anthracyclines, a class of chemotherapeutic agents ubiquitously applied in oncology, as an example of overlooked chromatin-targeting agents. We discuss our current understanding of this phenomenon and explore emerging chromatin-damaging agents as a basis for further studies to maximize their impact in modern cancer treatment.}, }
@article {pmid38823511, year = {2024}, author = {Powles, T and Chang, YH and Yamamoto, Y and Munoz, J and Reyes-Cosmelli, F and Peer, A and Cohen, G and Yu, EY and Lorch, A and Bavle, A and Homet Moreno, B and Markensohn, J and Edmondson, M and Chen, C and Cristescu, R and Peña, C and Lunceford, J and Gunduz, S}, title = {Pembrolizumab for advanced urothelial carcinoma: exploratory ctDNA biomarker analyses of the KEYNOTE-361 phase 3 trial.}, journal = {Nature medicine}, volume = {30}, number = {9}, pages = {2508-2516}, pmid = {38823511}, issn = {1546-170X}, mesh = {Humans ; *Antibodies, Monoclonal, Humanized/therapeutic use ; *Circulating Tumor DNA/blood/genetics ; *Biomarkers, Tumor/genetics/blood ; Female ; Male ; Aged ; Middle Aged ; Retrospective Studies ; Antineoplastic Agents, Immunological/therapeutic use ; Urologic Neoplasms/drug therapy/genetics/pathology/blood ; Carcinoma, Transitional Cell/drug therapy/genetics/blood/pathology/mortality ; Treatment Outcome ; Urinary Bladder Neoplasms/drug therapy/genetics/blood/pathology ; Progression-Free Survival ; }, abstract = {Circulating tumor DNA (ctDNA) is emerging as a potential biomarker in early-stage urothelial cancer, but its utility in metastatic disease remains unknown. In the phase 3 KEYNOTE-361 study, pembrolizumab with and without chemotherapy was compared with chemotherapy alone in patients with metastatic urothelial cancer. The study did not meet prespecified efficacy thresholds for statistical significance. To identify potential biomarkers of response, we retrospectively evaluated the association of pre- and posttreatment ctDNA with clinical outcomes in a subset of patients who received pembrolizumab (n = 130) or chemotherapy (n = 130) in KEYNOTE-361. Baseline ctDNA was associated with best overall response (BOR; P = 0.009), progression-free survival (P < 0.001) and overall survival (OS; P < 0.001) for pembrolizumab but not for chemotherapy (all; P > 0.05). Chemotherapy induced larger ctDNA decreases from baseline to treatment cycle 2 than pembrolizumab; however, change with pembrolizumab (n = 87) was more associated with BOR (P = 4.39 × 10[-5]) and OS (P = 7.07 × 10[-5]) than chemotherapy (n = 102; BOR: P = 1.01 × 10[-4]; OS: P = 0.018). Tumor tissue-informed versions of ctDNA change metrics were most associated with clinical outcomes but did not show a statistically significant independent value for explaining OS beyond radiographic change by RECIST v.1.1 when jointly modeled (pembrolizumab P = 0.364; chemotherapy P = 0.823). These results suggest distinct patterns in early ctDNA changes with immunotherapy and chemotherapy and differences in their association with long-term outcomes, which provide preliminary insights into the utility of liquid biopsies for treatment monitoring in metastatic urothelial cancer. Clinical trial registration: NCT02853305 .}, }
@article {pmid38823398, year = {2024}, author = {Oh, DY and He, AR and Bouattour, M and Okusaka, T and Qin, S and Chen, LT and Kitano, M and Lee, CK and Kim, JW and Chen, MH and Suksombooncharoen, T and Ikeda, M and Lee, MA and Chen, JS and Potemski, P and Burris, HA and Ostwal, V and Tanasanvimon, S and Morizane, C and Zaucha, RE and McNamara, MG and Avallone, A and Cundom, JE and Breder, V and Tan, B and Shimizu, S and Tougeron, D and Evesque, L and Petrova, M and Zhen, DB and Gillmore, R and Gupta, VG and Dayyani, F and Park, JO and Buchschacher, GL and Rey, F and Kim, H and Wang, J and Morgan, C and Rokutanda, N and Żotkiewicz, M and Vogel, A and Valle, JW}, title = {Durvalumab or placebo plus gemcitabine and cisplatin in participants with advanced biliary tract cancer (TOPAZ-1): updated overall survival from a randomised phase 3 study.}, journal = {The lancet. Gastroenterology &amp; hepatology}, volume = {9}, number = {8}, pages = {694-704}, doi = {10.1016/S2468-1253(24)00095-5}, pmid = {38823398}, issn = {2468-1253}, mesh = {Humans ; *Cisplatin/administration &amp; dosage/therapeutic use ; *Gemcitabine ; *Deoxycytidine/analogs &amp; derivatives/administration &amp; dosage/therapeutic use ; *Biliary Tract Neoplasms/drug therapy/mortality/pathology ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Male ; Female ; Middle Aged ; Double-Blind Method ; Aged ; *Antibodies, Monoclonal/administration &amp; dosage/therapeutic use/adverse effects ; Adult ; Survival Rate ; }, abstract = {BACKGROUND: In the preplanned interim analysis of the TOPAZ-1 study, durvalumab plus gemcitabine-cisplatin significantly improved overall survival versus placebo plus gemcitabine-cisplatin in participants with advanced biliary tract cancer. We aimed to report updated overall survival and safety data from TOPAZ-1 with additional follow-up and data maturity beyond the interim analysis.<br><br>METHODS: TOPAZ-1 was a phase 3, randomised, double-masked, placebo-controlled, global study done at 105 sites in 17 countries. Participants aged 18 years or older with unresectable, locally advanced, or metastatic biliary tract cancer were randomly assigned (1:1) to durvalumab plus gemcitabine-cisplatin or placebo plus gemcitabine-cisplatin using a computer-generated randomisation scheme, stratified by disease status and primary tumour location. Participants received durvalumab (1500 mg) or placebo on day 1 of each cycle every 3 weeks for up to eight cycles, plus gemcitabine (1000 mg/m[2]) and cisplatin (25 mg/m[2]) intravenously on days 1 and 8 of each cycle every 3 weeks for up to eight cycles, followed by durvalumab (1500 mg) or placebo monotherapy every 4 weeks until disease progression or other discontinuation criteria were met. Investigators and participants were masked to study treatment. The primary endpoint was overall survival. TOPAZ-1 met its primary endpoint at the preplanned interim analysis, and the study is active but no longer recruiting participants. Updated overall survival and safety data from TOPAZ-1, with additional follow-up (data cutoff Feb 25, 2022) and data maturity beyond the interim analysis, are reported here. Efficacy was assessed in the full analysis set (all randomly assigned participants). Safety was assessed in the safety analysis set (all participants who received at least one dose of study treatment). The TOPAZ-1 study is registered with ClinicalTrials.gov, NCT03875235.<br><br>FINDINGS: From April 16, 2019, to Dec 11, 2020, 914 participants were enrolled, 685 of whom were randomly assigned (341 to the durvalumab plus gemcitabine-cisplatin group and 344 to the placebo plus gemcitabine-cisplatin group). 345 (50%) participants were male and 340 (50%) were female. Median follow-up at the updated data cutoff was 23&#xb7;4 months (95% CI 20&#xb7;6-25&#xb7;2) in the durvalumab plus gemcitabine-cisplatin group and 22&#xb7;4 months (21&#xb7;4-23&#xb7;8) in the placebo plus gemcitabine-cisplatin group. At the updated data cutoff, 248 (73%) participants in the durvalumab plus gemcitabine-cisplatin group and 279 (81%) participants in the placebo plus gemcitabine-cisplatin group had died (median overall survival 12&#xb7;9 months [95% CI 11&#xb7;6-14&#xb7;1] vs 11&#xb7;3 months [10&#xb7;1-12&#xb7;5]; hazard ratio 0&#xb7;76 [95% CI 0&#xb7;64-0&#xb7;91]). Kaplan-Meier-estimated 24-month overall survival rates were 23&#xb7;6% (95% CI 18&#xb7;7-28&#xb7;9) in the durvalumab plus gemcitabine-cisplatin group and 11&#xb7;5% (7&#xb7;6-16&#xb7;2) in the placebo plus gemcitabine-cisplatin group. Maximum grade 3 or 4 adverse events occurred in 250 (74%) of 338 participants in the durvalumab plus gemcitabine-cisplatin group and 257 (75%) of 342 in the placebo plus gemcitabine-cisplatin group. The most common maximum grade 3 or 4 treatment-related adverse events were decreased neutrophil count (70 [21%] vs 86 [25%]), anaemia (64 [19%] vs 64 [19%]), and neutropenia (63 [19%] vs 68 [20%]).<br><br>INTERPRETATION: Durvalumab plus gemcitabine-cisplatin showed robust and sustained overall survival benefit with no new safety signals. Findings continue to support the regimen as a standard of care for people with untreated, advanced biliary tract cancer.<br><br>FUNDING: AstraZeneca.}, }
@article {pmid38822357, year = {2024}, author = {John, EM and Koo, J and Phipps, AI and Longacre, TA and Kurian, AW and Ingles, SA and Wu, AH and Hines, LM}, title = {Reproductive characteristics, menopausal status, race and ethnicity, and risk of breast cancer subtypes defined by ER, PR and HER2 status: the Breast Cancer Etiology in Minorities study.}, journal = {Breast cancer research : BCR}, volume = {26}, number = {1}, pages = {88}, pmid = {38822357}, issn = {1465-542X}, support = {1RB-0287//California Breast Cancer Research Program/ ; 7PB-0068//California Breast Cancer Research Program/ ; U01 CA164920/NH/NIH HHS/United States ; DAMD17-96-1-6071//U.S. Department of Defense/ ; U01 CA164920/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Middle Aged ; Pregnancy ; *Breast Neoplasms/epidemiology/ethnology/genetics/metabolism ; California/epidemiology ; Case-Control Studies ; Ethnic and Racial Minorities ; Ethnicity/statistics &amp; numerical data ; Hispanic or Latino/statistics &amp; numerical data ; *Menopause ; Parity ; *Receptor, ErbB-2/metabolism ; *Receptors, Estrogen/metabolism ; *Receptors, Progesterone/metabolism ; Reproductive History ; Risk Factors ; Asian ; Black or African American ; }, abstract = {BACKGROUND: Associations between reproductive factors and risk of breast cancer differ by subtype defined by joint estrogen receptor (ER), progesterone receptor (PR), and HER2 expression status. Racial and ethnic differences in the incidence of breast cancer subtypes suggest etiologic heterogeneity, yet data are limited because most studies have included non-Hispanic White women only.<br><br>METHODS: We analyzed harmonized data for 2,794 breast cancer cases and 4,579 controls, of whom 90% self-identified as African American, Asian American or Hispanic. Questionnaire data were pooled from three population-based studies conducted in California and data on tumor characteristics were obtained from the California Cancer Registry. The study sample included 1,530 luminal A (ER-positive and/or PR-positive, HER2-negative), 442 luminal B (ER-positive and/or PR-positive, HER2-positive), 578 triple-negative (TN; ER-negative, PR-negative, HER2-negative), and 244 HER2-enriched (ER-negative, PR-negative, HER2-positive) cases. We used multivariable unconditional logistic regression models to estimate subtype-specific ORs and 95% confidence intervals associated with parity, breast-feeding, and other reproductive characteristics by menopausal status and race and ethnicity.<br><br>RESULTS: Subtype-specific associations with reproductive factors revealed some notable differences by menopausal status and race and ethnicity. Specifically, higher parity without breast-feeding was associated with higher risk of luminal A and TN subtypes among premenopausal African American women. In contrast, among Asian American and Hispanic women, regardless of menopausal status, higher parity with a breast-feeding history was associated with lower risk of luminal A subtype. Among premenopausal women only, luminal A subtype was associated with older age at first full-term pregnancy (FTP), longer interval between menarche and first FTP, and shorter interval since last FTP, with similar OR estimates across the three racial and ethnic groups.<br><br>CONCLUSIONS: Subtype-specific associations with reproductive factors overall and by menopausal status, and race and ethnicity, showed some differences, underscoring that understanding etiologic heterogeneity in racially and ethnically diverse study samples is essential. Breast-feeding is likely the only reproductive factor that is potentially modifiable. Targeted efforts to promote and facilitate breast-feeding could help mitigate the adverse effects of higher parity among premenopausal African American women.}, }
@article {pmid38821639, year = {2024}, author = {Kulac, I and Roudier, MP and Haffner, MC}, title = {Molecular Pathology of Prostate Cancer.}, journal = {Clinics in laboratory medicine}, volume = {44}, number = {2}, pages = {161-180}, doi = {10.1016/j.cll.2023.08.003}, pmid = {38821639}, issn = {1557-9832}, mesh = {Humans ; Male ; Mutation ; *Prostatic Neoplasms/genetics/pathology/diagnosis ; Prostate/pathology ; }, abstract = {Molecular profiling studies have shed new light on the complex biology of prostate cancer. Genomic studies have highlighted that structural rearrangements are among the most common recurrent alterations. In addition, both germline and somatic mutations in DNA repair genes are enriched in patients with advanced disease. Primary prostate cancer has long been known to be multifocal, but recent studies demonstrate that a large fraction of prostate cancer shows evidence of multiclonality, suggesting that genetically distinct, independently arising tumor clones coexist. Metastatic prostate cancer shows a high level of morphologic and molecular diversity, which is associated with resistance to systemic therapies. The resulting high level of intratumoral heterogeneity has important implications for diagnosis and poses major challenges for the implementation of molecular studies. Here we provide a concise review of the molecular pathology of prostate cancer, highlight clinically relevant alterations, and discuss opportunities for molecular testing.}, }
@article {pmid38820500, year = {2024}, author = {Smith, MR and Jegede, OA and Martin, P and Till, BG and Parekh, SS and Yang, DT and Hsi, ED and Witzig, T and Dave, S and Scott, D and Hanson, C and Kostakoglu Shields, L and Abdel-Samad, N and Casulo, C and Bartlett, NL and Caimi, PF and Al Baghdadi, T and Blum, KA and Romer, MD and Inwards, DJ and Lerner, RE and Wagner, LI and Little, RF and Friedberg, JW and Leonard, JP and Kahl, BS}, title = {Randomized study of induction with bendamustine-rituximab ± bortezomib and maintenance with rituximab ± lenalidomide for MCL.}, journal = {Blood}, volume = {144}, number = {10}, pages = {1083-1092}, pmid = {38820500}, issn = {1528-0020}, support = {U10 CA180820/CA/NCI NIH HHS/United States ; U10 CA180794/CA/NCI NIH HHS/United States ; UG1 CA189828/CA/NCI NIH HHS/United States ; U10 CA180821/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; UG1 CA189863/CA/NCI NIH HHS/United States ; UG1 CA189957/CA/NCI NIH HHS/United States ; UG1 CA189971/CA/NCI NIH HHS/United States ; UG1 CA232760/CA/NCI NIH HHS/United States ; UG1 CA233234/CA/NCI NIH HHS/United States ; UG1 CA233277/CA/NCI NIH HHS/United States ; UG1 CA233320/CA/NCI NIH HHS/United States ; UG1 CA233328/CA/NCI NIH HHS/United States ; UG1 CA233331/CA/NCI NIH HHS/United States ; UG1 CA233339/CA/NCI NIH HHS/United States ; U10 CA180863/CA/NCI NIH HHS/United States ; UG1 CA233253/CA/NCI NIH HHS/United States ; P01 CA214274/CA/NCI NIH HHS/United States ; P01 CA214274/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Rituximab/administration &amp; dosage/therapeutic use ; *Bendamustine Hydrochloride/administration &amp; dosage/therapeutic use ; *Bortezomib/administration &amp; dosage/therapeutic use ; *Lenalidomide/administration &amp; dosage/therapeutic use ; Female ; Male ; Middle Aged ; Aged ; *Lymphoma, Mantle-Cell/drug therapy/mortality/pathology ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; *Maintenance Chemotherapy ; Aged, 80 and over ; Adult ; Induction Chemotherapy ; Progression-Free Survival ; }, abstract = {Although initial therapy of mantle cell lymphoma (MCL) is not standardized, bendamustine plus rituximab (BR) is commonly used in older patients. Rituximab (R) maintenance after induction is often used. Thus, the open-label, randomized phase 2 ECOG-ACRIN Cancer Research Group E1411 trial was designed to test 2 questions: (1) does addition of bortezomib to BR induction (BVR) and/or (2) addition of lenalidomide to rituximab (LR) maintenance improve progression-free survival (PFS) in patients with treatment-naïve MCL? From 2012 to 2016, 373 previously untreated patients, 87% aged ≥60 years, were enrolled in this trial. At a median follow-up of 7.5 years, there is no difference in the median PFS of BR compared with BVR (5.5 vs 6.4 years; hazard ratio [HR], 0.90; 90% confidence interval [CI], 0.70-1.16). There were no unexpected additional toxicities with BVR treatment compared with BR, with no impact on total dose/duration of treatment received. Independent of the induction treatment, addition of lenalidomide did not significantly improve PFS, with median PFS in R vs LR (5.9 vs 7.2 years; HR, 0.84; 90% CI, 0.62-1.15). Most patients completed the planned 24 cycles of LR at the scheduled dose. In summary, adding bortezomib to BR induction does not prolong PFS in treatment-naïve MCL, and LR maintenance was not associated with longer PFS compared with R alone after BR. Nonetheless, the >5-year median PFS outcomes in this prospective cooperative group trial indicate the efficacy of BR followed by R maintenance as highly effective initial therapy for older patients with MCL. This trial was registered at www.clinicaltrials.gov as #NCT01415752.}, }
@article {pmid38820378, year = {2024}, author = {Habtemariam, S and Hery, CM and Zhang, X and Yu, M and Mays, D and Adeyanju, T and Bernardo, B and Paskett, ED and , }, title = {Association between sociodemographics and change in alcohol or tobacco use behaviors during the COVID-19 pandemic.}, journal = {PloS one}, volume = {19}, number = {5}, pages = {e0304111}, pmid = {38820378}, issn = {1932-6203}, support = {P30 CA016058/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *COVID-19/epidemiology ; Middle Aged ; Male ; *Alcohol Drinking/epidemiology ; *Tobacco Use/epidemiology ; Aged ; Adult ; Ohio/epidemiology ; Pandemics ; SARS-CoV-2 ; Sociodemographic Factors ; Indiana/epidemiology ; Rural Population/statistics &amp; numerical data ; Surveys and Questionnaires ; Socioeconomic Factors ; }, abstract = {OBJECTIVE: To examine the association between various sociodemographic factors with alcohol and tobacco use behaviors during the COVID-19 pandemic.<br><br>METHODS: Participants from Ohio and Indiana were asked to participate in the 'Impact of COVID-19 on the Cancer Continuum Consortium' study (N = 32,989) from June-November 2020. Those who completed the survey and responded to key study questions were included (n = 5,374). Participants were asked about the frequency and type of alcohol and tobacco product used. Multivariable logistic regression was conducted to determine factors associated with the impact of COVID-19 on change in alcohol and/or tobacco use.<br><br>RESULTS: Mean age was 57 years old, 68% were female, 90% non-Hispanic white, 75% married, and 31% lived in rural counties. Out of 5,374 participants, 53% used alcohol-only (n = 2,833), 5% used tobacco-only (n = 255), 7% used both alcohol and tobacco (n = 395), and 35% used neither alcohol nor tobacco (n = 1,891). Urban county of residence (vs. rural) was associated with an increase in alcohol-use (p = 0.0001), change in alcohol products (p = 0.023), and an increase in tobacco use (p = 0.05). Among alcohol-only users, those who were younger (OR = 0.97), female (OR = 1.58), married (OR = 1.69), of high socioeconomic status (OR = 1.99), residing in urban counties (OR = 1.65), and had elevated financial (OR = 1.06) and employment concerns (OR = 1.28) were significantly more likely to report increased alcohol-use. Similarly, among tobacco users, those who were younger (OR = 0.97), female (OR = 2.79), married (OR = 2.16) or divorced (OR = 2.83), and had higher levels of neighborhood disadvantage (OR = 2.19) were significantly more likely to report increased tobacco-use.<br><br>CONCLUSIONS: Findings suggest targeted intervention and prevention strategies for young, female participants with elevated financial and employment concerns during the COVID-19 pandemic are necessary to mitigate risks associated with higher odds of alcohol and tobacco use. Our findings on alcohol and tobacco use may be a result of the unique social and economic influence of the pandemic on women.}, }
@article {pmid38820246, year = {2024}, author = {Telisinghe, L and Floyd, S and MacLeod, D and Schaap, A and Dunbar, R and Bwalya, J and Bell-Mandla, N and Piwowar-Manning, E and Donnell, D and Shaunaube, K and Bock, P and Fidler, S and Hayes, RJ and Ayles, HM and , }, title = {Incidence of self-reported tuberculosis treatment with community-wide universal testing and treatment for HIV and tuberculosis screening in Zambia and South Africa: A planned analysis of the HPTN 071 (PopART) cluster-randomised trial.}, journal = {PLoS medicine}, volume = {21}, number = {5}, pages = {e1004393}, pmid = {38820246}, issn = {1549-1676}, support = {UM1 AI068617/AI/NIAID NIH HHS/United States ; UM1 AI069521/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Zambia/epidemiology ; South Africa/epidemiology ; Adult ; *HIV Infections/epidemiology/diagnosis/drug therapy ; Incidence ; Female ; Male ; *Tuberculosis/epidemiology/diagnosis ; *Mass Screening/methods ; Young Adult ; Self Report ; Adolescent ; HIV Testing ; }, abstract = {BACKGROUND: HIV is a potent risk factor for tuberculosis (TB). Therefore, community-wide universal testing and treatment for HIV (UTT) could contribute to TB control, but evidence for this is limited. Community-wide TB screening can decrease population-level TB prevalence. Combining UTT with TB screening could therefore significantly impact TB control in sub-Saharan Africa, but to our knowledge there is no evidence for this combined approach.<br><br>METHODS AND FINDINGS: HPTN 071 (PopART) was a community-randomised trial conducted between November 2013 to July 2018; 21 Zambian and South African communities (with a total population of approximately 1 million individuals) were randomised to arms A (community-wide UTT and TB screening), B (community-wide universal HIV testing with treatment following national guidelines and TB screening), or C (standard-of-care). In a cohort of randomly selected adults (18 to 44 years) enrolled between 2013 and 2015 from all 21 communities (total size 38,474; 27,139 [71%] female; 8,004 [21%] HIV positive) and followed-up annually for 36 months to measure the population-level impact of the interventions, data on self-reported TB treatment in the previous 12 months (self-reported TB) were collected by trained research assistants and recorded using a structured questionnaire at each study visit. In this prespecified analysis of the trial, self-reported TB incidence rates were measured by calendar year between 2014 and 2017/2018. A p-value &#x2264;0.05 on hypothesis testing was defined as reaching statistical significance. Between January 2014 and July 2018, 38,287 individuals were followed-up: 494 self-reported TB during 104,877 person-years. Overall incidence rates were similar across all arms in 2014 and 2015 (0.33 to 0.46/100 person-years). In 2016 incidence rates were lower in arm A compared to C overall (adjusted rate ratio [aRR] 0.48 [95% confidence interval (95% CI) 0.28 to 0.81; p = 0.01]), with statistical significance reached. In 2017/2018, while incidence rates were lower in arm A compared to C, statistical significance was not reached (aRR 0.58 [95% CI 0.27 to 1.22; p = 0.13]). Among people living with HIV (PLHIV) incidence rates were lower in arm A compared to C in 2016 (RR 0.56 [95% CI 0.29 to 1.08; p = 0.08]) and 2017/2018 (RR 0.50 [95% CI 0.26 to 0.95; p = 0.04]); statistical significance was only reached in 2017/2018. Incidence rates in arms B and C were similar, overall and among PLHIV. Among HIV-negative individuals, there were too few events for cross-arm comparisons. Study limitations include the use of self-report which may have been subject to under-reporting, limited covariate adjustment due to the small number of events, and high losses to follow-up over time.<br><br>CONCLUSIONS: In this study, community-wide UTT and TB screening resulted in substantially lower TB incidence among PLHIV at population-level, compared to standard-of-care, with statistical significance reached in the final study year. There was also some evidence this translated to a decrease in self-reported TB incidence overall in the population. Reduction in arm A but not B suggests UTT drove the observed effect. Our data support the role of UTT in TB control, in addition to HIV control, in high TB/HIV burden settings.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov: NCT01900977.}, }
@article {pmid38816422, year = {2024}, author = {Hrytsenko, Y and Shea, B and Elgart, M and Kurniansyah, N and Lyons, G and Morrison, AC and Carson, AP and Haring, B and Mitchell, BD and Psaty, BM and Jaeger, BC and Gu, CC and Kooperberg, C and Levy, D and Lloyd-Jones, D and Choi, E and Brody, JA and Smith, JA and Rotter, JI and Moll, M and Fornage, M and Simon, N and Castaldi, P and Casanova, R and Chung, RH and Kaplan, R and Loos, RJF and Kardia, SLR and Rich, SS and Redline, S and Kelly, T and O'Connor, T and Zhao, W and Kim, W and Guo, X and Ida Chen, YD and ,  and Sofer, T}, title = {Machine learning models for predicting blood pressure phenotypes by combining multiple polygenic risk scores.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {12436}, pmid = {38816422}, issn = {2045-2322}, support = {K08 HL159318/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; R01 HL161012/HL/NHLBI NIH HHS/United States ; R01HL161012/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Machine Learning ; *Blood Pressure/genetics ; *Multifactorial Inheritance/genetics ; *Phenotype ; *Genome-Wide Association Study/methods ; Risk Factors ; Male ; Female ; Genetic Predisposition to Disease ; Models, Genetic ; Hypertension/genetics/physiopathology ; Middle Aged ; Genetic Risk Score ; }, abstract = {We construct non-linear machine learning (ML) prediction models for systolic and diastolic blood pressure (SBP, DBP) using demographic and clinical variables and polygenic risk scores (PRSs). We developed a two-model ensemble, consisting of a baseline model, where prediction is based on demographic and clinical variables only, and a genetic model, where we also include PRSs. We evaluate the use of a linear versus a non-linear model at both the baseline and the genetic model levels and assess the improvement in performance when incorporating multiple PRSs. We report the ensemble model's performance as percentage variance explained (PVE) on a held-out test dataset. A non-linear baseline model improved the PVEs from 28.1 to 30.1% (SBP) and 14.3% to 17.4% (DBP) compared with a linear baseline model. Including seven PRSs in the genetic model computed based on the largest available GWAS of SBP/DBP improved the genetic model PVE from 4.8 to 5.1% (SBP) and 4.7 to 5% (DBP) compared to using a single PRS. Adding additional 14 PRSs computed based on two independent GWASs further increased the genetic model PVE to 6.3% (SBP) and 5.7% (DBP). PVE differed across self-reported race/ethnicity groups, with primarily all non-White groups benefitting from the inclusion of additional PRSs. In summary, non-linear ML models improves BP prediction in models incorporating diverse populations.}, }
@article {pmid38816141, year = {2024}, author = {Salgado, M and Gálvez, C and Nijhuis, M and Kwon, M and Cardozo-Ojeda, EF and Badiola, J and Gorman, MJ and Huyveneers, LEP and Urrea, V and Bandera, A and Jensen, BO and Vandekerckhove, L and Jurado, M and Raj, K and Schulze Zur Wiesch, J and Bailén, R and Eberhard, JM and Nabergoj, M and Hütter, G and Saldaña-Moreno, R and Oldford, S and Barrett, L and Ramirez, MLM and Garba, S and Gupta, RK and Revollo, B and Ferra-Coll, C and Kuball, J and Alter, G and Sáez-Cirión, A and Diez-Martin, JL and Duke, ER and Schiffer, JT and Wensing, A and Martinez-Picado, J and , }, title = {Dynamics of virological and immunological markers of HIV persistence after allogeneic haematopoietic stem-cell transplantation in the IciStem cohort: a prospective observational cohort study.}, journal = {The lancet. HIV}, volume = {11}, number = {6}, pages = {e389-e405}, pmid = {38816141}, issn = {2352-3018}, support = {P01 AI178376/AI/NIAID NIH HHS/United States ; UM1 AI164561/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects ; *HIV Infections/immunology/virology ; Male ; Prospective Studies ; Female ; Adult ; Middle Aged ; HIV-1/immunology ; Transplantation, Homologous ; Biomarkers/blood ; Viral Load ; HIV Antibodies/blood ; }, abstract = {BACKGROUND: Allogeneic haematopoietic stem-cell transplantation (allo-HSCT) markedly reduces HIV reservoirs, but the mechanisms by which this occurs are only partly understood. In this study, we aimed to describe the dynamics of virological and immunological markers of HIV persistence after allo-HSCT.<br><br>METHODS: In this prospective observational cohort study, we analysed the viral reservoir and serological dynamics in IciStem cohort participants with HIV who had undergone allo-HSCT and were receiving antiretroviral therapy, ten of whom had received cells from donors with the CCR5&#x394;32 mutation. Participants from Belgium, Canada, Germany, Italy, the Netherlands, Spain, Switzerland, and the UK were included in the cohort both prospectively and retrospectively between June 1, 2014 and April 30, 2019. In the first 6 months after allo-HSCT, participants had monthly assessments, with annual assessments thereafter, with the protocol tailored to accommodate for the individual health status of each participant. HIV reservoirs were measured in blood and tissues and HIV-specific antibodies were measured in plasma. We used the Wilcoxon signed-rank test to compare data collected before and after allo-HSCT in participants for whom longitudinal data were available. When the paired test was not possible, we used the Mann-Whitney U test. We developed a mathematical model to study the factors influencing HIV reservoir reduction in people with HIV after allo-HSCT.<br><br>FINDINGS: We included 30 people with HIV with haematological malignancies who received a transplant between Sept 1, 2009 and April 30, 2019 and were enrolled within the IciStem cohort and included in this analysis. HIV reservoirs in peripheral blood were reduced immediately after full donor chimerism was achieved, generally accompanied by undetectable HIV-DNA in bone marrow, ileum, lymph nodes, and cerebrospinal fluid, regardless of donor CCR5 genotype. HIV-specific antibody levels and functionality values declined more slowly than direct HIV reservoir values, decaying significantly only months after full donor chimerism. Mathematical modelling suggests that allogeneic immunity mediated by donor cells is the main viral reservoir depletion mechanism after massive reservoir reduction during conditioning chemotherapy before allo-HSCT (half-life of latently infected replication-competent cells decreased from 44 months to 1&#xb7;5 months).<br><br>INTERPRETATION: Our work provides, for the first time, data on the effects of allo-HSCT in the context of HIV infection. Additionally, we raise the question of which marker can serve as the last reporter of the residual viraemia, postulating that the absence of T-cell immune responses might be a more reliable marker than antibody decline after allo-HSCT.<br><br>FUNDING: amfAR (American Foundation for AIDS Research; ARCHE Program), National Institutes of Health, National Institute of Allergy and Infectious Diseases, and Dutch Aidsfonds.}, }
@article {pmid38815238, year = {2024}, author = {Briercheck, EL and Ravishankar, S and Ahmed, EH and Carías Alvarado, CC and Barrios Menéndez, JC and Silva, O and Solórzano-Ortiz, E and Siliézar Tala, MM and Stevenson, P and Xu, Y and Wohns, AW and Enriquez-Vera, D and Barrionuevo, C and Yu, SC and Freud, AG and Oakes, C and Weigel, C and Weinstock, DM and Klimaszewski, HL and Ngankeu, A and Mutalima, N and Samayoa-Reyes, G and Newton, R and Rochford, R and Valvert, F and Natkunam, Y and Shustov, A and Baiocchi, RA and Warren, EH}, title = {Geographic EBV variants confound disease-specific variant interpretation and predict variable immune therapy responses.}, journal = {Blood advances}, volume = {8}, number = {14}, pages = {3731-3744}, pmid = {38815238}, issn = {2473-9537}, support = {T32 HL007093/HL/NHLBI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA239287/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R01 CA217138/CA/NCI NIH HHS/United States ; MC_UU_00033/1/MRC_/Medical Research Council/United Kingdom ; R01 AI141531/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Herpesvirus 4, Human/genetics ; *Epstein-Barr Virus Infections/immunology ; Genetic Variation ; Genome, Viral ; Immunotherapy ; }, abstract = {Epstein-Barr virus (EBV) is a potent carcinogen linked to hematologic and solid malignancies and causes significant global morbidity and mortality. Therapy using allogeneic EBV-specific lymphocytes shows promise in certain populations, but the impact of EBV genome variation on these strategies remains unexplored. To address this, we sequenced 217 EBV genomes, including hematologic malignancies from Guatemala, Peru, Malawi, and Taiwan, and analyzed them alongside 1307 publicly available EBV genomes from cancer, nonmalignant diseases, and healthy individuals across Africa, Asia, Europe, North America, and South America. These included, to our knowledge, the first natural killer (NK)/T-cell lymphoma (NKTCL) EBV genomes reported outside of East Asia. Our findings indicate that previously proposed EBV genome variants specific to certain cancer types are more closely tied to geographic origin than to cancer histology. This included variants previously reported to be specific to NKTCL but were prevalent in EBV genomes from other cancer types and healthy individuals in East Asia. After controlling for geographic region, we did identify multiple NKTCL-specific variants associated with a 7.8-fold to 21.9-fold increased risk. We also observed frequent variations in EBV genomes that affected peptide sequences previously reported to bind common major histocompatibility complex alleles. Finally, we found several nonsynonymous variants spanning the coding sequences of current vaccine targets BALF4, BKRF2, BLLF1, BXLF2, BZLF1, and BZLF2. These results highlight the need to consider geographic variation in EBV genomes when devising strategies for exploiting adaptive immune responses against EBV-related cancers, ensuring greater global effectiveness and equity in prevention and treatment.}, }
@article {pmid38815189, year = {2024}, author = {Elliott, MJ and Shen, S and Lam, DL and Brown, T and Lawson, MB and Iyengar, NM and Cescon, DW}, title = {Enhancing Early-Stage Breast Cancer Survivorship: Evidence-Based Strategies, Surveillance Testing, and Imaging Guidelines.}, journal = {American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting}, volume = {44}, number = {3}, pages = {e432564}, doi = {10.1200/EDBK_432564}, pmid = {38815189}, issn = {1548-8756}, mesh = {Humans ; *Breast Neoplasms ; Female ; *Survivorship ; *Cancer Survivors ; Neoplasm Staging ; Practice Guidelines as Topic ; Evidence-Based Medicine ; }, abstract = {Addressing the challenges of survivorship necessitates a comprehensive, patient-centered approach, focusing on mitigating risk through lifestyle modification, identifying distant recurrence, and optimization of breast imaging. This article will discuss the current and emerging clinical strategies for the survivorship period, advocating a multidisciplinary and comprehensive approach. In this manner, early-stage breast cancer survivors are empowered to navigate their journey with enhanced knowledge, facilitating a transition to life beyond cancer.}, }
@article {pmid39625272, year = {2023}, author = {Singer, J and Breen, LJ and Loggers, ET}, title = {Examining public stigma and expectations of grief following medical aid and dying in the US: A vignette-based experiment.}, journal = {Palliative &amp; supportive care}, volume = {21}, number = {2}, pages = {270-276}, doi = {10.1017/S1478951522000852}, pmid = {39625272}, issn = {1478-9523}, abstract = {OBJECTIVES: Families bereaved following Medical Aid in Dying (MAID)-related death express concerns about public stigma. As access to MAID expands, research examining MAID is needed, including understanding stigma toward family members. This study examines if stigmatization exists toward bereaved individuals whose family member utilized MAID at differing ages and assess if expectations of grief differ between bereaved individuals whose family member utilized MAID compared to bereaved individuals whose family member died of an illness.<br><br>METHODS: This study utilized a randomized, between-groups, vignette-based experiment to test the effects of cause of death (MAID vs. illness-related death) and age (28, 38, 70, and 80 years) of the deceased on indicators of public stigma. Participants (N = 428) were recruited from mTURK (Mage = 42.54; SDage = 16.50).<br><br>RESULTS: Analyses showed a statistically significant interaction between age and the mode of death (F(7, 400), p = 0.001, $\eta _{\rm p}^2$ = 0.06) and the main effect for age (F(5, 401), p = 0.004, $\eta _{\rm p}^2$ = 0.04) on expectations of grief, whereas emotional reactions and wanting social distance were not significant (p > 0.05). Participants expected more maladaptive grief among family members of 28- and 70-year-olds who died of illness compared to 28- or 38-year-olds who utilized MAID [28-year-old (M = 44.12, SD = 12.03) or 70-year-old (M = 44.32, SD = 10.29) illness-related death vs. 28-year-old (M = 39.3, SD = 11.56; p = 0.01) or 38-year-old (M = 38.71, SD = 11.56; p = 0.007) MAID-related death].<br><br>SIGNIFICANCE OF RESULTS: Findings suggest that direct stigma does not exist toward family members of individuals engaging in MAID. The American public may expect that family members of young individuals who utilize MAID are accepting of the death and expect them to experience fewer maladaptive grief symptoms. Future research should investigate differences in bereavement outcomes based on age of bereaved caregivers of individuals engaging in MAID.}, }
@article {pmid38831998, year = {2023}, author = {Einav, T and Khoo, Y and Singer, A}, title = {Quantitatively Visualizing Bipartite Datasets.}, journal = {Physical review. X}, volume = {13}, number = {2}, pages = {}, pmid = {38831998}, issn = {2160-3308}, support = {R01 GM136780/GM/NIGMS NIH HHS/United States ; }, abstract = {As experiments continue to increase in size and scope, a fundamental challenge of subsequent analyses is to recast the wealth of information into an intuitive and readily interpretable form. Often, each measurement conveys only the relationship between a pair of entries, and it is difficult to integrate these local interactions across a dataset to form a cohesive global picture. The classic localization problem tackles this question, transforming local measurements into a global map that reveals the underlying structure of a system. Here, we examine the more challenging bipartite localization problem, where pairwise distances are available only for bipartite data comprising two classes of entries (such as antibody-virus interactions, drug-cell potency, or user-rating profiles). We modify previous algorithms to solve bipartite localization and examine how each method behaves in the presence of noise, outliers, and partially observed data. As a proof of concept, we apply these algorithms to antibody-virus neutralization measurements to create a basis set of antibody behaviors, formalize how potently inhibiting some viruses necessitates weakly inhibiting other viruses, and quantify how often combinations of antibodies exhibit degenerate behavior.}, }
@article {pmid39148929, year = {2023}, author = {Koester, ST and Li, N and Dey, N}, title = {RET is a sex-biased regulator of intestinal tumorigenesis.}, journal = {Frontiers in gastroenterology (Lausanne, Switzerland)}, volume = {2}, number = {}, pages = {}, pmid = {39148929}, issn = {2813-1169}, support = {K08 DK111941/DK/NIDDK NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; U54 CA274374/CA/NCI NIH HHS/United States ; }, abstract = {Ret is implicated in colorectal cancer (CRC) as both a proto-oncogene and a tumor suppressor. We asked whether RET signaling regulates tumorigenesis in an Apc-deficient preclinical model of CRC. We observed a sex-biased phenotype: Apc [Min/+] Ret+/- females had significantly greater tumor burden than Apc [Min/+]Ret+/- males, a phenomenon not seen in Apc [Min/+] mice, which had equal distributions by sex. Dysfunctional RET signaling was associated with gene expression changes in diverse tumor signaling pathways in tumors and normal-appearing colon. Sex-biased gene expression differences mirroring tumor phenotypes were seen in 26 genes, including the Apc tumor suppressor gene. Ret and Tlr4 expression were significantly correlated in tumor samples from female but not male Apc [Min/+] Ret+/- mice. Antibiotics resulted in reduction of tumor burden, inverting the sex-biased phenotype such that microbiota-depleted Apc [Min/+] Ret+/- males had significantly more tumors than female littermates. Reconstitution of the microbiome rescued the sex-biased phenotype. Our findings suggest that RET represents a sexually dimorphic microbiome-mediated "switch" for regulation of tumorigenesis.}, }
@article {pmid39255401, year = {2022}, author = {Malik, HS}, title = {Driving lessons: a brief (personal) history of centromere drive.}, journal = {Genetics}, volume = {222}, number = {4}, pages = {}, pmid = {39255401}, issn = {1943-2631}, support = {R01 GM074108/GM/NIGMS NIH HHS/United States ; /NH/NIH HHS/United States ; R01-GM074108//Howard Hughes Medical Institution/ ; }, }
@article {pmid39086975, year = {2022}, author = {Shabaneh, TB and Moffett, HF and Stull, SM and Derezes, T and Tait, LJ and Park, S and Riddell, SR and Lajoie, MJ}, title = {Safety switch optimization enhances antibody-mediated elimination of CAR T cells.}, journal = {Frontiers in molecular medicine}, volume = {2}, number = {}, pages = {1026474}, pmid = {39086975}, issn = {2674-0095}, abstract = {Activation of a conditional safety switch has the potential to reverse serious toxicities arising from the administration of engineered cellular therapies, including chimeric antigen receptor (CAR) T cells. The functionally inert, non-immunogenic cell surface marker derived from human epidermal growth factor receptor (EGFRt) is a promising safety switch that has been used in multiple clinical constructs and can be targeted by cetuximab, a clinically available monoclonal antibody. However, this approach requires high and persistent cell surface expression of EGFRt to ensure that antibody-mediated depletion of engineered cells is rapid and complete. Here we show that incorporating a short juxtamembrane sequence into the EGFRt polypeptide enhances its expression on the surface of T cells and their susceptibility to antibody-dependent cellular cytotoxicity (ADCC). Incorporating this optimized variant (EGFRopt) into bicistronic and tricistronic CAR designs results in more rapid in vivo elimination of CAR T cells and robust termination of their effector activity compared to EGFRt. These studies establish EGFRopt as a superior safety switch for the development of next-generation cell-based therapeutics.}, }
@article {pmid39301523, year = {2022}, author = {Nelson, LE and Wilton, L and Whitfield, DL and Williams, GC and Mayer, KH and Komárek, A and Boyd, DT and Beauchamp, G and Fields, SD and Wheeler, DP and , }, title = {Client-Centered Care Coordination (C4[™]) for HIV/STI Prevention: a Theoretical, Conceptual, and Methodological Overview-HIV Prevention Trials Network (HPTN) 073.}, journal = {Sexuality research &amp; social policy : journal of NSRC : SR &amp; SP}, volume = {19}, number = {3}, pages = {1365-1382}, pmid = {39301523}, issn = {1868-9884}, support = {UM1 AI068617/AI/NIAID NIH HHS/United States ; }, abstract = {INTRODUCTION: There are few culturally informed, theory-driven evidence-based strategies to support PrEP use among Black MSM. This paper describes the theoretical foundation and conceptual development of C4[™] to support the prevention of HIV and other STIs.<br><br>METHODS: C4[&#x2122;] integrates self-determination theory with comprehensive risk counseling and services using an integrative anti-racism lens. C4[&#x2122;] was implemented in a 52-week HIV prevention demonstration project to facilitate PrEP use and adherence among Black MSM (N=225) in three US cities from 2014-2017.<br><br>RESULTS: PrEP use was 79%, with 91% of PrEP users starting within 30-days. 12-month retention in C4[&#x2122;] was 92%. Care coordination encounters focused primarily on clients' needs related to PrEP adherence (43%) and sexual health (19%). Over the 12-month period, a substantial proportion of the men made progress towards their PrEP adherence goals at the 8-week (83%), 26-week (75%) and 52-week (81%) study visits.<br><br>CONCLUSIONS: C4[&#x2122;] is a multi-level, multi-component intervention that dually targets individual-level motivations and capacities of Black MSM and the healthcare facility-level attitudes, behaviors and processes that characterize the climates where Black MSM receive services.<br><br>POLICY IMPLICATIONS: Public health policy efforts to scale-up PrEP may consider C4[&#x2122;] as a tool to optimize the use of PrEP and PrEP program retention with Black MSM. C4[&#x2122;] is also a tool for healthcare facilities to transform their models of service delivery towards improving the implementation PrEP services, including ensuring racial equity in the prevention impact of novel PrEP formulations such as long-acting injectable and potential future long-acting oral regimens.}, }
@article {pmid38994535, year = {2021}, author = {Grivas, P and Kiedrowski, LA and Sonpavde, GP and Gupta, SV and Thomas, RA and Gourdin, TS and Hardin, AI and Hamann, KM and Faltas, BM and Vogelzang, NJ}, title = {Spectrum of FGFR2/3 Alterations in Cell-Free DNA of Patients with Advanced Urothelial Carcinoma.}, journal = {Bladder cancer (Amsterdam, Netherlands)}, volume = {7}, number = {2}, pages = {143-148}, pmid = {38994535}, issn = {2352-3735}, abstract = {Detecting genomic alterations (GAs) in advanced urothelial carcinoma (aUC) can expand treatment options by identifying candidates for targeted therapies. Erdafitinib is FDA-approved for patients with platinum-refractory aUC with activating mutation or fusion in FGFR2/3. We explored the prevalence and spectrum of FGFR2/3 GAs identified with plasma cfDNA NGS testing (Guardant360) in 997 patients with aUC. FGFR2/3 GAs were detected in 201 patients (20%) with characterized activating GAs in 141 (14%). Our results indicate the Guardant360-based FGFR2/3 GA detection rate is similar to those described from previous studies employing tumor tissue testing, suggesting that plasma-based cfDNA NGS may non-invasively identify candidates for anti-FGFR targeted therapies.}, }
@article {pmid38993215, year = {2021}, author = {Nelson, AA and Cronk, RJ and Lemke, EA and Szabo, A and Khaki, AR and Diamantopoulos, LN and Grivas, P and Nezami, BG and MacLennan, GT and Zhang, T and Hoimes, CJ}, title = {Early Bone Metastases are Associated with Worse Outcomes in Metastatic Urothelial Carcinoma.}, journal = {Bladder cancer (Amsterdam, Netherlands)}, volume = {7}, number = {1}, pages = {33-42}, pmid = {38993215}, issn = {2352-3735}, support = {T32 CA009515/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Outcomes of patients with metastatic urothelial carcinoma (mUC) with early bone metastases (eBM) vs no early bone metastases (nBM) have not thoroughly been described in the age of immuno-oncology.<br><br>OBJECTIVE: To compare survival and other clinical outcomes in patients with eBM and nBM.<br><br>METHODS: We used a multi-institutional database of patients with mUC treated with systemic therapy. Demographic, metastatic site, treatment patterns, and clinical outcomes were recorded. Wilcoxon rank-sum, chi-square tests were performed. Survival was estimated by Kaplan-Meier method; multivariable Cox analysis was performed.<br><br>RESULTS: We identified 270 pts, 67% men, mean age 69&#xb1;11 years. At metastatic diagnosis, 27% had&#x2265;1 eBM and were more likely to have de novo vs. recurrent metastases (42% vs 19%, p&#x200a;<&#x200a;0.001). Patients with eBM had shorter overall survival (OS) vs. those with nBM, (6.1 vs 13.7 months, p&#x200a;<&#x200a;0.0001). On multivariable analysis, eBM independently associated with higher risk of death, HR&#x200a;=&#x200a;2.52 (95% CI: 1.75-3.63, p&#x200a;<&#x200a;0.0001). OS was shorter for patients with eBM who received initial immune checkpoint inhibitor vs platinum-based chemotherapy, (1.6 vs 9.1 months, p&#x200a;=&#x200a;0.02). Patients with eBM received higher opioid analgesic doses compared to patients with nBM and received quantitatively more palliative radiation.<br><br>CONCLUSIONS: Patients with mUC and eBM have poorer outcomes, may benefit less from anti-PD-1/PD-L1 therapy and represent an unmet need for novel therapeutic interventions. Dedicated clinical trials, biomarker validation to assist in patient selection, as well as consensus on reporting of non-measurable disease are required.}, }
@article {pmid39575442, year = {2019}, author = {Wang, Y and Chen, YQ}, title = {Estimating Attributable Life Expectancy Under the Proportional Mean Residual Life Model.}, journal = {Statistics in biosciences}, volume = {11}, number = {3}, pages = {659-676}, pmid = {39575442}, issn = {1867-1764}, support = {R01 CA172415/CA/NCI NIH HHS/United States ; R01 HD094682/HD/NICHD NIH HHS/United States ; R56 AI140953/AI/NIAID NIH HHS/United States ; R01 MH105857/MH/NIMH NIH HHS/United States ; R01 AI121259/AI/NIAID NIH HHS/United States ; R01 AI089341/AI/NIAID NIH HHS/United States ; }, abstract = {In population-based health research, the so-called population attributable fraction is an important quantity that calculates the percentage of excess risk of morbidity and mortality associated with modifiable risk factors for a given population. While the concept of "risk" is usually measured by event probabilities, in practice it may be of a more direct interest to know the excess life expectancy associated with the modifiable risk factors instead, particularly when mortality is of the ultimate concern. In this paper, we thus propose to study a novel quantity, termed "attributable life expectancy," to measure the population attributable fraction of life expectancy. We further develop a model-based approach for the attributable life expectancy under the Oakes-Dasu proportional mean residual life model, and establish its asymptotic properties for inferences. Numerical studies that includes Monte-Carlo simulations and an actual analysis of the mortality associated with smoking cessation in an Asia Cohort Consortium, are conducted to evaluate the performance of our proposed method.}, }
@article {pmid38815168, year = {2024}, author = {Garraway, IP and Carlsson, SV and Nyame, YA and Vassy, JL and Chilov, M and Fleming, M and Frencher, SK and George, DJ and Kibel, AS and King, SA and Kittles, R and Mahal, BA and Pettaway, CA and Rebbeck, T and Rose, B and Vince, R and Winn, RA and Yamoah, K and Oh, WK}, title = {Prostate Cancer Foundation Screening Guidelines for Black Men in the United States.}, journal = {NEJM evidence}, volume = {3}, number = {5}, pages = {EVIDoa2300289}, doi = {10.1056/EVIDoa2300289}, pmid = {38815168}, issn = {2766-5526}, support = {I01 CX002635/CX/CSRD VA/United States ; I01 HX003627/HX/HSRD VA/United States ; }, mesh = {Aged ; Humans ; Male ; Middle Aged ; *Black or African American ; *Early Detection of Cancer ; Mass Screening ; Practice Guidelines as Topic ; *Prostate-Specific Antigen/blood ; *Prostatic Neoplasms/diagnosis/ethnology/blood ; United States/epidemiology ; Adult ; }, abstract = {BACKGROUND: In the United States, Black men are at highest risk for being diagnosed with and dying from prostate cancer. Given this disparity, we examined relevant data to establish clinical prostate-specific antigen (PSA) screening guidelines for Black men in the United States.<br><br>METHODS: A comprehensive literature search identified 1848 unique publications for screening. Of those screened, 287 studies were selected for full-text review, and 264 were considered relevant and form the basis for these guidelines. The numbers were reported according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.<br><br>RESULTS: Three randomized controlled trials provided Level 1 evidence that regular PSA screening of men 50 to 74&#x2009;years of age of average risk reduced metastasis and prostate cancer death at 16 to 22&#x2009;years of follow-up. The best available evidence specifically for Black men comes from observational and modeling studies that consider age to obtain a baseline PSA, frequency of testing, and age when screening should end. Cohort studies suggest that discussions about baseline PSA testing between Black men and their clinicians should begin in the early 40s, and data from modeling studies indicate prostate cancer develops 3 to 9&#x2009;years earlier in Black men compared with non-Black men. Lowering the age for baseline PSA testing to 40 to 45&#x2009;years of age from 50 to 55&#x2009;years of age, followed by regular screening until 70&#x2009;years of age (informed by PSA values and health factors), could reduce prostate cancer mortality in Black men (approximately 30% relative risk reduction) without substantially increasing overdiagnosis.<br><br>CONCLUSIONS: These guidelines recommend that Black men should obtain information about PSA screening for prostate cancer. Among Black men who elect screening, baseline PSA testing should occur between ages 40 and 45. Depending on PSA value and health status, annual screening should be strongly considered. (Supported by the Prostate Cancer Foundation.).}, }
@article {pmid38814817, year = {2024}, author = {McGuinness, JE and Anderson, GL and Mutasa, S and Hershman, DL and Terry, MB and Tehranifar, P and Lew, DL and Yee, M and Brown, EA and Kairouz, SS and Kuwajerwala, N and Bevers, TB and Doster, JE and Zarwan, C and Kruper, L and Minasian, LM and Ford, L and Arun, B and Neuhouser, ML and Goodman, GE and Brown, PH and Ha, R and Crew, KD}, title = {Effects of vitamin D supplementation on a deep learning-based mammographic evaluation in SWOG S0812.}, journal = {JNCI cancer spectrum}, volume = {8}, number = {4}, pages = {}, pmid = {38814817}, issn = {2515-5091}, support = {U10 CA180819/CA/NCI NIH HHS/United States ; /NH/NIH HHS/United States ; R01CA226060/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Mammography ; *Deep Learning ; *Breast Neoplasms/diagnostic imaging/prevention &amp; control ; *Dietary Supplements ; *Breast Density/drug effects ; Middle Aged ; *Cholecalciferol/administration &amp; dosage ; Adult ; Vitamin D/administration &amp; dosage ; Premenopause ; Neural Networks, Computer ; Risk Assessment ; }, abstract = {Deep learning-based mammographic evaluations could noninvasively assess response to breast cancer chemoprevention. We evaluated change in a convolutional neural network-based breast cancer risk model applied to mammograms among women enrolled in SWOG S0812, which randomly assigned 208 premenopausal high-risk women to receive oral vitamin D3 20 000 IU weekly or placebo for 12 months. We applied the convolutional neural network model to mammograms collected at baseline (n = 109), 12 months (n = 97), and 24 months (n = 67) and compared changes in convolutional neural network-based risk score between treatment groups. Change in convolutional neural network-based risk score was not statistically significantly different between vitamin D and placebo groups at 12 months (0.005 vs 0.002, P = .875) or at 24 months (0.020 vs 0.001, P = .563). The findings are consistent with the primary analysis of S0812, which did not demonstrate statistically significant changes in mammographic density with vitamin D supplementation compared with placebo. There is an ongoing need to evaluate biomarkers of response to novel breast cancer chemopreventive agents.}, }
@article {pmid38814624, year = {2024}, author = {Newcomb, LF and Schenk, JM and Zheng, Y and Liu, M and Zhu, K and Brooks, JD and Carroll, PR and Dash, A and de la Calle, CM and Ellis, WJ and Filson, CP and Gleave, ME and Liss, MA and Martin, F and McKenney, JK and Morgan, TM and Tretiakova, MS and Wagner, AA and Nelson, PS and Lin, DW}, title = {Long-Term Outcomes in Patients Using Protocol-Directed Active Surveillance for Prostate Cancer.}, journal = {JAMA}, volume = {331}, number = {24}, pages = {2084-2093}, pmid = {38814624}, issn = {1538-3598}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; U01 CA224255/CA/NCI NIH HHS/United States ; }, mesh = {Aged ; Humans ; Male ; Middle Aged ; Biopsy ; *Clinical Protocols ; Disease Progression ; Neoplasm Grading ; Neoplasm Metastasis ; Neoplasm Recurrence, Local ; Prospective Studies ; Prostate/pathology ; *Prostate-Specific Antigen/blood ; *Prostatic Neoplasms/blood/mortality/pathology/therapy ; *Watchful Waiting ; Treatment Outcome ; North American People ; White ; Black or African American ; United States ; British Columbia ; }, abstract = {IMPORTANCE: Outcomes from protocol-directed active surveillance for favorable-risk prostate cancers are needed to support decision-making.<br><br>OBJECTIVE: To characterize the long-term oncological outcomes of patients receiving active surveillance in a multicenter, protocol-directed cohort.<br><br>The Canary Prostate Active Surveillance Study (PASS) is a prospective cohort study initiated in 2008. A cohort of 2155 men with favorable-risk prostate cancer and no prior treatment were enrolled at 10 North American centers through August 2022.<br><br>EXPOSURE: Active surveillance for prostate cancer.<br><br>MAIN OUTCOMES AND MEASURES: Cumulative incidence of biopsy grade reclassification, treatment, metastasis, prostate cancer mortality, overall mortality, and recurrence after treatment in patients treated after the first or subsequent surveillance biopsies.<br><br>RESULTS: Among 2155 patients with localized prostate cancer, the median follow-up was 7.2 years, median age was 63 years, 83% were White, 7% were Black, 90% were diagnosed with grade group 1 cancer, and median prostate-specific antigen (PSA) was 5.2 ng/mL. Ten years after diagnosis, the incidence of biopsy grade reclassification and treatment were 43% (95% CI, 40%-45%) and 49% (95% CI, 47%-52%), respectively. There were 425 and 396 patients treated after confirmatory or subsequent surveillance biopsies (median of 1.5 and 4.6 years after diagnosis, respectively) and the 5-year rates of recurrence were 11% (95% CI, 7%-15%) and 8% (95% CI, 5%-11%), respectively. Progression to metastatic cancer occurred in 21 participants and there were 3 prostate cancer-related deaths. The estimated rates of metastasis or prostate cancer-specific mortality at 10 years after diagnosis were 1.4% (95% CI, 0.7%-2%) and 0.1% (95% CI, 0%-0.4%), respectively; overall mortality in the same time period was 5.1% (95% CI, 3.8%-6.4%).<br><br>CONCLUSIONS AND RELEVANCE: In this study, 10 years after diagnosis, 49% of men remained free of progression or treatment, less than 2% developed metastatic disease, and less than 1% died of their disease. Later progression and treatment during surveillance were not associated with worse outcomes. These results demonstrate active surveillance as an effective management strategy for patients diagnosed with favorable-risk prostate cancer.}, }
@article {pmid38812783, year = {2024}, author = {Ghali, F and Holt, SK and Koehne, EL and Chen, JJ and Weg, ES and Liao, JJ and Zeng, J and Grivas, P and Hawley, JE and Hsieh, AC and Montgomery, RB and Wright, JL}, title = {Patterns of chemotherapy use with primary radiotherapy for localized bladder cancer in patients 65 or older.}, journal = {Frontiers in oncology}, volume = {14}, number = {}, pages = {1341655}, pmid = {38812783}, issn = {2234-943X}, support = {R01 CA276308/CA/NCI NIH HHS/United States ; R37 CA230617/CA/NCI NIH HHS/United States ; }, abstract = {INTRODUCTION: Bladder preservation with concurrent chemoradiotherapy after maximum transurethral resection of bladder tumor is an alternative to radical cystectomy in select patients with muscle invasive bladder cancer (MIBC). Concurrent administration of radio-sensitizing chemotherapy and radiation therapy (RT) has been shown to have superior disease control compared with RT alone and can often be administered with modest added toxicity. We sought to describe national patterns of chemotherapy use.<br><br>METHODS: The linked surveillance, epidemiology, and end results (SEER)-Medicare database was used to identify patients with cT2-4, N0/X, M0/X BC who received radiation between 2004 and 2018. Data on demographics, clinicopathologic factors, therapy and outcomes were extracted. Concurrent utilization of chemotherapy with RT was also identified (CRT). Multivariate logistic regression (MVA) models were used to explore factors associated with receipt of chemotherapy and overall survival (OS).<br><br>RESULTS: 2190 patients met inclusion criteria. Of these, 850 (38.8%) received no chemotherapy. Among those receiving chemotherapy, the most frequent regimens were single agent carboplatin, cisplatin, or gemcitabine. Factors that were independently associated with decreased likelihood of chemotherapy use were increasing age (OR 0.93, CI 0.92 - 0.95), Hispanic race (compared with White, OR 0.62, CI 0.39 - 0.99), cT3 or T4 (compared with cT2, OR 0.70, CI 0.55 - 0.90), and lower National Cancer Institute comorbidity index (OR 0.60, CI 0.51 - 0.70) (p < 0.05). Variables independently associated with increased likelihood of receipt of chemotherapy were married status (OR 1.28, CI 1.06 - 1.54), higher socioeconomic status (OR 1.31, CI 1.06 - 1.64), and later year of diagnosis (OR 1.09, CI 1.06 - 1.12). Receipt of concurrent chemotherapy with RT was associated with superior OS compared with RT alone.<br><br>CONCLUSION: Over a third of patients >/65 years old receiving curative-intent RT for MIBC do not receive concurrent chemotherapy. Considering the improvement in oncologic outcomes with CRT over RT alone and more options, such as low dose gemcitabine which can be administered with modest toxicity, efforts are needed to identify barriers to utilization and increase the use of radio-sensitizing chemotherapy.}, }
@article {pmid38810947, year = {2024}, author = {Rafati, M and McReynolds, LJ and Wang, Y and Hicks, B and Jones, K and Spellman, SR and He, M and Bolon, YT and Arrieta-Bolaños, E and Saultz, JN and Lee, SJ and Savage, SA and Gadalla, SM}, title = {Hemophagocytic Lymphohistiocytosis Gene Variants in Severe Aplastic Anemia and Their Impact on Hematopoietic Cell Transplantation Outcomes.}, journal = {Transplantation and cellular therapy}, volume = {30}, number = {8}, pages = {770.e1-770.e10}, pmid = {38810947}, issn = {2666-6367}, support = {U24 CA076518/CA/NCI NIH HHS/United States ; Z99 CA999999/ImNIH/Intramural NIH HHS/United States ; 27307C0011/ES/NIEHS NIH HHS/United States ; 27398C0011/ES/NIEHS NIH HHS/United States ; 27305C0011/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Lymphohistiocytosis, Hemophagocytic/genetics/therapy ; *Anemia, Aplastic/genetics/therapy ; *Hematopoietic Stem Cell Transplantation ; Female ; Male ; Adult ; Child ; Adolescent ; Child, Preschool ; Young Adult ; Middle Aged ; Treatment Outcome ; Genetic Variation ; Infant ; }, abstract = {Germline genetic testing for patients with severe aplastic anemia (SAA) is recommended to guide treatment, including the use of immunosuppressive therapy and/or adjustment of hematopoietic cell transplantation (HCT) modalities. Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory condition often associated with cytopenias with autosomal recessive (AR) or X-linked recessive (XLR) inheritance. HLH is part of the SAA differential diagnosis, and genetic testing may identify variants in HLH genes in patients with SAA. The impact of pathogenic/likely pathogenic (P/LP) variants in HLH genes on HCT outcomes in SAA is unclear. In this study, we aimed to determine the frequency of HLH gene variants in a large cohort of patients with acquired SAA and to evaluate their association(s) with HCT outcomes. The Transplant Outcomes in Aplastic Anemia project, a collaboration between the National Cancer Institute and the Center for International Blood and Marrow Transplant Research, collected genomic and clinical data from 824 patients who underwent HCT for SAA between 1989 and 2015. We excluded 140 patients with inherited bone marrow failure syndromes and used exome sequencing data from the remaining 684 patients with acquired SAA to identify P/LP variants in 14 HLH-associated genes (11 AR, 3 XLR) curated using American College of Medical Genetics and Genomics/Association of Molecular Pathology (ACMG/AMP) criteria. Deleterious variants of uncertain significance (del-VUS) were defined as those not meeting the ACMG/AMP P/LP criteria but with damaging predictions in ≥3 of 5 meta-predictors (BayesDel, REVEL, CADD, MetaSVM, and/or EIGEN). The Kaplan-Meier estimator was used to calculate the probability of overall survival (OS) after HCT, and the cumulative incidence calculator was used for other HCT outcomes, accounting for relevant competing risks. There were 46 HLH variants in 49 of the 684 patients (7.2%). Seventeen variants in 19 patients (2.8%) were P/LP; 8 of these were loss-of-function variants. Among the 19 patients with P/LP HLH variants, 16 (84%) had monoallelic variants in genes with AR inheritance, and 3 had variants in XLR genes. PRF1 was the most frequently affected gene (in 8 of the 19 patients). We found no statistically significant differences in transplantation-related factors between patients with and those without P/LP HLH variants. The 5-year survival probability was 89% (95% confidence interval [CI], 72% to 99%) in patients with P/LP HLH variants and 70% (95% CI, 53% to 85%) in those with del-VUS HLH variants, compared to 66% (95% CI, 62% to 70%) in those without variants (P = .16, log-rank test). The median time to neutrophil engraftment was 16 days for patients with P/LP HLH variants and 18 days in those with del-VUS HLH variants or without variants combined (P = .01, Gray's test). No statistically significant associations between P/LP HLH variants and the risk of acute or chronic graft-versus-host disease were noted. In this large cohort of patients with acquired SAA, we found that 2.8% of patients harbored a P/LP variant in an HLH gene. No negative effects of HLH gene variants on post-HCT survival were noted. The small number of patients with P/LP HLH variants limits the study's ability to provide conclusive evidence; nonetheless, our data suggest that there is no need for special transplantation considerations for patients with SAA carrying P/LP variants.}, }
@article {pmid38809988, year = {2024}, author = {Drew, DA and Kim, AE and Lin, Y and Qu, C and Morrison, J and Lewinger, JP and Kawaguchi, E and Wang, J and Fu, Y and Zemlianskaia, N and Díez-Obrero, V and Bien, SA and Dimou, N and Albanes, D and Baurley, JW and Wu, AH and Buchanan, DD and Potter, JD and Prentice, RL and Harlid, S and Arndt, V and Barry, EL and Berndt, SI and Bouras, E and Brenner, H and Budiarto, A and Burnett-Hartman, A and Campbell, PT and Carreras-Torres, R and Casey, G and Chang-Claude, J and Conti, DV and Devall, MAM and Figueiredo, JC and Gruber, SB and Gsur, A and Gunter, MJ and Harrison, TA and Hidaka, A and Hoffmeister, M and Huyghe, JR and Jenkins, MA and Jordahl, KM and Kundaje, A and Le Marchand, L and Li, L and Lynch, BM and Murphy, N and Nassir, R and Newcomb, PA and Newton, CC and Obón-Santacana, M and Ogino, S and Ose, J and Pai, RK and Palmer, JR and Papadimitriou, N and Pardamean, B and Pellatt, AJ and Peoples, AR and Platz, EA and Rennert, G and Ruiz-Narvaez, E and Sakoda, LC and Scacheri, PC and Schmit, SL and Schoen, RE and Stern, MC and Su, YR and Thomas, DC and Tian, Y and Tsilidis, KK and Ulrich, CM and Um, CY and van Duijnhoven, FJB and Van Guelpen, B and White, E and Hsu, L and Moreno, V and Peters, U and Chan, AT and Gauderman, WJ}, title = {Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer.}, journal = {Science advances}, volume = {10}, number = {22}, pages = {eadk3121}, pmid = {38809988}, issn = {2375-2548}, support = {P30 CA047904/CA/NCI NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; 001/WHO_/World Health Organization/International ; K01 DK120742/DK/NIDDK NIH HHS/United States ; P01 CA196569/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Colorectal Neoplasms/genetics/drug therapy ; *Anti-Inflammatory Agents, Non-Steroidal/pharmacology ; *Genome-Wide Association Study ; *Polymorphism, Single Nucleotide ; Aspirin/pharmacology ; Receptors, Prostaglandin E, EP4 Subtype/genetics/metabolism ; Male ; Genetic Predisposition to Disease ; Female ; Case-Control Studies ; Middle Aged ; Genetic Loci ; Aged ; }, abstract = {Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.}, }
@article {pmid38808634, year = {2024}, author = {Gobbo, M and Joy, J and Guedes, H and Shazib, MA and Anderson, C and Abdalla-Aslan, R and Peechatanan, K and Lajolo, C and Nasir, KS and Gueiros, LA and Nagarajan, N and Hafezi Motlagh, K and Kandwal, A and Rupe, C and Xu, Y and Ehrenpreis, ED and Tonkaboni, A and Epstein, JB and Bossi, P and Wardill, HR and Graff, SL}, title = {Emerging pharmacotherapy trends in preventing and managing oral mucositis induced by chemoradiotherapy and targeted agents.}, journal = {Expert opinion on pharmacotherapy}, volume = {25}, number = {6}, pages = {727-742}, doi = {10.1080/14656566.2024.2354451}, pmid = {38808634}, issn = {1744-7666}, support = {P30 CA086862/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Stomatitis/prevention &amp; control/etiology/drug therapy ; *Chemoradiotherapy/adverse effects/methods ; *Antineoplastic Agents/adverse effects ; *Neoplasms/drug therapy/radiotherapy ; *Quality of Life ; Molecular Targeted Therapy/adverse effects ; Animals ; Probiotics/therapeutic use/administration &amp; dosage ; }, abstract = {INTRODUCTION: The introduction of targeted therapy and immunotherapy has tremendously changed the clinical outcomes and prognosis of cancer patients. Despite innovative pharmacological therapies and improved radiotherapy (RT) techniques, patients continue to suffer from side effects, of which oral mucositis (OM) is still the most impactful, especially for quality of life.<br><br>AREAS COVERED: We provide an overview of current advances in cancer pharmacotherapy and RT, in relation to their potential to cause OM, and of the less explored and more recent literature reports related to the best management of OM. We have analyzed natural/antioxidant agents, probiotics, mucosal protectants and healing coadjuvants, pharmacotherapies, immunomodulatory and anticancer agents, photobiomodulation and the impact of technology.<br><br>EXPERT OPINION: The discovery of more precise pathophysiologic mechanisms of CT and RT-induced OM has outlined that OM has a multifactorial origin, including direct effects, oxidative damage, upregulation of immunologic factors, and effects on oral flora. A persistent upregulated immune response, associated with factors related to patients' characteristics, may contribute to more severe and long-lasting OM. The goal is strategies to conjugate individual patient, disease, and therapy-related factors to guide OM prevention or treatment. Despite further high-quality research is warranted, the issue of prevention is paramount in future strategies.}, }
@article {pmid38806464, year = {2024}, author = {Fitzgerald, K and Stephan, SB and Ma, N and Wu, QV and Stephan, MT}, title = {Liquid foam improves potency and safety of gene therapy vectors.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {4523}, pmid = {38806464}, issn = {2041-1723}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {*Genetic Therapy/methods ; *Genetic Vectors/genetics ; Animals ; Humans ; Mice ; Gene Transfer Techniques ; Methylcellulose/chemistry ; Transfection/methods ; Female ; Polysaccharides, Bacterial ; }, abstract = {Interest in gene therapy medicines is intensifying as the first wave of gene-correcting drugs is now reaching patient populations. However, efficacy and safety concerns, laborious manufacturing protocols, and the high cost of the therapeutics are still significant barriers in gene therapy. Here we describe liquid foam as a vehicle for gene delivery. We demonstrate that embedding gene therapy vectors (nonviral or viral) in a methylcellulose/xanthan gum-based foam formulation substantially boosts gene transfection efficiencies in situ, compared to liquid-based gene delivery. We further establish that our gene therapy foam is nontoxic and retained at the intended target tissue, thus minimizing both systemic exposure and targeting of irrelevant cell types. The foam can be applied locally or injected to fill body cavities so the vector is uniformly dispersed over a large surface area. Our technology may provide a safe, facile and broadly applicable option in a variety of clinical settings.}, }
@article {pmid38805324, year = {2024}, author = {Evenson, KR and Wen, F and Di, C and Kebede, M and LaMonte, MJ and Lee, IM and Tinker, LF and LaCroix, AZ and Howard, AG}, title = {Accelerometry-assessed physical activity and sedentary behavior patterns using single- and multi-component latent class analysis among postmenopausal women.}, journal = {Women's health (London, England)}, volume = {20}, number = {}, pages = {17455057241257361}, pmid = {38805324}, issn = {1745-5065}, support = {R01 CA227122/CA/NCI NIH HHS/United States ; R01 HL105065/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Sedentary Behavior ; *Postmenopause/physiology ; *Accelerometry ; *Exercise ; Cross-Sectional Studies ; Middle Aged ; *Latent Class Analysis ; Aged ; Aged, 80 and over ; Health Behavior ; }, abstract = {BACKGROUND: Patterns of physical activity and sedentary behavior among postmenopausal women are not well characterized.<br><br>OBJECTIVES: To describe the patterns of accelerometer-assessed physical activity and sedentary behavior among postmenopausal women.<br><br>DESIGN: Cross-sectional study.<br><br>METHODS: Women 63-97 years (n&#x2009;=&#x2009;6126) wore an ActiGraph GT3X&#x2009;+&#x2009;accelerometer on their hip for 1 week. Latent class analysis was used to classify women by patterns of percent of wake time in physical activity and sedentary behavior over the week.<br><br>RESULTS: On average, participants spent two-thirds of their day in sedentary behavior (62.3%), 21.1% in light low, 11.0% in light high, and 5.6% in moderate-to-vigorous physical activity. Five classes emerged for each single-component model for sedentary behavior and light low, light high, and moderate-to-vigorous physical activity. Six classes emerged for the multi-component model that simultaneously considered the four behaviors together.<br><br>CONCLUSION: Unique profiles were identified in both single- and multi-component models that can provide new insights into habitual patterns of physical activity and sedentary behavior among postmenopausal women.<br><br>IMPLICATIONS: The multi-component approach can contribute to refining public health guidelines that integrate recommendations for both enhancing age-appropriate physical activity levels and reducing time spent in sedentary behavior.}, }
@article {pmid38805234, year = {2024}, author = {Casto, AM and Song, H and Xie, H and Selke, S and Roychoudhury, P and Wu, MC and Wald, A and Greninger, AL and Johnston, C}, title = {Viral genomic variation and the severity of genital HSV-2 infection as quantified by shedding rate: a viral genome-wide association study.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiae283}, pmid = {38805234}, issn = {1537-6613}, abstract = {BACKGROUND: The clinical severity of genital HSV-2 infection varies widely among infected persons with some experiencing frequent genital lesions while others are asymptomatic. The viral genital shedding rate is closely associated with and has been established as a surrogate marker of clinical severity.<br><br>METHODS: To assess the relationship between viral genetics and shedding, we assembled a set of 145 persons who had the severity of their genital herpes quantified through determination of their HSV genital shedding rate. An HSV-2 sample from each person was sequenced and biallelic variants among these genomes were identified.<br><br>RESULTS: We found no association between metrics of genome-wide variation in HSV-2 and shedding rate. A viral genome-wide association study (vGWAS) identified the minor alleles of three individual unlinked variants as significantly associated with higher shedding rate (p<8.4x10-5): C44973T (A512T), a non-synonymous variant in UL22 (glycoprotein H); A74534G, a synonymous variant in UL36 (large tegument protein); and T119283C, an intergenic variant. We also found an association between the total number of minor alleles for the significant variants and shedding rate (p=6.6x10-7).<br><br>CONCLUSIONS: These results add to a growing body of literature for HSV suggesting a connection between viral genetic variation and clinically important phenotypes of infection.}, }
@article {pmid38805095, year = {2024}, author = {Zheng, J and Hsu, L}, title = {Risk projection for time-to-event outcome from population-based case-control studies leveraging summary statistics from the target population.}, journal = {Lifetime data analysis}, volume = {30}, number = {3}, pages = {549-571}, pmid = {38805095}, issn = {1572-9249}, support = {R01 CA189532/CA/NCI NIH HHS/United States ; R01 CA195789/CA/NCI NIH HHS/United States ; R01CA189532/NH/NIH HHS/United States ; R01CA195789/NH/NIH HHS/United States ; }, mesh = {Humans ; Case-Control Studies ; Risk Assessment/methods ; Risk Factors ; *Computer Simulation ; Models, Statistical ; Colorectal Neoplasms ; Proportional Hazards Models ; }, abstract = {Risk stratification based on prediction models has become increasingly important in preventing and managing chronic diseases. However, due to cost- and time-limitations, not every population can have resources for collecting enough detailed individual-level information on a large number of people to develop risk prediction models. A more practical approach is to use prediction models developed from existing studies and calibrate them with relevant summary-level information of the target population. Many existing studies were conducted under the population-based case-control design. Gail et al. (J Natl Cancer Inst 81:1879-1886, 1989) proposed to combine the odds ratio estimates obtained from case-control data and the disease incidence rates from the target population to obtain the baseline hazard function, and thereby the pure risk for developing diseases. However, the approach requires the risk factor distribution of cases from the case-control studies be same as the target population, which, if violated, may yield biased risk estimation. In this article, we propose two novel weighted estimating equation approaches to calibrate the baseline risk by leveraging the summary information of (some) risk factors in addition to disease-free probabilities from the targeted population. We establish the consistency and asymptotic normality of the proposed estimators. Extensive simulation studies and an application to colorectal cancer studies demonstrate the proposed estimators perform well for bias reduction in finite samples.}, }
@article {pmid38803064, year = {2024}, author = {Bannick, M and Donnell, D and Hayes, R and Laeyendecker, O and Gao, F}, title = {An enhanced cross-sectional HIV incidence estimator that incorporates prior HIV test results.}, journal = {Statistics in medicine}, volume = {43}, number = {17}, pages = {3125-3139}, pmid = {38803064}, issn = {1097-0258}, support = {S10 OD028685/OD/NIH HHS/United States ; R01AI177078/NH/NIH HHS/United States ; UM1AI068617/NH/NIH HHS/United States ; R01AI029168/NH/NIH HHS/United States ; R01 AI177078/AI/NIAID NIH HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; R01 AI029168/AI/NIAID NIH HHS/United States ; S10OD028685/NH/NIH HHS/United States ; }, mesh = {Humans ; *HIV Infections/epidemiology ; Incidence ; Cross-Sectional Studies ; *Algorithms ; Computer Simulation ; Models, Statistical ; Male ; Randomized Controlled Trials as Topic ; HIV Testing/statistics &amp; numerical data ; Female ; Sensitivity and Specificity ; }, abstract = {Incidence estimation of HIV infection can be performed using recent infection testing algorithm (RITA) results from a cross-sectional sample. This allows practitioners to understand population trends in the HIV epidemic without having to perform longitudinal follow-up on a cohort of individuals. The utility of the approach is limited by its precision, driven by the (low) sensitivity of the RITA at identifying recent infection. By utilizing results of previous HIV tests that individuals may have taken, we consider an enhanced RITA with increased sensitivity (and specificity). We use it to propose an enhanced estimator for incidence estimation. We prove the theoretical properties of the enhanced estimator and illustrate its numerical performance in simulation studies. We apply the estimator to data from a cluster-randomized trial to study the effect of community-level HIV interventions on HIV incidence. We demonstrate that the enhanced estimator provides a more precise estimate of HIV incidence compared to the standard estimator.}, }
@article {pmid38801746, year = {2024}, author = {Hill, JA and Martens, MJ and Young, JH and Bhavsar, K and Kou, J and Chen, M and Lee, LW and Baluch, A and Dhodapkar, MV and Nakamura, R and Peyton, K and Howard, DS and Ibrahim, U and Shahid, Z and Armistead, P and Westervelt, P and McCarty, J and McGuirk, J and Hamadani, M and DeWolf, S and Hosszu, K and Sharon, E and Spahn, A and Toor, AA and Waldvogel, S and Greenberger, LM and Auletta, JJ and Horowitz, MM and Riches, ML and Perales, MA}, title = {SARS-CoV-2 Vaccination in the First Year After Hematopoietic Cell Transplant or Chimeric Antigen Receptor T-Cell Therapy: A Prospective, Multicenter, Observational Study.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {79}, number = {2}, pages = {542-554}, pmid = {38801746}, issn = {1537-6591}, support = {//Kyowa Kirin/ ; //OptumHealth/ ; //Takeda Oncology Co/ ; //Xenikos BV/ ; //Talaris Therapeutics/ ; //Karyopharm Therapeutics/ ; //Sanofi Genzyme/ ; //MorphoSys/ ; U10HL069294//National Cancer Institute [NCI]/ ; //Karius/ ; //Vertex/ ; //OncoImmune, Inc/ ; //Orca Biosystems, Inc/ ; //Medexus, Merck &amp; Co./ ; //Kyowa Kirin International plc/ ; //Seagen, Inc/ ; P30 CA015704/CA/NCI NIH HHS/United States ; //Bristol Myers Squibb Co/ ; //HistoGenetics/ ; //Millennium/ ; U24 CA076518/CA/NCI NIH HHS/United States ; //Oncopeptides, Inc/ ; //Janssen Research &amp; Development, LLC/ ; //Miltenyi Biotec, Inc/ ; //AlloVir, Inc/ ; UG1 HL069315/HL/NHLBI NIH HHS/United States ; //Janssen/Johnson &amp; Johnson/ ; UG1 HL138645/HL/NHLBI NIH HHS/United States ; /HRSA/HRSA HHS/United States ; //Terumo Blood and Cell Technologies/ ; N00014-20-1-2705//Department of Health and Human Services [DHHS]/ ; //Adienne SA/ ; //Novartis/ ; //Kiadis Pharma/ ; //Actinium Pharmaceuticals, Inc/ ; //Bluebird Bio, Inc/ ; //Novartis Pharmaceuticals Corporation/ ; //Medical College of Wisconsin/ ; HHSH234200637015C//National Institute of Allergy and Infectious Diseases/ ; UG1 HL069246/HL/NHLBI NIH HHS/United States ; //TG Therapeutics/ ; //Pfizer, Inc/ ; //Kite Pharma, Inc/ ; P30 CA008748/CA/NCI NIH HHS/United States ; //Incyte Corporation/ ; //Pharmacyclics, LLC/ ; //Tscan/ ; //National Heart, Lung, and Blood Institute [NHLBI]/ ; //CytoSen Therapeutics, Inc/ ; //Gilead/ ; //Astellas Pharma US/ ; //Takeda Pharmaceuticals/ ; //Accenture/ ; //AbbVie/ ; //Gilead Company/ ; //Be the Match Foundation/ ; //Leukemia and Lymphoma Society/ ; //Adaptive Biotechnologies/ ; //National Marrow Donor Program/Be the Match/ ; //Multiple Myeloma Research Foundation/ ; //Stemcyte/ ; //DBA Eurofins Transplant Diagnostics/ ; //CareDx/ ; //Eurofins Viracor/ ; /NH/NIH HHS/United States ; //CSL Behring/ ; //Medac GmbH/ ; //GlaxoSmithKline/ ; //Fate Therapeutics/ ; //American Society for Transplantation and Cellular Therapy/ ; //Gamida-Cell, Ltd/ ; //NCI/ ; //Legend Biotech/ ; //Kadmon/ ; //Ossium Health, Inc/ ; //Vor Biopharma/ ; //Jasper Therapeutics/ ; //Jazz Pharmaceuticals, Inc/ ; //Iovance/ ; //U24CA076518/ ; //LabCorp/ ; //Omeros Corporation/ ; //Amgen, Inc/ ; //Magenta Therapeutics/ ; //Daiichi Sankyo Co, Ltd/ ; //Priothera/ ; //Office of Naval Research/ ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation ; *COVID-19 Vaccines/immunology/administration &amp; dosage ; Male ; Middle Aged ; Prospective Studies ; Female ; *COVID-19/prevention &amp; control/immunology ; *SARS-CoV-2/immunology ; Adult ; *Antibodies, Viral/blood ; *Antibodies, Neutralizing/blood ; Aged ; Vaccination ; Immunotherapy, Adoptive/methods ; Immunoglobulin G/blood ; Receptors, Chimeric Antigen/immunology ; Spike Glycoprotein, Coronavirus/immunology ; United States ; }, abstract = {BACKGROUND: The optimal timing of vaccination with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines after cellular therapy is incompletely understood. The objectives of this study are to determine whether humoral and cellular responses after SARS-CoV-2 vaccination differ if initiated <4 months versus 4-12 months after cellular therapy.<br><br>METHODS: We conducted a multicenter, prospective, observational study at 30 cancer centers in the United States. SARS-CoV-2 vaccination was administered as part of routine care. We obtained blood prior to and after vaccinations at up to 5 time points and tested for SARS-CoV-2 spike (anti-S) IgG in all participants and neutralizing antibodies for Wuhan D614G, Delta B.1.617.2, and Omicron B.1.1.529 strains, as well as SARS-CoV-2-specific T-cell receptors, in a subgroup.<br><br>RESULTS: We enrolled 466 allogeneic hematopoietic cell transplantation (HCT) (n = 231), autologous HCT (n = 170), and chimeric antigen receptor T-cell (CAR-T-cell) therapy (n = 65) recipients between April 2021 and June 2022. Humoral and cellular responses did not significantly differ among participants initiating vaccinations <4 months versus 4-12 months after cellular therapy. Anti-S IgG &#x2265;2500&#x2005;U/mL was correlated with high neutralizing antibody titers and attained by the last time point in 70%, 69%, and 34% of allogeneic HCT, autologous HCT, and CAR-T-cell recipients, respectively. SARS-CoV-2-specific T-cell responses were attained in 57%, 83%, and 58%, respectively. Pre-cellular therapy SARS-CoV-2 infection or vaccination and baseline B-cell count were key predictors of post-cellular therapy immunity.<br><br>CONCLUSIONS: These data support mRNA SARS-CoV-2 vaccination prior to, and reinitiation 3 to 4 months after, cellular therapies with allogeneic HCT, autologous HCT, and CAR-T-cell therapy.}, }
@article {pmid38798578, year = {2024}, author = {Zhang, Y and Spitzer, BW and Zhang, Y and Wallace, DA and Yu, B and Qi, Q and Argos, M and Avilés-Santa, ML and Boerwinkle, E and Daviglus, ML and Kaplan, R and Cai, J and Redline, S and Sofer, T}, title = {Untargeted Metabolome Atlas for Sleep Phenotypes in the Hispanic Community Health Study/Study of Latinos.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {38798578}, support = {HHSN268201300005C/HL/NHLBI NIH HHS/United States ; HHSN268201300004C/HL/NHLBI NIH HHS/United States ; HHSN268201300001C/HL/NHLBI NIH HHS/United States ; HHSN268201300003I/HL/NHLBI NIH HHS/United States ; N01HC65236/HL/NHLBI NIH HHS/United States ; N01HC65235/HL/NHLBI NIH HHS/United States ; R01 HL161012/HL/NHLBI NIH HHS/United States ; N01HC65234/HL/NHLBI NIH HHS/United States ; N01HC65233/HL/NHLBI NIH HHS/United States ; N01HC65237/HL/NHLBI NIH HHS/United States ; HHSN268201300003C/HL/NHLBI NIH HHS/United States ; R01 HL141824/HL/NHLBI NIH HHS/United States ; K99 HL166700/HL/NHLBI NIH HHS/United States ; R35 HL135818/HL/NHLBI NIH HHS/United States ; R01 AG080598/AG/NIA NIH HHS/United States ; }, abstract = {Sleep is essential to maintaining health and wellbeing of individuals, influencing a variety of outcomes from mental health to cardiometabolic disease. This study aims to assess the relationships between various sleep phenotypes and blood metabolites. Utilizing data from the Hispanic Community Health Study/Study of Latinos, we performed association analyses between 40 sleep phenotypes, grouped in several domains (i.e., sleep disordered breathing (SDB), sleep duration, timing, insomnia symptoms, and heart rate during sleep), and 768 metabolites measured via untargeted metabolomics profiling. Network analysis was employed to visualize and interpret the associations between sleep phenotypes and metabolites. The patterns of statistically significant associations between sleep phenotypes and metabolites differed by superpathways, and highlighted subpathways of interest for future studies. For example, some xenobiotic metabolites were associated with sleep duration and heart rate phenotypes (e.g. 1H-indole-7-acetic acid, 4-allylphenol sulfate), while ketone bodies and fatty acid metabolism metabolites were associated with sleep timing measures (e.g. 3-hydroxybutyrate (BHBA), 3-hydroxyhexanoylcarnitine (1)). Heart rate phenotypes had the overall largest number of detected metabolite associations. Many of these associations were shared with both SDB and with sleep timing phenotypes, while SDB phenotypes shared relatively few metabolite associations with sleep duration measures. A number of metabolites were associated with multiple sleep phenotypes, from a few domains. The amino acids vanillylmandelate (VMA) and 1-carboxyethylisoleucine were associated with the greatest number of sleep phenotypes, from all domains other than insomnia. This atlas of sleep-metabolite associations will facilitate hypothesis generation and further study of the metabolic underpinnings of sleep health.}, }
@article {pmid38798454, year = {2024}, author = {Buteyn, NJ and Burke, CG and Sartori, VJ and Deering-Gardner, E and DeBruine, ZJ and Kamarudin, D and Chandler, DP and Monovich, AC and Perez, MW and Yi, JS and Ries, RE and Alonzo, TA and Ryan, RJ and Meshinchi, S and Triche, TJ}, title = {EZH2-driven immune evasion defines high-risk pediatric AML with t(16;21) FUS::ERG gene fusion.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38798454}, issn = {2692-8205}, support = {R03 CA290259/CA/NCI NIH HHS/United States ; T32 CA251066/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; R01 AI171984/AI/NIAID NIH HHS/United States ; U10 CA180886/CA/NCI NIH HHS/United States ; }, abstract = {Despite decades of research, acute myeloid leukemia (AML) remains a remarkably lethal malignancy. While pediatric AML (pAML) carries a more favorable prognosis than adult AML, the past 25 years of large clinical trials have produced few improvements in pAML survival. Nowhere is this more evident than in patients carrying a t(16;21)(p11;q22) translocation, which yields the FUS::ERG fusion transcript. Patients with FUS::ERG-positive AML are often primary refractory, and most responders quickly relapse. In COG clinical trials, allogeneic stem cell transplantation was of no benefit to FUS::ERG pAML patients; 100% of transplanted patients succumbed to their disease. Expression of major histocompatibility complex (MHC) class I &amp; II and costimulatory molecules is absent at diagnosis in FUS::ERG AML, mirroring the epigenetic mechanism of post-transplant relapse seen in adult AML and its associated dismal outcomes. Here we show that this class-defining immune-repressive phenotype is driven by overexpression of the EZH2 histone lysine methyltransferase in vitro and in multiple clinical cohorts. We show that treatment with the FDA-approved EZH2 inhibitor tazemetostat along with IFN-γ reverses this phenotype, re-establishes MHC presentation, and severely impairs the viability of FUS::ERG AML cells. EZH2 inhibitors may thus provide the first targeted therapeutic option for patients with this high-risk subtype of pAML, with particular benefit as a bridge to successful allogeneic stem cell transplantation.}, }
@article {pmid38797981, year = {2024}, author = {Dai, JY and Georg Luebeck, E and Chang, ET and Clarke, CA and Hubbell, EA and Zhang, N and Duffy, SW}, title = {Strong association between reduction of late-stage cancers and reduction of cancer-specific mortality in meta-regression of randomized screening trials across multiple cancer types.}, journal = {Journal of medical screening}, volume = {31}, number = {4}, pages = {211-222}, pmid = {38797981}, issn = {1475-5793}, mesh = {Female ; Humans ; Male ; Colorectal Neoplasms/mortality/diagnosis ; *Early Detection of Cancer/methods/statistics &amp; numerical data ; Incidence ; Neoplasm Staging ; *Neoplasms/diagnosis/epidemiology/mortality/therapy ; Randomized Controlled Trials as Topic ; Regression Analysis ; }, abstract = {BACKGROUND: Late-stage cancer incidence has been proposed as an early surrogate for mortality in randomized controlled trials (RCTs) of cancer screening; however, its validity has not been systematically evaluated across screening RCTs of different cancers.<br><br>METHODS: We conducted a meta-regression analysis of cancer screening RCTs that reported both late-stage cancer incidence and cancer mortality. Based on a systematic literature review, we included 33 RCTs of screening programs targeting seven cancer types, including lung (n&#x2009;=&#x2009;12), colorectal (n&#x2009;=&#x2009;8), breast (n&#x2009;=&#x2009;5), and prostate (n&#x2009;=&#x2009;4), among others. We regressed the relative reduction of cancer mortality on the relative reduction of late-stage cancer incidence, inversely weighted for each RCT by the variance of estimated mortality reduction.<br><br>RESULTS: Across cancer types, the relative reduction of late-stage cancer incidence was linearly associated with the relative reduction of cancer mortality. Specifically, we observed this association for lung (R[2]&#x2009;=&#x2009;0.79 and 0.996 in three recent large trials), breast (R[2]&#x2009;=&#x2009;0.94), prostate (R[2]&#x2009;=&#x2009;0.98), and colorectal cancer (R[2]&#x2009;=&#x2009;0.75 for stage III/IV cancers and 0.93 for stage IV cancers). Trials with a 20% or greater reduction in late-stage cancers were more likely to achieve a significant reduction in cancer mortality. Our results also showed that no reduction of late-stage cancer incidence was associated with no or minimal reduction in cancer mortality.<br><br>CONCLUSIONS: Meta-regression of historical screening RCTs showed a strong linear association between reductions in late-stage cancer incidence and cancer mortality.}, }
@article {pmid38797526, year = {2024}, author = {Epperla, N and Hashmi, H and Ahn, KW and Allbee-Johnson, M and Chen, AI and Wirk, B and Kanakry, JA and Lekakis, L and Kharfan-Dabaja, MA and Scordo, M and Riedell, PA and Jain, T and Shadman, M and Sauter, C and Hamadani, M and Herrera, AF and Ahmed, S}, title = {Outcomes of patients with secondary central nervous system lymphoma treated with chimeric antigen receptor T-cell therapy: A CIBMTR analysis.}, journal = {British journal of haematology}, volume = {205}, number = {3}, pages = {1202-1207}, pmid = {38797526}, issn = {1365-2141}, support = {U24CA076518/CA/NCI NIH HHS/United States ; //Pediatric Transplantation and Cellular Therapy Consortium/ ; U24 CA076518/CA/NCI NIH HHS/United States ; N00014-24-1-2507//Office of Naval Research/ ; //Medical College of Wisconsin/ ; //Gateway for Cancer Research/ ; 75R60222C00011/HRSA/HRSA HHS/United States ; //NMDP/ ; //National Institute of Allergy and Infectious Diseases/ ; N00014-23-1-2057//Office of Naval Research/ ; P30 CA008748/CA/NCI NIH HHS/United States ; //National Heart, Lung and Blood Institute/ ; }, }
@article {pmid38796287, year = {2024}, author = {Hurvitz, SA and Kim, SB and Chung, WP and Im, SA and Park, YH and Hegg, R and Kim, MH and Tseng, LM and Petry, V and Chung, CF and Iwata, H and Hamilton, E and Curigliano, G and Xu, B and Egorov, A and Liu, Y and Cathcart, J and Bako, E and Tecson, K and Verma, S and Cortés, J}, title = {Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer patients with brain metastases from the randomized DESTINY-Breast03 trial.}, journal = {ESMO open}, volume = {9}, number = {5}, pages = {102924}, pmid = {38796287}, issn = {2059-7029}, mesh = {Humans ; Female ; *Breast Neoplasms/drug therapy/pathology ; *Brain Neoplasms/secondary/drug therapy ; *Trastuzumab/therapeutic use/pharmacology ; Middle Aged ; *Ado-Trastuzumab Emtansine/therapeutic use/pharmacology ; *Receptor, ErbB-2/metabolism ; Adult ; Aged ; Camptothecin/analogs &amp; derivatives/therapeutic use/pharmacology ; Antineoplastic Agents, Immunological/therapeutic use/pharmacology ; Immunoconjugates/therapeutic use/pharmacology ; Progression-Free Survival ; }, abstract = {BACKGROUND: DESTINY-Breast03 is a randomized, multicenter, open-label, phase III study of trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) previously treated with trastuzumab and a taxane. A statistically significant improvement in progression-free survival (PFS) versus T-DM1 was reported in the primary analysis. Here, we report exploratory efficacy data in patients with and without brain metastases (BMs) at baseline.<br><br>PATIENTS AND METHODS: Patients were randomly assigned 1 : 1 to receive T-DXd 5.4 mg/kg or T-DM1 3.6 mg/kg. Patients with clinically inactive/asymptomatic BMs were eligible. Lesions were measured as per modified RECIST, version 1.1. Outcomes included PFS by blinded independent central review (BICR), objective response rate (ORR), and intracranial ORR as per BICR.<br><br>RESULTS: As of 21 May 2021, 43/261 patients randomized to T-DXd and 39/263 patients randomized to T-DM1 had BMs at baseline, as per investigator assessment. Among patients with baseline BMs, 20/43 in the T-DXd arm and 19/39 in the T-DM1 arm had not received prior local BM treatment. For patients with BMs, median PFS was 15.0 months [95% confidence interval (CI) 12.5-22.2 months] for T-DXd versus 3.0 months (95% CI 2.8-5.8 months) for T-DM1; hazard ratio (HR) 0.25 (95% CI 0.13-0.45). For patients without BMs, median PFS was not reached (95% CI 22.4 months-not estimable) for T-DXd versus 7.1 months (95% CI 5.6-9.7 months) for T-DM1; HR 0.30 (95% CI 0.22-0.40). Confirmed systemic ORR was 67.4% for T-DXd versus 20.5% for T-DM1 and 82.1% for T-DXd versus 36.6% for T-DM1 for patients with and without BMs, respectively. Intracranial ORR was 65.7% with T-DXd versus 34.3% with T-DM1.<br><br>CONCLUSIONS: Patients with HER2-positive mBC whose disease progressed after trastuzumab and a taxane achieved a substantial benefit from treatment with T-DXd compared with T-DM1, including those with baseline BMs.}, }
@article {pmid38794258, year = {2024}, author = {Mayer, BT and Zhang, L and deCamp, AC and Yu, C and Sato, A and Angier, H and Seaton, KE and Yates, N and Ledgerwood, JE and Mayer, K and Caskey, M and Nussenzweig, M and Stephenson, K and Julg, B and Barouch, DH and Sobieszczyk, ME and Edupuganti, S and Kelley, CF and McElrath, MJ and Gelderblom, HC and Pensiero, M and McDermott, A and Gama, L and Koup, RA and Gilbert, PB and Cohen, MS and Corey, L and Hyrien, O and Tomaras, GD and Huang, Y}, title = {Impact of LS Mutation on Pharmacokinetics of Preventive HIV Broadly Neutralizing Monoclonal Antibodies: A Cross-Protocol Analysis of 16 Clinical Trials in People without HIV.}, journal = {Pharmaceutics}, volume = {16}, number = {5}, pages = {}, pmid = {38794258}, issn = {1999-4923}, support = {grant INV-032929//Bill and Melinda Gates Foundations/ ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI068635,//UNAID/ ; U01 AI069470/AI/NIAID NIH HHS/United States ; UM1 AI069412/AI/NIAID NIH HHS/United States ; UM1 AI069470/AI/NIAID NIH HHS/United States ; }, abstract = {Monoclonal antibodies are commonly engineered with an introduction of Met428Leu and Asn434Ser, known as the LS mutation, in the fragment crystallizable region to improve pharmacokinetic profiles. The LS mutation delays antibody clearance by enhancing binding affinity to the neonatal fragment crystallizable receptor found on endothelial cells. To characterize the LS mutation for monoclonal antibodies targeting HIV, we compared pharmacokinetic parameters between parental versus LS variants for five pairs of anti-HIV immunoglobin G1 monoclonal antibodies (VRC01/LS/VRC07-523LS, 3BNC117/LS, PGDM1400/LS PGT121/LS, 10-1074/LS), analyzing data from 16 clinical trials of 583 participants without HIV. We described serum concentrations of these monoclonal antibodies following intravenous or subcutaneous administration by an open two-compartment disposition, with first-order elimination from the central compartment using non-linear mixed effects pharmacokinetic models. We compared estimated pharmacokinetic parameters using the targeted maximum likelihood estimation method, accounting for participant differences. We observed lower clearance rate, central volume, and peripheral volume of distribution for all LS variants compared to parental monoclonal antibodies. LS monoclonal antibodies showed several improvements in pharmacokinetic parameters, including increases in the elimination half-life by 2.7- to 4.1-fold, the dose-normalized area-under-the-curve by 4.1- to 9.5-fold, and the predicted concentration at 4 weeks post-administration by 3.4- to 7.6-fold. Results suggest a favorable pharmacokinetic profile of LS variants regardless of HIV epitope specificity. Insights support lower dosages and/or less frequent dosing of LS variants to achieve similar levels of antibody exposure in future clinical applications.}, }
@article {pmid38790636, year = {2024}, author = {Tratnig-Frankl, P and Andrews, AR and Berkane, Y and Guinier, C and Goutard, M and Lupon, E and Lancia, HH and Morrison, ML and Roth, MB and Randolph, MA and Cetrulo, CL and Lellouch, AG}, title = {Exploring Iodide and Hydrogen Sulfide as ROS Scavengers to Delay Acute Rejection in MHC-Defined Vascularized Composite Allografts.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {5}, pages = {}, pmid = {38790636}, issn = {2076-3921}, support = {//Army Research Office/ ; //Fred Hutchinson Cancer Research Center/ ; }, abstract = {Vascularized composite allografts (VCA) face ischemic challenges due to their limited availability. Reperfusion following ischemia triggers oxidative stress and immune reactions, and scavenger molecules could mitigate ischemia-reperfusion injuries and, therefore, immune rejection. We compared two scavengers in a myocutaneous flap VCA model. In total, 18 myocutaneous flap transplants were performed in Major histocompatibility complex (MHC)-defined miniature swine. In the MATCH group (n = 9), donors and recipients had minor antigen mismatch, while the animals were fully mismatched in the MISMATCH group (n = 9). Grafts were pretreated with saline, sodium iodide (NaI), or hydrogen sulfide (H2S), stored at 4 °C for 3 h, and then transplanted. Flaps were monitored until clinical rejection without immunosuppression. In the MATCH group, flap survival did not significantly differ between the saline and hydrogen sulfide treatments (p = 0.483) but was reduced with the sodium iodide treatment (p = 0.007). In the MISMATCH group, survival was similar between the saline and hydrogen sulfide treatments (p = 0.483) but decreased with the sodium iodide treatment (p = 0.007). Rhabdomyolysis markers showed lower but non-significant levels in the experimental subgroups for both the MATCH and MISMATCH animals. This study provides insightful data for the field of antioxidant-based approaches in VCA and transplantation.}, }
@article {pmid38789721, year = {2024}, author = {Kramer, G and Blair, T and Bambina, S and Kaur, AP and Alice, A and Baird, J and Friedman, D and Dowdell, AK and Tomura, M and Grassberger, C and Piening, BD and Crittenden, MR and Gough, MJ}, title = {Fluorescence tracking demonstrates T cell recirculation is transiently impaired by radiation therapy to the tumor.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {11909}, pmid = {38789721}, issn = {2045-2322}, support = {R01 CA182311/CA/NCI NIH HHS/United States ; R01 CA244142/CA/NCI NIH HHS/United States ; R01CA182311/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Mice ; *CD8-Positive T-Lymphocytes/immunology/metabolism ; Lymph Nodes/radiation effects/pathology/immunology ; Lymphocytes, Tumor-Infiltrating/immunology/metabolism ; Neoplasms/radiotherapy/immunology/pathology ; Cell Tracking/methods ; Cell Line, Tumor ; Mice, Inbred C57BL ; Fluorescence ; }, abstract = {T cells recirculate through tissues and lymphatic organs to scan for their cognate antigen. Radiation therapy provides site-specific cytotoxicity to kill cancer cells but also has the potential to eliminate the tumor-specific T cells in field. To dynamically study the effect of radiation on CD8 T cell recirculation, we used the Kaede mouse model to photoconvert tumor-infiltrating cells and monitor their movement out of the field of radiation. We demonstrate that radiation results in loss of CD8 T cell recirculation from the tumor to the lymph node and to distant sites. Using scRNASeq, we see decreased proliferating CD8 T cells in the tumor following radiation therapy resulting in a proportional enrichment in exhausted phenotypes. By contrast, 5 days following radiation increased recirculation of T cells from the tumor to the tumor draining lymph node corresponds with increased immunosurveillance of the treated tumor. These data demonstrate that tumor radiation therapy transiently impairs systemic T cell recirculation from the treatment site to the draining lymph node and distant untreated tumors. This may inform timing therapies to improve systemic T cell-mediated tumor immunity.}, }
@article {pmid38789417, year = {2024}, author = {Keener, R and Chhetri, SB and Connelly, CJ and Taub, MA and Conomos, MP and Weinstock, J and Ni, B and Strober, B and Aslibekyan, S and Auer, PL and Barwick, L and Becker, LC and Blangero, J and Bleecker, ER and Brody, JA and Cade, BE and Celedon, JC and Chang, YC and Cupples, LA and Custer, B and Freedman, BI and Gladwin, MT and Heckbert, SR and Hou, L and Irvin, MR and Isasi, CR and Johnsen, JM and Kenny, EE and Kooperberg, C and Minster, RL and Naseri, T and Viali, S and Nekhai, S and Pankratz, N and Peyser, PA and Taylor, KD and Telen, MJ and Wu, B and Yanek, LR and Yang, IV and Albert, C and Arnett, DK and Ashley-Koch, AE and Barnes, KC and Bis, JC and Blackwell, TW and Boerwinkle, E and Burchard, EG and Carson, AP and Chen, Z and Chen, YI and Darbar, D and de Andrade, M and Ellinor, PT and Fornage, M and Gelb, BD and Gilliland, FD and He, J and Islam, T and Kaab, S and Kardia, SLR and Kelly, S and Konkle, BA and Kumar, R and Loos, RJF and Martinez, FD and McGarvey, ST and Meyers, DA and Mitchell, BD and Montgomery, CG and North, KE and Palmer, ND and Peralta, JM and Raby, BA and Redline, S and Rich, SS and Roden, D and Rotter, JI and Ruczinski, I and Schwartz, D and Sciurba, F and Shoemaker, MB and Silverman, EK and Sinner, MF and Smith, NL and Smith, AV and Tiwari, HK and Vasan, RS and Weiss, ST and Williams, LK and Zhang, Y and Ziv, E and Raffield, LM and Reiner, AP and ,  and ,  and ,  and Arvanitis, M and Greider, CW and Mathias, RA and Battle, A}, title = {Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {4417}, pmid = {38789417}, issn = {2041-1723}, support = {5K12GM123914//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01AG069120//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01 HL105756/HL/NHLBI NIH HHS/United States ; R35GM139580//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01 AI132476/AI/NIAID NIH HHS/United States ; R01 DK071891/DK/NIDDK NIH HHS/United States ; R35 GM139580/GM/NIGMS NIH HHS/United States ; R01HL153805//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01AG081244//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R35CA209974//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01HL105756//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01HL68959//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01HL079915//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01HL87681//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01 HL153805/HL/NHLBI NIH HHS/United States ; R01HL-120393//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; }, mesh = {Humans ; *Genome-Wide Association Study ; *Telomere/genetics/metabolism ; K562 Cells ; *Telomere Homeostasis/genetics ; Polymorphism, Single Nucleotide ; Gene Expression Regulation ; CRISPR-Cas Systems ; }, abstract = {Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation.}, }
@article {pmid38788713, year = {2024}, author = {Thirimanne, HN and Almiron-Bonnin, D and Nuechterlein, N and Arora, S and Jensen, M and Parada, CA and Qiu, C and Szulzewsky, F and English, CW and Chen, WC and Sievers, P and Nassiri, F and Wang, JZ and Klisch, TJ and Aldape, KD and Patel, AJ and Cimino, PJ and Zadeh, G and Sahm, F and Raleigh, DR and Shendure, J and Ferreira, M and Holland, EC}, title = {Meningioma transcriptomic landscape demonstrates novel subtypes with regional associated biology and patient outcome.}, journal = {Cell genomics}, volume = {4}, number = {6}, pages = {100566}, pmid = {38788713}, issn = {2666-979X}, support = {R35 CA253119/CA/NCI NIH HHS/United States ; }, mesh = {*Meningioma/genetics/pathology ; Humans ; *Transcriptome ; *Meningeal Neoplasms/genetics/pathology ; Male ; Female ; Middle Aged ; Gene Expression Regulation, Neoplastic ; Algorithms ; Gene Expression Profiling/methods ; }, abstract = {Meningiomas, although mostly benign, can be recurrent and fatal. World Health Organization (WHO) grading of the tumor does not always identify high-risk meningioma, and better characterizations of their aggressive biology are needed. To approach this problem, we combined 13 bulk RNA sequencing (RNA-seq) datasets to create a dimension-reduced reference landscape of 1,298 meningiomas. The clinical and genomic metadata effectively correlated with landscape regions, which led to the identification of meningioma subtypes with specific biological signatures. The time to recurrence also correlated with the map location. Further, we developed an algorithm that maps new patients onto this landscape, where the nearest neighbors predict outcome. This study highlights the utility of combining bulk transcriptomic datasets to visualize the complexity of tumor populations. Further, we provide an interactive tool for understanding the disease and predicting patient outcomes. This resource is accessible via the online tool Oncoscape, where the scientific community can explore the meningioma landscape.}, }
@article {pmid38787561, year = {2024}, author = {Gillespie, EF and Santos, PMG and Curry, M and Salz, T and Chakraborty, N and Caron, M and Fuchs, HE and Ledesma Vicioso, N and Mathis, N and Kumar, R and O'Brien, C and Patel, S and Guttmann, DM and Ostroff, JS and Salner, AL and Panoff, JE and McIntosh, AF and Pfister, DG and Vaynrub, M and Yang, JT and Lipitz-Snyderman, A}, title = {Implementation Strategies to Promote Short-Course Radiation for Bone Metastases.}, journal = {JAMA network open}, volume = {7}, number = {5}, pages = {e2411717}, pmid = {38787561}, issn = {2574-3805}, support = {K08 CA252640/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Bone Neoplasms/secondary/radiotherapy ; Female ; Male ; Middle Aged ; Prospective Studies ; *Quality Improvement ; Aged ; Guideline Adherence/statistics &amp; numerical data ; Practice Patterns, Physicians'/statistics &amp; numerical data ; }, abstract = {IMPORTANCE: For patients with nonspine bone metastases, short-course radiotherapy (RT) can reduce patient burden without sacrificing clinical benefit. However, there is great variation in uptake of short-course RT across practice settings.<br><br>OBJECTIVE: To evaluate whether a set of 3 implementation strategies facilitates increased adoption of a consensus recommendation to treat nonspine bone metastases with short-course RT (ie, &#x2264;5 fractions).<br><br>This prospective, stepped-wedge, cluster randomized quality improvement study was conducted at 3 community-based cancer centers within an existing academic-community partnership. Rollout was initiated in 3-month increments between October 2021 and May 2022. Participants included treating physicians and patients receiving RT for nonspine bone metastases. Data analysis was performed from October 2022 to May 2023.<br><br>EXPOSURES: Three implementation strategies-(1) dissemination of published consensus guidelines, (2) personalized audit-and-feedback reports, and (3) an email-based electronic consultation platform (eConsult)-were rolled out to physicians.<br><br>MAIN OUTCOMES AND MEASURES: The primary outcome was adherence to the consensus recommendation of short-course RT for nonspine bone metastases. Mixed-effects logistic regression at the bone metastasis level was used to model associations between the exposure of physicians to the set of strategies (preimplementation vs postimplementation) and short-course RT, while accounting for patient and physician characteristics and calendar time, with a random effect for physician. Physician surveys were administered before implementation and after implementation to assess feasibility, acceptability, and appropriateness of each strategy.<br><br>RESULTS: Forty-five physicians treated 714 patients (median [IQR] age at treatment start, 67 [59-75] years; 343 women [48%]) with 838 unique nonspine bone metastases during the study period. Implementing the set of strategies was not associated with use of short-course RT (odds ratio, 0.78; 95% CI, 0.45-1.34; P&#x2009;=&#x2009;.40), with unadjusted adherence rates of 53% (444 lesions) preimplementation vs 56% (469 lesions) postimplementation; however, the adjusted odds of adherence increased with calendar time (odds ratio, 1.68; 95% CI, 1.20-2.36; P&#x2009;=&#x2009;.003). All 3 implementation strategies were perceived as being feasible, acceptable, and appropriate; only the perception of audit-and-feedback appropriateness changed before vs after implementation (19 of 29 physicians [66%] vs 27 of 30 physicians [90%]; P&#x2009;=&#x2009;.03, Fisher exact test), with 20 physicians (67%) preferring reports quarterly.<br><br>CONCLUSIONS AND RELEVANCE: In this quality improvement study, a multicomponent set of implementation strategies was not associated with increased use of short-course RT within an academic-community partnership. However, practice improved with time, perhaps owing to secular trends or physician awareness of the study. Audit-and-feedback was more appropriate than anticipated. Findings support the need to investigate optimal approaches for promoting evidence-based radiation practice across settings.}, }
@article {pmid38787308, year = {2024}, author = {Farland, LV and Lind, KE and Roe, DJ and Saquib, N and Strickler, HD and Qi, L and Thomson, CA and Harris, HR}, title = {History of Infertility and Risk of Colorectal Cancer.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {33}, number = {8}, pages = {1129-1131}, pmid = {38787308}, issn = {1538-7755}, support = {HHSN268201600002C/HL/NHLBI NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; HD102403//Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)/ ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; R03 HD102403/HD/NICHD NIH HHS/United States ; }, mesh = {Humans ; *Colorectal Neoplasms/epidemiology/etiology ; Female ; Middle Aged ; Risk Factors ; Aged ; Postmenopause ; Infertility/epidemiology ; Proportional Hazards Models ; }, abstract = {BACKGROUND: There has been limited prior research on the association between infertility and risk of colorectal cancer.<br><br>METHODS: Data from postmenopausal women in the Women's Health Initiative were used to estimate the association between self-reported infertility (12 months of trying to get pregnant without achieving a pregnancy) and the risk of colorectal cancer using Cox proportional hazard models.<br><br>RESULTS: No association was observed between infertility and risk of postmenopausal colorectal cancer [RR, 0.97; 95% confidence interval (CI), 0.87-1.08], invasive colorectal cancer (RR, 0.99; 95% CI, 0.88-1.10), or colorectal cancer mortality (RR, 0.89; 95% CI, 0.71-1.12).<br><br>CONCLUSIONS: Infertility was not found to be associated with colorectal cancer risk among postmenopausal women. Risk did not vary by specific infertility diagnoses.<br><br>IMPACT: Infertility may not be associated with colorectal cancer risk.}, }
@article {pmid38786753, year = {2024}, author = {Prentice, RL}, title = {Intake Biomarkers for Nutrition and Health: Review and Discussion of Methodology Issues.}, journal = {Metabolites}, volume = {14}, number = {5}, pages = {}, pmid = {38786753}, issn = {2218-1989}, support = {HHSN268202100046C//National Heart Lung and Blood Institute/ ; HHSN268202100002C//National Heart Lung and Blood Institute/ ; HHSN268202100003C//National Heart Lung and Blood Institute/ ; P30 CA015704/CA/NCI NIH HHS/United States ; HHSN268202100004C//National Heart Lung and Blood Institute/ ; R01 CA119171/CA/NCI NIH HHS/United States ; HHSN271202100004C//National Heart Lung and Blood Institute/ ; HHSN268202100001C//National Heart Lung and Blood Institute/ ; }, abstract = {Metabolomics profiles from blood, urine, or other body fluids have the potential to assess intakes of foods and nutrients objectively, thereby strengthening nutritional epidemiology research. Metabolomics platforms may include targeted components that estimate the relative concentrations for individual metabolites in a predetermined set, or global components, typically involving mass spectrometry, that estimate relative concentrations more broadly. While a specific metabolite concentration usually correlates with the intake of a single food or food group, multiple metabolites may be correlated with the intake of certain foods or with specific nutrient intakes, each of which may be expressed in absolute terms or relative to total energy intake. Here, I briefly review the progress over the past 20 years on the development and application intake biomarkers for foods/food groups, nutrients, and dietary patterns, primarily by drawing from several recent reviews. In doing so, I emphasize the criteria and study designs for candidate biomarker identification, biomarker validation, and intake biomarker application. The use of intake biomarkers for diet and chronic disease association studies is still infrequent in nutritional epidemiology research. My comments here will derive primarily from our research group's recent contributions to the Women's Health Initiative cohorts. I will complete the contribution by describing some opportunities to build on the collective 20 years of effort, including opportunities related to the metabolomics profiling of blood and urine specimens from human feeding studies that approximate habitual diets.}, }
@article {pmid38783160, year = {2024}, author = {Scott, S and Devonshire, A and Dillon, R and Thiede, C and Cross, NCP and White, HE and Lo Cascio, L and Mokretar, K and Potter, N and Hourigan, CS and Radich, J and Corner, A and Laloux, V and Halliday, G and Dilks, D and Morrison, T and Gilmour, K and Cartwright, A and Whitby, L}, title = {Recommendations from the AML molecular MRD expert advisory board.}, journal = {Leukemia}, volume = {38}, number = {7}, pages = {1638-1641}, pmid = {38783160}, issn = {1476-5551}, mesh = {Humans ; *Leukemia, Myeloid, Acute/genetics/pathology ; *Advisory Committees ; *Neoplasm, Residual/diagnosis ; }, }
@article {pmid38781964, year = {2024}, author = {Edwards, KR and Schmidt, K and Homad, LJ and Kher, GM and Xu, G and Rodrigues, KA and Ben-Akiva, E and Abbott, J and Prlic, M and Newell, EW and De Rosa, SC and Irvine, DJ and Pancera, M and McGuire, AT}, title = {Vaccination with nanoparticles displaying gH/gL from Epstein-Barr virus elicits limited cross-protection against rhesus lymphocryptovirus.}, journal = {Cell reports. Medicine}, volume = {5}, number = {6}, pages = {101587}, pmid = {38781964}, issn = {2666-3791}, support = {R01 CA264646/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; *Macaca mulatta ; *Nanoparticles/chemistry ; *Herpesvirus 4, Human/immunology ; *Lymphocryptovirus/immunology ; *Vaccination/methods ; *Antibodies, Neutralizing/immunology ; Antibodies, Viral/immunology ; Epstein-Barr Virus Infections/immunology/prevention &amp; control/virology ; Viral Vaccines/immunology/administration &amp; dosage ; Adjuvants, Immunologic/administration &amp; dosage/pharmacology ; Humans ; Herpesviridae Infections/prevention &amp; control/immunology/virology ; }, abstract = {Epstein-Barr virus (EBV) is associated with infectious mononucleosis, cancer, and multiple sclerosis. A vaccine that prevents infection and/or EBV-associated morbidity is an unmet need. The viral gH/gL glycoprotein complex is essential for infectivity, making it an attractive vaccine target. Here, we evaluate the immunogenicity of a gH/gL nanoparticle vaccine adjuvanted with the Sigma Adjuvant System (SAS) or a saponin/monophosphoryl lipid A nanoparticle (SMNP) in rhesus macaques. Formulation with SMNP elicits higher titers of neutralizing antibodies and more vaccine-specific CD4[+] T cells. All but one animal in the SMNP group were infected after oral challenge with the EBV ortholog rhesus lymphocryptovirus (rhLCV). Their immune plasma had a 10- to 100-fold lower reactivity against rhLCV gH/gL compared to EBV gH/gL. Anti-EBV neutralizing monoclonal antibodies showed reduced binding to rhLCV gH/gL, demonstrating that EBV gH/gL neutralizing epitopes are poorly conserved on rhLCV gH/gL. Prevention of rhLCV infection despite antigenic disparity supports clinical development of gH/gL nanoparticle vaccines against EBV.}, }
@article {pmid38781746, year = {2024}, author = {Ferris, JS and Prest, MT and Hur, C and Chen, L and Elkin, EB and Melamed, A and Kong, CY and Myers, ER and Havrilesky, LJ and Blank, SV and Hazelton, WD and Wright, JD}, title = {Trends in uterine cancer incidence in the United States: The contribution of age, period and cohort effects.}, journal = {Gynecologic oncology}, volume = {187}, number = {}, pages = {151-162}, pmid = {38781746}, issn = {1095-6859}, support = {U01 CA265739/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; United States/epidemiology ; *Uterine Neoplasms/epidemiology ; Incidence ; Middle Aged ; Aged ; *SEER Program ; Adult ; Age Factors ; Cohort Effect ; Cohort Studies ; Aged, 80 and over ; Young Adult ; }, abstract = {OBJECTIVE: In the U.S., uterine cancer incidence is rising, with racial and ethnic minorities experiencing the largest increases. We performed age-period-cohort analyses using novel methods to examine the contribution of age at diagnosis (age), year of diagnosis (period), and birth cohort (cohort), to trends in uterine cancer incidence.<br><br>METHODS: We used uterine cancer incidence data from the Surveillance, Epidemiology, and End Result (SEER) 12 database (1992-2019), and performed hysterectomy-correction. We generated hexamaps to visualize age, period, and cohort effects, and used mutual information to estimate the percent contribution of age, period, and cohort effects, individually and combined, on uterine cancer incidence, overall and by race and ethnicity and histology.<br><br>RESULTS: Hexamaps showed an increase in uterine cancer in later time periods, and a cohort effect around 1933 showing a lower incidence compared with earlier and later cohorts. Age, period, and cohort effects combined contributed 86.6% (95% CI: 86.4%, 86.9%) to the incidence. Age effects had the greatest contribution (65.1%, 95% CI: 64.3%, 65.9), followed by cohort (20.7%, 95% CI: 20.1%, 21.3%) and period (14.2%, 95% CI: 13.7%, 14.8%) effects. Hexamaps showed higher incidence in recent years for non-Hispanic Blacks and non-endometrioid tumors.<br><br>CONCLUSIONS: Age effects had the largest contribution to uterine cancer incidence, followed by cohort and period effects overall and across racial and ethnic groups and histologies.<br><br>IMPACT: These findings can inform uterine cancer modeling studies on the effects of interventions that target risk factors which may vary across age, period, or cohort.}, }
@article {pmid38781686, year = {2024}, author = {Templin, T and Perez, MW and Sylvia, S and Leek, J and Sinnott-Armstrong, N}, title = {Addressing 6 challenges in generative AI for digital health: A scoping review.}, journal = {PLOS digital health}, volume = {3}, number = {5}, pages = {e0000503}, pmid = {38781686}, issn = {2767-3170}, support = {T32 HG000035/HG/NHGRI NIH HHS/United States ; }, abstract = {Generative artificial intelligence (AI) can exhibit biases, compromise data privacy, misinterpret prompts that are adversarial attacks, and produce hallucinations. Despite the potential of generative AI for many applications in digital health, practitioners must understand these tools and their limitations. This scoping review pays particular attention to the challenges with generative AI technologies in medical settings and surveys potential solutions. Using PubMed, we identified a total of 120 articles published by March 2024, which reference and evaluate generative AI in medicine, from which we synthesized themes and suggestions for future work. After first discussing general background on generative AI, we focus on collecting and presenting 6 challenges key for digital health practitioners and specific measures that can be taken to mitigate these challenges. Overall, bias, privacy, hallucination, and regulatory compliance were frequently considered, while other concerns around generative AI, such as overreliance on text models, adversarial misprompting, and jailbreaking, are not commonly evaluated in the current literature.}, }
@article {pmid38781541, year = {2024}, author = {Safyan, RA and Kim, E and Dekker, E and Homs, M and Aguirre, AJ and Koerkamp, BG and Chiorean, EG}, title = {Multidisciplinary Standards and Evolving Therapies for Patients With Pancreatic Cancer.}, journal = {American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting}, volume = {44}, number = {3}, pages = {e438598}, doi = {10.1200/EDBK_438598}, pmid = {38781541}, issn = {1548-8756}, mesh = {Humans ; *Pancreatic Neoplasms/therapy ; Combined Modality Therapy ; Carcinoma, Pancreatic Ductal/therapy ; Neoadjuvant Therapy/standards/methods ; Quality of Life ; Patient Care Team ; Palliative Care/methods ; }, abstract = {Pancreatic ductal adenocarcinoma (PDA) is a challenging disease that presents at an advanced stage and results in many symptoms that negatively influence patients' quality of life and reduce their ability to receive effective treatment. Early implementation of expert multidisciplinary care with nutritional support, exercise, and palliative care for both early-stage and advanced disease promises to maintain or improve the patients' physical, social, and psychological well-being, decrease aggressive interventions at the end of life, and ultimately improve survival. Moreover, advances in treatment strategies in the neoadjuvant and metastatic setting combined with novel therapeutic agents targeting the key drivers of the disease are leading to improvements in the care of patients with pancreatic cancer. Here, we emphasize the multidisciplinary supportive and therapeutic care of patients with PDA, review current guidelines and new developments of neoadjuvant and perioperative treatments for localized disease, as well as the treatment standards and the evolving field of precision oncology and immunotherapies for advanced PDA.}, }
@article {pmid38781539, year = {2024}, author = {Fenton, SE and VanderWeeler, DJ and Rebbeck, TR and Chen, DL}, title = {Advancing Prostate Cancer Care: Treatment Approaches to Precision Medicine, Biomarker Innovations, and Equitable Access.}, journal = {American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting}, volume = {44}, number = {3}, pages = {e433138}, doi = {10.1200/EDBK_433138}, pmid = {38781539}, issn = {1548-8756}, mesh = {Humans ; *Prostatic Neoplasms/therapy/diagnosis/genetics ; *Precision Medicine/methods ; Male ; *Biomarkers, Tumor ; Health Services Accessibility ; }, abstract = {Genetic testing and molecular imaging have great promise in the accurate diagnosis and treatment of #prostate #cancer, but only if they can be developed and implemented to achieve equitable benefit for all men.}, }
@article {pmid38781315, year = {2024}, author = {Wang, M and Robak, T and Maddocks, KJ and Phillips, T and Smith, SD and Gallinson, D and Calvo, R and Wun, CC and Munugalavadla, V and Jurczak, W}, title = {Acalabrutinib plus venetoclax and rituximab in treatment-naive mantle cell lymphoma: 2-year safety and efficacy analysis.}, journal = {Blood advances}, volume = {8}, number = {17}, pages = {4539-4548}, pmid = {38781315}, issn = {2473-9537}, mesh = {Humans ; *Lymphoma, Mantle-Cell/drug therapy ; Middle Aged ; Male ; Aged ; *Rituximab/therapeutic use/administration &amp; dosage/adverse effects ; Female ; *Sulfonamides/therapeutic use/administration &amp; dosage ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; *Pyrazines/administration &amp; dosage/therapeutic use/adverse effects ; *Benzamides/therapeutic use/administration &amp; dosage/adverse effects ; Bridged Bicyclo Compounds, Heterocyclic/therapeutic use/administration &amp; dosage/adverse effects ; Aged, 80 and over ; Adult ; Treatment Outcome ; COVID-19/mortality ; SARS-CoV-2 ; }, abstract = {This phase 1b study evaluated safety and efficacy of acalabrutinib, venetoclax, and rituximab (AVR) in treatment-naive mantle cell lymphoma (TN MCL). Patients received acalabrutinib from cycle 1 until progressive disease (PD) or undue toxicity, rituximab for 6 cycles with maintenance every other cycle through cycle 24 or until PD, and venetoclax, beginning at cycle 2, for 24 cycles. Twenty-one patients were enrolled; 95.2% completed induction (6 AVR cycles) and 47.6% continued acalabrutinib maintenance. Thirteen (61.9%) patients had grade 3-4 adverse events (AEs), most commonly neutropenia (33.3%). Seven (33.3%) patients had COVID-19 infection (6 [28.6%] serious AEs and 5 [23.8%] deaths, all among unvaccinated patients). There was no grade ≥3 atrial fibrillation, ventricular tachyarrhythmias, major hemorrhages, or tumor lysis syndrome. Overall response rate (ORR) was 100% (95% CI, 83.9-100.0) with 71.4% complete response. With median follow-up of 27.8 months, median progression-free survival (PFS) and overall survival (OS) were not reached. PFS rates at 1 and 2 years were 90.5% (95% CI, 67.0-97.5) and 63.2% (95% CI, 34.7-82.0), respectively; both were 95% after censoring COVID-19 deaths. OS rates at 1 and 2 years were 95.2% (95% CI, 70.7-99.3) and 75.2% (95% CI, 50.3-88.9), respectively; both were 100% after censoring COVID-19 deaths. Overall, 87.5% of patients with available minimal residual disease (MRD) data achieved MRD negativity (10-6; next-generation sequencing) during treatment. AVR represents a chemotherapy-free regimen for TN MCL and resulted in high ORR and high rates of MRD negativity. The trial was registered at www.ClinicalTrials.gov as #NCT02717624.}, }
@article {pmid38780994, year = {2024}, author = {Odebunmi, OO and Hughes, TD and Waters, AR and Urick, BY and Herron, C and Wangen, M and Rohweder, C and Ferrari, RM and Marciniak, MW and Wheeler, SB and Brenner, AT and Shah, PD}, title = {Findings From a National Survey of Older US Adults on Patient Willingness to Use Telehealth Services: Cross-Sectional Survey.}, journal = {Journal of medical Internet research}, volume = {26}, number = {}, pages = {e50205}, pmid = {38780994}, issn = {1438-8871}, support = {T32 CA116339/CA/NCI NIH HHS/United States ; U48 DP006400/DP/NCCDPHP CDC HHS/United States ; }, mesh = {Humans ; *Telemedicine/statistics &amp; numerical data ; Cross-Sectional Studies ; Middle Aged ; Aged ; Male ; Female ; United States ; Patient Acceptance of Health Care/statistics &amp; numerical data ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: Telehealth (telemedicine and telepharmacy) services increase access to patient services and ensure continuity of care. However, few studies have assessed factors that influence patients' willingness to use telehealth services, and we sought to investigate this.<br><br>OBJECTIVE: This study aims to examine respondents' (aged between 45 and 75 years) willingness to use telehealth services (telepharmacy and telemedicine) and the correlates of the willingness to use telehealth services.<br><br>METHODS: We administered a cross-sectional national survey of 1045 noninstitutionalized US adults aged between 45 and 75 years in March and April 2021. Multiple logistic regression analyses were used to identify demographic and health service use correlates of self-reported willingness to use telehealth services.<br><br>RESULTS: Overall willingness to use telemedicine was high (674/1045, 64.5%). Adults aged 55 years and older were less willing to use telemedicine (aged between 55 and 64 years: odds ratio [OR] 0.61, 95% CI 0.42-0.86; aged 65 years or older: OR 0.33, 95% CI 0.22-0.49) than those younger than 55 years. Those with a regular provider (OR 1.01, 95% CI 1-1.02) and long travel times (OR 1.75, 95% CI 1.03-2.98) were more willing to use telemedicine compared to those without a regular provider and had shorter travel times, respectively. Willingness to use telemedicine services increased from 64.5% (674/1045) to 83% (867/1045) if the service was low-cost or insurance-covered, was with their existing health care provider, or was easy-to-use. Overall willingness to use telepharmacy was 76.7% (801/1045). Adults aged older than 55 years were less willing to use telepharmacy (aged between 55 and 64 years: OR 0.57, 95% CI 0.38-0.86; aged 65 years or older: OR 0.24, 95% CI 0.15-0.37) than those younger than 55 years. Those who rated pharmacy service quality higher were more willing to use telepharmacy (OR 1.06, 95% CI 1.03-1.09) than those who did not.<br><br>CONCLUSIONS: Respondents were generally willing to use telehealth (telemedicine and telepharmacy) services, but the likelihood of their being willing to use telehealth decreased as they were older. For those initially unwilling (aged 55 years or older) to use telemedicine services, inexpensive or insurance-covered services were acceptable.}, }
@article {pmid38780941, year = {2024}, author = {Fisher, LH and Kee, JJ and Liu, A and Espinosa, CM and Randhawa, AK and Ludwig, J and Magaret, CA and Robinson, ST and Gilbert, PB and Hyrien, O and Kublin, JG and Rouphael, N and Falsey, AR and Sobieszczyk, ME and El Sahly, HM and Grinsztejn, B and Gray, GE and Kotloff, KL and Gay, CL and Leav, B and Hirsch, I and Struyf, F and Dunkle, LM and Neuzil, KM and Corey, L and Huang, Y and Goepfert, PA and Walsh, SR and Baden, LR and Janes, H and , }, title = {SARS-CoV-2 Viral Load in the Nasopharynx at Time of First Infection Among Unvaccinated Individuals: A Secondary Cross-Protocol Analysis of 4 Randomized Trials.}, journal = {JAMA network open}, volume = {7}, number = {5}, pages = {e2412835}, pmid = {38780941}, issn = {2574-3805}, support = {UM1 AI069423/AI/NIAID NIH HHS/United States ; U01 AI069496/AI/NIAID NIH HHS/United States ; UM1 AI069476/AI/NIAID NIH HHS/United States ; UM1 AI148576/AI/NIAID NIH HHS/United States ; U01 AI069470/AI/NIAID NIH HHS/United States ; UM1 AI069534/AI/NIAID NIH HHS/United States ; UM1 AI069470/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI069496/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; UM1 AI148689/AI/NIAID NIH HHS/United States ; UM1 AI148450/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *COVID-19 ; *Nasopharynx/virology ; *Viral Load/statistics &amp; numerical data ; Male ; *SARS-CoV-2 ; Female ; Adult ; Middle Aged ; COVID-19 Vaccines/therapeutic use ; Randomized Controlled Trials as Topic ; United States ; Aged ; }, abstract = {IMPORTANCE: SARS-CoV-2 viral load (VL) in the nasopharynx is difficult to quantify and standardize across settings, but it may inform transmission potential and disease severity.<br><br>OBJECTIVE: To characterize VL at COVID-19 diagnosis among previously uninfected and unvaccinated individuals by evaluating the association of demographic and clinical characteristics, viral variant, and trial with VL, as well as the ability of VL to predict severe disease.<br><br>This secondary cross-protocol analysis used individual-level data from placebo recipients from 4 harmonized, phase 3 COVID-19 vaccine efficacy trials sponsored by Moderna, AstraZeneca, Janssen, and Novavax. Participants were SARS-CoV-2 negative at baseline and acquired COVID-19 during the blinded phase of the trials. The setting included the US, Brazil, South Africa, Colombia, Argentina, Peru, Chile, and Mexico; start dates were July 27, 2020, to December 27, 2020; data cutoff dates were March 26, 2021, to July 30, 2021. Statistical analysis was performed from November 2022 to June 2023.<br><br>MAIN OUTCOMES AND MEASURES: Linear regression was used to assess the association of demographic and clinical characteristics, viral variant, and trial with polymerase chain reaction-measured log10 VL in nasal and/or nasopharyngeal swabs taken at the time of COVID-19 diagnosis.<br><br>RESULTS: Among 1667 participants studied (886 [53.1%] male; 995 [59.7%] enrolled in the US; mean [SD] age, 46.7 [14.7] years; 204 [12.2%] aged 65 years or older; 196 [11.8%] American Indian or Alaska Native, 150 [9%] Black or African American, 1112 [66.7%] White; 762 [45.7%] Hispanic or Latino), median (IQR) log10 VL at diagnosis was 6.18 (4.66-7.12) log10 copies/mL. Participant characteristics and viral variant explained only 5.9% of the variability in VL. The independent factor with the highest observed differences was trial: Janssen participants had 0.54 log10 copies/mL lower mean VL vs Moderna participants (95% CI, 0.20 to 0.87 log10 copies/mL lower). In the Janssen study, which captured the largest number of COVID-19 events and variants and used the most intensive post-COVID surveillance, neither VL at diagnosis nor averaged over days 1 to 28 post diagnosis was associated with COVID-19 severity.<br><br>CONCLUSIONS AND RELEVANCE: In this study of placebo recipients from 4 randomized phase 3 trials, high variability was observed in SARS-CoV-2 VL at the time of COVID-19 diagnosis, and only a fraction was explained by individual participant characteristics or viral variant. These results suggest challenges for future studies of interventions seeking to influence VL and elevates the importance of standardized methods for specimen collection and viral load quantitation.}, }
@article {pmid38778453, year = {2024}, author = {Tonorezos, ES and Chou, JF and Moskowitz, CS and Leisenring, WM and Friedman, DN and Sklar, CA and Dilley, KJ and Hudson, MM and Mertens, A and Armstrong, GT and Robison, LL and Meacham, LR and Oeffinger, KC}, title = {Risk of increased mortality in underweight survivors: A brief report from the Childhood Cancer Survivor Study.}, journal = {Pediatric blood &amp; cancer}, volume = {71}, number = {8}, pages = {e31080}, pmid = {38778453}, issn = {1545-5017}, support = {U24 CA055727/CA/NCI NIH HHS/United States ; CA21765/CA/NCI NIH HHS/United States ; //American Lebanese-Syrian Associated Charities/ ; P30 CA008748/CA/NCI NIH HHS/United States ; //Meg Bert&#xe9; Owen Fund/ ; P30 CA021765/CA/NCI NIH HHS/United States ; CA21765//St. Jude Children's Research Hospital/ ; CA55727/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Thinness/mortality ; Female ; Male ; *Cancer Survivors/statistics &amp; numerical data ; Adolescent ; Adult ; *Neoplasms/mortality/complications ; *Body Mass Index ; Young Adult ; Middle Aged ; Follow-Up Studies ; Child ; Child, Preschool ; Risk Factors ; Survival Rate ; Prognosis ; }, abstract = {BACKGROUND: Approximately 1 in 10 adult survivors of childhood cancer is underweight. Although the consequences of being overweight or obese have been well described, outcomes among childhood cancer survivors who are underweight are unknown.<br><br>OBJECTIVE: To determine whether underweight status increases the risk of mortality.<br><br>PROCEDURE: Cohort study: Marginal models with generalized estimating equations to evaluate the associations between body mass index (BMI), serious or life-threatening chronic conditions, and death in the setting of long-term follow-up questionnaires and National Death Index search.<br><br>PARTICIPANTS: Childhood cancer five-year survivors diagnosed during 1970-1986 in the Childhood Cancer Survivor Study Exposure: Underweight status, defined as body mass index (BMI) < 18.5 kg/m[2] compared with ideal body weight. Based on available literature on body weight and mortality from the general population, ideal body weight was defined as BMI 22.0-24.9 kg/m[2].<br><br>MAIN OUTCOMES: Overall mortality and cancer-specific mortality.<br><br>RESULTS: Of 9454 survivors (median age 35 years old (range, 17-58), an average of 17.5 years from diagnosis), 627 (6.6%) participants were underweight at baseline or follow-up questionnaire. Of 184 deaths, 29 were among underweight survivors. Underweight status was more common among females (9.1%&#xa0;vs. 4.5%, p&#xa0;<&#xa0;.01) and participants with younger age at diagnosis (8.2% for&#xa0;<&#xa0;5 years vs. 6.1% for&#xa0;&#x2265;5 years, p&#xa0;<&#xa0;.01), lower household income (8.9% for&#xa0;<&#xa0;$20,000&#xa0;vs. 6.0% for&#xa0;&#x2265; $20,000, p&#xa0;<&#xa0;.01), or a history of serious chronic condition (p&#xa0;=&#xa0;.05). After adjustment for these factors, in addition to prior smoking and a history of radiation therapy, the risk of all-cause mortality within two years of BMI report was increased (OR 2.85; 95% CI: 1.63-4.97; p&#xa0;<&#xa0;.01) for underweight survivors, compared with ideal-weight survivors.<br><br>CONCLUSIONS: Childhood cancer survivors who are underweight are at increased risk for late mortality that appears unrelated to smoking status, recognized chronic disease, or subsequent malignancy. Whether targeted nutritional interventions would ameliorate this risk is unknown.}, }
@article {pmid38777541, year = {2024}, author = {Kim, JY and Partridge, SC}, title = {Non-contrast Breast MR Imaging.}, journal = {Radiologic clinics of North America}, volume = {62}, number = {4}, pages = {661-678}, pmid = {38777541}, issn = {1557-8275}, support = {R01 CA207290/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Breast Neoplasms/diagnostic imaging ; Female ; *Breast/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; Diffusion Magnetic Resonance Imaging/methods ; Contrast Media ; }, abstract = {Considering the high cost of dynamic contrast-enhanced MR imaging and various contraindications and health concerns related to administration of intravenous gadolinium-based contrast agents, there is emerging interest in non-contrast-enhanced breast MR imaging. Diffusion-weighted MR imaging (DWI) is a fast, unenhanced technique that has wide clinical applications in breast cancer detection, characterization, prognosis, and predicting treatment response. It also has the potential to serve as a non-contrast MR imaging screening method. Standardized protocols and interpretation strategies can help to enhance the clinical utility of breast DWI. A variety of other promising non-contrast MR imaging techniques are in development, but currently, DWI is closest to clinical integration, while others are still mostly used in the research setting.}, }
@article {pmid38777538, year = {2024}, author = {Lowry, KP and Zuiderveld, CC}, title = {Artificial Intelligence for Breast Cancer Risk Assessment.}, journal = {Radiologic clinics of North America}, volume = {62}, number = {4}, pages = {619-625}, doi = {10.1016/j.rcl.2024.02.004}, pmid = {38777538}, issn = {1557-8275}, mesh = {Humans ; *Breast Neoplasms/diagnostic imaging ; Female ; *Artificial Intelligence ; Risk Assessment/methods ; *Mammography/methods ; Breast/diagnostic imaging ; Risk Factors ; Early Detection of Cancer/methods ; }, abstract = {Breast cancer risk prediction models based on common clinical risk factors are used to identify women eligible for high-risk screening and prevention. Unfortunately, these models have only modest discriminatory accuracy with disparities in performance in underrepresented race and ethnicity groups. The field of artificial intelligence (AI) and deep learning are rapidly advancing the field of breast cancer risk prediction with the development of mammography-based AI breast cancer risk models. Early studies suggest mammography-based AI risk models may perform better than traditional risk factor-based models with more equitable performance.}, }
@article {pmid38776400, year = {2024}, author = {Farhadfar, N and Rashid, N and Chen, K and DeVos, J and Wang, T and Ballen, K and Beitinjaneh, A and Bhatt, VR and Hamilton, BK and Hematti, P and Gadalla, SM and Solomon, SR and El Jurdi, N and Lee, CJ and MacMillan, ML and Rangarajan, HG and Schoemans, H and Sharma, A and Spellman, SR and Wingard, JR and Lee, SJ}, title = {Racial, ethnic, and socioeconomic diversity and outcomes of patients with graft-versus-host disease: a CIBMTR analysis.}, journal = {Blood advances}, volume = {8}, number = {18}, pages = {4963-4976}, pmid = {38776400}, issn = {2473-9537}, support = {27305C0011/ES/NIEHS NIH HHS/United States ; 27307C0011/ES/NIEHS NIH HHS/United States ; 27398C0011/ES/NIEHS NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Graft vs Host Disease/etiology ; Middle Aged ; Male ; Female ; Adult ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Ethnicity ; Aged ; Socioeconomic Factors ; Racial Groups ; Young Adult ; Adolescent ; Treatment Outcome ; Transplantation, Homologous ; }, abstract = {Socioeconomic status (SES) and race/ethnicity have been associated with the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HCT). Certain aspects of graft-versus-host disease (GVHD) management, such as the need for long-term care, prolonged immunosuppressive treatment, and close follow-up for complications, may exacerbate disparities. Adults (≥18 years) reported to the Center for International Blood and Marrow Transplant Research who underwent a first allo-HCT for acute leukemia, myelodysplastic syndrome, or myeloproliferative neoplasm between 2008 and 2018 were included. End points for those developing GVHD included overall survival (OS), transplant-related mortality (TRM), and disease relapse. Models were adjusted for patient- and transplant-related variables. A 2-sided P value < .01 was considered significant. Among the 14 825 allo-HCT recipients, 6259 (42.2%) and 6675 (45.0%) patients developed acute GVHD (aGVHD) and chronic GVHD (cGVHD), respectively. Among patients with aGVHD, non-Hispanic Black patients had increased TRM and overall mortality compared with non-Hispanic White patients; this association disappeared when severity of aGVHD was included in the model. Lower SES was associated with increased risk of disease relapse but not OS or TRM. In patients who developed cGVHD, race and ethnicity were not associated with OS, TRM, or disease relapse. However, the highest quartile of annual household income (≥$80 000) had improved OS and reduced TRM compared with the lowest quartile, after adjusting for race and ethnicity. In summary, race/ethnicity and SES are associated with outcomes after GVHD. Optimizing the health care resources available to low SES patients and strategies to minimize the risk of severe GVHD in non-Hispanic Black patients may improve long-term outcomes.}, }
@article {pmid38775966, year = {2024}, author = {Sun, V and Thomson, CA and Crane, TE and Arnold, KB and Guthrie, KA and Freylersythe, SG and Braun-Inglis, C and Jones, L and Carmichael, JC and Messick, C and Flaherty, D and Ambrale, S and Cohen, SA and Krouse, RS}, title = {Baseline characteristics and recruitment for SWOG S1820: altering intake, managing bowel symptoms in survivors of rectal cancer (AIMS-RC).}, journal = {Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer}, volume = {32}, number = {6}, pages = {371}, pmid = {38775966}, issn = {1433-7339}, support = {R21 CA236057/CA/NCI NIH HHS/United States ; R21CA236057/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Rectal Neoplasms/surgery ; Male ; Female ; Middle Aged ; *Cancer Survivors/psychology ; Aged ; *Quality of Life ; Adult ; Patient Selection ; Self Efficacy ; Feasibility Studies ; }, abstract = {PURPOSE: Many survivors of rectal cancer experience persistent bowel dysfunction. There are few evidence-based symptom management interventions to improve bowel control. The purpose of this study is to describe recruitment and pre-randomization baseline sociodemographic, health status, and clinical characteristics for SWOG S1820, a trial of the Altering Intake, Managing Symptoms in Rectal Cancer (AIMS-RC) intervention.<br><br>METHODS: SWOG S1820 aimed to determine the preliminary efficacy, feasibility, and acceptability of AIMS-RC, a symptom management intervention for bowel health, comparing intervention to attention control. Survivors with a history of cancers of the rectosigmoid colon or rectum, within 6-24&#xa0;months of primary treatment completion, with a post-surgical permanent ostomy or anastomosis, and over 18&#xa0;years of age were enrolled. Outcomes included total bowel function, low anterior resection syndrome, quality of life, motivation for managing bowel health, self-efficacy for managing symptoms, positive and negative affect, and study feasibility and acceptability.<br><br>RESULTS: The trial completed accrual over a 29-month period and enrolled 117 participants from 34 institutions across 17 states and one US Pacific territory. At baseline, most enrolled participants reported self-imposed diet adjustments after surgery, persistent dietary intolerances, and bowel discomfort post-treatment, with high levels of constipation and diarrhea (grades 1-4).<br><br>CONCLUSIONS: SWOG S1820 was able to recruit, in a timely manner, a study cohort that is demographically representative of US survivors of rectal cancer. Baseline characteristics illustrate the connection between diet/eating and bowel symptoms post-treatment, with many participants reporting diet adjustments and persistent inability to be comfortable with dietary intake.<br><br>GOV REGISTRATION DATE: 12/19/2019.<br><br>GOV IDENTIFIER: NCT#04205955.}, }
@article {pmid38775011, year = {2024}, author = {Lyman, GH and Kuderer, NM}, title = {Artificial Intelligence in Cancer Clinical Research: II. Development and Validation of Clinical Prediction Models.}, journal = {Cancer investigation}, volume = {42}, number = {6}, pages = {447-451}, doi = {10.1080/07357907.2024.2354991}, pmid = {38775011}, issn = {1532-4192}, mesh = {Humans ; *Artificial Intelligence ; *Neoplasms ; Biomedical Research/methods ; }, }
@article {pmid38774470, year = {2024}, author = {Hoellerbauer, P and Kufeld, M and Arora, S and Mitchell, K and Girard, EJ and Herman, JA and Olson, JM and Paddison, PJ}, title = {FBXO42 activity is required to prevent mitotic arrest, spindle assembly checkpoint activation and lethality in glioblastoma and other cancers.}, journal = {NAR cancer}, volume = {6}, number = {2}, pages = {zcae021}, pmid = {38774470}, issn = {2632-8674}, support = {R01 NS119650/NS/NINDS NIH HHS/United States ; }, abstract = {Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. To identify genes differentially required for the viability of GBM stem-like cells (GSCs), we performed functional genomic lethality screens comparing GSCs and control human neural stem cells. Among top-scoring hits in a subset of GBM cells was the F-box-containing gene FBXO42, which was also predicted to be essential in ∼15% of cell lines derived from a broad range of cancers. Mechanistic studies revealed that, in sensitive cells, FBXO42 activity prevents chromosome alignment defects, mitotic cell cycle arrest and cell death. The cell cycle arrest, but not the cell death, triggered by FBXO42 inactivation could be suppressed by brief exposure to a chemical inhibitor of Mps1, a key spindle assembly checkpoint (SAC) kinase. FBXO42's cancer-essential function requires its F-box and Kelch domains, which are necessary for FBXO42's substrate recognition and targeting by SCF (SKP1-CUL1-F-box protein) ubiquitin ligase complex. However, none of FBXO42's previously proposed targets, including ING4, p53 and RBPJ, were responsible for the observed phenotypes. Instead, our results suggest that FBOX42 alters the activity of one or more proteins that perturb chromosome-microtubule dynamics in cancer cells, which in turn leads to induction of the SAC and cell death.}, }
@article {pmid38774467, year = {2024}, author = {Bryce, AH and Crawford, ED and Agarwal, N and Hussain, MH and Beltran, H and Cooperberg, MR and Petrylak, DP and Shore, N and Spratt, DE and Tagawa, ST and Antonarakis, ES and Aparicio, AM and Armstrong, AJ and Boike, TP and Calais, J and Carducci, MA and Chapin, BF and Cookson, MS and Davis, JW and Dorff, T and Eggener, SE and Feng, FY and Gleave, M and Higano, C and Iagaru, A and Morgans, AK and Morris, M and Murray, KS and Poage, W and Rettig, MB and Sartor, O and Scher, HI and Sieber, P and Small, E and Srinivas, S and Yu, EY and Zhang, T and Koo, PJ}, title = {Expert Perspectives on Controversies in Metastatic Castration-Resistant Prostate Cancer Management: Narrative Review and Report of the First US Prostate Cancer Conference Part 2.}, journal = {JU open plus}, volume = {2}, number = {4}, pages = {}, pmid = {38774467}, issn = {2771-554X}, support = {P30 CA077598/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Management strategies for metastatic castration-resistant prostate cancer (mCRPC) have rapidly shifted in recent years. As novel imaging and therapeutic approaches have made their way to the clinic, providers are encountering increasingly challenging clinical scenarios, with limited guidance from the current literature.<br><br>MATERIALS AND METHODS: The US Prostate Cancer Conference (USPCC) is a multidisciplinary meeting of prostate cancer experts intended to address the many challenges of prostate cancer management. At the first annual USPCC meeting, areas of controversy and consensus were identified during a 2-day meeting that included expert presentations, full-panel discussions, and postdiscussion responses to questions developed by the USPCC cochairs and session moderators.<br><br>RESULTS: This narrative review covers the USPCC expert discussion and perspectives relevant to mCRPC, including neuroendocrine/aggressive-variant prostate cancer (NEPC/AVPC). Areas of broad agreement identified among USPCC experts include the benefits of poly (ADP-ribose) polymerase (PARP) inhibitors for patients with BRCA1/2 mutations, the use of radioligand therapy in patients with prostate-specific membrane antigen (PSMA)-positive mCRPC, and the need for clinical trials that address real-world clinical questions, including the performance of novel therapies when compared with modern standard-of-care treatment. Ongoing areas of controversy and uncertainty included the appropriateness of PARP inhibitors in patients with non-BRCA1/2 mutations, the optimal definition of PSMA positivity, and systemic therapies for patients with NEPC/AVPC after progression on platinum-based therapies.<br><br>CONCLUSIONS: The first annual USPCC meeting identified several areas of controversy in the management of mCRPC, highlighting the urgent need for clinical trials designed to facilitate treatment selection and sequencing in this heterogeneous disease state.}, }
@article {pmid38774466, year = {2024}, author = {Crawford, ED and Bryce, AH and Hussain, MH and Agarwal, N and Beltran, H and Cooperberg, MR and Petrylak, DP and Shore, N and Spratt, DE and Tagawa, ST and Antonarakis, ES and Aparicio, AM and Armstrong, AJ and Boike, TP and Calais, J and Carducci, MA and Chapin, BF and Cookson, MS and Davis, JW and Dorff, T and Eggener, SE and Feng, FY and Gleave, M and Higano, C and Iagaru, A and Morgans, AK and Morris, M and Murray, KS and Poage, W and Rettig, MB and Sartor, O and Scher, HI and Sieber, P and Small, E and Srinivas, S and Yu, EY and Zhang, T and Koo, PJ}, title = {Expert Perspectives on Controversies in Castration-Sensitive Prostate Cancer Management: Narrative Review and Report of the First US Prostate Cancer Conference Part 1.}, journal = {JU open plus}, volume = {2}, number = {4}, pages = {}, pmid = {38774466}, issn = {2771-554X}, support = {P30 CA077598/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: Castration-sensitive prostate cancer (CSPC) is a complex and heterogeneous condition encompassing a range of clinical presentations. As new approaches have expanded management options, clinicians are left with myriad questions and controversies regarding the optimal individualized management of CSPC.<br><br>MATERIALS AND METHODS: The US Prostate Cancer Conference (USPCC) multidisciplinary panel was assembled to address the challenges of prostate cancer management. The first annual USPCC meeting included experts in urology, medical oncology, radiation oncology, and nuclear medicine. USPCC co-chairs and session moderators identified key areas of controversy and uncertainty in prostate cancer management and organized the sessions with multidisciplinary presentations and discussion. Throughout the meeting, experts responded to questions prepared by chairs and moderators to identify areas of agreement and controversy.<br><br>RESULTS: The USPCC panel discussion and question responses for CSPC-related topics are presented. Key advances in CSPC management endorsed by USPCC experts included the development and clinical utilization of gene expression classifiers and artificial intelligence (AI) models for risk stratification and treatment selection in specific patient populations, the use of advanced imaging modalities in patients with clinically localized unfavorable intermediate or high-risk disease and those with biochemical recurrence, recommendations of doublet or triplet therapy for metastatic CSPC (mCSPC), and consideration of prostate and/or metastasis-directed radiation therapy in select patients with mCSPC.<br><br>CONCLUSIONS: CSPC is a diverse disease with many therapeutic options and the potential for adverse outcomes associated with either undertreatment or overtreatment. Future studies are needed to validate and clinically integrate novel technologies, including genomics, AI, and advanced imaging, to optimize outcomes among patients with CSPC.}, }
@article {pmid38773986, year = {2024}, author = {Wang, CY and de Dieu Tapsoba, J and Duggan, C and McTiernan, A}, title = {Generalized Linear Models with Covariate Measurement Error and Zero-Inflated Surrogates.}, journal = {Mathematics (Basel, Switzerland)}, volume = {12}, number = {2}, pages = {}, pmid = {38773986}, issn = {2227-7390}, support = {R01 CA077572/CA/NCI NIH HHS/United States ; R01 HL130483/HL/NHLBI NIH HHS/United States ; R03 CA235122/CA/NCI NIH HHS/United States ; R21 CA239168/CA/NCI NIH HHS/United States ; }, abstract = {Epidemiological studies often encounter a challenge due to exposure measurement error when estimating an exposure-disease association. A surrogate variable may be available for the true unobserved exposure variable. However, zero-inflated data are encountered frequently in the surrogate variables. For example, many nutrient or physical activity measures may have a zero value (or a low detectable value) among a group of individuals. In this paper, we investigate regression analysis when the observed surrogates may have zero values among some individuals of the whole study cohort. A naive regression calibration without taking into account a probability mass of the surrogate variable at 0 (or a low detectable value) will be biased. We developed a regression calibration estimator which typically can have smaller biases than the naive regression calibration estimator. We propose an expected estimating equation estimator which is consistent under the zero-inflated surrogate regression model. Extensive simulations show that the proposed estimator performs well in terms of bias correction. These methods are applied to a physical activity intervention study.}, }
@article {pmid38773281, year = {2024}, author = {Rathje, K and Gagelmann, N and Salit, RB and Schroeder, T and Gurnari, C and Pagliuca, S and Panagiota, V and Rautenberg, C and Cassinat, B and Thol, F and Robin, M and Oechsler, S and Heuser, M and Rubio, MT and Maciejewski, JP and Reinhardt, HC and Scott, BL and Kröger, N}, title = {Anti-T-lymphocyte globulin improves GvHD-free and relapse-free survival in myelofibrosis after matched related or unrelated donor transplantation.}, journal = {Bone marrow transplantation}, volume = {59}, number = {8}, pages = {1154-1160}, pmid = {38773281}, issn = {1476-5365}, mesh = {Humans ; *Graft vs Host Disease/mortality/prevention &amp; control ; *Primary Myelofibrosis/therapy/mortality ; *Antilymphocyte Serum/therapeutic use ; Middle Aged ; Female ; Male ; Adult ; *Hematopoietic Stem Cell Transplantation/methods ; Aged ; *Unrelated Donors ; Disease-Free Survival ; Transplantation Conditioning/methods ; Allografts ; Young Adult ; }, abstract = {Acute and chronic graft-versus-host disease (GvHD) are major complications of allogeneic hematopoietic cell transplantation (alloHCT). In vivo T-cell depletion with anti-T-lymphocyte globulin (ATLG) as part of the conditioning regimen prior to alloHCT is frequently used as GvHD prophylaxis, but data on its role in myelofibrosis is scarce. We took advantage of an international collaborative network to investigate the impact of ATLG in myelofibrosis undergoing first alloHCT. We included 707 patients (n = 469 ATLG and n = 238 non-ATLG prophylaxis). The cumulative incidence of acute GvHD grade II-IV was 30% for the ATLG group vs. 56% for the non-ATLG group (P < 0.001). Acute GvHD grade III-IV occurred in 20% vs. 25%, respectively (P = 0.01). Incidence of mild-to-severe chronic GvHD was 49% vs. 50% (P = 0.52), while ATLG showed significantly lower rates of severe chronic GvHD (7% vs. 18%; P = 0.04). GvHD-free and relapse-free survival (GRFS) at 6 years was 45% for the ATLG group vs. 37% for the non-ATLG group (P = 0.02), driven by significantly improved GRFS of ATLG in matched related and matched unrelated donors. No significant differences in risk for relapse, non-relapse mortality, and overall survival were observed. Multivariable modeling for GRFS showed a 48% reduced risk of GvHD, relapse, or death when using ATLG.}, }
@article {pmid38772931, year = {2024}, author = {Geczik, AM and Michels, KA and Anderson, GL and Falk, RT and Farland, LV and Manson, JE and Shadyab, AH and Pfeiffer, RM and Xu, X and Trabert, B}, title = {Associations of tubal ligation and hysterectomy with serum androgen and estrogen metabolites among postmenopausal women in the Women's Health Initiative Observational Study.}, journal = {Cancer causes &amp; control : CCC}, volume = {35}, number = {9}, pages = {1283-1295}, pmid = {38772931}, issn = {1573-7225}, support = {Z01 CP010126/ImNIH/Intramural NIH HHS/United States ; HHSN268201100001I/HL/NHLBI NIH HHS/United States ; HHSN268201100004I/HL/NHLBI NIH HHS/United States ; ZIA CP010126/ImNIH/Intramural NIH HHS/United States ; HHSN268201100046C/HL/NHLBI NIH HHS/United States ; HHSN268201100003C/WH/WHI NIH HHS/United States ; HHSN268201100002C/WH/WHI NIH HHS/United States ; HHSN268201100003I/HL/NHLBI NIH HHS/United States ; HHSN268201100002I/HL/NHLBI NIH HHS/United States ; HHSN268201100001C/WH/WHI NIH HHS/United States ; HHSN268201100004C/WH/WHI NIH HHS/United States ; HHSN271201100004C/AG/NIA NIH HHS/United States ; Z99 CA999999/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Humans ; Female ; *Hysterectomy/statistics &amp; numerical data ; *Postmenopause/blood ; *Sterilization, Tubal/statistics &amp; numerical data ; Middle Aged ; *Androgens/blood ; Aged ; *Estrogens/blood ; Women's Health ; }, abstract = {PURPOSE: Hysterectomy is associated with subsequent changes in circulating hormone levels, but the evidence of an association for tubal ligation is unclear. We evaluated whether circulating concentrations of androgens and estrogens differ by tubal ligation or hysterectomy status in postmenopausal women from the Women's Health Initiative (WHI)-Observational Study (OS).<br><br>METHODS: Serum androgens and estrogens were measured in 920 postmenopausal women who did not use menopausal hormone therapy at the time of blood draw, of whom 139 self-reported a history of tubal ligation and 102 reported hysterectomy (with intact ovaries). Geometric mean hormone concentrations (GMs) and 95% confidence intervals (CIs) associated with a history of tubal ligation or hysterectomy (ever/never), as well as time since procedures, were estimated using adjusted linear regression with inverse probability of sampling weights to account for selection.<br><br>RESULTS: Circulating levels of 12 androgen/androgen metabolites and 20 estrogen/estrogen metabolites did not differ by tubal ligation status. Among women reporting prior hysterectomy compared to women without hysterectomy, we observed lower levels of several androgens (e.g., testosterone (nmol/L): GMyes 0.46 [95% CI:0.37-0.57] vs. GMno 0.62 [95% CI:0.53-0.72]) and higher levels of estrogen metabolites, for example, 2-hydroxyestrone-3-methyl ether (GMyes 11.1 [95% CI:8.95-13.9] pmol/L vs. GMno 8.70 [95% CI:7.38-10.3]) and 4-methoxyestrone (GMyes 6.50 [95% CI:5.05-8.37] vs. GMno 4.92 [95% CI:4.00-6.05]).<br><br>CONCLUSION: While we did not observe associations between prior tubal ligation and postmenopausal circulating hormone levels, our findings support that prior hysterectomy was associated with lower circulating testosterone levels and higher levels of some estrogen metabolites, which may have implications for future hormone-related disease risks.}, }
@article {pmid38772835, year = {2024}, author = {Chihana, R and Jin Kee, J and Moodie, Z and Huang, Y and Janes, H and Dadabhai, S and Roxby, AC and Allen, M and Kassim, S and Naicker, V and Innes, C and Naicker, N and Dubula, T and Grunenberg, N and Malahleha, M and Kublin, JG and Bekker, LG and Gray, G and Kumwenda, J and Laher, F}, title = {Factors associated with reactogenicity to an investigational HIV vaccine regimen in HIV vaccine trials network 702.}, journal = {Vaccine}, volume = {42}, number = {20}, pages = {125991}, pmid = {38772835}, issn = {1873-2518}, support = {UM1 AI069469/AI/NIAID NIH HHS/United States ; UM1 AI069518/AI/NIAID NIH HHS/United States ; UM1 AI154463/AI/NIAID NIH HHS/United States ; UM1 AI069453/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *AIDS Vaccines/adverse effects/administration &amp; dosage/immunology ; Female ; Male ; Adult ; Young Adult ; *HIV Infections/prevention &amp; control ; Adolescent ; Double-Blind Method ; Vaccine Efficacy ; }, abstract = {BACKGROUND: Reactogenicity informs vaccine safety, and may influence vaccine uptake. We evaluated factors associated with reactogenicity in HVTN 702, a typical HIV vaccine efficacy trial with multiple doses and products.<br><br>METHODS: HVTN 702, a phase 2b/3 double-blind placebo-controlled trial, randomized 5404 African participants aged 18-35&#xa0;years without HIV to placebo, or ALVAC-HIV (vCP2438) at months 0, 1 and ALVAC-HIV (vCP2438)&#xa0;+&#xa0;Bivalent Subtype C gp120/MF59 at months 3, 6, 12 and 18. Using multivariate logistic regression, we evaluated associations between reactogenicity with clinical, sociodemographic and laboratory variables.<br><br>RESULTS: More vaccine than placebo-recipients reported local symptoms (all p&#xa0;<&#xa0;0.001), arthralgia (p&#xa0;=&#xa0;0.008), chills (p&#xa0;=&#xa0;0.012) and myalgia (p&#xa0;<&#xa0;0.001). Reactogenicity was associated with female sex at birth (ORv&#xa0;=&#xa0;2.50, ORp&#xa0;=&#xa0;1.81, both p&#xa0;<&#xa0;0.001) and geographic region. Amongst vaccine-recipients, each year of age was associated with 3&#xa0;% increase in reactogenicity (OR&#xa0;=&#xa0;1.03, p&#xa0;=&#xa0;0.002).<br><br>CONCLUSION: Vaccine receipt, female sex at birth, older age, and region may affect reactogenicity.}, }
@article {pmid38772003, year = {2024}, author = {Ramaswami, R and Uldrick, TS}, title = {Reflecting the Real World of Cancer Care - The Impact of Broadening Trial Eligibility.}, journal = {NEJM evidence}, volume = {3}, number = {4}, pages = {EVIDe2400011}, doi = {10.1056/EVIDe2400011}, pmid = {38772003}, issn = {2766-5526}, mesh = {Humans ; *Neoplasms/therapy/epidemiology ; *Clinical Trials as Topic ; Patient Selection ; Eligibility Determination ; }, }
@article {pmid38771997, year = {2024}, author = {Sankar, K and Redman, MW and Dragnev, KH and Henick, BS and Iams, WT and Blanke, CD and Herbst, RS and Gray, JE and Reckamp, KL}, title = {Pragmaticism in Cancer Clinical Trials.}, journal = {American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting}, volume = {44}, number = {3}, pages = {e100040}, doi = {10.1200/EDBK_100040}, pmid = {38771997}, issn = {1548-8756}, mesh = {Humans ; *Neoplasms/therapy ; *Clinical Trials as Topic ; Research Design ; Pragmatic Clinical Trials as Topic/methods ; Medical Oncology/methods ; }, abstract = {Clinical trials are essential for advancing oncology treatment strategies and have contributed significantly to the decline in cancer mortality rates over the past decades. Traditional explanatory trials, focused on establishing intervention efficacy in ideal settings, often lack generalizability and may not reflect real-world patient care scenarios. Furthermore, increasing complexity in cancer clinical trial design has led to challenges such as protocol deviations, slow enrollment leading to lengthened durations of trial, and escalating costs. By contrast, pragmatic trials aim to assess intervention effectiveness in more representative patient populations under routine clinical conditions. Here, we review the principles, methodologies, challenges, and advantages of incorporating pragmatic features (PFs) into cancer clinical trials. We illustrate the application of pragmatic trial designs in oncology and discuss the QUASAR collaborative, TAPUR study, and the ongoing PRAGMATICA-LUNG trial. Although not all oncology trials may be amenable to adopting fully pragmatic designs, integration of PFs when feasible will enhance trial generalizability and real-world applicability. Project Pragmatica and similar initiatives advocate for the integration of real-world practice with clinical trials, fostering a nuanced approach to oncology research that balances efficacy and effectiveness assessments, ultimately with a goal of improving patient outcomes.}, }
@article {pmid38771739, year = {2024}, author = {Grivas, P and Garralda, E and Meric-Bernstam, F and Mellinghoff, IK and Goyal, L and Harding, JJ and Dees, EC and Bahleda, R and Azad, NS and Karippot, A and Kurzrock, R and Tabernero, J and Kononen, J and Ng, MCH and Mehta, R and Uboha, NV and Bigot, F and Boni, V and Bowyer, SE and Breder, V and Cervantes, A and Chan, N and Cleary, JM and Dhawan, M and Eefsen, RL and Ewing, J and Graham, DM and Guren, TK and Won Kim, J and Koynov, K and Oh, DY and Redman, R and Yen, CJ and Spetzler, D and Roubaudi-Fraschini, MC and Nicolas-Metral, V and Ait-Sarkouh, R and Zanna, C and Ennaji, A and Pokorska-Bocci, A and Flaherty, KT}, title = {Evaluating Debio 1347 in Patients with FGFR Fusion-Positive Advanced Solid Tumors from the FUZE Multicenter, Open-Label, Phase II Basket Trial.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {30}, number = {20}, pages = {4572-4583}, doi = {10.1158/1078-0432.CCR-24-0012}, pmid = {38771739}, issn = {1557-3265}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; Male ; Middle Aged ; Aged ; *Neoplasms/drug therapy/genetics/pathology ; Adult ; Oncogene Proteins, Fusion/genetics ; Aged, 80 and over ; Receptor, Fibroblast Growth Factor, Type 1/genetics/antagonists &amp; inhibitors ; Receptor, Fibroblast Growth Factor, Type 3/genetics/antagonists &amp; inhibitors ; Treatment Outcome ; Protein Kinase Inhibitors/therapeutic use/adverse effects/administration &amp; dosage ; }, abstract = {PURPOSE: This multicenter phase II basket trial investigated the efficacy, safety, and pharmacokinetics of Debio 1347, an investigational, oral, highly selective, ATP-competitive, small molecule inhibitor of FGFR1-3, in patients with solid tumors harboring a functional FGFR1-3 fusion.<br><br>PATIENTS AND METHODS: Eligible adults had a previously treated locally advanced (unresectable) or metastatic biliary tract (cohort 1), urothelial (cohort 2), or another histologic cancer type (cohort 3). Debio 1347 was administered at 80 mg once daily, continuously, in 28-day cycles. The primary endpoint was the objective response rate. Secondary endpoints included duration of response, progression-free survival, overall survival, pharmacokinetics, and incidence of adverse events.<br><br>RESULTS: Between March 22, 2019, and January 8, 2020, 63 patients were enrolled and treated, 30 in cohort 1, 4 in cohort 2, and 29 in cohort 3. An unplanned preliminary statistical review showed that the efficacy of Debio 1347 was lower than predicted, and the trial was terminated. In total, 3 of 58 evaluable patients had partial responses, representing an objective response rate of 5%, with a further 26 (45%) having stable disease (&#x2265;6 weeks duration). Grade &#x2265;3 treatment-related adverse events occurred in 22 (35%) of 63 patients, with the most common being hyperphosphatemia (13%) and stomatitis (5%). Two patients (3%) discontinued treatment due to adverse events.<br><br>CONCLUSIONS: Debio 1347 had manageable toxicity; however, the efficacy in patients with tumors harboring FGFR fusions did not support further clinical evaluation in this setting. Our transcriptomic-based analysis characterized in detail the incidence and nature of FGFR fusions across solid tumors. See related commentary by Hage Chehade et al., p. 4549.}, }
@article {pmid38771118, year = {2024}, author = {Heldman, MR and Greninger, AL and Hill, JA}, title = {The iciHHV-6 sense: sensing the source and relevance of human herpesvirus 6 (HHV-6) DNA in the transplant recipient with inherited chromosomally integrated HHV-6.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiae269}, pmid = {38771118}, issn = {1537-6613}, }
@article {pmid38771037, year = {2024}, author = {Phan, T and Kumar, L and Woo, M and Sadowska-Klasa, A and Castor, J and Pepper, G and Fisher, CE and Limaye, AP}, title = {Evaluation of the Tasso+ blood self-collection device for quantitation of plasma cytomegalovirus (CMV) DNAemia in adult solid organ transplant recipients (SOTr).}, journal = {Microbiology spectrum}, volume = {12}, number = {7}, pages = {e0003024}, pmid = {38771037}, issn = {2165-0497}, support = {K23 HL143050/HL/NHLBI NIH HHS/United States ; U01 AI163090/AI/NIAID NIH HHS/United States ; AI163090//HHS | National Institutes of Health (NIH)/ ; }, mesh = {Humans ; *Cytomegalovirus Infections/diagnosis/blood/virology ; *Transplant Recipients ; *DNA, Viral/blood ; *Cytomegalovirus/isolation &amp; purification/genetics ; Middle Aged ; Male ; Female ; Adult ; *Viral Load/methods ; *Organ Transplantation ; Aged ; Blood Specimen Collection/methods/instrumentation ; Real-Time Polymerase Chain Reaction/methods/instrumentation ; Viremia/virology/diagnosis ; }, abstract = {UNLABELLED: Quantitative monitoring of cytomegalovirus (CMV) DNAemia in venous blood is standard in solid organ transplant recipients (SOTr) but is limited by the need for phlebotomy facilities and personnel. The aim of the study was to evaluate the Tasso+ capillary blood (CB) self-collection device for quantitation of plasma CMV DNAemia. Thirty adult SOTr with suspected CMV DNAemia were enrolled to have a supervised Tasso+ CB sample collection within 24 h of a venous sample. CMV DNA was quantitated in paired samples by using the Abbott M2000 Real-Time qPCR instrument. The participants were provided with a study-specific survey that measured patient acceptability of the Tasso+ device compared with venipuncture. A Tasso + CB sample was successfully collected in 28/30 (93%) patients, and 44 paired samples were analyzed. Concordance for detection of CMV DNAemia above the limit of detection (LOD) was 91% (42/44), and the Tasso + CB sample was estimated to be 95% sensitive at a viral load (VL) of 308 IU/mL. Among samples with a quantifiable DNAemia result with both methods (N = 31), there was excellent correlation between methods (Spearman R[2] = 0.99). The difference in CMV VL between venous and Tasso+ CB samples was not dependent on time (P > 0.1). Of 12 who completed the survey, 11 (92%) expressed a preference for Tasso+ CB collection over venipuncture. Collection of CB with the Tasso+ device is feasible, patient-acceptable, and yields generally comparable CMV DNAemia load to standard venous samples, but with lower sensitivity. Future studies to optimize and evaluate this methodology for patient self-collected samples are warranted.<br><br>IMPORTANCE: We evaluate an FDA-cleared blood self-collection device (Tasso+) and demonstrate that it is patient-acceptable and yields a liquid blood sample with quantitative CMV DNAemia results comparable to those of standard venipuncture samples. This opens up possibilities for self-blood collection to monitor for CMV and potentially other viruses in transplant and other at-risk populations.}, }
@article {pmid38770213, year = {2024}, author = {Yoke, LH and Boeckh, M and Beieler, AM}, title = {Integrating Infectious Disease Advanced Practice Providers in the Workforce: An Educational Step Forward.}, journal = {Open forum infectious diseases}, volume = {11}, number = {5}, pages = {ofae232}, pmid = {38770213}, issn = {2328-8957}, }
@article {pmid38769689, year = {2024}, author = {Kockerols, C and Valk, PJM and Dulucq, S and Nicolini, FE and Mahon, FX and Atallah, E and Mauro, MJ and Radich, JP and Bernardi, S and Russo, D and Farina, M and Mori, S and Gambacorti-Passerini, C and Civettini, I and Lu, L and Yeung, D and Branford, S and Colafigli, G and Breccia, M and Hogenbirk, P and van Rosmalen, J and Cornelissen, JJ and Westerweel, PE}, title = {BCR::ABL1 digital PCR for treatment-free remission prediction in chronic myeloid leukemia patients: An individual participant data meta-analysis.}, journal = {American journal of hematology}, volume = {99}, number = {8}, pages = {1632-1635}, doi = {10.1002/ajh.27359}, pmid = {38769689}, issn = {1096-8652}, support = {848101002/ZONMW_/ZonMw/Netherlands ; }, mesh = {Female ; Humans ; Male ; *Fusion Proteins, bcr-abl/genetics ; *Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis/genetics ; Polymerase Chain Reaction/methods ; }, }
@article {pmid38769663, year = {2024}, author = {Alsouqi, A and Ahmed, G and Wang, J and Cassanello, G and Szabo, A and Rojek, AE and Riedell, PA and Awan, F and Samples, L and Shadman, M and Hu, M and Bachanova, V and Wesson, W and Ahmed, N and Iqbal, M and Kharfan-Dabaja, MA and Scordo, M and Johnson, PC and Chen, YB and Ito, S and Hamadani, M and Frigault, M}, title = {Chimeric antigen receptor T-cell therapy in secondary central nervous system lymphoma: A multicenter analysis.}, journal = {American journal of hematology}, volume = {99}, number = {8}, pages = {1624-1627}, doi = {10.1002/ajh.27354}, pmid = {38769663}, issn = {1096-8652}, mesh = {Humans ; *Central Nervous System Neoplasms/therapy ; *Immunotherapy, Adoptive ; Male ; Female ; *Receptors, Chimeric Antigen/therapeutic use ; Middle Aged ; Aged ; Adult ; Lymphoma/therapy ; }, }
@article {pmid38768908, year = {2024}, author = {Portuguese, AJ and Yeh, AC and Banerjee, R and Holmberg, L and Wuliji, N and Green, DJ and Mielcarek, M and Gopal, AK and Gooley, T and Stevenson, P and Cowan, AJ}, title = {Optimizing Autologous Stem Cell Transplantation in Multiple Myeloma: The Impact of Intensive Chemomobilization.}, journal = {Transplantation and cellular therapy}, volume = {30}, number = {8}, pages = {774.e1-774.e12}, pmid = {38768908}, issn = {2666-6367}, support = {T32 HL007093/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Multiple Myeloma/therapy ; Male ; Middle Aged ; Female ; *Transplantation, Autologous ; Retrospective Studies ; Aged ; Peripheral Blood Stem Cell Transplantation/methods ; Cyclams/therapeutic use/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Benzylamines ; Granulocyte Colony-Stimulating Factor/administration &amp; dosage/therapeutic use ; Adult ; Hematopoietic Stem Cell Transplantation/methods ; }, abstract = {Most transplant-eligible multiple myeloma (MM) patients undergo autologous peripheral blood stem cell collection (PBSC) using G-CSF with on-demand plerixafor (G ± P). Chemomobilization (CM) can be used as a salvage regimen after G ± P failure or for debulking residual tumor burden ahead of autologous peripheral blood stem cell transplantation (ASCT). Prior studies utilizing cyclophosphamide-based CM have not shown long-term benefits. At our center, intensive CM (ICM) using a PACE- or HyperCVAD-based regimen has been used to mitigate "excessive" residual disease based on plasma cell (PC) burden or MM-related biomarkers. Given the lack of efficacy of non-ICM, we sought to determine the impact of ICM on event-free survival (EFS), defined as death, progressive disease, or unplanned treatment escalation. We performed a retrospective study of newly diagnosed MM patients who collected autologous PBSCs with the intent to proceed immediately to ASCT at our center between 7/2020 and 2/2023. Patients were excluded if they underwent a tandem autologous or sequential autologous-allogeneic transplant, had primary PC leukemia, received non-ICM treatment (i.e., cyclophosphamide and/or etoposide), or had previously failed G ± P mobilization. To appropriately evaluate the impact of ICM among those who potentially could have received it, we utilized a propensity score matching (PSM) approach whereby ICM patients were compared to a cohort of non-CM patients matched on pre-ASCT factors most strongly associated with the receipt of ICM. Of 451 patients identified, 61 (13.5%) received ICM (PACE-based, n = 45; hyper-CVAD-based, n = 16). Post-ICM/pre-ASCT, 11 patients (18%) required admission for neutropenic fever and/or infection. Among 51 evaluable patients, the overall response rate was 31%; however, 46 of 55 evaluable patients (84%) saw a reduction in M-spike and/or involved free light chains. Among those evaluated with longitudinal peripheral blood flow cytometry (n = 8), 5 patients (63%) cleared circulating blood PCs post-ICM. Compared to patients mobilized with non-CM, ICM patients collected a slightly greater median number of CD34[+] cells (10.8 versus 10.2 × 10[6]/kg, P = .018). The median follow-up was 30.6 months post-ASCT. In a PSM multivariable analysis, ICM was associated with significantly improved EFS (hazard ratio [HR] 0.30, 95% CI 0.14 to 0.67, P = .003), but not improved OS (HR 0.38, 95% CI 0.10 to 1.44, P = .2). ICM was associated with longer post-ASCT inpatient duration (+4.1 days, 95% CI, 2.4 to 5.8, P < .001), more febrile days (+0.96 days, 95% CI 0.50 to 1.4, P < .001), impaired platelet engraftment (HR 0.23, 95% CI 0.06 to 0.87, P = .031), more bacteremia (OR 3.41, 95% CI 1.20 to 9.31, P = .018), and increased antibiotic usage (cefepime: +2.3 doses, 95% CI 0.39 to 4.1, P = .018; vancomycin: +1.0 doses, 95% CI 0.23 to 1.8, P = .012). ICM was independently associated with improved EFS in a matched analysis involving MM patients with excessive disease burden at pre-ASCT workup. This benefit came at the cost of longer inpatient duration, more febrile days, greater incidence of bacteremia, and increased antibiotic usage in the immediate post-ASCT setting. Our findings suggest that ICM could be considered for a subset of MM patients, but its use must be weighed carefully against additional toxicity.}, }
@article {pmid38768492, year = {2024}, author = {Chow, EJ and Lynch, JB and Zerr, DM and Riedo, FX and Fairchok, M and Pergam, SA and Baliga, CS and Pauk, J and Lewis, J and Duchin, JS}, title = {Lessons From the COVID-19 Pandemic: Updating Our Approach to Masking in Health Care Facilities.}, journal = {Annals of internal medicine}, volume = {177}, number = {5}, pages = {689}, doi = {10.7326/L23-0449}, pmid = {38768492}, issn = {1539-3704}, mesh = {*COVID-19/epidemiology/prevention &amp; control ; Humans ; *Masks ; *SARS-CoV-2 ; *Pandemics ; Health Facilities ; }, }
@article {pmid38767893, year = {2024}, author = {Steinbach, G}, title = {The Physician's Calling and Science Promote Health Equity and Outcomes.}, journal = {JAMA pediatrics}, volume = {178}, number = {7}, pages = {728-729}, doi = {10.1001/jamapediatrics.2024.1236}, pmid = {38767893}, issn = {2168-6211}, mesh = {Humans ; *Health Equity ; Physician's Role ; }, }
@article {pmid38767452, year = {2024}, author = {Rashidi, A and Ebadi, M and Rehman, TU and Elhusseini, H and Kazadi, D and Halaweish, H and Khan, MH and Hoeschen, A and Cao, Q and Luo, X and Kabage, AJ and Lopez, S and Ramamoorthy, S and Holtan, SG and Weisdorf, DJ and Khoruts, A and Staley, C}, title = {Multi-omics Analysis of a Fecal Microbiota Transplantation Trial Identifies Novel Aspects of Acute GVHD Pathogenesis.}, journal = {Cancer research communications}, volume = {4}, number = {6}, pages = {1454-1466}, pmid = {38767452}, issn = {2767-9764}, support = {KL2 TR002492/TR/NCATS NIH HHS/United States ; UL1 TR002494/TR/NCATS NIH HHS/United States ; KL2TR002492//Foundation for the National Institutes of Health (FNIH)/ ; UL1TR002494//Foundation for the National Institutes of Health (FNIH)/ ; P30CA07759//HHS | NIH | National Cancer Institute (NCI)/ ; Chainbreaker grant//UMN | Clinical and Translational Science Institute, University of Minnesota (CTSI)/ ; n/a//Achieving Cures Together/ ; }, mesh = {Humans ; *Graft vs Host Disease/microbiology/immunology ; *Fecal Microbiota Transplantation ; *Gastrointestinal Microbiome ; Male ; Female ; Middle Aged ; *Hematopoietic Stem Cell Transplantation/methods/adverse effects ; Adult ; Leukemia, Myeloid, Acute/therapy/microbiology/immunology ; Transplantation, Homologous/methods/adverse effects ; Faecalibacterium ; Aged ; Acute Disease ; Feces/microbiology ; Metabolome ; Multiomics ; }, abstract = {UNLABELLED: Acute GVHD (aGVHD) is a major complication of allogeneic hematopoietic cell transplantation (alloHCT) associated with gut microbiota disruptions. However, whether therapeutic microbiota modulation prevents aGVHD is unknown. We conducted a randomized, placebo-controlled trial of third-party fecal microbiota transplantation (FMT) administered at the peak of microbiota injury in 100 patients with acute myeloid leukemia receiving induction chemotherapy and alloHCT recipients. Despite improvements in microbiome diversity, expansion of commensals, and shrinkage of potential pathogens, aGVHD occurred more frequently after FMT than placebo. Although this unexpected finding could be explained by clinical differences between the two arms, we asked whether a microbiota explanation might be also present. To this end, we performed multi-omics analysis of preintervention and postintervention gut microbiome and serum metabolome. We found that postintervention expansion of Faecalibacterium, a commensal genus with gut-protective and anti-inflammatory properties under homeostatic conditions, predicted a higher risk for aGVHD. Faecalibacterium expansion occurred predominantly after FMT and was due to engraftment of unique donor taxa, suggesting that donor Faecalibacterium-derived antigens might have stimulated allogeneic immune cells. Faecalibacterium and ursodeoxycholic acid (an anti-inflammatory secondary bile acid) were negatively correlated, offering an alternative mechanistic explanation. In conclusion, we demonstrate context dependence of microbiota effects where a normally beneficial bacteria may become detrimental in disease. While FMT is a broad, community-level intervention, it may need precision engineering in ecologically complex settings where multiple perturbations (e.g., antibiotics, intestinal damage, alloimmunity) are concurrently in effect.<br><br>SIGNIFICANCE: Post-FMT expansion of Faecalibacterium, associated with donor microbiota engraftment, predicted a higher risk for aGVHD in alloHCT recipients. Although Faecalibacterium is a commensal genus with gut-protective and anti-inflammatory properties under homeostatic conditions, our findings suggest that it may become pathogenic in the setting of FMT after alloHCT. Our results support a future trial with precision engineering of the FMT product used as GVHD prophylaxis after alloHCT.}, }
@article {pmid38766244, year = {2024}, author = {Rubio, AA and Baharani, VA and Dadonaite, B and Parada, M and Abernathy, ME and Wang, Z and Lee, YE and Eso, MR and Phung, J and Ramos, I and Chen, T and Nesr, GE and Bloom, JD and Bieniasz, PD and Nussenzweig, MC and Barnes, CO}, title = {Bispecific antibodies with broad neutralization potency against SARS-CoV-2 variants of concern.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38766244}, issn = {2692-8205}, support = {R01 AI141707/AI/NIAID NIH HHS/United States ; T32 GM136568/GM/NIGMS NIH HHS/United States ; U24 GM129541/GM/NIGMS NIH HHS/United States ; UL1 TR001866/TR/NCATS NIH HHS/United States ; }, abstract = {The ongoing emergence of SARS-CoV-2 variants of concern (VOCs) that reduce the effectiveness of antibody therapeutics necessitates development of next-generation antibody modalities that are resilient to viral evolution. Here, we characterized N-terminal domain (NTD) and receptor binding domain (RBD)-specific monoclonal antibodies previously isolated from COVID-19 convalescent donors for their activity against emergent SARS-CoV-2 VOCs. Among these, the NTD-specific antibody C1596 displayed the greatest breadth of binding to VOCs, with cryo-EM structural analysis revealing recognition of a distinct NTD epitope outside of the site i antigenic supersite. Given C1596's favorable binding profile, we designed a series of bispecific antibodies (bsAbs) termed CoV2-biRNs, that featured both NTD and RBD specificities. Notably, two of the C1596-inclusive bsAbs, CoV2-biRN5 and CoV2-biRN7, retained potent in vitro neutralization activity against all Omicron variants tested, including XBB.1.5, EG.5.1, and BA.2.86, contrasting the diminished potency of parental antibodies delivered as monotherapies or as a cocktail. Furthermore, prophylactic delivery of CoV2-biRN5 significantly reduced the viral load within the lungs of K18-hACE2 mice following challenge with SARS-CoV-2 XBB.1.5. In conclusion, our NTD-RBD bsAbs offer promising potential for the design of resilient, next-generation antibody therapeutics against SARS-CoV-2 VOCs.}, }
@article {pmid38765965, year = {2024}, author = {Tenthorey, JL and Del Banco, S and Ramzan, I and Klingenberg, H and Liu, C and Emerman, M and Malik, HS}, title = {Indels allow antiviral proteins to evolve functional novelty inaccessible by missense mutations.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38765965}, issn = {2692-8205}, support = {P50 AI150476/AI/NIAID NIH HHS/United States ; }, abstract = {Antiviral proteins often evolve rapidly at virus-binding interfaces to defend against new viruses. We investigated whether antiviral adaptation via missense mutations might face limits, which insertion or deletion mutations (indels) could overcome. We report one such case of a nearly insurmountable evolutionary challenge: the human anti-retroviral protein TRIM5α requires more than five missense mutations in its specificity-determining v1 loop to restrict a divergent simian immunodeficiency virus (SIV). However, duplicating just one amino acid in v1 enables human TRIM5α to potently restrict SIV in a single evolutionary step. Moreover, natural primate TRIM5α v1 loops have evolved indels that confer novel antiviral specificities. Thus, indels enable antiviral proteins to overcome viral challenges inaccessible by missense mutations, revealing the potential of these often-overlooked mutations in driving protein innovation.}, }
@article {pmid38764793, year = {2023}, author = {Savonen, C and Wright, C and Hoffman, A and Humphries, E and Cox, K and Tan, F and Leek, J}, title = {Motivation, inclusivity, and realism should drive data science education.}, journal = {F1000Research}, volume = {12}, number = {}, pages = {1240}, pmid = {38764793}, issn = {2046-1402}, mesh = {*Motivation ; Humans ; *Data Science/education ; Curriculum ; Teaching ; }, abstract = {Data science education provides tremendous opportunities but remains inaccessible to many communities. Increasing the accessibility of data science to these communities not only benefits the individuals entering data science, but also increases the field's innovation and potential impact as a whole. Education is the most scalable solution to meet these needs, but many data science educators lack formal training in education. Our group has led education efforts for a variety of audiences: from professional scientists to high school students to lay audiences. These experiences have helped form our teaching philosophy which we have summarized into three main ideals: 1) motivation, 2) inclusivity, and 3) realism. 20 we also aim to iteratively update our teaching approaches and curriculum as we find ways to better reach these ideals. In this manuscript we discuss these ideals as well practical ideas for how to implement these philosophies in the classroom.}, }
@article {pmid38763862, year = {2024}, author = {Koehne, EL and Bakaloudi, DR and Ghali, F and Nyame, Y and Schade, GR and Grivas, P and Yezefski, TA and Hawley, JE and Yu, EY and Hsieh, AC and Montgomery, RB and Psutka, SP and Gore, JL and Wright, JL}, title = {Adjuvant Chemotherapy and Survival After Radical Cystectomy in Histologic Subtype Bladder Cancer.}, journal = {Clinical genitourinary cancer}, volume = {22}, number = {3}, pages = {102100}, doi = {10.1016/j.clgc.2024.102100}, pmid = {38763862}, issn = {1938-0682}, mesh = {Humans ; *Urinary Bladder Neoplasms/pathology/surgery/mortality/drug therapy ; *Cystectomy ; Male ; Female ; Aged ; Chemotherapy, Adjuvant/statistics &amp; numerical data ; Retrospective Studies ; Middle Aged ; Carcinoma, Transitional Cell/surgery/mortality/pathology/drug therapy ; Survival Rate ; }, abstract = {OBJECTIVES: Patients with histologic subtype bladder cancer (HSBC) suffer worse outcomes than those with conventional urothelial carcinoma (UC). We sought to characterize the use of adjuvant chemotherapy (AC) in HSBC after radical cystectomy (RC) using the National Cancer Database (NCDB).<br><br>MATERIALS AND METHODS: We retrospectively queried the NCDB (2006-2019) for patients with non-metastatic bladder cancer (BC) who underwent RC (N = 45,797). Patients were stratified by histologic subtype and receipt of AC. Multivariable logistic regression determined associations of demographic and clinicopathologic features with receipt of AC. Multivariable Cox regression evaluated associations between receipt of any AC and overall survival (OS).<br><br>RESULTS: We identified 4,469 patients with HSBC classified as squamous, adenocarcinoma, small cell, sarcomatoid, micropapillary, or plasmacytoid. Squamous comprised 31% of the HSBC cohort, followed by small cells and micropapillary. Black patients were presented with a higher prevalence of adenocarcinoma (119/322, 37.0%). Use of AC was highest in plasmacytoid and small cell (30% each) and lowest in squamous (11%). Neuroendocrine histology was independently associated with greater odds of receiving AC (HR 1.6, 95% CI 1.37-1.87), while squamous cell histology was associated with lower odds (HR 0.61, 95% CI 0.53-0.71). On multivariable Cox regression analysis, treatment with AC was associated with significantly longer OS (HR 0.69, 95% CI 0.59-0.81) and for squamous, sarcomatoid, and micropapillary cohorts after stratified by subtype.<br><br>CONCLUSIONS: AC was variably used among patients with HSBC and was associated with OS benefit in such patients.}, }
@article {pmid38763441, year = {2024}, author = {Lugossy, AM and Anton, K and Dako, F and Dixon, RG and DuCharme, PA and Duggan, C and Durand, MA and Einstein, SA and Elahi, A and Kesselman, A and Kulinski, LF and Mango, VL and Pollack, EB and Scheel, JR and Schweitzer, A and Svolos, P and Wetherall, M and Mollura, DJ}, title = {Building Radiology Equity: Themes from the 2023 RAD-AID Conference on International Radiology and Global Health.}, journal = {Journal of the American College of Radiology : JACR}, volume = {21}, number = {8}, pages = {1194-1200}, doi = {10.1016/j.jacr.2024.04.025}, pmid = {38763441}, issn = {1558-349X}, mesh = {*Global Health ; *Radiology/organization &amp; administration ; Humans ; Health Equity ; Capacity Building ; Artificial Intelligence ; Developing Countries ; Congresses as Topic ; Diagnostic Imaging ; }, abstract = {Low- and middle-income countries are significantly impacted by the global scarcity of medical imaging services. Medical imaging is an essential component for diagnosis and guided treatment, which is needed to meet the current challenges of increasing chronic diseases and preparedness for acute-care response. We present some key themes essential for improving global health equity, which were discussed at the 2023 RAD-AID Conference on International Radiology and Global Health. They include (1) capacity building, (2) artificial intelligence, (3) community-based patient navigation, (4) organizational design for multidisciplinary global health strategy, (5) implementation science, and (6) innovation. Although not exhaustive, these themes should be considered influential as we guide and expand global health radiology programs in low- and middle-income countries in the coming years.}, }
@article {pmid38763416, year = {2024}, author = {Atallah, R and Ahmed, N and Ayoobkhan, F and Saif, MSI and Logan, E and Shrestha, A and Anwer, F and Mahmoudjafari, Z and Mushtaq, MU and Hashmi, H and Ganguly, S and McGuirk, J and Shebli, A and Abdallah, AO and Banerjee, R and Alkharabsheh, O}, title = {TACTUM: Trends in Access to Cellular Therapies in Multiple Myeloma, Perspectives of Treating Versus Referring Physicians.}, journal = {Transplantation and cellular therapy}, volume = {30}, number = {9}, pages = {925.e1-925.e6}, doi = {10.1016/j.jtct.2024.05.011}, pmid = {38763416}, issn = {2666-6367}, mesh = {*Multiple Myeloma/therapy ; Humans ; Surveys and Questionnaires ; Health Services Accessibility ; Immunotherapy, Adoptive/methods ; Referral and Consultation ; Oncologists ; Male ; Female ; }, abstract = {Chimeric antigen receptor T cell therapy (CAR-T) and bispecific T cell engagers (TCE) for multiple myeloma (MM) are readily available at many large US medical centers. However, many potentially eligible patients may not be referred to the specialized centers administering these therapies. Perspectives regarding potential barriers for MM cellular therapy from referring-center oncologists (ROs) versus treating-center oncologists (TOs) have not been reported previously. We conducted TACTUM-23, a survey of US oncologists who treat MM, to identify perceived barriers to these cellular therapies. This 24-question survey, which focused on demographics and perceived barriers to CAR-T and TCE, was conducted between June and August 2023. Of 247 oncologists, 37 (15%) completed the survey including 26 (70%) TOs who prescribed both CAR-T and TCEs, 4 (11%) TOs who only prescribed TCEs, and 7 (19%) ROs who referred patients. The top RO-stated barrier to CAR-T was financial toxicity, while the top TO-stated barrier to CAR-T was leukapheresis/ manufacturing slot availability. The top RO-stated barrier to TCE was financial toxicity, while the top TO-stated barrier to TCE was the hospitalization requirement. In conclusion, financial concerns are perceived by ROs to be the top barrier to both CAR-T and TCEs in myeloma. In contrast, TOs perceive logistical concerns to be the top barrier. Interventions to lower financial toxicity during these therapies, and outreach to raise awareness of such interventions among ROs, are needed alongside strategies to streamline manufacturing (for CAR-T) and monitoring.}, }
@article {pmid38763098, year = {2024}, author = {Zych, MG and Hatch, EM}, title = {Small spaces, big problems: The abnormal nucleoplasm of micronuclei and its consequences.}, journal = {Current opinion in structural biology}, volume = {87}, number = {}, pages = {102839}, doi = {10.1016/j.sbi.2024.102839}, pmid = {38763098}, issn = {1879-033X}, mesh = {Humans ; Animals ; *Cell Nucleus/metabolism ; Micronuclei, Chromosome-Defective ; Nuclear Envelope/metabolism ; Chromatin/metabolism ; Mitosis ; }, abstract = {Micronuclei (MN) form from missegregated chromatin that recruits its own nuclear envelope during mitotic exit and are a common consequence of chromosomal instability. MN are unstable due to errors in nuclear envelope organization and frequently rupture, leading to loss of compartmentalization, loss of nuclear functions, and major changes in genome stability and gene expression. However, recent work found that, even prior to rupture, nuclear processes can be severely defective in MN, which may contribute to rupture-associated defects and have lasting consequences for chromatin structure and function. In this review we discuss work that highlights nuclear function defects in intact MN, including their mechanisms and consequences, and how biases in chromosome missegregation into MN may affect the penetrance of these defects. Illuminating the nuclear environment of MN demonstrates that MN formation alone has major consequences for both the genome and cell and provides new insight into how nuclear content is regulated.}, }
@article {pmid38762348, year = {2024}, author = {Kim, R and Tehfe, M and Kavan, P and Chaves, J and Kortmansky, JS and Chen, EX and Lieu, CH and Wong, L and Fakih, M and Spencer, K and Zhao, Q and Predoiu, R and Li, C and Leconte, P and Adelberg, D and Chiorean, EG}, title = {Pembrolizumab Plus mFOLFOX7 or FOLFIRI for Microsatellite Stable/Mismatch Repair-Proficient Metastatic Colorectal Cancer: KEYNOTE-651 Cohorts B and D.}, journal = {Clinical colorectal cancer}, volume = {23}, number = {2}, pages = {118-127.e6}, doi = {10.1016/j.clcc.2024.03.001}, pmid = {38762348}, issn = {1938-0674}, mesh = {Humans ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects/administration &amp; dosage ; *Leucovorin/administration &amp; dosage/adverse effects/therapeutic use ; *Fluorouracil/administration &amp; dosage/adverse effects ; Female ; Male ; Middle Aged ; *Colorectal Neoplasms/drug therapy/genetics/pathology ; Aged ; *Camptothecin/analogs &amp; derivatives/administration &amp; dosage/therapeutic use/adverse effects ; *Antibodies, Monoclonal, Humanized/administration &amp; dosage/adverse effects ; Adult ; *Organoplatinum Compounds/administration &amp; dosage/therapeutic use ; Microsatellite Instability/drug effects ; DNA Mismatch Repair ; Irinotecan/administration &amp; dosage/adverse effects ; Oxaliplatin/administration &amp; dosage ; Aged, 80 and over ; }, abstract = {BACKGROUND: The phase 1b KEYNOTE-651 study evaluated pembrolizumab plus chemotherapy in microsatellite stable or mismatch repair-proficient metastatic colorectal cancer.<br><br>PATIENTS AND METHODS: Patients with microsatellite stable or mismatch repair-proficient metastatic colorectal cancer received pembrolizumab 200 mg every 3 weeks plus 5-fluorouracil, leucovorin, oxaliplatin (previously untreated; cohort B) or 5-fluorouracil, leucovorin, irinotecan (previously treated with fluoropyrimidine plus oxaliplatin; cohort D) every 2 weeks. Primary end point was safety; investigator-assessed objective response rate per RECIST v1.1 was secondary and biomarker analysis was exploratory.<br><br>RESULTS: Thirty-one patients were enrolled in cohort B and 32 in cohort D; median follow-up was 30.2 and 33.5 months, respectively. One dose-limiting toxicity (grade 3 small intestine obstruction) occurred in cohort D. In cohort B, grade 3 or 4 treatment-related adverse events (AEs) occurred in 18 patients (58%), most commonly neutropenia and decreased neutrophil count (n&#x202f;=&#x202f;5 each). In cohort D, grade 3 or 4 treatment-related AEs occurred in 17 patients (53%), most commonly neutropenia (n&#x202f;=&#x202f;7). No grade 5 treatment-related AEs occurred. Objective response rate was 61% in cohort B (KRAS wildtype: 71%; KRAS mutant: 53%) and 25% in cohort D (KRAS wildtype: 47%; KRAS mutant: 6%). In both cohorts, PD-L1 combined positive score and T-cell-inflamed gene expression profiles were higher and HER2 expression was lower in responders than nonresponders. No association between tumor mutational burden and response was observed.<br><br>CONCLUSION: Pembrolizumab plus 5-fluorouracil, leucovorin, oxaliplatin/5-fluorouracil, leucovorin, irinotecan demonstrated an acceptable AE profile. Efficacy data appeared comparable with current standard of care (including by KRAS mutation status). Biomarker analyses were hypothesis-generating, warranting further exploration.<br><br>GOV IDENTIFIER: ClinicalTrials.gov; NCT03374254.}, }
@article {pmid38761816, year = {2024}, author = {Ober Shepherd, BL and Scott, PT and Hutter, JN and Lee, C and McCauley, MD and Guzman, I and Bryant, C and McGuire, S and Kennedy, J and Chen, WH and Hajduczki, A and Mdluli, T and Valencia-Ruiz, A and Amare, MF and Matyas, GR and Rao, M and Rolland, M and Mascola, JR and De Rosa, SC and McElrath, MJ and Montefiori, DC and Serebryannyy, L and McDermott, AB and Peel, SA and Collins, ND and Joyce, MG and Robb, ML and Michael, NL and Vasan, S and Modjarrad, K and , }, title = {SARS-CoV-2 recombinant spike ferritin nanoparticle vaccine adjuvanted with Army Liposome Formulation containing monophosphoryl lipid A and QS-21: a phase 1, randomised, double-blind, placebo-controlled, first-in-human clinical trial.}, journal = {The Lancet. Microbe}, volume = {5}, number = {6}, pages = {e581-e593}, pmid = {38761816}, issn = {2666-5247}, support = {UM1 AI108568/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *COVID-19 Vaccines/immunology/administration &amp; dosage/adverse effects ; Double-Blind Method ; Adult ; Male ; Female ; *COVID-19/prevention &amp; control/immunology ; *SARS-CoV-2/immunology ; *Nanoparticles/administration &amp; dosage ; *Ferritins ; *Lipid A/analogs &amp; derivatives/administration &amp; dosage/pharmacology/immunology ; *Liposomes/administration &amp; dosage ; *Spike Glycoprotein, Coronavirus/immunology ; Saponins/administration &amp; dosage/immunology/pharmacology/adverse effects ; Antibodies, Viral/blood ; Middle Aged ; Adjuvants, Immunologic/administration &amp; dosage/pharmacology ; Adjuvants, Vaccine/administration &amp; dosage ; Antibodies, Neutralizing/blood ; Young Adult ; Nanovaccines ; }, abstract = {BACKGROUND: A self-assembling SARS-CoV-2 WA-1 recombinant spike ferritin nanoparticle (SpFN) vaccine co-formulated with Army Liposomal Formulation (ALFQ) adjuvant containing monophosphoryl lipid A and QS-21 (SpFN/ALFQ) has shown protective efficacy in animal challenge models. This trial aims to assess the safety and immunogenicity of SpFN/ALFQ in a first-in-human clinical trial.<br><br>METHODS: In this phase 1, randomised, double-blind, placebo-controlled, first-in-human clinical trial, adults were randomly assigned (5:5:2) to receive 25 &#x3bc;g or 50 &#x3bc;g of SpFN/ALFQ or saline placebo intramuscularly at day 1 and day 29, with an optional open-label third vaccination at day 181. Enrolment and randomisation occurred sequentially by group; randomisation was done by an interactive web-based randomisation system and only designated unmasked study personnel had access to the randomisation code. Adults were required to be seronegative and unvaccinated for inclusion. Local and systemic reactogenicity, adverse events, binding and neutralising antibodies, and antigen-specific T-cell responses were quantified. For safety analyses, exact 95% Clopper-Pearson CIs for the probability of any incidence of an unsolicited adverse event was computed for each group. For immunogenicity results, CIs for binary variables were computed using the exact Clopper-Pearson methodology, while CIs for geometric mean titres were based on 10&#x2009;000 empirical bootstrap samples. Post-hoc, paired one-sample t tests were used to assess the increase in mean log-10 neutralising antibody titres between day&#xa0;29 and day 43 (after the second vaccination) for the primary SARS-CoV-2 targets of interest. This trial is registered at ClinicalTrials.gov, NCT04784767, and is closed to new participants.<br><br>FINDINGS: Between April 7, and June 29, 2021, 29 participants were enrolled in the study. 20 individuals were assigned to receive 25 &#x3bc;g SpFN/ALFQ, four to 50 &#x3bc;g SpFN/ALFQ, and five to placebo. Neutralising antibody responses peaked at day 43, 2 weeks after the second dose. Neutralisation activity against multiple omicron subvariants decayed more slowly than against the D614G or beta variants until 5 months after second vaccination for both dose groups. CD4[+] T-cell responses were elicited 4 weeks after the first dose and were boosted after a second dose of SpFN/ALFQ for both dose groups. Neutralising antibody titres against early omicron subvariants and clade 1 sarbecoviruses were detectable after two immunisations and peaked after the third immunisation for both dose groups. Neutralising antibody titres against XBB.1.5 were detected after three vaccinations. Passive IgG transfer from vaccinated volunteers into Syrian golden hamsters controlled replication of SARS-CoV-1 after challenge.<br><br>INTERPRETATION: SpFN/ALFQ was well tolerated and elicited robust and durable binding antibody and neutralising antibody titres against a broad panel of SARS-CoV-2 variants and other sarbecoviruses.<br><br>FUNDING: US Department of Defense, Defense Health Agency.}, }
@article {pmid38761800, year = {2024}, author = {Williams, WB and Alam, SM and Ofek, G and Erdmann, N and Montefiori, DC and Seaman, MS and Wagh, K and Korber, B and Edwards, RJ and Mansouri, K and Eaton, A and Cain, DW and Martin, M and Hwang, J and Arus-Altuz, A and Lu, X and Cai, F and Jamieson, N and Parks, R and Barr, M and Foulger, A and Anasti, K and Patel, P and Sammour, S and Parsons, RJ and Huang, X and Lindenberger, J and Fetics, S and Janowska, K and Niyongabo, A and Janus, BM and Astavans, A and Fox, CB and Mohanty, I and Evangelous, T and Chen, Y and Berry, M and Kirshner, H and Van Itallie, E and Saunders, KO and Wiehe, K and Cohen, KW and McElrath, MJ and Corey, L and Acharya, P and Walsh, SR and Baden, LR and Haynes, BF}, title = {Vaccine induction of heterologous HIV-1-neutralizing antibody B cell lineages in humans.}, journal = {Cell}, volume = {187}, number = {12}, pages = {2919-2934.e20}, doi = {10.1016/j.cell.2024.04.033}, pmid = {38761800}, issn = {1097-4172}, support = {U54 AI170752/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *AIDS Vaccines/immunology ; *HIV-1/immunology ; *Antibodies, Neutralizing/immunology ; *B-Lymphocytes/immunology ; *HIV Antibodies/immunology ; HIV Infections/immunology/virology ; Cell Lineage ; Liposomes ; env Gene Products, Human Immunodeficiency Virus/immunology ; Mutation ; HIV Envelope Protein gp41/immunology ; }, abstract = {A critical roadblock to HIV vaccine development is the inability to induce B cell lineages of broadly neutralizing antibodies (bnAbs) in humans. In people living with HIV-1, bnAbs take years to develop. The HVTN 133 clinical trial studied a peptide/liposome immunogen targeting B cell lineages of HIV-1 envelope (Env) membrane-proximal external region (MPER) bnAbs (NCT03934541). Here, we report MPER peptide-liposome induction of polyclonal HIV-1 B cell lineages of mature bnAbs and their precursors, the most potent of which neutralized 15% of global tier 2 HIV-1 strains and 35% of clade B strains with lineage initiation after the second immunization. Neutralization was enhanced by vaccine selection of improbable mutations that increased antibody binding to gp41 and lipids. This study demonstrates proof of concept for rapid vaccine induction of human B cell lineages with heterologous neutralizing activity and selection of antibody improbable mutations and outlines a path for successful HIV-1 vaccine development.}, }
@article {pmid38761799, year = {2024}, author = {Sheward, DJ and Pushparaj, P and Das, H and Greaney, AJ and Kim, C and Kim, S and Hanke, L and Hyllner, E and Dyrdak, R and Lee, J and Dopico, XC and Dosenovic, P and Peacock, TP and McInerney, GM and Albert, J and Corcoran, M and Bloom, JD and Murrell, B and Karlsson Hedestam, GB and Hällberg, BM}, title = {Structural basis of broad SARS-CoV-2 cross-neutralization by affinity-matured public antibodies.}, journal = {Cell reports. Medicine}, volume = {5}, number = {6}, pages = {101577}, pmid = {38761799}, issn = {2666-3791}, support = {R01 AI141707/AI/NIAID NIH HHS/United States ; }, mesh = {*SARS-CoV-2/immunology ; Humans ; *Antibodies, Viral/immunology ; *COVID-19/immunology/virology ; *Spike Glycoprotein, Coronavirus/immunology/chemistry/genetics ; *Antibodies, Neutralizing/immunology ; *Antibodies, Monoclonal/immunology/chemistry ; Cross Reactions/immunology ; Cryoelectron Microscopy ; Neutralization Tests ; }, abstract = {Descendants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant now account for almost all SARS-CoV-2 infections. The Omicron variant and its sublineages have spike glycoproteins that are highly diverged from the pandemic founder and first-generation vaccine strain, resulting in significant evasion from monoclonal antibody therapeutics and vaccines. Understanding how commonly elicited antibodies can broaden to cross-neutralize escape variants is crucial. We isolate IGHV3-53, using "public" monoclonal antibodies (mAbs) from an individual 7 months post infection with the ancestral virus and identify antibodies that exhibit potent and broad cross-neutralization, extending to the BA.1, BA.2, and BA.4/BA.5 sublineages of Omicron. Deep mutational scanning reveals these mAbs' high resistance to viral escape. Structural analysis via cryoelectron microscopy of a representative broadly neutralizing antibody, CAB-A17, in complex with the Omicron BA.1 spike highlights the structural underpinnings of this broad neutralization. By reintroducing somatic hypermutations into a germline-reverted CAB-A17, we delineate the role of affinity maturation in the development of cross-neutralization by a public class of antibodies.}, }
@article {pmid38761334, year = {2024}, author = {Sandfort, TGM and Kreniske, P and Mbeda, C and Reynolds, D and Tshabalala, G and Madiwati, B and Ogendo, A and Dominquez, K and Panchia, R and Gondwe, D and Hamilton, EL and Guo, X and Cummings, V}, title = {Interest in I-PrEP and Willingness to Participate in Clinical Trials Among Men and Transfeminine Persons Who have Sex with Men in Sub-Saharan Africa: Quantitative and Qualitative Findings from HPTN 075.}, journal = {AIDS and behavior}, volume = {28}, number = {7}, pages = {2361-2377}, pmid = {38761334}, issn = {1573-3254}, support = {K01 MH122319/MH/NIMH NIH HHS/United States ; UM1AI068617//National Institute of Allergy and Infectious Diseases/ ; R21 MH130217/MH/NIMH NIH HHS/United States ; K01MH122319//National Institute of Mental Health and Neurosciences/ ; P30 MH043520/MH/NIMH NIH HHS/United States ; UM1AI068619//National Institute of Allergy and Infectious Diseases/ ; UM1 AI069453/AI/NIAID NIH HHS/United States ; UM1AI068613//National Institute of Allergy and Infectious Diseases/ ; T32MH019139//National Institute of Mental Health and Neurosciences/ ; UM1 AI068619/AI/NIAID NIH HHS/United States ; UM1 AI068613/AI/NIAID NIH HHS/United States ; P30MH43520//National Institute of Mental Health and Neurosciences/ ; UM1 AI068617/AI/NIAID NIH HHS/United States ; T32 MH019139/MH/NIMH NIH HHS/United States ; R21MH130217//National Institute of Mental Health and Neurosciences/ ; }, mesh = {Humans ; Male ; Adult ; *HIV Infections/prevention &amp; control/psychology ; *Homosexuality, Male/psychology/statistics &amp; numerical data ; *Qualitative Research ; *Pre-Exposure Prophylaxis ; *Patient Acceptance of Health Care/psychology/statistics &amp; numerical data ; Young Adult ; Adolescent ; Africa South of the Sahara ; Anti-HIV Agents/therapeutic use ; Transgender Persons/psychology/statistics &amp; numerical data ; Interviews as Topic ; Surveys and Questionnaires ; Sexual and Gender Minorities/psychology ; Clinical Trials as Topic ; Social Stigma ; Female ; Kenya ; }, abstract = {This study explored interest in injectable PrEP (I-PrEP) and willingness to participate in clinical trials testing new biomedical HIV prevention strategies among men and transfeminine persons who have sex with men (MSM &amp; TGP), using data collected in the HIV Prevention Trials Network (HPTN) 075 study, which took place at sites in Kenya, Malawi, and South Africa. Data result from a survey among 267 18-44 years old HIV negative participants, complemented with semi-structured interviews with 80 purposively recruited persons. Correlations coefficients were calculated to identify demographic and psychosocial factors associated with interest in I-PrEP. Qualitative interviews were analyzed using concept-driven and subsequent data-driven coding. Most surveyed participants expressed an interest in I-PrEP. Quantitatively, only being interested in other HIV prevention measures was associated with interest in I-PrEP. Qualitatively, most participants preferred I-PrEP to O-PrEP and remained interested in I-PrEP despite barriers such as the somewhat invasive nature of the procedure and potential side effects of I-PrEP. Interest in I-PrEP was driven by the possibility of avoiding sexual or HIV stigma. Access to healthcare and altruism-such as assisting in the development of new HIV prevention methods-positively impacted willingness to participate in clinical trials. With I-PrEP favored by most participants, it is potentially a critical tool to prevent HIV infection among MSM &amp; TGP in sub-Saharan Africa, with the mitigation of stigma as a major advance. Recruitment of MSM &amp; TGP in biobehavioral clinical trials seems feasible, with altruistic reasons and receiving I-PrEP and free medical care as major motivators.}, }
@article {pmid38760413, year = {2024}, author = {Ajkunic, A and Sayar, E and Roudier, MP and Patel, RA and Coleman, IM and De Sarkar, N and Hanratty, B and Adil, M and Zhao, J and Zaidi, S and True, LD and Sperger, JM and Cheng, HH and Yu, EY and Montgomery, RB and Hawley, JE and Ha, G and Persse, T and Galipeau, P and Lee, JK and Harmon, SA and Corey, E and Lang, JM and Sawyers, CL and Morrissey, C and Schweizer, MT and Gulati, R and Nelson, PS and Haffner, MC}, title = {Assessment of TROP2, CEACAM5 and DLL3 in metastatic prostate cancer: Expression landscape and molecular correlates.}, journal = {NPJ precision oncology}, volume = {8}, number = {1}, pages = {104}, pmid = {38760413}, issn = {2397-768X}, support = {R50 CA221836/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; R37 CA286450/CA/NCI NIH HHS/United States ; P01 CA163227/CA/NCI NIH HHS/United States ; R01 CA266452/CA/NCI NIH HHS/United States ; R01 CA234715/CA/NCI NIH HHS/United States ; P50 CA092629/CA/NCI NIH HHS/United States ; }, abstract = {Therapeutic approaches targeting proteins on the surface of cancer cells have emerged as an important strategy for precision oncology. To capitalize on the potential impact of drugs targeting surface proteins, detailed knowledge about the expression patterns of the target proteins in tumor tissues is required. In castration-resistant prostate cancer (CRPC), agents targeting prostate-specific membrane antigen (PSMA) have demonstrated clinical activity. However, PSMA expression is lost in a significant number of CRPC tumors. The identification of additional cell surface targets is necessary to develop new therapeutic approaches. Here, we performed a comprehensive analysis of the expression heterogeneity and co-expression patterns of trophoblast cell-surface antigen 2 (TROP2), delta-like ligand 3 (DLL3), and carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) in CRPC samples from a rapid autopsy cohort. We show that DLL3 and CEACAM5 exhibit the highest expression in neuroendocrine prostate cancer (NEPC), while TROP2 is expressed across different CRPC molecular subtypes, except for NEPC. We further demonstrated that AR alterations were associated with higher expression of PSMA and TROP2. Conversely, PSMA and TROP2 expression was lower in RB1-altered tumors. In addition to genomic alterations, we show a tight correlation between epigenetic states, particularly histone H3 lysine 27 methylation (H3K27me3) at the transcriptional start site and gene body of TACSTD2 (encoding TROP2), DLL3, and CEACAM5, and their respective protein expression in CRPC patient-derived xenografts. Collectively, these findings provide insights into patterns and determinants of expression of TROP2, DLL3, and CEACAM5 with implications for the clinical development of cell surface targeting agents in CRPC.}, }
@article {pmid38759123, year = {2024}, author = {Othus, M and Freidlin, B and Korn, EL}, title = {Avoiding Delays in Reporting Time-to-Event Randomized Trials: Calendar Backstops and Other Approaches.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {42}, number = {31}, pages = {3753-3760}, pmid = {38759123}, issn = {1527-7755}, support = {U10 CA180819/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Randomized Controlled Trials as Topic ; Research Design/standards ; Time Factors ; Neoplasms/therapy ; }, abstract = {New oncology therapies that extend patients' lives beyond initial expectations and improving later-line treatments can lead to complications in clinical trial design and conduct. In particular, for trials with event-based analyses, the time to observe all the protocol-specified events can exceed the finite follow-up of a clinical trial or can lead to much delayed release of outcome data. With the advent of multiple classes of oncology therapies leading to much longer survival than in the past, this issue in clinical trial design and conduct has become increasingly important in recent years. We propose a straightforward prespecified backstop rule for trials with a time-to-event analysis and evaluate the impact of the rule with both simulated and real-world trial data. We then provide recommendations for implementing the rule across a range of oncology clinical trial settings.}, }
@article {pmid38759092, year = {2024}, author = {Guo, X and Ping, J and Yang, Y and Su, X and Shu, XO and Wen, W and Chen, Z and Zhang, Y and Tao, R and Jia, G and He, J and Cai, Q and Zhang, Q and Giles, GG and Pearlman, R and Rennert, G and Vodicka, P and Phipps, A and Gruber, SB and Casey, G and Peters, U and Long, J and Lin, W and Zheng, W}, title = {Large-Scale Alternative Polyadenylation-Wide Association Studies to Identify Putative Cancer Susceptibility Genes.}, journal = {Cancer research}, volume = {84}, number = {16}, pages = {2707-2719}, pmid = {38759092}, issn = {1538-7445}, support = {R37 CA227130/CA/NCI NIH HHS/United States ; R01 CA235553/CA/NCI NIH HHS/United States ; R01 CA269589/CA/NCI NIH HHS/United States ; R37CA227130//National Cancer Institute (NCI)/ ; R01 CA202981/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Genetic Predisposition to Disease ; *Polyadenylation ; *Genome-Wide Association Study ; *Neoplasms/genetics ; *3' Untranslated Regions/genetics ; Quantitative Trait Loci ; Polymorphism, Single Nucleotide ; Female ; Male ; Gene Expression Regulation, Neoplastic ; RNA, Messenger/genetics/metabolism ; Cell Line, Tumor ; }, abstract = {Alternative polyadenylation (APA) modulates mRNA processing in the 3'-untranslated regions (3' UTR), affecting mRNA stability and translation efficiency. Research into genetically regulated APA has the potential to provide insights into cancer risk. In this study, we conducted large APA-wide association studies to investigate associations between APA levels and cancer risk. Genetic models were built to predict APA levels in multiple tissues using genotype and RNA sequencing data from 1,337 samples from the Genotype-Tissue Expression project. Associations of genetically predicted APA levels with cancer risk were assessed by applying the prediction models to data from large genome-wide association studies of six common cancers among European ancestry populations: breast, ovarian, prostate, colorectal, lung, and pancreatic cancers. A total of 58 risk genes (corresponding to 76 APA sites) were associated with at least one type of cancer, including 25 genes previously not linked to cancer susceptibility. Of the identified risk APAs, 97.4% and 26.3% were supported by 3'-UTR APA quantitative trait loci and colocalization analyses, respectively. Luciferase reporter assays for four selected putative regulatory 3'-UTR variants demonstrated that the risk alleles of 3'-UTR variants, rs324015 (STAT6), rs2280503 (DIP2B), rs1128450 (FBXO38), and rs145220637 (LDHA), significantly increased the posttranscriptional activities of their target genes compared with reference alleles. Furthermore, knockdown of the target genes confirmed their ability to promote proliferation and migration. Overall, this study provides insights into the role of APA in the genetic susceptibility to common cancers. Significance: Systematic evaluation of associations of alternative polyadenylation with cancer risk reveals 58 putative susceptibility genes, highlighting the contribution of genetically regulated alternative polyadenylation of 3'UTRs to genetic susceptibility to cancer.}, }
@article {pmid38758320, year = {2024}, author = {Smith-Peavler, E and Sircy, LM and Nelson, DE and McClelland, EE}, title = {Two Methods of Measuring Cryptococcus neoformans Fungal Burden in Macrophages.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2775}, number = {}, pages = {211-221}, pmid = {38758320}, issn = {1940-6029}, mesh = {*Cryptococcus neoformans ; *Macrophages/microbiology/immunology/metabolism ; *Cryptococcosis/microbiology/immunology ; *Microscopy, Fluorescence/methods ; Animals ; Mice ; Colony Count, Microbial/methods ; Humans ; }, abstract = {The ability of C. neoformans to survive and replicate within host phagocytes enables it to evade the immune system and allows for persistence of the infection. As such, measuring fungal burden of C. neoformans strains-and indeed how drug treatments can influence fungal burden-provides important information about C. neoformans pathogenesis. In this chapter, we describe two methods that may be used to appraise fungal burden: a standard end-point colony-formation assay for calculating the average number of yeast per host cell and a fluorescence microscopy-based method that may be used to measure changes in fungal burden in individual living macrophages in real time.}, }
@article {pmid38758104, year = {2024}, author = {Huang, YH and Loftfield, E and Argirion, I and Adami, HO and Albanes, D and Chan, AT and Fedirko, V and Fraser, GE and Freedman, ND and Giles, GG and Hartge, P and Katzke, V and Knutsen, SF and Lacey, J and Liao, LM and Luo, J and Milne, RL and O'Brien, KM and Peters, U and Poynter, JN and Purdue, MP and Robien, K and Sandin, S and Sandler, DP and Setiawan, VW and Kang, JH and Simon, TG and Sinha, R and VoPham, T and Weinstein, SJ and White, E and Zhang, X and Zhu, B and McGlynn, KA and Campbell, PT and Lee, MH and Koshiol, J}, title = {Association of tea and coffee consumption and biliary tract cancer risk: The Biliary Tract Cancers Pooling Project.}, journal = {Hepatology (Baltimore, Md.)}, volume = {79}, number = {6}, pages = {1324-1336}, pmid = {38758104}, issn = {1527-3350}, support = {ZIA CP010218/ImNIH/Intramural NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; Y99 CA999999/CA/NCI NIH HHS/United States ; Z99 CA999999/ImNIH/Intramural NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; Z01 ES044005/ImNIH/Intramural NIH HHS/United States ; P50 CA127003/CA/NCI NIH HHS/United States ; 14136/CRUK_/Cancer Research UK/United Kingdom ; C8221/A29017/CRUK_/Cancer Research UK/United Kingdom ; 1000143/MRC_/Medical Research Council/United Kingdom ; MR/M012190/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Coffee ; *Tea ; Male ; Female ; Middle Aged ; *Biliary Tract Neoplasms/epidemiology/etiology ; Aged ; Incidence ; Gallbladder Neoplasms/epidemiology/etiology/prevention &amp; control ; Risk Factors ; Adult ; Bile Duct Neoplasms/epidemiology/etiology ; }, abstract = {BACKGROUND AND AIMS: Tea and coffee are widely consumed beverages worldwide. We evaluated their association with biliary tract cancer (BTC) incidence.<br><br>APPROACH AND RESULTS: We pooled data from 15 studies in the Biliary Tract Cancers Pooling Project to evaluate associations between tea and coffee consumption and biliary tract cancer development. We categorized participants as nondrinkers (0 cup/day), moderate drinkers (>0 and <3 cups/day), and heavy drinkers (&#x2265;3 cups/day). We estimated multivariable HRs and 95% CIs using Cox models. During 29,911,744 person-years of follow-up, 851 gallbladder, 588 intrahepatic bile duct, 753 extrahepatic bile duct, and 458 ampulla of Vater cancer cases were diagnosed. Individuals who drank tea showed a statistically significantly lower incidence rate of gallbladder cancer (GBC) relative to tea nondrinkers (HR=0.77; 95% CI, 0.64-0.91), and intrahepatic bile duct cancer (IHBDC) had an inverse association (HR=0.81; 95% CI, 0.66-1.00). However, no associations were observed for extrahepatic bile duct cancer (EHBDC) or ampulla of Vater cancer (AVC). In contrast, coffee consumption was positively associated with GBC, with a higher incidence rate for individuals consuming more coffee (HR<3 cups/day =1.29; 95% CI, 1.01-1.66; HR&#x2265;3 cups/day =1.49; 95% CI, 1.11-1.99, Ptrend=0.01) relative to coffee nondrinkers. However, there was no association between coffee consumption and GBC when restricted to coffee drinkers. There was little evidence of associations between coffee consumption and other biliary tract cancers.<br><br>CONCLUSIONS: Tea consumption was associated with a lower incidence of GBC and possibly IHBDC. Further research is warranted to replicate the observed positive association between coffee and GBC.}, }
@article {pmid38757844, year = {2024}, author = {Gelderblom, HC and Corey, L and Barouch, DH}, title = {The potential of broadly neutralizing antibodies for HIV prevention.}, journal = {Journal of the International AIDS Society}, volume = {27}, number = {5}, pages = {e26257}, pmid = {38757844}, issn = {1758-2652}, support = {AI068614/GF/NIH HHS/United States ; AI177687/GF/NIH HHS/United States ; AI164556/GF/NIH HHS/United States ; AI128751/GF/NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; AI145801/GF/NIH HHS/United States ; AI149670/GF/NIH HHS/United States ; AI169615/GF/NIH HHS/United States ; }, mesh = {Humans ; *HIV Infections/prevention &amp; control/immunology ; *HIV Antibodies/immunology ; Antibodies, Neutralizing/immunology ; Broadly Neutralizing Antibodies/immunology/therapeutic use ; AIDS Vaccines/immunology ; HIV-1/immunology ; }, }
@article {pmid38757809, year = {2024}, author = {Kim, JH and Schulte, AJ and Sarver, AL and Lee, D and Angelos, MG and Frantz, AM and Forster, CL and O'Brien, TD and Cornax, I and O'Sullivan, MG and Cheng, N and Lewellen, M and Oseth, L and Kumar, S and Bullman, S and Pedamallu, CS and Goyal, SM and Meyerson, M and Lund, TC and Breen, M and Lindblad-Toh, K and Dickerson, EB and Kaufman, DS and Modiano, JF}, title = {Hemangiosarcoma Cells Promote Conserved Host-derived Hematopoietic Expansion.}, journal = {Cancer research communications}, volume = {4}, number = {6}, pages = {1467-1480}, pmid = {38757809}, issn = {2767-9764}, support = {P30 CA077598/CA/NCI NIH HHS/United States ; R03 CA191713/CA/NCI NIH HHS/United States ; R50 CA211249/CA/NCI NIH HHS/United States ; 1R03CA191713-01//HHS | NIH | National Cancer Institute (NCI)/ ; #02759//American Kennel Club Canine Health Foundation (CHF)/ ; #422//American Kennel Club Canine Health Foundation (CHF)/ ; 1889-G//American Kennel Club Canine Health Foundation (CHF)/ ; JHK15MN-004//National Canine Cancer Foundation (NCCF)/ ; D10-501//Morris Animal Foundation (MAF)/ ; n/a//Cancerfonden (Swedish Cancer Society)/ ; CA211249//HHS | NIH | National Cancer Institute (NCI)/ ; P30 CA077598/CA/NCI NIH HHS/United States ; CA191225//U.S. Department of Defense (DOD)/ ; }, mesh = {*Hemangiosarcoma/pathology/veterinary/genetics ; Dogs ; Animals ; Humans ; Mice ; Tumor Microenvironment ; Hematopoietic Stem Cells/pathology ; Hematopoiesis ; Cell Differentiation ; }, abstract = {UNLABELLED: Hemangiosarcoma and angiosarcoma are soft-tissue sarcomas of blood vessel-forming cells in dogs and humans, respectively. These vasoformative sarcomas are aggressive and highly metastatic, with disorganized, irregular blood-filled vascular spaces. Our objective was to define molecular programs which support the niche that enables progression of canine hemangiosarcoma and human angiosarcoma. Dog-in-mouse hemangiosarcoma xenografts recapitulated the vasoformative and highly angiogenic morphology and molecular characteristics of primary tumors. Blood vessels in the tumors were complex and disorganized, and they were lined by both donor and host cells. In a series of xenografts, we observed that the transplanted hemangiosarcoma cells created exuberant myeloid hyperplasia and gave rise to lymphoproliferative tumors of mouse origin. Our functional analyses indicate that hemangiosarcoma cells generate a microenvironment that supports expansion and differentiation of hematopoietic progenitor populations. Furthermore, gene expression profiling data revealed hemangiosarcoma cells expressed a repertoire of hematopoietic cytokines capable of regulating the surrounding stromal cells. We conclude that canine hemangiosarcomas, and possibly human angiosarcomas, maintain molecular properties that provide hematopoietic support and facilitate stromal reactions, suggesting their potential involvement in promoting the growth of hematopoietic tumors.<br><br>SIGNIFICANCE: We demonstrate that hemangiosarcomas regulate molecular programs supporting hematopoietic expansion and differentiation, providing insights into their potential roles in creating a permissive stromal-immune environment for tumor progression.}, }
@article {pmid38756173, year = {2024}, author = {Wittenauer, R and Shah, PD and Bacci, JL and Stergachis, A}, title = {Locations and characteristics of pharmacy deserts in the United States: a geospatial study.}, journal = {Health affairs scholar}, volume = {2}, number = {4}, pages = {qxae035}, pmid = {38756173}, issn = {2976-5390}, abstract = {Pharmacies are important health care access points, but no national map currently exists of where pharmacy deserts are located. This cross-sectional study used pharmacy address data and Census Bureau surveys to define pharmacy deserts at the census tract level in all 50 US states and the District of Columbia. We also compared sociodemographic characteristics of pharmacy desert vs non-pharmacy desert communities. Nationally, 15.8 million (4.7%) of all people in the United States live in pharmacy deserts, spanning urban and rural settings in all 50 states. On average, communities that are pharmacy deserts have a higher proportion of people who have a high school education or less, have no health insurance, have low self-reported English ability, have an ambulatory disability, and identify as a racial or ethnic minority. While, on average, pharmacies are the most accessible health care setting in the United States, many people still do not have access to them. Further, the people living in pharmacy deserts are often marginalized groups who have historically faced structural barriers to health care. This study demonstrates a need to improve access to pharmacies and pharmacy services to advance health equity.}, }
@article {pmid38755519, year = {2024}, author = {Ronsley, R and Karvonen, KA and Cole, B and Paulson, V and Stevens, J and Crotty, EE and Hauptman, J and Lee, A and Stasi, SM and Lockwood, CM and Leary, SES}, title = {Detection of tumor-derived cell-free DNA in cerebrospinal fluid using a clinically validated targeted sequencing panel for pediatric brain tumors.}, journal = {Journal of neuro-oncology}, volume = {168}, number = {2}, pages = {215-224}, pmid = {38755519}, issn = {1573-7373}, support = {T32CA009351//Seattle Children's Pediatric Brain Tumor Research Fund (PBTRF), Brotman Baty Institute (BBI) for Precision Medicine, Ruth L. Kirschstein National Research Service Award Institutional Research Training Grant/ ; }, mesh = {Humans ; Child ; *Brain Neoplasms/genetics/cerebrospinal fluid/diagnosis ; Male ; Female ; Child, Preschool ; Adolescent ; Infant ; *Circulating Tumor DNA/cerebrospinal fluid/genetics/blood ; *High-Throughput Nucleotide Sequencing/methods ; *Biomarkers, Tumor/genetics/cerebrospinal fluid ; Cell-Free Nucleic Acids/cerebrospinal fluid/genetics/blood ; Liquid Biopsy/methods ; Mutation ; }, abstract = {PURPOSE: Clinical sequencing of tumor DNA is necessary to render an integrated diagnosis and select therapy for children with primary central nervous system (CNS) tumors, but neurosurgical biopsy is not without risk. In this study, we describe cell-free DNA (cfDNA) in blood and cerebrospinal fluid (CSF) as sources for "liquid biopsy" in pediatric brain tumors.<br><br>METHODS: CSF samples were collected by lumbar puncture, ventriculostomy, or surgery from pediatric patients with CNS tumors. Following extraction, CSF-derived cfDNA was sequenced using UW-OncoPlex&#x2122;, a clinically validated next-generation sequencing platform. CSF-derived cfDNA results and paired plasma and tumor samples concordance was also evaluated.<br><br>RESULTS: Seventeen CSF samples were obtained from 15 pediatric patients with primary CNS tumors. Tumor types included medulloblastoma (n&#x2009;=&#x2009;7), atypical teratoid/rhabdoid tumor (n&#x2009;=&#x2009;2), diffuse midline glioma with H3 K27 alteration (n&#x2009;=&#x2009;4), pilocytic astrocytoma (n&#x2009;=&#x2009;1), and pleomorphic xanthoastrocytoma (n&#x2009;=&#x2009;1). CSF-derived cfDNA was detected in 9/17 (53%) of samples, and sufficient for sequencing in 8/10 (80%) of extracted samples. All somatic mutations and copy-number variants were also detected in matched tumor tissue, and tumor-derived cfDNA was absent in plasma samples and controls. Tumor-derived cfDNA alterations were detected in the absence of cytological evidence of malignant cells in as little as 200&#xa0;&#xb5;l of CSF. Several clinically relevant alterations, including a KIAA1549::BRAF fusion were detected.<br><br>CONCLUSIONS: Clinically relevant genomic alterations are detectable using CSF-derived cfDNA across a range of pediatric brain tumors. Next-generation sequencing platforms are capable of producing a high yield of DNA alterations with 100% concordance rate with tissue analysis.}, }
@article {pmid38755430, year = {2024}, author = {McQuade, E and Sánchez, H and Hidalgo, J and Cabello, R and Fernandez, R and Jones, J and Duerr, A and Lankowski, A}, title = {HIV Risk Behaviors and the Use of Geosocial Networking Dating Apps among Men Who have Sex with Men and Transgender Women in Lima, Peru: a Cross-Sectional Study.}, journal = {AIDS and behavior}, volume = {28}, number = {8}, pages = {2547-2558}, pmid = {38755430}, issn = {1573-3254}, support = {NIH P30 AI027757//Center for AIDS Research, University of Washington/ ; NIH T32 AI07140//University of Washington/ ; K23 MH126781/MH/NIMH NIH HHS/United States ; T32 AI007140/AI/NIAID NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; TL1 TR002318/TR/NCATS NIH HHS/United States ; UL1 TR002319/TR/NCATS NIH HHS/United States ; KL2 TR002317/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; Male ; Peru/epidemiology ; Cross-Sectional Studies ; *HIV Infections/prevention &amp; control/epidemiology/psychology ; *Transgender Persons/psychology/statistics &amp; numerical data ; Adult ; Female ; *Homosexuality, Male/psychology/statistics &amp; numerical data ; *Sexual Partners ; *Mobile Applications ; *Risk-Taking ; *Sexual Behavior/psychology ; Young Adult ; Social Networking ; Adolescent ; Middle Aged ; Surveys and Questionnaires ; Sexual and Gender Minorities/psychology/statistics &amp; numerical data ; }, abstract = {Geosocial networking dating apps (GSN apps) are an increasingly widespread technology used by populations throughout the world to facilitate sexual encounters. Studies from a variety of settings suggest a possible association between GSN app use and HIV risk behaviors, including among sexual and gender minority populations such as men who have sex with men (MSM) and transgender women (TW). However, it remains unclear to what extent GSN apps play a causal role. We explored the relationship between GSN app use and sexual risk behaviors among MSM and TW in Lima, Peru by analyzing data from a multi-site cross-sectional survey assessing both general and partner-specific sexual behaviors. We performed bivariate analysis to estimate the association of GSN app use with different individual and partner-specific factors, then fit multivariable regression models adjusting for age and education. Among 741 total participants (698 MSM, 43 TW), 64% met at least one sex partner in the prior three months using a GSN app. GSN app users were significantly more likely to report engaging in HIV risk behaviors in general, including condomless receptive anal sex, group sex, transactional sex, and sex under the influence of alcohol or drugs. Having condomless anal sex with a given partner was not associated with meeting that partner via GSN app. These findings highlight GSN app users as a particularly vulnerable subpopulation among MSM and TW in Lima. GSN apps could provide a useful vehicle for targeted HIV prevention efforts for priority populations in Peru.}, }
@article {pmid38755171, year = {2024}, author = {Perofsky, AC and Hansen, CL and Burstein, R and Boyle, S and Prentice, R and Marshall, C and Reinhart, D and Capodanno, B and Truong, M and Schwabe-Fry, K and Kuchta, K and Pfau, B and Acker, Z and Lee, J and Sibley, TR and McDermot, E and Rodriguez-Salas, L and Stone, J and Gamboa, L and Han, PD and Adler, A and Waghmare, A and Jackson, ML and Famulare, M and Shendure, J and Bedford, T and Chu, HY and Englund, JA and Starita, LM and Viboud, C}, title = {Impacts of human mobility on the citywide transmission dynamics of 18 respiratory viruses in pre- and post-COVID-19 pandemic years.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {4164}, pmid = {38755171}, issn = {2041-1723}, support = {75D30122C14368//U.S. Department of Health &amp; Human Services | Centers for Disease Control and Prevention (CDC)/ ; }, mesh = {Humans ; *COVID-19/transmission/epidemiology ; *SARS-CoV-2/isolation &amp; purification ; Washington/epidemiology ; Pandemics ; Cities/epidemiology ; Seasons ; Travel/statistics &amp; numerical data ; }, abstract = {Many studies have used mobile device location data to model SARS-CoV-2 dynamics, yet relationships between mobility behavior and endemic respiratory pathogens are less understood. We studied the effects of population mobility on the transmission of 17 endemic viruses and SARS-CoV-2 in Seattle over a 4-year period, 2018-2022. Before 2020, visits to schools and daycares, within-city mixing, and visitor inflow preceded or coincided with seasonal outbreaks of endemic viruses. Pathogen circulation dropped substantially after the initiation of COVID-19 stay-at-home orders in March 2020. During this period, mobility was a positive, leading indicator of transmission of all endemic viruses and lagging and negatively correlated with SARS-CoV-2 activity. Mobility was briefly predictive of SARS-CoV-2 transmission when restrictions relaxed but associations weakened in subsequent waves. The rebound of endemic viruses was heterogeneously timed but exhibited stronger, longer-lasting relationships with mobility than SARS-CoV-2. Overall, mobility is most predictive of respiratory virus transmission during periods of dramatic behavioral change and at the beginning of epidemic waves.}, }
@article {pmid38753751, year = {2024}, author = {Shields, AF and Chen, DL}, title = {Positron Emission Tomography Imaging of Tumor Proliferation and DNA Repair.}, journal = {Cancer journal (Sudbury, Mass.)}, volume = {30}, number = {3}, pages = {170-175}, doi = {10.1097/PPO.0000000000000724}, pmid = {38753751}, issn = {1540-336X}, mesh = {Humans ; *Positron-Emission Tomography/methods ; *DNA Repair ; *Cell Proliferation ; *Neoplasms/diagnostic imaging/pathology/genetics/diagnosis/metabolism ; Fluorodeoxyglucose F18 ; Radiopharmaceuticals ; Molecular Imaging/methods ; }, abstract = {Positron emission tomography (PET) is an established tool for molecular imaging of cancers, and its role in diagnosis, staging, and phenotyping continues to evolve and expand rapidly. PET imaging of increased glucose utilization with 18F-fluorodeoxyglucose is now entrenched in clinical oncology practice for improving prognostication and treatment response assessment. Additional critical processes for cancer cell survival can also be imaged by PET, helping to inform individualized treatment selections for patients by improving our understanding of cell survival mechanisms and identifying relevant active mechanisms in each patient. The critical importance of quantifying cell proliferation and DNA repair pathways for prognosis and treatment selection is highlighted by the nearly ubiquitous use of the Ki-67 index, an established histological quantitative measure of cell proliferation, and BRCA mutation testing for treatment selection. This review focuses on PET advances in imaging and quantifying cell proliferation and poly(ADP-ribose)polymerase expression that can be used to complement cancer phenotyping approaches that will identify the most effective treatments for each individual patient.}, }
@article {pmid38753616, year = {2024}, author = {Pidala, J and Carpenter, PA and Onstad, L and Pavletic, SZ and Hamilton, BK and Chen, GL and Farhadfar, N and Hall, M and Lee, SJ}, title = {Study protocol: Close Assessment and Testing for Chronic Graft-vs.-Host disease (CATCH).}, journal = {PloS one}, volume = {19}, number = {5}, pages = {e0298026}, pmid = {38753616}, issn = {1932-6203}, mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; Biomarkers ; Chronic Disease ; *Graft vs Host Disease/diagnosis/etiology ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Longitudinal Studies ; Prospective Studies ; Transplantation, Homologous ; Multicenter Studies as Topic ; }, abstract = {Chronic graft-versus-host disease (GVHD) is an immune-mediated disorder that causes significant late morbidity and mortality following allogeneic hematopoietic cell transplantation. The "Close Assessment and Testing for Chronic GVHD (CATCH)" study is a multi-center Chronic GVHD Consortium prospective, longitudinal cohort study designed to enroll patients before hematopoietic cell transplantation and follow them closely to capture the development of chronic GVHD and to identify clinical and biologic biomarkers of chronic GVHD onset. Data are collected pre-transplant and every two months through one-year post-transplant with chart review thereafter. Evaluations include clinician assessment of chronic GVHD and its manifestations, patient-reported outcomes, multiple biospecimens (blood, saliva, tears, buccal mucosa and fecal samples, biopsies of skin and mouth), laboratory testing, and medical record abstraction. This report describes the rationale, design, and methods of the CATCH study, and invites collaboration with other investigators to leverage this resource. trial registration: This study is registered at www.clinicaltrials.gov as NCT04188912.}, }
@article {pmid38753606, year = {2024}, author = {Hoffman, AM and Wright, C}, title = {Ten simple rules for teaching an introduction to R.}, journal = {PLoS computational biology}, volume = {20}, number = {5}, pages = {e1012018}, pmid = {38753606}, issn = {1553-7358}, mesh = {*Computational Biology/education ; *Teaching ; Humans ; Software ; }, }
@article {pmid38753445, year = {2024}, author = {Bodansky, A and Yu, DJ and Rallistan, A and Kalaycioglu, M and Boonyaratanakornkit, J and Green, DJ and Gauthier, J and Turtle, CJ and Zorn, K and O'Donovan, B and Mandel-Brehm, C and Asaki, J and Kortbawi, H and Kung, AF and Rackaityte, E and Wang, CY and Saxena, A and de Dios, K and Masi, G and Nowak, RJ and O'Connor, KC and Li, H and Diaz, VE and Saloner, R and Casaletto, KB and Gontrum, EQ and Chan, B and Kramer, JH and Wilson, MR and Utz, PJ and Hill, JA and Jackson, SW and Anderson, MS and DeRisi, JL}, title = {Unveiling the proteome-wide autoreactome enables enhanced evaluation of emerging CAR T cell therapies in autoimmunity.}, journal = {The Journal of clinical investigation}, volume = {134}, number = {13}, pages = {}, pmid = {38753445}, issn = {1558-8238}, support = {U2C TR002818/TR/NCATS NIH HHS/United States ; R21 AI164590/AI/NIAID NIH HHS/United States ; T32 GM141323/GM/NIGMS NIH HHS/United States ; R01 AR073938/AR/NIAMS NIH HHS/United States ; RF1 AG032289/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; R01 AG072475/AG/NIA NIH HHS/United States ; R01 AI114780/AI/NIAID NIH HHS/United States ; R01 AG032289/AG/NIA NIH HHS/United States ; U01 CA247548/CA/NCI NIH HHS/United States ; R21 AI142198/AI/NIAID NIH HHS/United States ; U54 NS115054/NS/NINDS NIH HHS/United States ; R01 AR075813/AR/NIAMS NIH HHS/United States ; K12 HD000850/HD/NICHD NIH HHS/United States ; }, mesh = {Humans ; *Proteome ; *Autoantibodies/immunology ; *Autoimmunity ; Female ; Autoimmune Diseases/immunology/therapy ; Male ; Immunotherapy, Adoptive/methods ; B-Cell Maturation Antigen/immunology/metabolism ; Adult ; Receptors, Chimeric Antigen/immunology/metabolism ; Antigens, CD19/immunology ; Middle Aged ; }, abstract = {Given the global surge in autoimmune diseases, it is critical to evaluate emerging therapeutic interventions. Despite numerous new targeted immunomodulatory therapies, comprehensive approaches to apply and evaluate the effects of these treatments longitudinally are lacking. Here, we leveraged advances in programmable-phage immunoprecipitation methodology to explore the modulation, or lack thereof, of autoantibody profiles, proteome-wide, in both health and disease. Using a custom set of over 730,000 human-derived peptides, we demonstrated that each individual, regardless of disease state, possesses a distinct and complex constellation of autoreactive antibodies. For each individual, the set of resulting autoreactivites constituted a unique immunological fingerprint, or "autoreactome," that was remarkably stable over years. Using the autoreactome as a primary output, we evaluated the relative effectiveness of various immunomodulatory therapies in altering autoantibody repertoires. We found that therapies targeting B cell maturation antigen (BCMA) profoundly altered an individual's autoreactome, while anti-CD19 and anti-CD20 therapies had minimal effects. These data both confirm that the autoreactome comprises autoantibodies secreted by plasma cells and strongly suggest that BCMA or other plasma cell-targeting therapies may be highly effective in treating currently refractory autoantibody-mediated diseases.}, }
@article {pmid38753353, year = {2024}, author = {Banerjee, R and Mikhael, JR}, title = {How can we stamp out high-risk myeloma?.}, journal = {Blood}, volume = {143}, number = {20}, pages = {2015-2016}, doi = {10.1182/blood.2024024140}, pmid = {38753353}, issn = {1528-0020}, mesh = {*Multiple Myeloma/pathology ; Humans ; }, }
@article {pmid38750526, year = {2024}, author = {Han, S and Phasouk, K and Zhu, J and Fong, Y}, title = {Optimizing deep learning-based segmentation of densely packed cells using cell surface markers.}, journal = {BMC medical informatics and decision making}, volume = {24}, number = {1}, pages = {124}, pmid = {38750526}, issn = {1472-6947}, support = {Vaccine and Infectious Diseases Division Faculty Initiative Fund//Fred Hutchinson Cancer Research Center/ ; S10 OD028685/OD/NIH HHS/United States ; U18 TR003208/TR/NCATS NIH HHS/United States ; AI143773, S10OD028685/NH/NIH HHS/United States ; R01 AI143773/AI/NIAID NIH HHS/United States ; }, mesh = {*Deep Learning ; Humans ; Image Processing, Computer-Assisted/methods ; Herpes Simplex ; Skin/diagnostic imaging ; Biomarkers ; }, abstract = {BACKGROUND: Spatial molecular profiling depends on accurate cell segmentation. Identification and quantitation of individual cells in dense tissues, e.g. highly inflamed tissue caused by viral infection or immune reaction, remains a challenge.<br><br>METHODS: We first assess the performance of 18 deep learning-based cell segmentation models, either pre-trained or trained by us using two public image sets, on a set of immunofluorescence images stained with immune cell surface markers in skin tissue obtained during human herpes simplex virus (HSV) infection. We then further train eight of these models using up to 10,000+ training instances from the current image set. Finally, we seek to improve performance by tuning parameters of the most successful method from the previous step.<br><br>RESULTS: The best model before fine-tuning achieves a mean Average Precision (mAP) of 0.516. Prediction performance improves substantially after training. The best model is the cyto model from Cellpose. After training, it achieves an mAP of 0.694; with further parameter tuning, the mAP reaches 0.711.<br><br>CONCLUSION: Selecting the best model among the existing approaches and further training the model with images of interest produce the most gain in prediction performance. The performance of the resulting model compares favorably to human performance. The imperfection of the final model performance can be attributed to the moderate signal-to-noise ratio in the imageset.}, }
@article {pmid38750138, year = {2024}, author = {Wang, TP and Ahn, KW and Shadman, M and Kaur, M and Ahmed, N and Bacher, U and Cerny, J and Chen, A and Epperla, N and Frigault, M and Grover, N and Haverkos, B and Hill, B and Hossain, N and Iqbal, M and Jain, T and Krem, MM and Maakaron, J and Modi, D and Alhaj Moustafa, M and Riedell, P and Savani, B and Sica, RA and Sureda, A and Wudhikarn, K and Herrera, AF and Sauter, C and Hamadani, M and Jimenez Jimenez, A}, title = {Chimeric antigen receptor T-cell infusion for large B-cell lymphoma in complete remission: a center for international blood and marrow transplant research analysis.}, journal = {Leukemia}, volume = {38}, number = {7}, pages = {1564-1569}, pmid = {38750138}, issn = {1476-5551}, support = {K12 CA226330/CA/NCI NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; Middle Aged ; Female ; *Immunotherapy, Adoptive/methods/adverse effects ; Adult ; Aged ; *Remission Induction ; *Lymphoma, Large B-Cell, Diffuse/therapy/immunology ; Young Adult ; Receptors, Chimeric Antigen/immunology ; Survival Rate ; Follow-Up Studies ; Antigens, CD19/immunology ; Pathologic Complete Response ; }, abstract = {CD19 CAR T-cell (CAR-T) therapy is commonly administered to patients with relapsed or refractory large B-cell lymphomas (LBCL), but salvage or bridging therapy can sometimes lead to a complete response (CR) prior to infusion. Limited studies have assessed the outcomes of patients infused in CR. A total of 134 patients with LBCL in CR prior to CAR-T infusion were identified from the CIBMTR registry, with median prior lines of therapy of 3 (range 2-9). At two years post-infusion, the probability of progression-free survival was 43.5% (95% CI 34.4-52.8) and the probability of overall survival was 63.8% (95% CI 54.4-72.6). The cumulative incidence rates of non-relapse mortality and relapse/progression at two years were 9.2% (95% CI 4.5-15.4) and 47.3% (95% CI 38.2-56.6), respectively. The rate of grade 3 or higher cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were 2.2% and 8.2%, respectively. In summary, CAR-T in heavily pretreated patients with LBCL who are in CR following two or more lines of prior therapy demonstrate that a subset of patients may remain free of progression at two years. Additionally, the toxicity profile was impressive with very low rates of grade 3 CRS and ICANS.}, }
@article {pmid38749303, year = {2024}, author = {Papadimitriou, N and Kim, A and Kawaguchi, ES and Morrison, J and Diez-Obrero, V and Albanes, D and Berndt, SI and Bézieau, S and Bien, SA and Bishop, DT and Bouras, E and Brenner, H and Buchanan, DD and Campbell, PT and Carreras-Torres, R and Chan, AT and Chang-Claude, J and Conti, DV and Devall, MA and Dimou, N and Drew, DA and Gruber, SB and Harrison, TA and Hoffmeister, M and Huyghe, JR and Joshi, AD and Keku, TO and Kundaje, A and Küry, S and Le Marchand, L and Lewinger, JP and Li, L and Lynch, BM and Moreno, V and Newton, CC and Obón-Santacana, M and Ose, J and Pellatt, AJ and Peoples, AR and Platz, EA and Qu, C and Rennert, G and Ruiz-Narvaez, E and Shcherbina, A and Stern, MC and Su, YR and Thomas, DC and Thomas, CE and Tian, Y and Tsilidis, KK and Ulrich, CM and Um, CY and Visvanathan, K and Wang, J and White, E and Woods, MO and Schmit, SL and Macrae, F and Potter, JD and Hopper, JL and Peters, U and Murphy, N and Hsu, L and Gunter, MJ and Gauderman, WJ}, title = {Genome-wide interaction study of dietary intake of fibre, fruits, and vegetables with risk of colorectal cancer.}, journal = {EBioMedicine}, volume = {104}, number = {}, pages = {105146}, pmid = {38749303}, issn = {2352-3964}, support = {U01 CA206110/CA/NCI NIH HHS/United States ; U01 CA272529/CA/NCI NIH HHS/United States ; R01 CA263318/CA/NCI NIH HHS/United States ; P01 CA196569/CA/NCI NIH HHS/United States ; 001/WHO_/World Health Organization/International ; }, mesh = {Humans ; *Fruit ; *Colorectal Neoplasms/genetics/etiology ; *Dietary Fiber/administration &amp; dosage ; *Vegetables ; *Genome-Wide Association Study ; *Polymorphism, Single Nucleotide ; *Genetic Predisposition to Disease ; *Gene-Environment Interaction ; Genotype ; Diet ; Male ; Female ; Risk Factors ; }, abstract = {BACKGROUND: Consumption of fibre, fruits and vegetables have been linked with lower colorectal cancer (CRC) risk. A genome-wide gene-environment (G × E) analysis was performed to test whether genetic variants modify these associations.<br><br>METHODS: A pooled sample of 45 studies including up to 69,734 participants (cases: 29,896; controls: 39,838) of European ancestry were included. To identify G&#xa0;&#xd7;&#xa0;E interactions, we used the traditional 1--degree-of-freedom (DF) G&#xa0;&#xd7;&#xa0;E test and to improve power a 2-step procedure and a 3DF joint test that investigates the association between a genetic variant and dietary exposure, CRC risk and G&#xa0;&#xd7;&#xa0;E interaction simultaneously.<br><br>FINDINGS: The 3-DF joint test revealed two significant loci with p-value <5&#xa0;&#xd7;&#xa0;10[-8]. Rs4730274 close to the SLC26A3 gene showed an association with fibre (p-value: 2.4&#xa0;&#xd7;&#xa0;10[-3]) and G&#xa0;&#xd7;&#xa0;fibre interaction with CRC (OR per quartile of fibre increase&#xa0;=&#xa0;0.87, 0.80, and 0.75 for CC, TC, and TT genotype, respectively; G&#xa0;&#xd7;&#xa0;E p-value: 1.8&#xa0;&#xd7;&#xa0;10[-7]). Rs1620977 in the NEGR1 gene showed an association with fruit intake (p-value: 1.0&#xa0;&#xd7;&#xa0;10[-8]) and G&#xa0;&#xd7;&#xa0;fruit interaction with CRC (OR per quartile of fruit increase&#xa0;=&#xa0;0.75, 0.65, and 0.56 for AA, AG, and GG genotype, respectively; G&#xa0;&#xd7;&#xa0;E -p-value: 0.029).<br><br>INTERPRETATION: We identified 2 loci associated with fibre and fruit intake that also modify the association of these dietary factors with CRC risk. Potential mechanisms include chronic inflammatory intestinal disorders, and gut function. However, further studies are needed for mechanistic validation and replication of findings.<br><br>FUNDING: National Institutes of Health, National Cancer Institute. Full funding details for the individual consortia are provided in acknowledgments.}, }
@article {pmid38749027, year = {2024}, author = {Di, M and Su, CT and Cowan, AJ and Gopal, AK and Banerjee, R}, title = {Mitigating time toxicity in lymphoma and multiple myeloma.}, journal = {Leukemia &amp; lymphoma}, volume = {65}, number = {10}, pages = {1418-1429}, doi = {10.1080/10428194.2024.2352086}, pmid = {38749027}, issn = {1029-2403}, mesh = {Humans ; *Multiple Myeloma/therapy/drug therapy ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Disease Management ; Lymphoma/therapy/diagnosis/etiology/drug therapy ; Time Factors ; Drug-Related Side Effects and Adverse Reactions/diagnosis/etiology ; Immunotherapy, Adoptive/adverse effects/methods ; }, abstract = {The concept of time toxicity in oncology refers to the presence of frequent healthcare-related interactions that can interfere with patient well-being. In this review, we examine several manifestations of time toxicity in non-Hodgkin lymphoma and multiple myeloma and discuss their impact on decision-making with patients. For example, time toxicity may influence the choice of chemoimmunotherapy versus lenalidomide-rituximab in follicular lymphoma. In myeloma, it may inform the optimal dosing schedule for proteasome inhibitors and bisphosphonates. In both malignancies, varying time toxicity profiles are a key distinction between chimeric antigen receptor T-cell therapies and bispecific antibodies. We outline the challenges with measuring time toxicity as a trial endpoint but discuss its importance as a consideration for patient care, both in standard-of-care settings and in clinical trials. Throughout the review, we highlight strategies to lower the time toxicity of therapies in lymphoma and myeloma without compromising their efficacy or patient safety.}, }
@article {pmid38748943, year = {2024}, author = {Harris, HR and Davis, CP and Terry, KL}, title = {Epidemiologic Methods to Advance Our Understanding of Ovarian Cancer Risk.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {42}, number = {22}, pages = {2619-2621}, doi = {10.1200/JCO.24.00602}, pmid = {38748943}, issn = {1527-7755}, mesh = {Humans ; *Ovarian Neoplasms/epidemiology ; Female ; Risk Factors ; Risk Assessment ; }, }
@article {pmid38748774, year = {2024}, author = {Luk, IS and Bridgwater, CM and Yu, A and Boila, LD and Yáñez-Bartolomé, M and Lampano, AE and Hulahan, TS and Boukhali, M and Kathiresan, M and Macarulla, T and Kenerson, HL and Yamamoto, N and Sokolov, D and Engstrom, IA and Sullivan, LB and Lampe, PD and Cooper, JA and Yeung, RS and Tian, TV and Haas, W and Saha, SK and Kugel, S}, title = {SRC inhibition enables formation of a growth suppressive MAGI1-PP2A complex in isocitrate dehydrogenase-mutant cholangiocarcinoma.}, journal = {Science translational medicine}, volume = {16}, number = {747}, pages = {eadj7685}, pmid = {38748774}, issn = {1946-6242}, support = {R37 CA241472/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; K08 CA194268/CA/NCI NIH HHS/United States ; R01 CA255015/CA/NCI NIH HHS/United States ; R21 CA231486/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Adaptor Proteins, Signal Transducing/metabolism ; Bile Duct Neoplasms/pathology/metabolism/genetics/drug therapy ; Cell Adhesion Molecules/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; *Cholangiocarcinoma/drug therapy/pathology/metabolism/genetics ; *Dasatinib/pharmacology ; *Isocitrate Dehydrogenase/metabolism/genetics ; *Mutation/genetics ; Phosphorylation/drug effects ; Ribosomal Protein S6 Kinases, 70-kDa/metabolism ; Signal Transduction/drug effects ; *src-Family Kinases/metabolism/antagonists &amp; inhibitors ; Guanylate Kinases/genetics/metabolism ; Protein Phosphatase 2/genetics/metabolism ; }, abstract = {Intrahepatic cholangiocarcinoma (ICC) is an aggressive bile duct malignancy that frequently exhibits isocitrate dehydrogenase (IDH1/IDH2) mutations. Mutant IDH (IDHm) ICC is dependent on SRC kinase for growth and survival and is hypersensitive to inhibition by dasatinib, but the molecular mechanism underlying this sensitivity is unclear. We found that dasatinib reduced p70 S6 kinase (S6K) and ribosomal protein S6 (S6), leading to substantial reductions in cell size and de novo protein synthesis. Using an unbiased phosphoproteomic screen, we identified membrane-associated guanylate kinase, WW, and PDZ domain containing 1 (MAGI1) as an SRC substrate in IDHm ICC. Biochemical and functional assays further showed that SRC inhibits a latent tumor-suppressing function of the MAGI1-protein phosphatase 2A (PP2A) complex to activate S6K/S6 signaling in IDHm ICC. Inhibiting SRC led to activation and increased access of PP2A to dephosphorylate S6K, resulting in cell death. Evidence from patient tissue and cell line models revealed that both intrinsic and extrinsic resistance to dasatinib is due to increased phospho-S6 (pS6). To block pS6, we paired dasatinib with the S6K/AKT inhibitor M2698, which led to a marked reduction in pS6 in IDHm ICC cell lines and patient-derived organoids in vitro and substantial growth inhibition in ICC patient-derived xenografts in vivo. Together, these results elucidated the mechanism of action of dasatinib in IDHm ICC, revealed a signaling complex regulating S6K phosphorylation independent of mTOR, suggested markers for dasatinib sensitivity, and described a combination therapy for IDHm ICC that may be actionable in the clinic.}, }
@article {pmid38747556, year = {2024}, author = {Jiang, MZ and Gaynor, SM and Li, X and Van Buren, E and Stilp, A and Buth, E and Wang, FF and Manansala, R and Gogarten, SM and Li, Z and Polfus, LM and Salimi, S and Bis, JC and Pankratz, N and Yanek, LR and Durda, P and Tracy, RP and Rich, SS and Rotter, JI and Mitchell, BD and Lewis, JP and Psaty, BM and Pratte, KA and Silverman, EK and Kaplan, RC and Avery, C and North, KE and Mathias, RA and Faraday, N and Lin, H and Wang, B and Carson, AP and Norwood, AF and Gibbs, RA and Kooperberg, C and Lundin, J and Peters, U and Dupuis, J and Hou, L and Fornage, M and Benjamin, EJ and Reiner, AP and Bowler, RP and Lin, X and Auer, PL and Raffield, LM and , }, title = {Whole genome sequencing based analysis of inflammation biomarkers in the Trans-Omics for Precision Medicine (TOPMed) consortium.}, journal = {Human molecular genetics}, volume = {33}, number = {16}, pages = {1429-1441}, pmid = {38747556}, issn = {1460-2083}, support = {OT3 HL142478/HL/NHLBI NIH HHS/United States ; U01 AG068221/AG/NIA NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; //NHGRI/ ; U01 HG012064/HG/NHGRI NIH HHS/United States ; R01 HL092577/HL/NHLBI NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; OT3 HL142480/HL/NHLBI NIH HHS/United States ; KL2 TR002490/TR/NCATS NIH HHS/United States ; /NH/NIH HHS/United States ; //NIMH/ ; R01 HG010297/HG/NHGRI NIH HHS/United States ; //NHLBI BioData Catalyst Fellowship/ ; //NHLBI/ ; 1OT3HL142479-01//BioData Catalyst/ ; R01HL163560/HB/NHLBI NIH HHS/United States ; R01 HL076784/HL/NHLBI NIH HHS/United States ; OT3 HL142481/HL/NHLBI NIH HHS/United States ; R01 HL163560/HL/NHLBI NIH HHS/United States ; //NINDS/ ; KL2TR002490/NH/NIH HHS/United States ; OT3 HL147154/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; //NIDA/ ; 75N92019D00031/HL/NHLBI NIH HHS/United States ; OT3 HL142479/HL/NHLBI NIH HHS/United States ; //NCI/ ; //NHLBI TOPMed Fellowship/ ; U01 HG009088/HG/NHGRI NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; R01 AG028321/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Precision Medicine/methods ; *Biomarkers ; *Inflammation/genetics ; *Genome-Wide Association Study/methods ; *Whole Genome Sequencing/methods ; Polymorphism, Single Nucleotide ; Quantitative Trait Loci ; Genetic Predisposition to Disease ; Female ; Interleukin-6/genetics ; }, abstract = {Inflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38 465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program (with varying sample size by trait, where the minimum sample size was n = 737 for MMP-1). We identified 22 distinct single-variant associations across 6 traits-E-selectin, intercellular adhesion molecule 1, interleukin-6, lipoprotein-associated phospholipase A2 activity and mass, and P-selectin-that remained significant after conditioning on previously identified associations for these inflammatory biomarkers. We further expanded upon known biomarker associations by pairing the single-variant analysis with a rare variant set-based analysis that further identified 19 significant rare variant set-based associations with 5 traits. These signals were distinct from both significant single variant association signals within TOPMed and genetic signals observed in prior studies, demonstrating the complementary value of performing both single and rare variant analyses when analyzing quantitative traits. We also confirm several previously reported signals from semi-quantitative proteomics platforms. Many of these signals demonstrate the extensive allelic heterogeneity and ancestry-differentiated variant-trait associations common for inflammation biomarkers, a characteristic we hypothesize will be increasingly observed with well-powered, large-scale analyses of complex traits.}, }
@article {pmid38747505, year = {2024}, author = {Mo, G and Lee, SY and Coffey, DG and Voillet, V and Kirsch, IR and Gottardo, R and Smythe, KS and Yeung, CCS and Greenbaum, A and Green, DJ and Maloney, DG and Till, BG}, title = {Long-term Remissions Following CD20-Directed Chimeric Antigen Receptor-Adoptive T-cell Therapy.}, journal = {Blood cancer discovery}, volume = {5}, number = {4}, pages = {258-266}, pmid = {38747505}, issn = {2643-3249}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; //Fred Hutchinson Cancer Center (FHCRC)/ ; //David and Patricia Giuliani Family Foundation/ ; //Damon Runyon Cancer Research Foundation (DRCRF)/ ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Antigens, CD20/immunology ; *Receptors, Chimeric Antigen/immunology ; *Immunotherapy, Adoptive/methods ; Middle Aged ; Male ; *Remission Induction ; Female ; Aged ; Lymphoma, Follicular/therapy/immunology ; Pilot Projects ; T-Lymphocytes/immunology/transplantation ; Treatment Outcome ; }, abstract = {Chimeric antigen receptor (CAR) T-cell therapy produces high response rates in refractory B-cell non-Hodgkin lymphoma, but long-term data are minimal to date. In this study, we present long-term follow-up of a pilot trial testing a CD20-targeting third-generation CAR in patients with relapsed B-cell lymphomas following cyclophosphamide-only lymphodepletion. Two of the three patients in the trial, with mantle cell lymphoma and follicular lymphoma, had remissions lasting more than 7 years, though they ultimately relapsed. The absence of B-cell aplasia in both patients suggested a lack of functional CAR T-cell persistence, leading to the hypothesis that endogenous immune responses were responsible for these long-term remissions. Correlative immunologic analyses supported this hypothesis, with evidence of new humoral and cellular antitumor immune responses proximal to clinical response time points. Collectively, our results suggest that CAR T-cell therapy may facilitate epitope spreading and endogenous immune response formation in lymphomas. Significance: Two of three patients treated with CD20-targeted CAR T-cell therapy had long-term remissions, with evidence of endogenous antitumor immune response formation. Further investigation is warranted to develop conditions that promote epitope spreading in lymphomas.}, }
@article {pmid38746451, year = {2024}, author = {Snedeker, J and Davis, BEM and Ranjan, R and Wooten, M and Blundon, J and Chen, X}, title = {Reduced Levels of Lagging Strand Polymerases Shape Stem Cell Chromatin.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38746451}, issn = {2692-8205}, support = {T32 GM007231/GM/NIGMS NIH HHS/United States ; R01 HD102474/HD/NICHD NIH HHS/United States ; F31 GM115149/GM/NIGMS NIH HHS/United States ; F31 HD104526/HD/NICHD NIH HHS/United States ; R35 GM127075/GM/NIGMS NIH HHS/United States ; T32 GM141804/GM/NIGMS NIH HHS/United States ; }, abstract = {Stem cells display asymmetric histone inheritance while non-stem progenitor cells exhibit symmetric patterns in the Drosophila male germline lineage. Here, we report that components involved in lagging strand synthesis, such as DNA polymerase α and δ (Polα and Polδ), have significantly reduced levels in stem cells compared to progenitor cells. Compromising Polα genetically induces the replication-coupled histone incorporation pattern in progenitor cells to be indistinguishable from that in stem cells, which can be recapitulated using a Polα inhibitor in a concentration-dependent manner. Furthermore, stem cell-derived chromatin fibers display a higher degree of old histone recycling by the leading strand compared to progenitor cell-derived chromatin fibers. However, upon reducing Polα levels in progenitor cells, the chromatin fibers now display asymmetric old histone recycling just like GSC-derived fibers. The old versus new histone asymmetry is comparable between stem cells and progenitor cells at both S-phase and M-phase. Together, these results indicate that developmentally programmed expression of key DNA replication components is important to shape stem cell chromatin. Furthermore, manipulating one crucial DNA replication component can induce replication-coupled histone dynamics in non-stem cells in a manner similar to that in stem cells.}, }
@article {pmid38746248, year = {2024}, author = {Simon, S and Bugos, G and Prins, R and Rajan, A and Palani, A and Heyer, K and Stevens, A and Zeng, L and Thompson, K and Price, JP and Kluesner, MK and Jaeger-Ruckstuhl, C and Shabaneh, TB and Olson, JM and Su, X and Riddell, SR}, title = {Sensitive bispecific chimeric T cell receptors for cancer therapy.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {38746248}, issn = {2693-5015}, support = {P01 CA018029/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA114536/CA/NCI NIH HHS/United States ; R21 CA286364/CA/NCI NIH HHS/United States ; }, abstract = {The expression of a synthetic chimeric antigen receptor (CAR) to redirect antigen specificity of T cells is transforming the treatment of hematological malignancies and autoimmune diseases [1-7]. In cancer, durable efficacy is frequently limited by the escape of tumors that express low levels or lack the target antigen [8-12]. These clinical results emphasize the need for immune receptors that combine high sensitivity and multispecificity to improve outcomes. Current mono- and bispecific CARs do not faithfully recapitulate T cell receptor (TCR) function and require high antigen levels on tumor cells for recognition [13-17]. Here, we describe a novel synthetic chimeric TCR (ChTCR) that exhibits superior antigen sensitivity and is readily adapted for bispecific targeting. Bispecific ChTCRs mimic TCR structure, form classical immune synapses, and exhibit TCR-like proximal signaling. T cells expressing Bi-ChTCRs more effectively eliminated tumors with heterogeneous antigen expression in vivo compared to T cells expressing optimized bispecific CARs. The Bi-ChTCR architecture is resilient and can be designed to target multiple B cell lineage and multiple myeloma antigens. Our findings identify a broadly applicable approach for engineering T cells to target hematologic malignancies with heterogeneous antigen expression, thereby overcoming the most frequent mechanism of relapse after current CAR T therapies.}, }
@article {pmid38744973, year = {2024}, author = {Zhou, T and Zhang, R and Jia, D and Doty, RT and Munday, AD and Gao, D and Xin, L and Abkowitz, JL and Duan, Z and Ma, J}, title = {GAGE-seq concurrently profiles multiscale 3D genome organization and gene expression in single cells.}, journal = {Nature genetics}, volume = {56}, number = {8}, pages = {1701-1711}, pmid = {38744973}, issn = {1546-1718}, support = {R01 HG007352/HG/NHGRI NIH HHS/United States ; UG3 CA268202/CA/NCI NIH HHS/United States ; R01HG012303//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; UM1 HG011593/HG/NHGRI NIH HHS/United States ; R01 HG012303/HG/NHGRI NIH HHS/United States ; R61 DA047010/DA/NIDA NIH HHS/United States ; UM1 HG011586/HG/NHGRI NIH HHS/United States ; }, mesh = {*Single-Cell Analysis/methods ; Animals ; Humans ; Mice ; Genome/genetics ; Transcriptome ; Gene Expression Profiling/methods ; Hematopoiesis/genetics ; }, abstract = {The organization of mammalian genomes features a complex, multiscale three-dimensional (3D) architecture, whose functional significance remains elusive because of limited single-cell technologies that can concurrently profile genome organization and transcriptional activities. Here, we introduce genome architecture and gene expression by sequencing (GAGE-seq), a scalable, robust single-cell co-assay measuring 3D genome structure and transcriptome simultaneously within the same cell. Applied to mouse brain cortex and human bone marrow CD34[+] cells, GAGE-seq characterized the intricate relationships between 3D genome and gene expression, showing that multiscale 3D genome features inform cell-type-specific gene expression and link regulatory elements to target genes. Integration with spatial transcriptomic data revealed in situ 3D genome variations in mouse cortex. Observations in human hematopoiesis unveiled discordant changes between 3D genome organization and gene expression, underscoring a complex, temporal interplay at the single-cell level. GAGE-seq provides a powerful, cost-effective approach for exploring genome structure and gene expression relationships at the single-cell level across diverse biological contexts.}, }
@article {pmid38743457, year = {2024}, author = {Boonyaratanakornkit, J and Wang, Q and Nader, A and Kimball, L and Stevens-Ayers, T and Levkova, M and Blazevic, R and Nguyen, J and Wright, J and Castor, J and Greninger, AL and Ford, E and Mielcarek, M and Fordred, S and Han, J and Boeckh, M and Waghmare, A}, title = {The Effect of Gastrointestinal Graft-Versus-Host Disease and Diarrhea on the Pharmacokinetic Profile of Sotrovimab in Hematopoietic Stem Cell Transplant Recipients.}, journal = {The Journal of infectious diseases}, volume = {230}, number = {3}, pages = {670-679}, doi = {10.1093/infdis/jiae236}, pmid = {38743457}, issn = {1537-6613}, support = {//American Society for Transplantation and Cellular Therapy/ ; //National Marrow Donor Program/ ; //GSK/ ; //Vir Biotechnology/ ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects ; *Graft vs Host Disease/drug therapy ; Male ; Female ; Middle Aged ; *Diarrhea/drug therapy ; Adult ; *Antibodies, Monoclonal, Humanized/pharmacokinetics/therapeutic use/administration &amp; dosage ; Aged ; SARS-CoV-2/immunology ; COVID-19 Drug Treatment ; Transplant Recipients ; COVID-19 ; }, abstract = {BACKGROUND: Monoclonal antibodies (mAbs) are utilized broadly to treat cancer and infectious diseases, and mAb exposure (serum concentration over time) is one predictor of overall treatment efficacy. Herein, we present findings from a clinical trial evaluating the pharmacokinetics of the long-acting mAb sotrovimab targeting severe acute respiratory syndrome coronavirus 2 in hematopoietic cell transplant (HCT) recipients.<br><br>METHODS: All participants received an intravenous infusion of sotrovimab within 1 week prior to initiating the pretransplant preparative regimen. The serum concentration of sotrovimab was measured longitudinally for up to 24 weeks posttransplant.<br><br>RESULTS: Compared to non-HCT participants, we found that mAb clearance was 10% and 26% higher in autologous and allogeneic HCT recipients, respectively. Overall sotrovimab exposure was approximately 15% lower in HCT recipients compared to non-HCT recipients. Exposure was significantly reduced in HCT recipients who developed diarrhea and lower gastrointestinal graft-versus-host disease (GVHD) posttransplant.<br><br>CONCLUSIONS: These data show that sotrovimab exposure may be reduced in HCT recipients, possibly related to increased gastrointestinal clearance in patients with GVHD. This phenomenon has implications for dose selection and duration of efficacy with sotrovimab and potentially other mAbs in this vulnerable patient population. Thus, mAb dose regimens developed in non-HCT populations may have to be optimized when applied to HCT populations.}, }
@article {pmid38742743, year = {2024}, author = {Epplein, M and McCall, SJ and Wang, F and Alagesan, P and Brown, H and Wawrzynski, J and Labriola, C and Zuzul, R and Cook, C and Dillon, M and Hyslop, T and Patierno, SR and Salama, NR and Garman, KS}, title = {Prevalence of the cagA Virulence Factor Varies by Race Among Helicobacter pylori -Infected Patients Undergoing Upper Endoscopy.}, journal = {Clinical and translational gastroenterology}, volume = {15}, number = {6}, pages = {e1}, pmid = {38742743}, issn = {2155-384X}, support = {R01 DK135169/GF/NIH HHS/United States ; DK135169/DK/NIDDK NIH HHS/United States ; P20 CA251657/GF/NIH HHS/United States ; P30 CA014236/GF/NIH HHS/United States ; P20 CA251657/CA/NCI NIH HHS/United States ; R01 DK135169/DK/NIDDK NIH HHS/United States ; P30 CA014236/CA/NCI NIH HHS/United States ; CA251657/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Antigens, Bacterial/analysis ; *Bacterial Proteins ; Black or African American/statistics &amp; numerical data ; Gastric Mucosa/microbiology/pathology ; *Helicobacter Infections/diagnosis/epidemiology/microbiology ; *Helicobacter pylori/isolation &amp; purification ; Prevalence ; Retrospective Studies ; Stomach Neoplasms/microbiology/epidemiology ; *Virulence Factors/analysis ; White People/statistics &amp; numerical data ; }, abstract = {INTRODUCTION: We designed a race-conscious study to assess the presence of Helicobacter pylori v irulence factor cagA in a retrospective cohort of patients with active H. pylori infection.<br><br>METHODS: We compared cagA status by race in gastric tissue samples from 473 patients diagnosed with active H. pylori infection from 2015 to 2019.<br><br>RESULTS: H. pylori + Black patients were 2 times more likely to be cagA + than H. pylori + White patients (82% vs 36%, P < .0001).<br><br>DISCUSSION: Presence of cagA is common among endoscopy patients with active H. pylori infection; appropriate testing and treatment of H. pylori can both reduce gastric cancer risk and address health disparities.}, }
@article {pmid38741226, year = {2024}, author = {Kirchhoff, AC and Waters, AR and Liu, Q and Ji, X and Yasui, Y and Yabroff, KR and Conti, RM and Huang, IC and Henderson, T and Leisenring, WM and Armstrong, GT and Nathan, PC and Park, ER}, title = {Health insurance among survivors of childhood cancer following Affordable Care Act implementation.}, journal = {Journal of the National Cancer Institute}, volume = {116}, number = {9}, pages = {1466-1478}, pmid = {38741226}, issn = {1460-2105}, support = {P30 CA021765/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; CA55727/CA/NCI NIH HHS/United States ; //St Jude Children's Research Hospital/ ; CA21765//Cancer Center Support/ ; //American Lebanese-Syrian Associated Charities/ ; //Huntsman Cancer Foundation/ ; //National Cancer Institute's/ ; //National Research Service/ ; //Lineberger Comprehensive Cancer Center/ ; T32 CA116339/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Patient Protection and Affordable Care Act ; *Cancer Survivors/statistics &amp; numerical data ; Female ; Male ; United States/epidemiology ; *Insurance Coverage/statistics &amp; numerical data ; Adult ; *Insurance, Health/statistics &amp; numerical data ; *Neoplasms/therapy/economics/epidemiology ; Cross-Sectional Studies ; Adolescent ; Child ; Young Adult ; Medicaid/statistics &amp; numerical data ; Siblings ; Medically Uninsured/statistics &amp; numerical data ; Middle Aged ; }, abstract = {BACKGROUND: The Affordable Care Act (ACA) increased private nonemployer health insurance options, expanded Medicaid eligibility, and provided preexisting health condition protections. We evaluated insurance coverage among long-term adult survivors of childhood cancer pre- and post-ACA implementation.<br><br>METHODS: Using the multicenter Childhood Cancer Survivor Study, we included participants from 2 cross-sectional surveys: pre-ACA (2007-2009; survivors: n&#x2009;=&#x2009;7505; siblings: n&#x2009;=&#x2009;2175) and post-ACA (2017-2019; survivors: n&#x2009;=&#x2009;4030; siblings: n&#x2009;=&#x2009;987). A subset completed both surveys (1840 survivors; 646 siblings). Multivariable regression models compared post-ACA insurance coverage and type (private, public, uninsured) between survivors and siblings and identified associated demographic and clinical factors. Multinomial models compared gaining and losing insurance vs staying the same among survivors and siblings who participated in both surveys.<br><br>RESULTS: The proportion with insurance was higher post-ACA (survivors pre-ACA 89.1% to post-ACA 92.0% [+2.9%]; siblings pre-ACA 90.9% to post-ACA 95.3% [+4.4%]). Post-ACA insurance increase in coverage was higher among those aged 18-25 years (survivors: +15.8% vs +2.3% or less ages 26 years and older; siblings +17.8% vs +4.2% or less ages 26 years and older). Survivors were more likely to have public insurance than siblings post-ACA (18.4% vs 6.9%; odds ratio [OR]&#x2009;=&#x2009;1.7, 95% confidence interval [CI] = 1.1 to 2.6). Survivors with severe chronic conditions (OR&#x2009;=&#x2009;4.7, 95% CI = 3.0 to 7.3) and those living in Medicaid expansion states (OR&#x2009;=&#x2009;2.4, 95% CI = 1.7 to 3.4) had increased odds of public insurance coverage post-ACA. Among the subset completing both surveys, low- and mid-income survivors (<$40 000 and <$60&#x200a;000, respectively) experienced insurance losses and gains in reference to highest household income survivors (&#x2265;$100&#x200a;000), relative to odds of keeping the same insurance status.<br><br>CONCLUSIONS: Post-ACA, more childhood cancer survivors and siblings had health insurance, although disparities remain in coverage.}, }
@article {pmid38741126, year = {2024}, author = {Blanco-Melo, D and Campbell, MA and Zhu, H and Dennis, TPW and Modha, S and Lytras, S and Hughes, J and Gatseva, A and Gifford, RJ}, title = {A novel approach to exploring the dark genome and its application to mapping of the vertebrate virus fossil record.}, journal = {Genome biology}, volume = {25}, number = {1}, pages = {120}, pmid = {38741126}, issn = {1474-760X}, support = {MC_UU_12014/12/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; *Vertebrates/genetics/virology ; *Genome ; *Fossils ; *Phylogeny ; Evolution, Molecular ; Humans ; Gene Transfer, Horizontal ; Viruses/genetics ; Genomics/methods ; Endogenous Retroviruses/genetics ; DNA Transposable Elements ; }, abstract = {BACKGROUND: Genomic regions that remain poorly understood, often referred to as the dark genome, contain a variety of functionally relevant and biologically informative features. These include endogenous viral elements (EVEs)-virus-derived sequences that can dramatically impact host biology and serve as a virus fossil record. In this study, we introduce a database-integrated genome screening (DIGS) approach to investigate the dark genome in silico, focusing on EVEs found within vertebrate genomes.<br><br>RESULTS: Using DIGS on 874 vertebrate genomes, we uncover approximately 1.1 million EVE sequences, with over 99% originating from endogenous retroviruses or transposable elements that contain EVE DNA. We show that the remaining 6038 sequences represent over a thousand distinct horizontal gene transfer events across 10 virus families, including some that have not previously been reported as EVEs. We explore the genomic and phylogenetic characteristics of non-retroviral EVEs and determine their rates of acquisition during vertebrate evolution. Our study uncovers novel virus diversity, broadens knowledge of virus distribution among vertebrate hosts, and provides new insights into the ecology and evolution of vertebrate viruses.<br><br>CONCLUSIONS: We comprehensively catalog and analyze EVEs within 874 vertebrate genomes, shedding light on the distribution, diversity, and long-term evolution of viruses and reveal their extensive impact on vertebrate genome evolution. Our results demonstrate the power of linking a relational database management system to a similarity search-based screening pipeline for in silico exploration of the dark genome.}, }
@article {pmid38741014, year = {2024}, author = {Jia, G and Ping, J and Guo, X and Yang, Y and Tao, R and Li, B and Ambs, S and Barnard, ME and Chen, Y and Garcia-Closas, M and Gu, J and Hu, JJ and Huo, D and John, EM and Li, CI and Li, JL and Nathanson, KL and Nemesure, B and Olopade, OI and Pal, T and Press, MF and Sanderson, M and Sandler, DP and Shu, XO and Troester, MA and Yao, S and Adejumo, PO and Ahearn, T and Brewster, AM and Hennis, AJM and Makumbi, T and Ndom, P and O'Brien, KM and Olshan, AF and Oluwasanu, MM and Reid, S and Butler, EN and Huang, M and Ntekim, A and Qian, H and Zhang, H and Ambrosone, CB and Cai, Q and Long, J and Palmer, JR and Haiman, CA and Zheng, W}, title = {Genome-wide association analyses of breast cancer in women of African ancestry identify new susceptibility loci and improve risk prediction.}, journal = {Nature genetics}, volume = {56}, number = {5}, pages = {819-826}, pmid = {38741014}, issn = {1546-1718}, support = {P30 ES010126/ES/NIEHS NIH HHS/United States ; U01 CA164974/CA/NCI NIH HHS/United States ; R01 CA235553/CA/NCI NIH HHS/United States ; T32 GM150375/GM/NIGMS NIH HHS/United States ; P20 CA233307/CA/NCI NIH HHS/United States ; R01 CA242929/CA/NCI NIH HHS/United States ; R01 MD013452/MD/NIMHD NIH HHS/United States ; P30 CA068485/CA/NCI NIH HHS/United States ; Z01 ES044005/ImNIH/Intramural NIH HHS/United States ; R01 CA202981/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Genome-Wide Association Study/methods ; *Genetic Predisposition to Disease ; *Breast Neoplasms/genetics ; *Polymorphism, Single Nucleotide ; *Black People/genetics ; Case-Control Studies ; Risk Factors ; Triple Negative Breast Neoplasms/genetics ; Alleles ; Multifactorial Inheritance/genetics ; Middle Aged ; Genetic Loci ; White People/genetics ; }, abstract = {We performed genome-wide association studies of breast cancer including 18,034 cases and 22,104 controls of African ancestry. Genetic variants at 12 loci were associated with breast cancer risk (P < 5 × 10[-8]), including associations of a low-frequency missense variant rs61751053 in ARHGEF38 with overall breast cancer (odds ratio (OR) = 1.48) and a common variant rs76664032 at chromosome 2q14.2 with triple-negative breast cancer (TNBC) (OR = 1.30). Approximately 15.4% of cases with TNBC carried six risk alleles in three genome-wide association study-identified TNBC risk variants, with an OR of 4.21 (95% confidence interval = 2.66-7.03) compared with those carrying fewer than two risk alleles. A polygenic risk score (PRS) showed an area under the receiver operating characteristic curve of 0.60 for the prediction of breast cancer risk, which outperformed PRS derived using data from females of European ancestry. Our study markedly increases the population diversity in genetic studies for breast cancer and demonstrates the utility of PRS for risk prediction in females of African ancestry.}, }
@article {pmid38740820, year = {2024}, author = {Aubert, M and Haick, AK and Strongin, DE and Klouser, LM and Loprieno, MA and Stensland, L and Santo, TK and Huang, ML and Hyrien, O and Stone, D and Jerome, KR}, title = {Gene editing for latent herpes simplex virus infection reduces viral load and shedding in vivo.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {4018}, pmid = {38740820}, issn = {2041-1723}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P50 AR065139/AR/NIAMS NIH HHS/United States ; R01 AI132599/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; *Gene Editing/methods ; Female ; *Dependovirus/genetics ; Mice ; *Herpesvirus 1, Human/genetics/physiology ; *Herpes Simplex/genetics/virology/therapy ; *Viral Load ; *Virus Shedding ; Disease Models, Animal ; Virus Latency/genetics ; Humans ; Genetic Vectors/genetics ; Vero Cells ; Genetic Therapy/methods ; Herpes Genitalis/therapy/virology ; DNA, Viral/genetics ; }, abstract = {Anti-HSV therapies are only suppressive because they do not eliminate latent HSV present in ganglionic neurons, the source of recurrent disease. We have developed a potentially curative approach against HSV infection, based on gene editing using HSV-specific meganucleases delivered by adeno-associated virus (AAV) vectors. Gene editing performed with two anti-HSV-1 meganucleases delivered by a combination of AAV9, AAV-Dj/8, and AAV-Rh10 can eliminate 90% or more of latent HSV DNA in mouse models of orofacial infection, and up to 97% of latent HSV DNA in mouse models of genital infection. Using a pharmacological approach to reactivate latent HSV-1, we demonstrate that ganglionic viral load reduction leads to a significant decrease of viral shedding in treated female mice. While therapy is well tolerated, in some instances, we observe hepatotoxicity at high doses and subtle histological evidence of neuronal injury without observable neurological signs or deficits. Simplification of the regimen through use of a single serotype (AAV9) delivering single meganuclease targeting a duplicated region of the HSV genome, dose reduction, and use of a neuron-specific promoter each results in improved tolerability while retaining efficacy. These results reinforce the curative potential of gene editing for HSV disease.}, }
@article {pmid38740628, year = {2024}, author = {Giguere, R and Balán, IC and Kutner, BA and Choi, SK and Tingler, R and Johnson, S and Macagna, N and Webster, J and Liu, A and Chariyalertsak, S and Hoesley, C and Gonzales, P and Ho, K and Kayange, N and Palanee-Phillips, T and Brown, E and Zemanek, J and Jacobson, CE and Doncel, GF and Piper, J and Bauermeister, JA and , }, title = {History of Rectal Product Use and Country of Residence Influence Preference for Rectal Microbicide Dosage Forms Among Young Sexual and Gender Minorities: A Multi-country Trial Comparing Placebo Douche, Suppository, and Insert Products.}, journal = {AIDS and behavior}, volume = {28}, number = {8}, pages = {2577-2589}, pmid = {38740628}, issn = {1573-3254}, support = {K23MH124569/MH/NIMH NIH HHS/United States ; U01 AI069496/AI/NIAID NIH HHS/United States ; UM1 AI068633/AI/NIAID NIH HHS/United States ; UM1 AI068615/AI/NIAID NIH HHS/United States ; P30 MH043520/MH/NIMH NIH HHS/United States ; K23 MH124569/MH/NIMH NIH HHS/United States ; UM1AI068615//Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ ; AID-OAA-A-14-00010//United States Agency for International Development/ ; UM1 AI106707/AI/NIAID NIH HHS/United States ; P30MH043520/MH/NIMH NIH HHS/United States ; UM1AI106707//Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ ; U01 AI068633/AI/NIAID NIH HHS/United States ; U01 AI069463/AI/NIAID NIH HHS/United States ; UM1AI068633//Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases/ ; }, mesh = {Humans ; Male ; Thailand ; *HIV Infections/prevention &amp; control ; *Administration, Rectal ; Malawi ; *Sexual and Gender Minorities/psychology ; United States ; Adult ; Female ; Young Adult ; South Africa ; *Homosexuality, Male/psychology ; Suppositories ; Adolescent ; Peru ; Patient Preference ; Sexual Behavior ; Transgender Persons/psychology ; Anti-Infective Agents/administration &amp; dosage ; Placebos/administration &amp; dosage ; Dosage Forms ; }, abstract = {The DESIRE Study (MTN-035) explored product preference among three placebo rectal microbicide (RM) formulations, a rectal douche (RD), a suppository, and an insert, among 210 sexually active transgender people and men who have sex with men in five counties: the United States, Peru, Thailand, South Africa, and Malawi. Participants used each product prior to receptive anal sex (RAS) for 1 month, following a randomly assigned sequence, then selected their preferred product via computer assisted self-interview. In-depth interviews examined reasons for preference. We compared product preference and prior product use by country to explore whether geographic location and experience with the similar products impacted preference. A majority in the United States (56%) and Peru (58%) and nearly half in South Africa (48%) preferred the douche. Most in Malawi (59%) preferred the suppository, while half in Thailand (50%) and nearly half in South Africa (47%) preferred the insert. Participants who preferred the douche described it as quick and easy, already routinized, and serving a dual purpose of cleansing and protecting. Those who preferred the insert found it small, portable, discreet, with quick dissolution. Those who preferred the suppository found the size and shape acceptable and liked the added lubrication it provided. Experience with product use varied by country. Participants with RD experience were significantly more likely to prefer the douche (p = 0.03). Diversifying availability of multiple RM dosage forms can increase uptake and improve HIV prevention efforts globally.}, }
@article {pmid38740030, year = {2024}, author = {Necchi, A and Roumiguié, M and Kamat, AM and Shore, ND and Boormans, JL and Esen, AA and Lebret, T and Kandori, S and Bajorin, DF and Krieger, LEM and Niglio, SA and Uchio, EM and Seo, HK and de Wit, R and Singer, EA and Grivas, P and Nishiyama, H and Li, H and Baranwal, P and Van den Sigtenhorst-Fijlstra, M and Kapadia, E and Kulkarni, GS}, title = {Pembrolizumab monotherapy for high-risk non-muscle-invasive bladder cancer without carcinoma in situ and unresponsive to BCG (KEYNOTE-057): a single-arm, multicentre, phase 2 trial.}, journal = {The Lancet. Oncology}, volume = {25}, number = {6}, pages = {720-730}, doi = {10.1016/S1470-2045(24)00178-5}, pmid = {38740030}, issn = {1474-5488}, mesh = {Humans ; *Urinary Bladder Neoplasms/drug therapy/pathology ; *Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects ; Male ; Female ; Aged ; *BCG Vaccine/therapeutic use/administration &amp; dosage/adverse effects ; Middle Aged ; Antineoplastic Agents, Immunological/therapeutic use/adverse effects ; Carcinoma in Situ/drug therapy/pathology ; Neoplasm Invasiveness ; Aged, 80 and over ; Non-Muscle Invasive Bladder Neoplasms ; }, abstract = {BACKGROUND: The KEYNOTE-057 trial evaluated activity and safety of pembrolizumab in patients with BCG-unresponsive high-risk non-muscle-invasive bladder cancer who were ineligible for or declined radical cystectomy. In cohort A (patients with carcinoma in situ, with or without papillary tumours) of the KEYNOTE-057 study, pembrolizumab monotherapy led to a complete response rate of 41% at 3 months, and 46% of responders maintained a response lasting at least 12 months. Here, we evaluate pembrolizumab monotherapy in cohort B of patients with papillary tumours without carcinoma in situ.<br><br>METHODS: KEYNOTE-057 is a single-arm, phase 2 study in 54 sites (hospitals and cancer centres) in 14 countries. Cohort B eligible patients were aged 18 years and older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had BCG-unresponsive high-risk non-muscle-invasive bladder cancer with papillary tumours (high-grade Ta or any-grade T1) without carcinoma in situ. Transurethral resection of bladder tumour within 12 weeks of first pembrolizumab dose was required. Patients received pembrolizumab 200 mg intravenously every 3 weeks for a maximum of 35 cycles. Primary endpoint was 12-month disease-free survival of high-risk non-muscle-invasive bladder cancer or progressive disease as assessed by cystoscopy, cytology, and central pathology and radiology review. Activity was assessed in all patients who received at least one dose of the study drug and had a baseline evaluation. Safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov number, NCT02625961, and is ongoing.<br><br>FINDINGS: Between April 12, 2016, and June 17, 2021, 132 patients (104 [79%] men and 28 [21%] women) who had received a median of ten (IQR 9-15) previous BCG instillations were enrolled into cohort B of the study. Patients received a median of 10 cycles (IQR 6-27) of pembrolizumab. At data cutoff date, Oct 20, 2022, median follow-up was 45&#xb7;4 months (IQR 36&#xb7;4-59&#xb7;3) and five (4%) of 132 patients remained on treatment. The 12-month disease-free survival was 43&#xb7;5% (95% CI 34&#xb7;9-51&#xb7;9). Treatment-related adverse events occurred in 97 (73%) of 132 patients; 19 (14%) had a grade 3 or 4 treatment-related adverse event; the most common grade 3 or 4 treatment-related adverse events were colitis (in three [2%] patients) and diarrhoea (in two [2%]). 17 (13%) of 132 patients experienced serious treatment-related adverse events, of which colitis (three patients [2%]) was most common. No treatment-related deaths occurred.<br><br>INTERPRETATION: Pembrolizumab monotherapy showed antitumour activity and manageable toxicity in patients with BCG-unresponsive high-risk Ta or T1 bladder cancer without carcinoma in situ and could potentially be a suitable treatment option for patients who decline or are ineligible for radical cystectomy. Findings will need to be confirmed in a randomised controlled trial.<br><br>FUNDING: Merck Sharp &amp; Dohme.}, }
@article {pmid38738881, year = {2024}, author = {Schwartz, LF and Stratton, KL and Leisenring, WM and Rodriguez, SM and Alston, S and McDonald, A and Vukadinovich, C and Rinehardt, D and Oeffinger, KC and Chow, EJ and Krull, KR and Brinkman, TM and Nathan, PC and Tan, MM and McCrae, JS and Burkhardt, T and Ness, KK and Armstrong, GT and Henderson, TO}, title = {Adverse Childhood Experiences, Resilience, and Cardiovascular Disease in Adult Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {33}, number = {8}, pages = {1132-1136}, pmid = {38738881}, issn = {1538-7755}, support = {U24 CA055727/CA/NCI NIH HHS/United States ; K12 CA139160/CA/NCI NIH HHS/United States ; L40 CA274778/CA/NCI NIH HHS/United States ; //American Lebanese Syrian Associated Charities (ALSAC)/ ; CA21765//National Cancer Institute (NCI)/ ; P30 CA021765/CA/NCI NIH HHS/United States ; CA55727//National Cancer Institute (NCI)/ ; K12 CA139160-12//National Cancer Institute (NCI)/ ; }, mesh = {Humans ; Female ; Male ; *Cardiovascular Diseases/epidemiology ; *Cancer Survivors/psychology/statistics &amp; numerical data ; Case-Control Studies ; Adult ; *Adverse Childhood Experiences/statistics &amp; numerical data/psychology ; *Neoplasms/psychology/epidemiology ; *Resilience, Psychological ; Child ; Middle Aged ; Young Adult ; Adolescent ; }, abstract = {BACKGROUND: The impact of adverse childhood experiences (ACE, e.g., abuse, neglect, and/or household dysfunction experienced before the age of 18) and resilience on risk for cardiovascular disease (CVD) has not previously been investigated in adult survivors of childhood cancer.<br><br>METHODS: We conducted a nested case-control study among long-term, adult-aged survivors of childhood cancer from the Childhood Cancer Survivor Study. Self-report questionnaires ascertained ACEs and resilience, and scores were compared between cases with serious/life-threatening CVD and controls without CVD matched on demographic and cardiotoxic treatment factors.<br><br>RESULTS: Among 95 cases and 261 controls, the mean ACE score was 1.4 for both groups; 53.4% of survivors endorsed &#x2265;1 ACE. No association was observed between ACEs or resilience and CVD in adjusted models.<br><br>CONCLUSIONS: ACEs and resilience do not appear to contribute to CVD risk for adult survivors of childhood cancer with cardiotoxic treatment exposures.<br><br>IMPACT: Although not associated with CVD in this population, ACEs are associated with serious health issues in other populations. Therefore, future studies could investigate the effects of ACEs on other health outcomes affecting childhood cancer survivors.}, }
@article {pmid38736375, year = {2024}, author = {Pholsena, TN and Lewis, FM and Phillips, F and Loggers, ET and Yockel, MR and Zahlis, EH and Shands, ME}, title = {Advanced parental cancer and adolescents: Parenting issues and challenges.}, journal = {Palliative &amp; supportive care}, volume = {}, number = {}, pages = {1-6}, doi = {10.1017/S1478951524000774}, pmid = {38736375}, issn = {1478-9523}, abstract = {BACKGROUND: An estimated 609,820 child-rearing adults in 2023 died from advanced cancer, affecting 153,675 dependent children. Although children are known to suffer significant distress when a parent is diagnosed with cancer, few studies have described parents' views of their adolescent's behavioral response to their advanced cancer or what the parent did to interpret or manage that response.<br><br>OBJECTIVES: To describe patient-reported concerns about their adolescent and how they responded to their adolescent's behavior.<br><br>METHODS: Single occasion interviews were administered to 6 adolescent-rearing parents with Stage IV cancer. Interviews were analyzed using inductive content analysis by trained coders. Trustworthiness of results was protected through peer debriefing, coding to consensus, and maintaining an audit trail.<br><br>RESULTS: The core construct that explained study data was Being There without Taking Over, comprised of 4 domains: Struggling to Read My Child, Attempting to Talk with My Child about My Cancer, Trying to Maintain Optimism, and Understanding My Child.<br><br>CONCLUSIONS: Parents were deeply concerned about the impact of their advanced cancer on their adolescent but were unable to distinguish between cancer-related distress and adolescent angst. They feared initiating cancer-related discussions and struggled with their own feelings of guilt and parental inadequacy but did not turn to professionals for help.<br><br>SIGNIFICANCE OF RESULTS: Adolescent-rearing patients with advanced disease need to be triaged into services that offer a framework from which parents can interpret their child's behavior and learn ways to have adolescent-appropriate conversations about the cancer. Such services should also help parents gain skills to manage feelings of parental inadequacy and guilt. In the absence of services, parents struggle and do not know how to interpret and respond to their adolescent's cancer-related behavior.}, }
@article {pmid38736319, year = {2024}, author = {Chlebowski, RT and Aragaki, AK and Pan, K and Simon, MS and Neuhouser, ML and Haque, R and Rohan, TE and Wactawski-Wende, J and Orchard, TS and Mortimer, JE and Lane, D and Kaunitz, AM and Desai, P and Wild, RA and Barac, A and Manson, JE}, title = {Breast cancer incidence and mortality by metabolic syndrome and obesity: The Women's Health Initiative.}, journal = {Cancer}, volume = {130}, number = {18}, pages = {3147-3156}, doi = {10.1002/cncr.35318}, pmid = {38736319}, issn = {1097-0142}, support = {R01 CA10921/CA/NCI NIH HHS/United States ; R01 CA119171/CA/NCI NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; R01 CA10921/CA/NCI NIH HHS/United States ; R01 CA119171/CA/NCI NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Breast Neoplasms/mortality/epidemiology ; *Metabolic Syndrome/epidemiology/complications/mortality ; *Obesity/complications/epidemiology ; Middle Aged ; Incidence ; Aged ; *Postmenopause ; *Body Mass Index ; Women's Health ; Risk Factors ; }, abstract = {BACKGROUND: In the Women's Health Initiative (WHI) randomized trial, dietary intervention significantly reduced breast cancer mortality, especially in women with more metabolic syndrome (MetS) components. Therefore, this study investigated the associations of MetS and obesity with postmenopausal breast cancer after long-term follow-up in the WHI clinical trials.<br><br>METHODS: A total of 68,132 postmenopausal women, without prior breast cancer and with normal mammogram, were entered into WHI randomized clinical trials; 63,330 women with an entry MetS score comprised the study population. At entry, body mass index (BMI) was determined; MetS score (0, 1-2, and 3-4) included the following: (1) high waist circumference (&#x2265;88 cm), (2) high blood pressure (systolic &#x2265;130 mm Hg and/or diastolic &#x2265;85 mm Hg, or hypertension history), (3) high-cholesterol history, and (4) diabetes history. Study outcomes included breast cancer incidence, breast cancer mortality, deaths after breast cancer, and results by hormone receptor status.<br><br>RESULTS: After a >20-year mortality follow-up, a higher MetS score (3-4), adjusted for BMI, was significantly associated with more poor prognosis, estrogen receptor (ER)-positive, progesterone receptor (PR)-negative cancers (p&#xa0;=&#xa0;.03), 53% more deaths after breast cancer (p&#xa0;<&#xa0;.001), and 44% higher breast cancer mortality (p&#xa0;=&#xa0;.03). Obesity status, adjusted for MetS score, was significantly associated with more good prognosis, ER-positive, PR-positive cancers (p&#xa0;<&#xa0;.001), more total breast cancers (p&#xa0;<&#xa0;.001), and more deaths after breast cancer (p&#xa0;<&#xa0;.001), with higher breast cancer mortality only in women with severe obesity (BMI, &#x2265;35 kg/m[2]; p&#xa0;<&#xa0;.001).<br><br>CONCLUSIONS: MetS and obesity status have independent, but differential, adverse associations with breast cancer receptor subtypes and breast cancer mortality risk. Both represent separate targets for breast cancer prediction and prevention strategies.}, }
@article {pmid38734236, year = {2024}, author = {Miranda, RN and Amador, C and Chan, JKC and Guitart, J and Rech, KL and Medeiros, LJ and Naresh, KN and , }, title = {Fifth Edition of the World Health Organization Classification of Tumors of the Hematopoietic and Lymphoid Tissues: Mature T-Cell, NK-Cell, and Stroma-Derived Neoplasms of Lymphoid Tissues.}, journal = {Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc}, volume = {37}, number = {8}, pages = {100512}, doi = {10.1016/j.modpat.2024.100512}, pmid = {38734236}, issn = {1530-0285}, mesh = {Humans ; *World Health Organization ; *Killer Cells, Natural/pathology/immunology ; T-Lymphocytes/immunology/pathology ; Lymphoid Tissue/pathology/immunology ; Stromal Cells/pathology/immunology ; Hematologic Neoplasms/pathology/classification/immunology ; }, abstract = {This review focuses on mature T cells, natural killer (NK) cells, and stroma-derived neoplasms in the fifth edition of the World Health Organization classification of hematolymphoid tumors, including changes from the revised fourth edition. Overall, information has expanded, primarily due to advancements in genomic understanding. The updated classification adopts a hierarchical format. The updated classification relies on a multidisciplinary approach, incorporating insights from a diverse group of pathologists, clinicians, and geneticists. Indolent NK-cell lymphoproliferative disorder of the gastrointestinal tract, Epstein-Barr virus-positive nodal T- and NK-cell lymphoma, and several stroma-derived neoplasms of lymphoid tissues have been newly introduced or included. The review also provides guidance on how the fifth edition of the World Health Organization classification of hematolymphoid tumors can be applied in routine clinical practice.}, }
@article {pmid38732035, year = {2024}, author = {Watanabe, R and Miura, N and Kurata, M and Kitazawa, R and Kikugawa, T and Saika, T}, title = {Unveiling the Genomic Landscape of Intraductal Carcinoma of the Prostate Using Spatial Gene Expression Analysis.}, journal = {International journal of molecular sciences}, volume = {25}, number = {9}, pages = {}, pmid = {38732035}, issn = {1422-0067}, support = {22K09449//Japan Society for the Promotion of Science/ ; Medical Research Grants//Takeda Science Foundation/ ; N/A//Japanese Foundation for Prostate Research/ ; Young Research Grant//Japanese Urological Association/ ; N/A//Takahashi Industrial and Economic Research Foundation/ ; }, mesh = {Male ; Humans ; *Prostatic Neoplasms/genetics/pathology/metabolism ; *Gene Expression Regulation, Neoplastic ; *Tumor Microenvironment/genetics ; Biomarkers, Tumor/genetics ; Gene Expression Profiling/methods ; Carcinoma, Ductal/genetics/pathology/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism ; Transcriptome ; Receptors, CCR5 ; }, abstract = {Intraductal carcinoma of the prostate (IDCP) has recently attracted increasing interest owing to its unfavorable prognoses. To effectively identify the IDCP-specific gene expression profile, we took a novel approach of characterizing a typical IDCP case using spatial gene expression analysis. A formalin-fixed, paraffin-embedded sample was subjected to Visium CytAssist Spatial Gene Expression analysis. IDCP within invasive prostate cancer sites was recognized as a distinct cluster separate from other invasive cancer clusters. Highly expressed genes defining the IDCP cluster, such as MUC6, MYO16, NPY, and KLK12, reflected the aggressive nature of high-grade prostate cancer. IDCP sites also showed increased hypoxia markers HIF1A, BNIP3L, PDK1, and POGLUT1; decreased fibroblast markers COL1A2, DCN, and LUM; and decreased immune cell markers CCR5 and FCGR3A. Overall, these findings indicate that the hypoxic tumor microenvironment and reduced recruitment of fibroblasts and immune cells, which reflect morphological features of IDCP, may influence the aggressiveness of high-grade prostate cancer.}, }
@article {pmid38731931, year = {2024}, author = {Wakabayashi, N and Yagishita, Y and Joshi, T and Kensler, TW}, title = {Dual Deletion of Keap1 and Rbpjκ Genes in Liver Leads to Hepatomegaly and Hypercholesterolemia.}, journal = {International journal of molecular sciences}, volume = {25}, number = {9}, pages = {}, pmid = {38731931}, issn = {1422-0067}, support = {1R35CA197222-21A7/NH/NIH HHS/United States ; }, mesh = {Animals ; *Kelch-Like ECH-Associated Protein 1/metabolism/genetics ; Mice ; *Hypercholesterolemia/genetics/metabolism/pathology ; *Liver/metabolism/pathology ; *Hepatomegaly/genetics/metabolism/pathology ; *Immunoglobulin J Recombination Signal Sequence-Binding Protein/genetics/metabolism ; NF-E2-Related Factor 2/metabolism/genetics ; Lipid Metabolism/genetics ; Gene Deletion ; Signal Transduction ; Cholesterol/metabolism ; Mice, Knockout ; Male ; Bile Acids and Salts/metabolism ; }, abstract = {The hepatic deletion of Rbpjκ (Rbpj[F/F]::AlbCre) in the mouse leads to exhibition of the Alagille syndrome phenotype during early postnatal liver development with hyperlipidemia and cholestasis due to attenuated disruption of NOTCH signaling. Given the roles of NRF2 signaling in the regulation of lipid metabolism and bile ductal formation, it was anticipated that these symptoms could be alleviated by enhancing NRF2 signaling in the Rbpj[F/F]::AlbCre mouse by hepatic deletion of Keap1 in compound Keap1[F/F]::Rbpj[F/F]::AlbCre mice. Unexpectedly, these mice developed higher hepatic and plasma cholesterol levels with more severe cholestatic liver damage during the pre-weaning period than in the Rbpj[F/F]::AlbCre mice. In addition, hypercholesterolemia and hepatic damage were sustained throughout the growth period unlike in the Rbpj[F/F]::AlbCre mouse. These enhanced abnormalities in lipid metabolism appear to be due to NRF2-dependent changes in gene expression related to cholesterol synthetic and subsequent bile acid production pathways. Notably, the hepatic expression of Cyp1A7 and Abcb11 genes involved in bile acid homeostasis was significantly reduced in Keap1[F/F]::Rbpj[F/F]::AlbCre compared to Rbpj[F/F]::AlbCre mice. The accumulation of liver cholesterol and the weakened capacity for bile excretion during the 3 pre-weaning weeks in the Keap1[F/F]::Rbpj[F/F]::AlbCre mice may aggravate hepatocellular damage level caused by both excessive cholesterol and residual bile acid toxicity in hepatocytes. These results indicate that a tuned balance of NOTCH and NRF2 signaling is of biological importance for early liver development after birth.}, }
@article {pmid38730407, year = {2024}, author = {Johnson, AM and Zhou, C and Haviland, M and Mendoza, JA}, title = {Evaluation of a walking school bus program: a cluster randomized controlled trial.}, journal = {The international journal of behavioral nutrition and physical activity}, volume = {21}, number = {1}, pages = {55}, pmid = {38730407}, issn = {1479-5868}, support = {K01 HL171860/HL/NHLBI NIH HHS/United States ; R01 CA163146/CA/NCI NIH HHS/United States ; R01CA16314601//Foundation for the National Institutes of Health/ ; }, mesh = {Humans ; *Walking/statistics &amp; numerical data ; Female ; Male ; Child ; *Schools ; *Transportation/methods ; Health Promotion/methods ; Washington ; Texas ; Students ; Exercise ; Motor Vehicles ; Accelerometry ; Poverty ; Program Evaluation ; Cluster Analysis ; }, abstract = {BACKGROUND: The purpose of this study was to investigate the effects of a walking school bus intervention on children's active commuting to school.<br><br>METHODS: We conducted a randomized controlled trial (RCT) in Houston, Texas (Year 1) and Seattle, Washington (Years 2-4) from 2012 to 2016. The study had a two-arm, cluster randomized design comparing the intervention (walking school bus and education materials) to the control (education materials) over one school year October/November - May/June). Twenty-two schools that served lower income families participated. Outcomes included percentage of days students' active commuting to school (primary, measured via survey) and moderate-to-vigorous physical activity (MVPA, measured via accelerometry). Follow-up took place in May or June. We used linear mixed-effects models to estimate the association between the intervention and outcomes of interest.<br><br>RESULTS: Total sample was 418 students [Mage=9.2 (SD&#x2009;=&#x2009;0.9) years; 46% female], 197 (47%) in the intervention group. The intervention group showed a significant increase compared with the control group over time in percentage of days active commuting (&#x3b2;&#x2009;=&#x2009;9.04; 95% CI: 1.10, 16.98; p&#x2009;=&#x2009;0.015) and MVPA minutes/day (&#x3b2;&#x2009;=&#x2009;4.31; 95% CI: 0.70, 7.91; p&#x2009;=&#x2009;0.02).<br><br>CONCLUSIONS: These findings support implementation of walking school bus programs that are inclusive of school-age children from lower income families to support active commuting to school and improve physical activity.<br><br>TRAIL REGISTRATION: This RCT is registered at clinicaltrials.gov (NCT01626807).}, }
@article {pmid38730398, year = {2024}, author = {Ortblad, KF and Kuo, AP and Mogere, P and Roche, SD and Kiptinness, C and Wairimu, N and Gakuo, S and Baeten, JM and Ngure, K}, title = {Low selection of HIV PrEP refills at private pharmacies among clients who initiated PrEP at public clinics: findings from a mixed-methods study in Kenya.}, journal = {BMC health services research}, volume = {24}, number = {1}, pages = {618}, pmid = {38730398}, issn = {1472-6963}, mesh = {Humans ; Kenya ; *HIV Infections/prevention &amp; control ; Male ; Female ; *Pre-Exposure Prophylaxis/methods ; Adult ; *Pharmacies/statistics &amp; numerical data ; Anti-HIV Agents/therapeutic use ; Young Adult ; }, abstract = {BACKGROUND: In Africa, the delivery of HIV pre-exposure prophylaxis (PrEP) at public healthcare clinics is challenged by understaffing, overcrowding, and HIV-associated stigma, often resulting in low PrEP uptake and continuation among clients. Giving clients the option to refill PrEP at nearby private pharmacies, which are often more convenient and have shorter wait times, may address these challenges and improve PrEP continuation.<br><br>METHODS: This mixed methods study used an explanatory sequential design. At two public clinics in Kiambu County, Kenya, clients&#x2009;&#x2265;&#x2009;18&#xa0;years initiating PrEP were given the option to refill PrEP&#xa0;at the clinic where they initiated for free or at one of three nearby private pharmacies for 300 Kenyan Shillings (~&#x2009;$3 US Dollars). The providers at these pharmacies (pharmacists and pharmaceutical technologists) were trained in PrEP service delivery using a prescribing checklist and provider-assisted HIV self-testing, both with remote clinician oversight. Clients were followed up to seven months, with scheduled refill visits at one, four, and seven months. The primary outcomes were selection of pharmacy-based PrEP refills and PrEP continuation. Following pilot completion, 15 in-depth interviews (IDIs) with clients who refilled PrEP&#xa0;were completed. We used descriptive statistics and thematic analysis to assess study outcomes.<br><br>RESULTS: From November 2020 to November 2021, 125 PrEP clients were screened and 106 enrolled. The majority (59%, 63/106) of clients were women and the median age was 31&#xa0;years (IQR 26-38&#xa0;years). Over 292 client-months of follow-up, 41 clients (39%) refilled PrEP; only three (3%) at a participating pharmacy. All clients who completed IDIs refilled PrEP at clinics. The reasons why clients did not refill PrEP at pharmacies included: a preference for clinic-delivered PrEP services (i.e., pre-existing relationships, access to other services), concerns about pharmacy-delivered PrEP services (i.e., mistrust, lower quality care, costs), and lack of knowledge of this refill location.<br><br>CONCLUSIONS: These findings suggest that clients who initiate PrEP at public clinics in Kenya may have already overcome barriers to clinic-delivered PrEP services and prefer PrEP access there. To reach new populations that could benefit from PrEP, a stand-alone model of pharmacy-delivered PrEP services may be needed.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov: NCT04558554 [registered: June 5, 2020].}, }
@article {pmid38729566, year = {2024}, author = {Goetz, MP and Toi, M and Huober, J and Sohn, J and Trédan, O and Park, IH and Campone, M and Chen, SC and Manso, LM and Paluch-Shimon, S and Freedman, OC and O'Shaughnessy, J and Pivot, X and Tolaney, SM and Hurvitz, SA and Llombart-Cussac, A and André, V and Saha, A and van Hal, G and Shahir, A and Iwata, H and Johnston, SRD}, title = {Abemaciclib plus a nonsteroidal aromatase inhibitor as initial therapy for HR+, HER2- advanced breast cancer: final overall survival results of MONARCH 3.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {35}, number = {8}, pages = {718-727}, doi = {10.1016/j.annonc.2024.04.013}, pmid = {38729566}, issn = {1569-8041}, mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Middle Aged ; *Aminopyridines/administration &amp; dosage/therapeutic use ; Anastrozole/therapeutic use/administration &amp; dosage ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; *Aromatase Inhibitors/therapeutic use/administration &amp; dosage ; *Benzimidazoles/administration &amp; dosage/therapeutic use ; *Breast Neoplasms/drug therapy/pathology/mortality ; Double-Blind Method ; *Letrozole/administration &amp; dosage/therapeutic use ; Progression-Free Survival ; Receptor, ErbB-2/metabolism/antagonists &amp; inhibitors ; Receptors, Estrogen/metabolism ; Receptors, Progesterone/metabolism ; }, abstract = {BACKGROUND: In MONARCH 2, the addition of abemaciclib to fulvestrant significantly improved both progression-free survival (PFS) and overall survival (OS) in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) with disease progression on prior endocrine therapy. In MONARCH 3, the addition of abemaciclib to a nonsteroidal aromatase inhibitor (NSAI) as initial therapy for HR+, HER2- ABC significantly improved PFS. Here, we present the prespecified final OS results for MONARCH 3.<br><br>PATIENTS AND METHODS: MONARCH 3 is a randomized, double-blind, phase III study of abemaciclib plus NSAI (anastrozole or letrozole) versus placebo plus NSAI in postmenopausal women with HR+, HER2- ABC without prior systemic therapy in the advanced setting. The primary objective was investigator-assessed PFS; OS was a gated secondary endpoint, and chemotherapy-free survival was an exploratory endpoint.<br><br>RESULTS: A total of 493 women were randomized 2 : 1 to receive abemaciclib plus NSAI (n&#xa0;= 328) or placebo plus NSAI (n&#xa0;= 165). After a median follow-up of 8.1 years, there were 198 OS events (60.4%) in the abemaciclib arm and 116 (70.3%) in the placebo arm (hazard ratio, 0.804; 95% confidence interval 0.637-1.015; P&#xa0;= 0.0664, non-significant). Median OS was 66.8 versus 53.7 months for abemaciclib versus placebo. In the subgroup with visceral disease, there were 113 OS events (65.3%) in the abemaciclib arm and 65 (72.2%) in the placebo arm (hazard ratio, 0.758; 95% confidence interval 0.558-1.030; P&#xa0;= 0.0757, non-significant). Median OS was 63.7 months versus 48.8 months for abemaciclib versus placebo. The previously demonstrated PFS benefit was sustained, and chemotherapy-free survival numerically improved with the addition of abemaciclib. No new safety signals were observed.<br><br>CONCLUSIONS: Abemaciclib combined with an NSAI resulted in clinically meaningful improvement in median OS (intent-to-treat population: 13.1 months; subgroup with visceral disease: 14.9 months) in patients with HR+ HER2- ABC; however, statistical significance was not reached.}, }
@article {pmid38728385, year = {2024}, author = {Andrews, JS and Boonyaratanakornkit, JB and Krusinska, E and Allen, S and Posada, JA}, title = {Assessment of the Impact of RNase in Patients With Severe Fatigue Related to Post-Acute Sequelae of SARS-CoV-2 Infection: A Randomized Phase 2 Trial of RSLV-132.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {79}, number = {3}, pages = {635-642}, doi = {10.1093/cid/ciae205}, pmid = {38728385}, issn = {1537-6591}, support = {//Resolve Therapeutics/ ; }, mesh = {Humans ; Female ; Male ; *Fatigue/etiology/virology ; Middle Aged ; Double-Blind Method ; *COVID-19/complications ; *SARS-CoV-2 ; Adult ; Post-Acute COVID-19 Syndrome ; COVID-19 Drug Treatment ; RNA, Viral/blood ; Ribonucleases/therapeutic use ; Aged ; }, abstract = {BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and RNA debris persist in viral reservoirs for weeks to months following infection, potentially triggering interferon production and chronic inflammation. RSLV-132 is a biologic drug composed of catalytically active human RNase1 fused to human IgG1 Fc and is designed to remain in circulation and digest extracellular RNA. We hypothesized that removal of SARS-CoV-2 viral RNA from latent reservoirs may improve inflammation, neuroinflammation, and fatigue associated with post-acute sequelae of SARS-CoV-2 infection (PASC).<br><br>METHODS: This was a phase 2, double-blind, placebo-controlled randomized clinical trial in participants with a 24-week history of PASC and severe fatigue. The primary endpoint of the trial assessed the impact of 6 intravenous doses of RSLV-132 on the mean change from baseline at day 71 in the Patient-Reported Outcomes Measurement Information System Fatigue Short Form 7a (PROMIS Fatigue SF 7a).<br><br>RESULTS: A statistically significant difference on day 71 was not observed with respect to the primary or secondary endpoints. This was likely due to a placebo response that increased during the trial. Statistically significant improvement in fatigue as measured by the PROMIS Fatigue SF 7a, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), and Physicians Global Assessment (PGA) instruments were observed earlier in the trial, with women demonstrating greater responses to RSLV-132 than men.<br><br>CONCLUSION: While fatigue was not statistically significantly improved at Day 71, earlier timepoints revealed statistically significant improvement in fatigue and physician global assessment. The data suggest eliminating latent viral RNA by increasing serum RNase activity may improve fatigue in PASC patients. Women may respond better to this approach than men. Future studies will aim to confirm these findings.}, }
@article {pmid38728244, year = {2024}, author = {Anderson, LJ and Paulsen, L and Miranda, G and Syrjala, KL and Graf, SA and Chauncey, TR and Garcia, JM}, title = {Neuromuscular electrical stimulation for physical function maintenance during hematopoietic stem cell transplantation: Study protocol.}, journal = {PloS one}, volume = {19}, number = {5}, pages = {e0302970}, pmid = {38728244}, issn = {1932-6203}, support = {I01 BX002807/BX/BLRD VA/United States ; IK2 RX003245/RX/RRD VA/United States ; R01 AG061558/AG/NIA NIH HHS/United States ; R01 CA239208/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; Body Composition ; Electric Stimulation/methods ; *Electric Stimulation Therapy/methods ; Fatigue/therapy ; Hematologic Neoplasms/therapy ; *Hematopoietic Stem Cell Transplantation/methods ; *Quality of Life ; Transplantation, Autologous ; Randomized Controlled Trials as Topic ; }, abstract = {Hematopoietic stem cell transplantation is a common life-saving treatment for hematologic malignancies, though can lead to long-term functional impairment, fatigue, muscle atrophy, with decreased quality of life. Although traditional exercise has helped reduce these effects, it is inconsistently recommended and infrequently maintained, and most patients remain sedentary during and after treatment. There is need for alternative rehabilitation strategies, like neuromuscular electrical stimulation, that may be more amenable to the capabilities of hematopoietic stem cell transplant recipients. Patients receiving autologous HCT are being enroled in a randomized controlled trial with 1:1 (neuromuscular electrical stimulation:sham) design stratified by diagnosis and sex. Physical function, body composition, quality of life, and fatigue are assessed prior to hematopoietic stem cell transplant (prior to initiating preparatory treatment) and 24±5 days post hematopoietic stem cell transplant (Follow-up 1); physical function and quality of life are also assessed 6-months post hematopoietic stem cell transplant (Follow-up 2). The primary outcome is between-group difference in the 6-minute walk test change scores (Follow-up 1-Pre-transplant; final enrolment goal N = 23/group). We hypothesize that 1) neuromuscular electrical stimulation will attenuate hematopoietic stem cell transplant-induced adverse effects on physical function, muscle mass, quality of life, and fatigue compared to sham at Follow-up 1, and 2) Pre-transplant physical function will significantly predict fatigue and quality of life at Follow-up 2. We will also describe feasibility and acceptability of neuromuscular electrical stimulation during hematopoietic stem cell transplant. This proposal will improve rehabilitative patient care and quality of life by determining efficacy and feasibility of a currently underutilized therapeutic strategy aimed at maintaining daily function and reducing the impact of a potent and widely used cancer treatment. This trial is registered with clinicaltrials.gov (NCT04364256).}, }
@article {pmid38728140, year = {2024}, author = {Stjepić, V and Nakamura, M and Hui, J and Parkhurst, SM}, title = {Two Septin complexes mediate actin dynamics during cell wound repair.}, journal = {Cell reports}, volume = {43}, number = {5}, pages = {114215}, pmid = {38728140}, issn = {2211-1247}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 GM111635/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Actins/metabolism ; Actomyosin/metabolism ; Contractile Proteins/metabolism ; Drosophila melanogaster/metabolism ; *Drosophila Proteins/metabolism ; Microfilament Proteins ; *Septins/metabolism ; *Wound Healing ; }, abstract = {Cells have robust wound repair systems to prevent further damage or infection and to quickly restore cell cortex integrity when exposed to mechanical and chemical stress. Actomyosin ring formation and contraction at the wound edge are major events during closure of the plasma membrane and underlying cytoskeleton during cell wound repair. Here, we show that all five Drosophila Septins are required for efficient cell wound repair. Based on their different recruitment patterns and knockdown/mutant phenotypes, two distinct Septin complexes, Sep1/Sep2/Pnut and Sep4/Sep5/Pnut, are assembled to regulate actin ring assembly, contraction, and remodeling during the repair process. Intriguingly, we find that these two Septin complexes have different F-actin bending activities. In addition, we find that Anillin regulates the recruitment of only one of two Septin complexes upon wounding. Our results demonstrate that two functionally distinct Septin complexes work side by side to discretely regulate actomyosin ring dynamics during cell wound repair.}, }
@article {pmid38728029, year = {2024}, author = {Bhatt, NS and Goodman, P and Leisenring, WM and Armstrong, GT and Chow, EJ and Hudson, MM and Krull, KR and Nathan, PC and Oeffinger, KC and Robison, LL and Kirchhoff, AC and Mulrooney, DA}, title = {Chronic Health Conditions and Longitudinal Employment in Survivors of Childhood Cancer.}, journal = {JAMA network open}, volume = {7}, number = {5}, pages = {e2410731}, pmid = {38728029}, issn = {2574-3805}, support = {P30 CA021765/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; Male ; *Cancer Survivors/statistics &amp; numerical data/psychology ; *Employment/statistics &amp; numerical data ; Adult ; Chronic Disease/epidemiology ; Retrospective Studies ; Longitudinal Studies ; *Neoplasms/epidemiology/psychology ; Adolescent ; Child ; Young Adult ; Middle Aged ; United States/epidemiology ; }, abstract = {IMPORTANCE: Employment is an important factor in quality of life and provides social and economic support. Longitudinal data on employment and associations with chronic health conditions for adult survivors of childhood cancer are lacking.<br><br>OBJECTIVE: To evaluate longitudinal trends in employment among survivors of childhood cancer.<br><br>Retrospective cohort study of 5-year cancer survivors diagnosed at age 20 years or younger between 1970 and 1986 enrolled in the multi-institutional Childhood Cancer Survivor Study (CCSS). Sex-stratified employment status at baseline (2002 to 2004) and follow-up (2014 to 2016) was compared with general population rates from the Behavioral Risk Factor Surveillance System cohort. Data were analyzed from July 2021 to June 2022.<br><br>EXPOSURES: Cancer therapy and preexisting and newly developed chronic health conditions.<br><br>MAIN OUTCOMES AND MEASURES: Standardized prevalence ratios of employment (full-time or part-time, health-related unemployment, unemployed, not in labor force) among adult (aged &#x2265;25 years) survivors between baseline and follow-up compared with the general population. Longitudinal assessment of negative employment transitions (full-time to part-time or unemployed at follow-up).<br><br>RESULTS: Female participants (3076 participants at baseline; 2852 at follow-up) were a median (range) age of 33 (25-53) years at baseline and 42 (27-65) years at follow-up; male participants (3196 participants at baseline; 2557 at follow-up) were 33 (25-54) and 43 (28-64) years, respectively. The prevalence of full-time or part-time employment at baseline and follow-up was 2215 of 3076 (71.3%) and 1933 of 2852 (64.8%) for female participants and 2753 of 3196 (85.3%) and 2079 of 2557 (77.3%) for male participants, respectively, with declining standardized prevalence ratios over time (female participant baseline, 1.01; 95% CI, 0.98-1.03; follow-up, 0.94; 95% CI, 0.90-0.98; P&#x2009;<&#x2009;.001; male participant baseline, 0.96; 95% CI, 0.94-0.97; follow-up, 0.92; 95% CI, 0.89-0.95; P&#x2009;=&#x2009;.02). While the prevalence of health-related unemployment increased (female participants, 11.6% to 17.2%; male participants, 8.1% to 17.1%), the standardized prevalence ratio remained higher than the general population and declined over time (female participant baseline, 3.78; 95% CI, 3.37-4.23; follow-up, 2.23; 95% CI, 1.97-2.51; P&#x2009;<&#x2009;.001; male participant baseline, 3.12; 95% CI, 2.71-3.60; follow-up, 2.61; 95% CI, 2.24-3.03; P&#x2009;=&#x2009;.002). Among survivors employed full-time at baseline (1488 female participants; 1933 male participants), 285 female participants (19.2%) and 248 male participants (12.8%) experienced a negative employment transition (median [range] follow-up, 11.5 [9.4-13.8] years). Higher numbers and grades of chronic health conditions were significantly associated with these transitions.<br><br>CONCLUSIONS AND RELEVANCE: In this retrospective analysis of adult survivors of childhood cancer, significant declines in employment and increases in health-related unemployment among cancer survivors compared with the general population were identified. A substantial portion of survivors in the midcareer age range fell out of the workforce. Awareness among clinicians, caregivers, and employers may facilitate clinical counseling and occupational provisions for supportive work accommodations.}, }
@article {pmid38726844, year = {2024}, author = {Cohen, M and Graf, SA}, title = {Could protein kinase inhibitors become a next generation pharmacotherapy for non-Hodgkin's lymphoma?.}, journal = {Expert opinion on pharmacotherapy}, volume = {25}, number = {6}, pages = {637-640}, doi = {10.1080/14656566.2024.2354915}, pmid = {38726844}, issn = {1744-7666}, mesh = {Humans ; *Protein Kinase Inhibitors/therapeutic use ; *Lymphoma, Non-Hodgkin/drug therapy ; *Antineoplastic Agents/therapeutic use ; }, }
@article {pmid38726832, year = {2024}, author = {Kampouri, E and Little, JS and Crocchiolo, R and Hill, JA}, title = {Human herpesvirus-6, HHV-8 and parvovirus B19 after allogeneic hematopoietic cell transplant: the lesser-known viral complications.}, journal = {Current opinion in infectious diseases}, volume = {37}, number = {4}, pages = {245-253}, pmid = {38726832}, issn = {1473-6527}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects ; *Herpesvirus 8, Human ; *Parvovirus B19, Human/isolation &amp; purification ; *Herpesvirus 6, Human ; Parvoviridae Infections/epidemiology/diagnosis ; Antiviral Agents/therapeutic use ; Roseolovirus Infections/epidemiology/virology/diagnosis ; Transplantation, Homologous/adverse effects ; Herpesviridae Infections/epidemiology/virology ; }, abstract = {PURPOSE OF REVIEW: Viral infections continue to burden allogeneic hematopoietic cell transplant (HCT) recipients. We review the epidemiology, diagnosis, and management of human herpesvirus (HHV)-6, HHV-8 and parvovirus B19 following HCT.<br><br>RECENT FINDINGS: Advances in HCT practices significantly improved outcomes but impact viral epidemiology: post-transplant cyclophosphamide for graft-versus-host disease prevention increases HHV-6 reactivation risk while the impact of letermovir for CMV prophylaxis - and resulting decrease in broad-spectrum antivirals - is more complex. Beyond the well established HHV-6 encephalitis, recent evidence implicates HHV-6 in pneumonitis. Novel less toxic therapeutic approaches (brincidofovir, virus-specific T-cells) may enable preventive strategies in the future. HHV-8 is the causal agent of Kaposi's sarcoma, which is only sporadically reported after HCT, but other manifestations are possible and not well elucidated. Parvovirus B19 can cause severe disease post-HCT, frequently manifesting with anemia, but can also be easily overlooked due to lack of routine screening and ambiguity of manifestations.<br><br>SUMMARY: Studies should establish the contemporary epidemiology of HHV-6, and other more insidious viruses, such as HHV-8 and parvovirus B19 following HCT and should encompass novel cellular therapies. Standardized and readily available diagnostic methods are key to elucidate epidemiology and optimize preventive and therapeutic strategies to mitigate the burden of infection.}, }
@article {pmid38726320, year = {2024}, author = {Xu, Y and Miller, CP and Tykodi, SS and Akilesh, S and Warren, EH}, title = {Signaling crosstalk between tumor endothelial cells and immune cells in the microenvironment of solid tumors.}, journal = {Frontiers in cell and developmental biology}, volume = {12}, number = {}, pages = {1387198}, pmid = {38726320}, issn = {2296-634X}, abstract = {Tumor-associated endothelial cells (TECs) are crucial mediators of immune surveillance and immune escape in the tumor microenvironment (TME). TECs driven by angiogenic growth factors form an abnormal vasculature which deploys molecular machinery to selectively promote the function and recruitment of immunosuppressive cells while simultaneously blocking the entry and function of anti-tumor immune cells. TECs also utilize a similar set of signaling regulators to promote the metastasis of tumor cells. Meanwhile, the tumor-infiltrating immune cells further induce the TEC anergy by secreting pro-angiogenic factors and prevents further immune cell penetration into the TME. Understanding the complex interactions between TECs and immune cells will be needed to successfully treat cancer patients with combined therapy to achieve vasculature normalization while augmenting antitumor immunity. In this review, we will discuss what is known about the signaling crosstalk between TECs and tumor-infiltrating immune cells to reveal insights and strategies for therapeutic targeting.}, }
@article {pmid38725300, year = {2024}, author = {Bouras, E and Gill, D and Zuber, V and Murphy, N and Dimou, N and Aleksandrova, K and Lewis, SJ and Martin, RM and Yarmolinsky, J and Albanes, D and Brenner, H and Castellví-Bel, S and Chan, AT and Cheng, I and Gruber, S and Van Guelpen, B and Li, CI and Le Marchand, L and Newcomb, PA and Ogino, S and Pellatt, A and Schmit, SL and Wolk, A and Wu, AH and Peters, U and Gunter, MJ and Tsilidis, KK}, title = {Identification of potential mediators of the relationship between body mass index and colorectal cancer: a Mendelian randomization analysis.}, journal = {International journal of epidemiology}, volume = {53}, number = {3}, pages = {}, pmid = {38725300}, issn = {1464-3685}, support = {001/WHO_/World Health Organization/International ; MC_UU_00011/1/MRC_/Medical Research Council/United Kingdom ; /CRUK_/Cancer Research UK/United Kingdom ; }, mesh = {Humans ; *Colorectal Neoplasms/genetics/epidemiology ; *Mendelian Randomization Analysis ; *Body Mass Index ; Risk Factors ; *Obesity/genetics/epidemiology ; Insulin-Like Growth Factor I/metabolism ; Alcohol Drinking/epidemiology ; }, abstract = {BACKGROUND: Colorectal cancer (CRC) is the third-most-common cancer worldwide and its rates are increasing. Elevated body mass index (BMI) is an established risk factor for CRC, although the molecular mechanisms behind this association remain unclear. Using the Mendelian randomization (MR) framework, we aimed to investigate the mediating effects of putative biomarkers and other CRC risk factors in the association between BMI and CRC.<br><br>METHODS: We selected as mediators biomarkers of established cancer-related mechanisms and other CRC risk factors for which a plausible association with obesity exists, such as inflammatory biomarkers, glucose homeostasis traits, lipids, adipokines, insulin-like growth factor 1 (IGF1), sex hormones, 25-hydroxy-vitamin D, smoking, physical activity (PA) and alcohol consumption. We used inverse-variance weighted MR in the main univariable analyses and performed sensitivity analyses (weighted-median, MR-Egger, Contamination Mixture). We used multivariable MR for the mediation analyses.<br><br>RESULTS: Genetically predicted BMI was positively associated with CRC risk [odds ratio per SD (5&#x2009;kg/m2) = 1.17, 95% CI: 1.08-1.24, P-value&#x2009;=&#x2009;1.4&#x2009;&#xd7;&#x2009;10-5] and robustly associated with nearly all potential mediators. Genetically predicted IGF1, fasting insulin, low-density lipoprotein cholesterol, smoking, PA and alcohol were associated with CRC risk. Evidence for attenuation was found for IGF1 [explained 7% (95% CI: 2-13%) of the association], smoking (31%, 4-57%) and PA (7%, 2-11%). There was little evidence for pleiotropy, although smoking was bidirectionally associated with BMI and instruments were weak for PA.<br><br>CONCLUSIONS: The effect of BMI on CRC risk is possibly partly mediated through plasma IGF1, whereas the attenuation of the BMI-CRC association by smoking and PA may reflect confounding and shared underlying mechanisms rather than mediation.}, }
@article {pmid38725043, year = {2024}, author = {Luo, K and Taryn, A and Moon, EH and Peters, BA and Solomon, SD and Daviglus, ML and Kansal, MM and Thyagarajan, B and Gellman, MD and Cai, J and Burk, RD and Knight, R and Kaplan, RC and Cheng, S and Rodriguez, CJ and Qi, Q and Yu, B}, title = {Gut microbiota, blood metabolites, and left ventricular diastolic dysfunction in US Hispanics/Latinos.}, journal = {Microbiome}, volume = {12}, number = {1}, pages = {85}, pmid = {38725043}, issn = {2049-2618}, support = {R01 HL141824/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Gastrointestinal Microbiome ; Female ; Middle Aged ; Male ; *Hispanic or Latino ; *Ventricular Dysfunction, Left/microbiology/blood ; United States ; Dysbiosis/microbiology ; Aged ; Bacteria/classification/isolation &amp; purification ; Metabolome ; Echocardiography ; }, abstract = {BACKGROUND: Left ventricular diastolic dysfunction (LVDD) is an important precursor of heart failure (HF), but little is known about its relationship with gut dysbiosis and microbial-related metabolites. By leveraging the multi-omics data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a study with population at high burden of LVDD, we aimed to characterize gut microbiota associated with LVDD and identify metabolite signatures of gut dysbiosis and incident LVDD.<br><br>RESULTS: We included up to 1996 Hispanic/Latino adults (mean age: 59.4 years; 67.1% female) with comprehensive echocardiography assessments, gut microbiome, and blood metabolome data. LVDD was defined through a composite criterion involving tissue Doppler assessment and left atrial volume index measurements. Among 1996 participants, 916 (45.9%) had prevalent LVDD, and 212 out of 594 participants without LVDD at baseline developed incident LVDD over a median 4.3 years of follow-up. Using multivariable-adjusted analysis of compositions of microbiomes (ANCOM-II) method, we identified 7 out of 512 dominant gut bacterial species (prevalence > 20%) associated with prevalent LVDD (FDR-q < 0.1), with inverse associations being found for Intestinimonas_massiliensis, Clostridium_phoceensis, and Bacteroide_coprocola and positive associations for Gardnerella_vaginali, Acidaminococcus_fermentans, Pseudomonas_aeruginosa, and Necropsobacter_massiliensis. Using multivariable adjusted linear regression, 220 out of 669 circulating metabolites with detection rate > 75% were associated with the identified LVDD-related bacterial species (FDR-q < 0.1), with the majority being linked to Intestinimonas_massiliensis, Clostridium_phoceensis, and Acidaminococcus_fermentans. Furthermore, 46 of these bacteria-associated metabolites, mostly glycerophospholipids, secondary bile acids, and amino acids, were associated with prevalent LVDD (FDR-q < 0.1), 21 of which were associated with incident LVDD (relative risk ranging from 0.81 [p = 0.001, for guanidinoacetate] to 1.25 [p = 9 &#xd7; 10[-5], for 1-stearoyl-2-arachidonoyl-GPE (18:0/20:4)]). The inclusion of these 21 bacterial-related metabolites significantly improved the prediction of incident LVDD compared with a traditional risk factor model (the area under the receiver operating characteristic curve [AUC]&#xa0;= 0.73 vs 0.70, p = 0.001). Metabolite-based proxy association analyses revealed the inverse associations of Intestinimonas_massilliensis and Clostridium_phoceensis and the positive association of Acidaminococcus_fermentans with incident LVDD.<br><br>CONCLUSION: In this study of US Hispanics/Latinos, we identified multiple gut bacteria and related metabolites linked to LVDD, suggesting their potential roles in this preclinical HF entity. Video Abstract.}, }
@article {pmid38724463, year = {2024}, author = {Grauwet, K and Berger, T and Kann, MC and Silva, H and Larson, R and Leick, MB and Bailey, SR and Bouffard, AA and Millar, D and Gallagher, K and Turtle, CJ and Frigault, MJ and Maus, MV}, title = {Stealth transgenes enable CAR-T cells to evade host immune responses.}, journal = {Journal for immunotherapy of cancer}, volume = {12}, number = {5}, pages = {}, pmid = {38724463}, issn = {2051-1426}, support = {R01 CA238268/CA/NCI NIH HHS/United States ; T32 AI007529/AI/NIAID NIH HHS/United States ; T32 CA009216/CA/NCI NIH HHS/United States ; T32 GM007306/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Receptors, Chimeric Antigen/immunology/genetics ; *Immunotherapy, Adoptive/methods ; Transgenes ; T-Lymphocytes/immunology ; }, abstract = {BACKGROUND: Adoptive cell therapy, such as chimeric antigen receptor (CAR)-T cell therapy, has improved patient outcomes for hematological malignancies. Currently, four of the six FDA-approved CAR-T cell products use the FMC63-based αCD19 single-chain variable fragment, derived from a murine monoclonal antibody, as the extracellular binding domain. Clinical studies demonstrate that patients develop humoral and cellular immune responses to the non-self CAR components of autologous CAR-T cells or donor-specific antigens of allogeneic CAR-T cells, which is thought to potentially limit CAR-T cell persistence and the success of repeated dosing.<br><br>METHODS: In this study, we implemented a one-shot approach to prevent rejection of engineered T cells by simultaneously reducing antigen presentation and the surface expression of both Classes of the major histocompatibility complex (MHC) via expression of the viral inhibitors of transporter associated with antigen processing (TAPi) in combination with a transgene coding for shRNA targeting class II MHC transactivator (CIITA). The optimal combination was screened in vitro by flow cytometric analysis and mixed lymphocyte reaction assays and was validated in vivo in mouse models of leukemia and lymphoma. Functionality was assessed in an autologous setting using patient samples and in an allogeneic setting using an allogeneic mouse model.<br><br>RESULTS: The combination of the Epstein-Barr virus TAPi and an shRNA targeting CIITA was efficient and effective at reducing cell surface MHC classes I and II in &#x3b1;CD19 'stealth' CAR-T cells while retaining in vitro and in vivo antitumor functionality. Mixed lymphocyte reaction assays and IFN&#x3b3; ELISpot assays performed with T cells from patients previously treated with autologous &#x3b1;CD19 CAR-T cells confirm that CAR T cells expressing the stealth transgenes evade allogeneic and autologous anti-CAR responses, which was further validated in vivo. Importantly, we noted anti-CAR-T cell responses in patients who had received multiple CAR-T cell infusions, and this response was reduced on in vitro restimulation with autologous CARs containing the stealth transgenes.<br><br>CONCLUSIONS: Together, these data suggest that the proposed stealth transgenes may reduce the immunogenicity of autologous and allogeneic cellular therapeutics. Moreover, patient data indicate that repeated doses of autologous FMC63-based &#x3b1;CD19 CAR-T cells significantly increased the anti-CAR T cell responses in these patients.}, }
@article {pmid38723650, year = {2024}, author = {Juraska, M and Early, AM and Li, L and Schaffner, SF and Lievens, M and Khorgade, A and Simpkins, B and Hejazi, NS and Benkeser, D and Wang, Q and Mercer, LD and Adjei, S and Agbenyega, T and Anderson, S and Ansong, D and Bii, DK and Buabeng, PBY and English, S and Fitzgerald, N and Grimsby, J and Kariuki, SK and Otieno, K and Roman, F and Samuels, AM and Westercamp, N and Ockenhouse, CF and Ofori-Anyinam, O and Lee, CK and MacInnis, BL and Wirth, DF and Gilbert, PB and Neafsey, DE}, title = {Genotypic analysis of RTS,S/AS01E malaria vaccine efficacy against parasite infection as a function of dosage regimen and baseline malaria infection status in children aged 5-17 months in Ghana and Kenya: a longitudinal phase 2b randomised controlled trial.}, journal = {The Lancet. Infectious diseases}, volume = {24}, number = {9}, pages = {1025-1036}, pmid = {38723650}, issn = {1474-4457}, support = {R37 AI054165/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Malaria Vaccines/administration &amp; dosage/immunology ; Ghana ; Kenya/epidemiology ; Infant ; Male ; Female ; *Malaria, Falciparum/prevention &amp; control/epidemiology ; Genotype ; Longitudinal Studies ; Vaccine Efficacy ; Plasmodium falciparum/immunology/genetics ; Malaria/prevention &amp; control ; }, abstract = {BACKGROUND: The first licensed malaria vaccine, RTS,S/AS01E, confers moderate protection against symptomatic disease. Because many malaria infections are asymptomatic, we conducted a large-scale longitudinal parasite genotyping study of samples from a clinical trial exploring how vaccine dosing regimen affects vaccine efficacy.<br><br>METHODS: Between Sept 28, 2017, and Sept 25, 2018, 1500 children aged 5-17 months were randomly assigned (1:1:1:1:1) to receive four different RTS,S/AS01E regimens or a rabies control vaccine in a phase 2b open-label clinical trial in Ghana and Kenya. Participants in the four RTS,S groups received two full doses at month 0 and month 1 and either full doses at month 2 and month 20 (group R012-20); full doses at month 2, month 14, month 26, and month 38 (group R012-14); fractional doses at month 2, month 14, month 26, and month 38 (group Fx012-14; early fourth dose); or fractional doses at month 7, month 20, and month 32 (group Fx017-20; delayed third dose). We evaluated the time to the first new genotypically detected infection and the total number of new infections during two follow-up periods (12 months and 20 months) in more than 36&#x2009;000 dried blood spot specimens from 1500 participants. To study vaccine effects on time to the first new infection, we defined vaccine efficacy as one minus the hazard ratio (HR; RTS,S vs control) of the first new infection. We performed a post-hoc analysis of vaccine efficacy based on malaria infection status at first vaccination and force of infection by month 2. This trial (MAL-095) is registered with ClinicalTrials.gov, NCT03281291.<br><br>FINDINGS: We observed significant and similar vaccine efficacy (25-43%; 95% CI union 9-53) against first new infection for all four RTS,S/AS01E regimens across both follow-up periods (12 months and 20 months). Each RTS,S/AS01E regimen significantly reduced the mean number of new infections in the 20-month follow-up period by 1&#xb7;1-1&#xb7;6 infections (95% CI union 0&#xb7;6-2&#xb7;1). Vaccine efficacy against first new infection was significantly higher in participants who were infected with malaria (68%; 95% CI 50-80) than in those who were uninfected (37%; 23-48) at the first vaccination (p=0&#xb7;0053).<br><br>INTERPRETATION: All tested dosing regimens blocked some infections to a similar degree. Improved vaccine efficacy in participants infected during vaccination could suggest new strategies for highly efficacious malaria vaccine development and implementation.<br><br>FUNDING: GlaxoSmithKline Biologicals SA, PATH, Bill &amp; Melinda Gates Foundation, and the German Federal Ministry of Education and Research.}, }
@article {pmid38723638, year = {2024}, author = {Verma, S and Dufort, MJ and Olsen, TM and Kimmel, S and Labuda, JC and Scharffenberger, S and McGuire, AT and Harrison, OJ}, title = {Antigen-level resolution of commensal-specific B cell responses can be enabled by phage display screening coupled with B cell tetramers.}, journal = {Immunity}, volume = {57}, number = {6}, pages = {1428-1441.e8}, pmid = {38723638}, issn = {1097-4180}, support = {R01 AI158624/AI/NIAID NIH HHS/United States ; R21 AI171921/AI/NIAID NIH HHS/United States ; T32 GM136534/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *B-Lymphocytes/immunology ; Mice ; Mice, Inbred C57BL ; Peyer's Patches/immunology ; Lymphocyte Activation/immunology ; Antigens, Bacterial/immunology ; Somatic Hypermutation, Immunoglobulin ; Peptide Library ; Lymph Nodes/immunology ; Cell Surface Display Techniques ; Symbiosis/immunology ; Immunoglobulin G/immunology ; Immunoglobulin A/immunology ; }, abstract = {Induction of commensal-specific immunity contributes to tissue homeostasis, yet the mechanisms underlying induction of commensal-specific B cells remain poorly understood in part due to a lack of tools to identify these cells. Using phage display, we identified segmented filamentous bacteria (SFB) antigens targeted by serum and intestinal antibodies and generated B cell tetramers to track SFB-specific B cells in gut-associated lymphoid tissues. We revealed a compartmentalized response in SFB-specific B cell activation, with a gradient of immunoglobulin A (IgA), IgG1, and IgG2b isotype production along Peyer's patches contrasted by selective production of IgG2b within mesenteric lymph nodes. V(D)J sequencing and monoclonal antibody generation identified somatic hypermutation driven affinity maturation to SFB antigens under homeostatic conditions. Combining phage display and B cell tetramers will enable investigation of the ontogeny and function of commensal-specific B cell responses in tissue immunity, inflammation, and repair.}, }
@article {pmid38723632, year = {2024}, author = {Dareng, EO and Coetzee, SG and Tyrer, JP and Peng, PC and Rosenow, W and Chen, S and Davis, BD and Dezem, FS and Seo, JH and Nameki, R and Reyes, AL and Aben, KKH and Anton-Culver, H and Antonenkova, NN and Aravantinos, G and Bandera, EV and Beane Freeman, LE and Beckmann, MW and Beeghly-Fadiel, A and Benitez, J and Bernardini, MQ and Bjorge, L and Black, A and Bogdanova, NV and Bolton, KL and Brenton, JD and Budzilowska, A and Butzow, R and Cai, H and Campbell, I and Cannioto, R and Chang-Claude, J and Chanock, SJ and Chen, K and Chenevix-Trench, G and ,  and Chiew, YE and Cook, LS and DeFazio, A and Dennis, J and Doherty, JA and Dörk, T and du Bois, A and Dürst, M and Eccles, DM and Ene, G and Fasching, PA and Flanagan, JM and Fortner, RT and Fostira, F and Gentry-Maharaj, A and Giles, GG and Goodman, MT and Gronwald, J and Haiman, CA and Håkansson, N and Heitz, F and Hildebrandt, MAT and Høgdall, E and Høgdall, CK and Huang, RY and Jensen, A and Jones, ME and Kang, D and Karlan, BY and Karnezis, AN and Kelemen, LE and Kennedy, CJ and Khusnutdinova, EK and Kiemeney, LA and Kjaer, SK and Kupryjanczyk, J and Labrie, M and Lambrechts, D and Larson, MC and Le, ND and Lester, J and Li, L and Lubiński, J and Lush, M and Marks, JR and Matsuo, K and May, T and McLaughlin, JR and McNeish, IA and Menon, U and Missmer, S and Modugno, F and Moffitt, M and Monteiro, AN and Moysich, KB and Narod, SA and Nguyen-Dumont, T and Odunsi, K and Olsson, H and Onland-Moret, NC and Park, SK and Pejovic, T and Permuth, JB and Piskorz, A and Prokofyeva, D and Riggan, MJ and Risch, HA and Rodríguez-Antona, C and Rossing, MA and Sandler, DP and Setiawan, VW and Shan, K and Song, H and Southey, MC and Steed, H and Sutphen, R and Swerdlow, AJ and Teo, SH and Terry, KL and Thompson, PJ and Vestrheim Thomsen, LC and Titus, L and Trabert, B and Travis, R and Tworoger, SS and Valen, E and Van Nieuwenhuysen, E and Edwards, DV and Vierkant, RA and Webb, PM and ,  and Weinberg, CR and Weise, RM and Wentzensen, N and White, E and Winham, SJ and Wolk, A and Woo, YL and Wu, AH and Yan, L and Yannoukakos, D and Zeinomar, N and Zheng, W and Ziogas, A and Berchuck, A and Goode, EL and Huntsman, DG and Pearce, CL and Ramus, SJ and Sellers, TA and ,  and Freedman, ML and Lawrenson, K and Schildkraut, JM and Hazelett, D and Plummer, JT and Kar, S and Jones, MR and Pharoah, PDP and Gayther, SA}, title = {Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions.}, journal = {American journal of human genetics}, volume = {111}, number = {6}, pages = {1061-1083}, pmid = {38723632}, issn = {1537-6605}, support = {R00 CA256519/CA/NCI NIH HHS/United States ; R01 CA211707/CA/NCI NIH HHS/United States ; R21 CA220078/CA/NCI NIH HHS/United States ; P30 CA015083/CA/NCI NIH HHS/United States ; R01 CA248288/CA/NCI NIH HHS/United States ; R01 CA207456/CA/NCI NIH HHS/United States ; R01 CA211575/CA/NCI NIH HHS/United States ; K08 CA241318/CA/NCI NIH HHS/United States ; P50 CA136393/CA/NCI NIH HHS/United States ; R01 CA204954/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Genome-Wide Association Study ; *Polymorphism, Single Nucleotide ; *Ovarian Neoplasms/genetics/pathology ; *Genetic Predisposition to Disease ; Carcinoma, Ovarian Epithelial/genetics ; Transcriptome ; Risk Factors ; Genomics/methods ; Case-Control Studies ; Multiomics ; }, abstract = {To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5 × 10[-8]) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value <10[-5]). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue datasets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (false discovery rate <0.05). Finally, by integrating genome-wide HiChIP interactome analysis with transcriptome-wide association study (TWAS), variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8, and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by a genome-wide association study.}, }
@article {pmid38722664, year = {2024}, author = {Kopmar, NE and Quach, K and Gooley, TA and Martino, CH and Cherian, S and Percival, MM and Halpern, AB and Ghiuzeli, CM and Oehler, VG and Abkowitz, JL and Walter, RB and Cassaday, RD}, title = {Dose-Adjusted EPOCH Plus Inotuzumab Ozogamicin in Adults With Relapsed or Refractory B-Cell ALL: A Phase 1 Dose-Escalation Trial.}, journal = {JAMA oncology}, volume = {10}, number = {7}, pages = {961-965}, pmid = {38722664}, issn = {2374-2445}, mesh = {Humans ; *Inotuzumab Ozogamicin/administration &amp; dosage ; Male ; Female ; Middle Aged ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects/administration &amp; dosage ; Adult ; *Etoposide/administration &amp; dosage/adverse effects ; *Doxorubicin/administration &amp; dosage/adverse effects ; *Cyclophosphamide/administration &amp; dosage/therapeutic use/adverse effects ; *Vincristine/administration &amp; dosage/adverse effects/therapeutic use ; *Prednisone/administration &amp; dosage/adverse effects/therapeutic use ; Aged ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/mortality/pathology ; Maximum Tolerated Dose ; Dose-Response Relationship, Drug ; }, abstract = {IMPORTANCE: Options for adults with relapsed or refractory B-cell acute lymphoblastic leukemia or lymphoma (B-ALL) are limited, and new approaches are needed. Inotuzumab ozogamicin (InO) has been combined with low-intensity chemotherapy, with modest improvements over historical controls, and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH) treatment is safe and active for newly diagnosed ALL.<br><br>OBJECTIVE: To assess the safety and clinical activity of DA-EPOCH and InO in adults with relapsed or refractory B-ALL.<br><br>This single-center, single-arm, nonrandomized, phase 1 dose-escalation trial included adults with relapsed or refractory CD22+ B-ALL and was conducted between September 2019 and November 2022. At least 5% blood or marrow blasts or measurable extramedullary disease (EMD) was required for enrollment.<br><br>INTERVENTIONS: DA-EPOCH was given on days 1 to 5, while InO was given on day 8 and day 15 of a 28-day cycle. Three dose levels were studied using a bayesian optimal interval design.<br><br>MAIN OUTCOMES AND MEASURES: The primary outcome was the maximum tolerated dose of InO when combined with DA-EPOCH, defined as the highest dose level that produced a rate of dose-limiting toxicity below 33%. Secondary objectives included response rates, survival estimates, and descriptions of toxic effects.<br><br>RESULTS: A total of 24 participants were screened and enrolled (median age, 46 [range, 28-76] years; 15 [62%] male). The median number of lines of prior therapy was 3 (range, 1-12). Three of 11 participants (27%) treated at the highest dose level (InO, 0.6 mg/m2, on day 8 and day 15) experienced dose-limiting toxicity, making this the maximum tolerated dose. No deaths occurred during the study, and only 1 patient (4%; 95% CI, 0.1%-21%) developed sinusoidal obstructive syndrome after poststudy allograft. The morphologic complete response rate was 84% (95% CI, 60%-97%), 88% (95% CI, 62%-98%) of which was measurable residual disease negative by flow cytometry. Five of 6 participants with EMD experienced treatment response. The overall response rate was 83% (95% CI, 63%-95%). Median overall survival, duration of response, and event-free survival were 17.0 (95% CI, 8.4-not reached), 15.0 (95% CI, 6.7-not reached), and 9.6 (95% CI, 4.5-not reached) months, respectively.<br><br>CONCLUSIONS: In this study, adding InO to DA-EPOCH in adults with relapsed or refractory B-ALL was feasible, with high response rates and sinusoidal obstructive syndrome occurring rarely in a heavily pretreated population. Many patients were able to proceed to poststudy consolidative allogeneic hematopoietic cell transplant and/or chimeric antigen receptor T-cell therapy. Further investigation of this combination is warranted.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03991884.}, }
@article {pmid38721745, year = {2024}, author = {Tarantelli, C and Wald, D and Munz, N and Spriano, F and Bruscaggin, A and Cannas, E and Cascione, L and Gaudio, E and Arribas, AJ and Manjappa, S and Golino, G and Scalise, L and Cacciapuoti, MT and Zucca, E and Stathis, A and Inghirami, G and Van Berkel, PH and Rossi, D and Caimi, PF and Zammarchi, F and Bertoni, F}, title = {Targeting CD19-positive lymphomas with the antibodydrug conjugate loncastuximab tesirine: preclinical evidence of activity as a single agent and in combination therapy.}, journal = {Haematologica}, volume = {109}, number = {10}, pages = {3314-3326}, pmid = {38721745}, issn = {1592-8721}, mesh = {Humans ; Animals ; Mice ; *Immunoconjugates/pharmacology/therapeutic use ; *Antigens, CD19/metabolism ; Cell Line, Tumor ; *Xenograft Model Antitumor Assays ; *Antineoplastic Combined Chemotherapy Protocols/pharmacology/therapeutic use ; Lymphoma/drug therapy/pathology/metabolism ; Drug Synergism ; Antibodies, Monoclonal, Humanized/pharmacology/therapeutic use ; Antibodies, Monoclonal/pharmacology ; Benzodiazepines ; }, abstract = {Antibody-drug conjugates (ADC) represent one of the most successful therapeutic approaches introduced into clinical practice in the last few years. Loncastuximab tesirine (ADCT-402) is a CD19-targeting ADC in which the antibody is conjugated through a protease cleavable dipeptide linker to a pyrrolobenzodiazepine dimer warhead (SG3199). Based on the results of a phase II study, loncastuximab tesirine was recently approved for adult patients with relapsed/refractory large B-cell lymphoma. We assessed the activity of loncastuximab tesirine using in vitro and in vivo models of lymphomas, correlated its activity with levels of CD19 expression, and identified combination partners providing synergy with the ADC. Loncastuximab tesirine was tested across 60 lymphoma cell lines. It had strong cytotoxic activity in B-cell lymphoma cell lines. The in vitro activity was correlated with the level of CD19 expression and intrinsic sensitivity of cell lines to the ADC's warhead. Loncastuximab tesirine was more potent than other anti-CD19 ADC (coltuximab ravtansine, huB4-DGN462), although the pattern of activity across cell lines was correlated. The activity of loncastuximab tesirine was also largely correlated with cell line sensitivity to R-CHOP. Combinatorial in vitro and in vivo experiments identified the benefit of adding loncastuximab tesirine to other agents, especially BCL2 and PI3K inhibitors. Our data support the further development of loncastuximab tesirine for use as a single agent and in combination for patients affected by mature B-cell neoplasms. The results also highlight the importance of CD19 expression and the existence of lymphoma populations characterized by resistance to multiple therapies.}, }
@article {pmid38721740, year = {2024}, author = {Rashidi, A}, title = {Cachexia during anti-leukemia chemotherapy: it is not "just" the chemo.}, journal = {Haematologica}, volume = {109}, number = {10}, pages = {3091-3093}, pmid = {38721740}, issn = {1592-8721}, mesh = {Humans ; *Cachexia/etiology/drug therapy ; Leukemia/drug therapy ; Antineoplastic Combined Chemotherapy Protocols/adverse effects/therapeutic use ; Antineoplastic Agents/adverse effects/therapeutic use ; }, }
@article {pmid38720547, year = {2024}, author = {Ruplin, A and Segal, E and McFarlane, T}, title = {Review of drug-drug interactions in patients with prostate cancer.}, journal = {Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners}, volume = {30}, number = {6}, pages = {1057-1072}, pmid = {38720547}, issn = {1477-092X}, mesh = {Humans ; *Drug Interactions ; Male ; *Prostatic Neoplasms/drug therapy ; *Antineoplastic Agents/therapeutic use/adverse effects/pharmacokinetics ; Polypharmacy ; }, abstract = {OBJECTIVE: The objective of this review is to provide an overview of common drug-drug interactions (DDIs) associated with prostate cancer treatments and outline recommendations for managing polypharmacy.<br><br>DATA SOURCES: A literature search of PubMed, Embase, and CINAHL was carried out to identify pharmacokinetic and pharmacodynamic changes caused by DDIs that are relevant for prostate cancer patients, DDIs between prostate cancer therapies and co-administered medications (both prescription and over-the-counter), and measures to prevent DDIs. Medication package inserts were used to identify the impact of DDI on the prostate cancer therapy and suggested interventions.<br><br>DATA SUMMARY: No DDIs are expected for the LHRH agonists leuprolide acetate, histrelin, goserelin, or leuprolide mesylate. However, DDIs have been reported for GnRH antagonists, anti-androgens, PARP inhibitors, and taxanes. Although there are no confirmed DDIs for sipuleucel-T to date, it is not generally recommended to use sipuleucel-T concurrently with immunosuppressive medications. Interventions to prevent DDIs include the use of software that can detect clinically significant DDIs, up-to-date medication reconciliation, the inclusion of dedicated clinical pharmacists in cancer treatment teams, and patient/caregiver education.<br><br>CONCLUSIONS: Prostate cancer patients have a high risk of potential DDIs due to numerous new anti-cancer therapies, the increased use of treatment combinations, and the likelihood of comorbid conditions also requiring drug therapy. Drug-drug interaction screening software, up-to-date medication reconciliation, inclusion of oncology pharmacists on healthcare teams, and patient/caregiver education will aid the development of treatment plans that focus on achieving an optimal risk-benefit profile whilst reducing the risk of DDIs.}, }
@article {pmid38720086, year = {2024}, author = {Desautels, TA and Arrildt, KT and Zemla, AT and Lau, EY and Zhu, F and Ricci, D and Cronin, S and Zost, SJ and Binshtein, E and Scheaffer, SM and Dadonaite, B and Petersen, BK and Engdahl, TB and Chen, E and Handal, LS and Hall, L and Goforth, JW and Vashchenko, D and Nguyen, S and Weilhammer, DR and Lo, JK and Rubinfeld, B and Saada, EA and Weisenberger, T and Lee, TH and Whitener, B and Case, JB and Ladd, A and Silva, MS and Haluska, RM and Grzesiak, EA and Earnhart, CG and Hopkins, S and Bates, TW and Thackray, LB and Segelke, BW and ,  and Lillo, AM and Sundaram, S and Bloom, JD and Diamond, MS and Crowe, JE and Carnahan, RH and Faissol, DM}, title = {Computationally restoring the potency of a clinical antibody against Omicron.}, journal = {Nature}, volume = {629}, number = {8013}, pages = {878-885}, pmid = {38720086}, issn = {1476-4687}, support = {75N93019C00051/AI/NIAID NIH HHS/United States ; 75N93019C00074/AI/NIAID NIH HHS/United States ; R01 AI141707/AI/NIAID NIH HHS/United States ; R01 AI157155/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Female ; Humans ; Mice ; *Antibodies, Monoclonal/chemistry/immunology ; *Antibodies, Neutralizing/chemistry/immunology ; *Antibodies, Viral/chemistry/immunology ; COVID-19/immunology/virology ; Mutation ; Neutralization Tests ; *SARS-CoV-2/classification/genetics/immunology ; Spike Glycoprotein, Coronavirus/chemistry/genetics/immunology ; DNA Mutational Analysis ; Antigenic Drift and Shift/genetics/immunology ; *Drug Design/methods ; *Computer Simulation ; }, abstract = {The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs[1-3] and revealed how quickly viral escape can curtail effective options[4,5]. When the SARS-CoV-2 Omicron variant emerged in 2021, many antibody drug products lost potency, including Evusheld and its constituent, cilgavimab[4-6]. Cilgavimab, like its progenitor COV2-2130, is a class 3 antibody that is compatible with other antibodies in combination[4] and is challenging to replace with existing approaches. Rapidly modifying such high-value antibodies to restore efficacy against emerging variants is a compelling mitigation strategy. We sought to redesign and renew the efficacy of COV2-2130 against Omicron BA.1 and BA.1.1 strains while maintaining efficacy against the dominant Delta variant. Here we show that our computationally redesigned antibody, 2130-1-0114-112, achieves this objective, simultaneously increases neutralization potency against Delta and subsequent variants of concern, and provides protection in vivo against the strains tested: WA1/2020, BA.1.1 and BA.5. Deep mutational scanning of tens of thousands of pseudovirus variants reveals that 2130-1-0114-112 improves broad potency without increasing escape liabilities. Our results suggest that computational approaches can optimize an antibody to target multiple escape variants, while simultaneously enriching potency. Our computational approach does not require experimental iterations or pre-existing binding data, thus enabling rapid response strategies to address escape variants or lessen escape vulnerabilities.}, }
@article {pmid38718133, year = {2024}, author = {Olayiwola, O and Castillejo, A and Louella, M and Supercharger, M and Harlow, E and Dee, L and Abdallah, K and Kityo-Mutuluuza, C and Adair, JE and Orentas, R and Dubé, K}, title = {Nothing about us without us: Advocacy and engagement in genetic medicine.}, journal = {Science translational medicine}, volume = {16}, number = {746}, pages = {eadn2401}, doi = {10.1126/scitranslmed.adn2401}, pmid = {38718133}, issn = {1946-6242}, mesh = {Humans ; *Patient Advocacy ; *Anemia, Sickle Cell/genetics ; Genetic Therapy ; }, abstract = {The development of new genetic medicines to treat sickle cell disease highlights the need for greater collaboration between researchers and people with lived experiences. Drawing on the adage "Nothing about us, without us," we call for increased investments in community advocacy and engagement.}, }
@article {pmid38718130, year = {2024}, author = {Doxzen, KW and Adair, JE and Fonseca Bazzo, YM and Bukini, D and Cornetta, K and Dalal, V and Guerino-Cunha, RL and Hongeng, S and Jotwani, G and Kityo-Mutuluuza, C and Lakshmanan, K and Mahlangu, J and Makani, J and Mathews, V and Ozelo, MC and Rangarajan, S and Scholefield, J and Batista Silva Júnior, J and McCune, JM}, title = {The translational gap for gene therapies in low- and middle-income countries.}, journal = {Science translational medicine}, volume = {16}, number = {746}, pages = {eadn1902}, doi = {10.1126/scitranslmed.adn1902}, pmid = {38718130}, issn = {1946-6242}, mesh = {Humans ; *Genetic Therapy ; *Developing Countries ; *Translational Research, Biomedical ; }, abstract = {Gene therapies are designed to address the root cause of disease. As scientific understanding of disease prevention, diagnosis, and treatment improves in tandem with technological innovation, gene therapies have the potential to become safe and effective treatment options for a wide range of genetic and nongenetic diseases. However, as the medical scope of gene therapies expands, consideration must be given to those who will benefit and what proactive steps must be taken to widen development and access potential, particularly in regions carrying a high disease burden.}, }
@article {pmid38716804, year = {2024}, author = {Nakasone, ES and Zemla, TJ and Yu, M and Lin, SY and Ou, FS and Carter, K and Innocenti, F and Saltz, L and Grady, WM and Cohen, SA}, title = {Evaluating the utility of ZNF331 promoter methylation as a prognostic and predictive marker in stage III colon cancer: results from CALGB 89803 (Alliance).}, journal = {Epigenetics}, volume = {19}, number = {1}, pages = {2349980}, pmid = {38716804}, issn = {1559-2308}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *DNA Methylation ; Female ; *Promoter Regions, Genetic ; *Colonic Neoplasms/genetics/pathology ; Male ; Middle Aged ; *Biomarkers, Tumor/genetics/metabolism ; Aged ; Prognosis ; Neoplasm Staging ; Transcription Factors/genetics/metabolism ; Adult ; Trefoil Factor-3 ; }, abstract = {While epigenomic alterations are common in colorectal cancers (CRC), few epigenomic biomarkers that risk-stratify patients have been identified. We thus sought to determine the potential of ZNF331 promoter hypermethylation (mZNF331) as a prognostic and predictive marker in colon cancer. We examined the association of mZNF331 with clinicopathologic features, relapse, survival, and treatment efficacy in patients with stage III colon cancer treated within a randomized adjuvant chemotherapy trial (CALGB/Alliance89803). Residual tumour tissue was available for genomic DNA extraction and methylation analysis for 385 patients. ZNF331 promoter methylation status was determined by bisulphite conversion and fluorescence-based real-time polymerase chain reaction. Kaplan-Meier estimator and Cox proportional hazard models were used to assess the prognostic and predictive role of mZNF331 in this well-annotated dataset, adjusting for clinicopathologic features and standard molecular markers. mZNF331 was observed in 267/385 (69.4%) evaluable cases. Histopathologic features were largely similar between patients with mZNF331 compared to unmethylated ZNF331 (unmZNFF31). There was no significant difference in disease-free or overall survival between patients with mZNF331 versus unmZNF331 colon cancers, even when adjusting for clinicopathologic features and molecular marker status. Similarly, there was no difference in disease-free or overall survival across treatment arms when stratified by ZNF331 methylation status. While ZNF331 promoter hypermethylation is frequently observed in CRC, our current study of a small subset of patients with stage III colon cancer suggests limited applicability as a prognostic marker. Larger studies may provide more insight and clarity into the applicability of mZNF331 as a prognostic and predictive marker.}, }
@article {pmid38716731, year = {2024}, author = {Cross, DL and Layton, ED and Yu, KK and Smith, MT and Aguilar, MS and Li, S and Wilcox, EC and Chapuis, AG and Mayanja-Kizza, H and Stein, CM and Boom, WH and Hawn, TR and Bradley, P and Newell, EW and Seshadri, C}, title = {MR1-restricted T cell clonotypes are associated with "resistance" to Mycobacterium tuberculosis infection.}, journal = {JCI insight}, volume = {9}, number = {9}, pages = {}, pmid = {38716731}, issn = {2379-3708}, support = {R01 AI124348/AI/NIAID NIH HHS/United States ; 75N93019C00071/AI/NIAID NIH HHS/United States ; 75N93022D00005/AI/NIAID NIH HHS/United States ; 75N99020D00005/OF/ORFDO NIH HHS/United States ; R01 AI146072/AI/NIAID NIH HHS/United States ; 75N95020D00005/DA/NIDA NIH HHS/United States ; 75N93023D00005/AI/NIAID NIH HHS/United States ; 75N92020D00005/HL/NHLBI NIH HHS/United States ; R01 AI125189/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Mycobacterium tuberculosis/immunology ; Uganda ; Adult ; Male ; Minor Histocompatibility Antigens/immunology/genetics ; Female ; Tuberculosis/immunology/microbiology ; T-Lymphocytes/immunology ; Latent Tuberculosis/immunology/microbiology ; Clone Cells/immunology ; Disease Resistance/immunology/genetics ; Young Adult ; Histocompatibility Antigens Class I ; }, abstract = {T cells are required for protective immunity against Mycobacterium tuberculosis. We recently described a cohort of Ugandan household contacts of tuberculosis cases who appear to "resist" M. tuberculosis infection (resisters; RSTRs) and showed that these individuals harbor IFN-γ-independent T cell responses to M. tuberculosis-specific peptide antigens. However, T cells also recognize nonprotein antigens via antigen-presenting systems that are independent of genetic background, known as donor-unrestricted T cells (DURTs). We used tetramer staining and flow cytometry to characterize the association between DURTs and "resistance" to M. tuberculosis infection. Peripheral blood frequencies of most DURT subsets were comparable between RSTRs and latently infected controls (LTBIs). However, we observed a 1.65-fold increase in frequency of MR1-restricted T (MR1T) cells among RSTRs in comparison with LTBIs. Single-cell RNA sequencing of 18,251 MR1T cells sorted from 8 donors revealed 5,150 clonotypes that expressed a common transcriptional program, the majority of which were private. Sequencing of the T cell receptor α/T cell receptor δ (TCRα/δ) repertoire revealed several DURT clonotypes were expanded among RSTRs, including 2 MR1T clonotypes that recognized mycobacteria-infected cells in a TCR-dependent manner. Overall, our data reveal unexpected donor-specific diversity in the TCR repertoire of human MR1T cells as well as associations between mycobacteria-reactive MR1T clonotypes and resistance to M. tuberculosis infection.}, }
@article {pmid38714703, year = {2024}, author = {Pershad, Y and Mack, T and Poisner, H and Jakubek, YA and Stilp, AM and Mitchell, BD and Lewis, JP and Boerwinkle, E and Loos, RJF and Chami, N and Wang, Z and Barnes, K and Pankratz, N and Fornage, M and Redline, S and Psaty, BM and Bis, JC and Shojaie, A and Silverman, EK and Cho, MH and Yun, JH and DeMeo, D and Levy, D and Johnson, AD and Mathias, RA and Taub, MA and Arnett, D and North, KE and Raffield, LM and Carson, AP and Doyle, MF and Rich, SS and Rotter, JI and Guo, X and Cox, NJ and Roden, DM and Franceschini, N and Desai, P and Reiner, AP and Auer, PL and Scheet, PA and Jaiswal, S and Weinstock, JS and Bick, AG}, title = {Determinants of mosaic chromosomal alteration fitness.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {3800}, pmid = {38714703}, issn = {2041-1723}, support = {R01 HL105756/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; R01 AG083736/AG/NIA NIH HHS/United States ; T32 GM007347/GM/NIGMS NIH HHS/United States ; R01 MD012765/MD/NIMHD NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; DP5 OD029586/OD/NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; R01 DK117445/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; *Mosaicism ; *Chromosome Aberrations ; *Clonal Hematopoiesis/genetics ; Male ; Female ; Genome-Wide Association Study ; Janus Kinase 2/genetics ; Telomerase/genetics/metabolism ; Loss of Heterozygosity ; Cross-Sectional Studies ; Mutation ; Middle Aged ; Hematopoietic Stem Cells/metabolism ; Polymorphism, Single Nucleotide ; Aged ; }, abstract = {Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (R[2] = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using population-level distributions of clonal fraction. Among individuals with JAK2 V617F clonal hematopoiesis of indeterminate potential or mCAs affecting the JAK2 gene on chromosome 9, PACER score was strongly correlated with erythrocyte count. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified a TCL1A locus variant associated with mCA clonal expansion rate, with suggestive variants in NRIP1 and TERT.}, }
@article {pmid38714193, year = {2024}, author = {Chakrabarti, R and Gillespie, K and Walke, JT and Fernandes, M and Almeida, A and Chery-Karschney, L and Kanjee, U and Skillman, KM and White, J and Babar, PH and Pereira, L and Mascarenhas, A and Vaz, M and Khandeparkar, A and Gomes, E and Janes, H and Rathod, PK and Duraisingh, MT}, title = {Descriptive, Hospital-Based, 10-Year Study of Malaria Transmission in Goa, a Southwest Indian State in the Malaria Elimination Phase.}, journal = {The American journal of tropical medicine and hygiene}, volume = {111}, number = {1}, pages = {11-25}, pmid = {38714193}, issn = {1476-1645}, support = {U19 AI089688/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; India/epidemiology ; Adolescent ; Female ; Adult ; Male ; Child ; Middle Aged ; Young Adult ; Child, Preschool ; Infant ; *Malaria/transmission/epidemiology/prevention &amp; control ; Aged ; Seasons ; Hospitals/statistics &amp; numerical data ; Disease Eradication ; Malaria, Falciparum/epidemiology/transmission/prevention &amp; control ; }, abstract = {The South Asia International Center of Excellence for Malaria Research, an NIH-funded collaborative program, investigated the epidemiology of malaria in the Indian state of Goa through health facility-based data collected from the Goa Medical College and Hospital (GMC), the state's largest tertiary healthcare facility, between 2012 and 2021. Our study investigated region-specific spatial and temporal patterns of malaria transmission in Goa and the factors driving such patterns. Over the past decade, the number of malaria cases, inpatients, and deaths at the GMC decreased significantly after a peak in 2014-2015. However, the proportion of severe malaria cases increased over the study period. Also, a trend of decreasing average parasitemia and increasing average gametocyte density suggests a shift toward submicroscopic infections and an increase in transmission commitment characteristic of low-transmission regions. Although transmission occurred throughout the year, 75% of the cases occurred between June and December, overlapping with the monsoon (June-October), which featured rainfall above yearly average, minimal diurnal temperature variation, and high relative humidity. Sociodemographic factors also had a significant association with malaria cases, with cases being more frequent in the 15-50-year-old age group, men, construction workers, and people living in urban areas within the GMC catchment region. Our environmental model of malaria transmission projects almost negligible transmission at the beginning of 2025 (annual parasitic index: 0.0095, 95% CI: 0.0075-0.0114) if the current control measures continue undisrupted.}, }
@article {pmid38714104, year = {2024}, author = {Bantjes, J and Hunt, X and Cuijpers, P and Kazdin, AE and Kennedy, CJ and Luedtke, A and Malenica, I and Petukhova, M and Sampson, N and Zainal, NH and Davids, C and Dunn-Coetzee, M and Gerber, R and Stein, DJ and Kessler, RC}, title = {Comparative effectiveness of remote digital gamified and group CBT skills training interventions for anxiety and depression among college students: Results of a three-arm randomised controlled trial.}, journal = {Behaviour research and therapy}, volume = {178}, number = {}, pages = {104554}, doi = {10.1016/j.brat.2024.104554}, pmid = {38714104}, issn = {1873-622X}, mesh = {Humans ; *Cognitive Behavioral Therapy/methods ; Female ; Male ; Young Adult ; *Students/psychology ; Depression/therapy/psychology ; Adult ; Adolescent ; Treatment Outcome ; Psychotherapy, Group/methods ; Anxiety Disorders/therapy ; Anxiety/therapy/psychology ; Universities ; South Africa ; Mobile Applications ; Depressive Disorder/therapy/psychology ; }, abstract = {Digital interventions can enhance access to healthcare in under-resourced settings. However, guided digital interventions may be costly for low- and middle-income countries, despite their effectiveness. In this randomised control trial, we evaluated the effectiveness of two digital interventions designed to address this issue: (1) a Cognitive Behavioral Therapy Skills Training (CST) intervention that increased scalability by using remote online group administration; and (2) the SuperBetter gamified self-guided CBT skills training app, which uses other participants rather than paid staff as guides. The study was implemented among anxious and/or depressed South African undergraduates (n = 371) randomised with equal allocation to Remote Group CST, SuperBetter, or a MoodFlow mood monitoring control. Symptoms were assessed with the Generalized Anxiety Disorder-7 (GAD-7) and the Patient Health Questionnaire-9 (PHQ-9). Intention-to-treat analysis found effect sizes at the high end of prior digital intervention trials, including significantly higher adjusted risk differences (ARD; primary outcome) in joint anxiety/depression remission at 3-months and 6-months for Remote Group CST (ARD = 23.3-18.9%, p = 0.001-0.035) and SuperBetter (ARD = 12.7-22.2%, p = 0.047-0.006) than MoodFlow and mean combined PHQ-9/GAD-7 scores (secondary outcome) significantly lower for Remote Group CST and SuperBetter than MoodFlow. These results illustrate how innovative delivery methods can increase the scalability of standard one-on-one guided digital interventions. PREREGISTRATION INTERNATIONAL STANDARD RANDOMISED CONTROLLED TRIAL NUMBER (ISRTCN) SUBMISSION #: 47,089,643.}, }
@article {pmid38713891, year = {2024}, author = {Byrne, EH and Song, H and Srinivasan, S and Fredricks, DN and Reed, SD and Guthrie, KA and Wu, M and Mitchell, CM}, title = {Association between vaginal microbiota and vaginal inflammatory immune markers in postmenopausal women.}, journal = {Menopause (New York, N.Y.)}, volume = {31}, number = {7}, pages = {575-581}, pmid = {38713891}, issn = {1530-0374}, support = {R01 AG048209/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Female ; *Vagina/microbiology/immunology ; *Postmenopause ; Middle Aged ; *Microbiota ; *Biomarkers ; *Inflammation ; Cytokines ; Lactobacillus ; RNA, Ribosomal, 16S/genetics ; Estradiol ; Aged ; }, abstract = {OBJECTIVE: In premenopausal individuals, vaginal microbiota diversity and lack of Lactobacillus dominance are associated with greater mucosal inflammation, which is linked to a higher risk of cervical dysplasia and infections. It is not known if the association between the vaginal microbiota and inflammation is present after menopause, when the vaginal microbiota is generally higher-diversity and fewer people have Lactobacillus dominance.<br><br>METHODS: This is a post hoc analysis of a subset of postmenopausal individuals enrolled in a randomized trial for treatment of moderate-severe vulvovaginal discomfort that compared vaginal moisturizer, estradiol, or placebo. Vaginal fluid samples from 0, 4, and 12 weeks were characterized using 16S rRNA gene sequencing (microbiota) and MesoScale Discovery (vaginal fluid immune markers: IL-1b, IL-1a, IL-2, IL-6, IL-18, IL-10, IL-9, IL-13, IL-8, IP10, MIP1a, MIP1b, MIP3a). Global associations between cytokines and microbiota (assessed by relative abundance of individual taxa and Shannon index for alpha, or community, diversity) were explored, adjusting for treatment arm, using linear mixed models, principal component analysis, and Generalized Linear Mixed Model + Microbiome Regression-based Kernel Association Test (GLMM-MiRKAT).<br><br>RESULTS: A total of 119 individuals with mean age of 61 years were included. At baseline, 29.5% of participants had a Lactobacillus -dominant vaginal microbiota. Across all timepoints, alpha diversity (Shannon index, P = 0.003) was highly associated with immune markers. Individual markers that were associated with Lactobacillus dominance were similar to those observed in premenopausal people: IL-10, IL-1b, IL-6, IL-8 (false discovery rate [FDR] < 0.01), IL-13 (FDR = 0.02), and IL-2 (FDR = 0.09). Over 12 weeks, change in alpha diversity was associated with change in cytokine concentration (Shannon, P = 0.018), with decreased proinflammatory cytokine concentrations observed with decreasing alpha diversity.<br><br>CONCLUSIONS: In this cohort of postmenopausal individuals, Lactobacillus dominance and lower alpha diversity were associated with lower concentrations of inflammatory immune markers, as has been reported in premenopausal people. This suggests that after menopause lactobacilli continue to have beneficial effects on vaginal immune homeostasis, despite lower prevalence.}, }
@article {pmid38713408, year = {2024}, author = {Moser, JC and Bhatia, S and Amin, A and Pavlick, AC and Betts, KA and Du, EX and Poretta, T and Shelley, K and Srinivasan, S and Sakkal, LA and Palaia, J and Lobo, M and Pe Benito, M and Linton, JA and Chen, Y and Xu, C and Yin, L and Sundar, M and Weber, J}, title = {Clinical outcomes of adjuvant nivolumab in resected stage III melanoma: comparison of CheckMate 238 trial and real-world data.}, journal = {Cancer immunology, immunotherapy : CII}, volume = {73}, number = {7}, pages = {116}, pmid = {38713408}, issn = {1432-0851}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Antineoplastic Agents, Immunological/therapeutic use ; Chemotherapy, Adjuvant/methods ; *Melanoma/drug therapy/mortality/pathology/surgery ; *Neoplasm Staging ; *Nivolumab/therapeutic use ; Skin Neoplasms/drug therapy/mortality/pathology/surgery ; Treatment Outcome ; }, abstract = {OBJECTIVES: Nivolumab is approved as adjuvant therapy for resected stage III/IV melanoma based on the phase 3 CheckMate 238 trial. This analysis compared outcomes from CheckMate 238 with those from the real-world Flatiron Health electronic health record-derived de-identified database in patients with resected stage III melanoma (per AJCC-8) treated with adjuvant nivolumab.<br><br>MATERIALS: Outcomes included baseline characteristics, overall survival (OS) in the CheckMate 238 cohort (randomization until death or last known alive), and real-world overall survival (rwOS) in the Flatiron Health cohort (nivolumab initiation until death or data cutoff). rwOS was compared with OS using unadjusted and adjusted Cox proportional hazards models. Inverse probability of treatment weighting (IPTW) was combined with the adjusted model to reduce baseline discrepancies.<br><br>RESULTS: The CheckMate 238 and real-world cohorts included 369 and 452 patients, respectively (median age, 56.0 and 63.0&#xa0;years; median follow-up, 61.4 vs. 25.5&#xa0;months). rwOS was not different from OS in the unadjusted (hazard ratio [HR] 1.27; 95% CI 0.92-1.74), adjusted (HR 1.01; 95% CI 0.67-1.54), and adjusted IPTW (HR 1.07; 95% CI 0.70-1.63) analyses. In the adjusted analysis, 2-year OS and rwOS rates were 84%. Median OS and rwOS were not reached. After IPTW, OS and rwOS were not different (HR 1.07; 95% CI 0.70-1.64).<br><br>CONCLUSIONS: In this comparative analysis, OS in the CheckMate 238 trial was similar to rwOS in the Flatiron Health database after adjustments in patients with resected stage III melanoma (per AJCC-8) treated with adjuvant nivolumab, validating the trial results.}, }
@article {pmid38712673, year = {2024}, author = {Ravandi, F and Subklewe, M and Walter, RB and Vachhani, P and Ossenkoppele, G and Buecklein, V and Döhner, H and Jongen-Lavrencic, M and Baldus, CD and Fransecky, L and Pardee, TS and Kantarjian, H and Yen, PK and Mukundan, L and Panwar, B and Yago, MR and Agarwal, S and Khaldoyanidi, SK and Stein, A}, title = {Safety and tolerability of AMG 330 in adults with relapsed/refractory AML: a phase 1a dose-escalation study.}, journal = {Leukemia &amp; lymphoma}, volume = {65}, number = {9}, pages = {1281-1291}, doi = {10.1080/10428194.2024.2346755}, pmid = {38712673}, issn = {1029-2403}, mesh = {Humans ; Male ; *Leukemia, Myeloid, Acute/drug therapy/pathology/diagnosis ; Female ; Middle Aged ; Adult ; Aged ; *Antibodies, Bispecific/administration &amp; dosage/adverse effects/therapeutic use ; Treatment Outcome ; Young Adult ; Maximum Tolerated Dose ; Drug Resistance, Neoplasm/drug effects ; Sialic Acid Binding Ig-like Lectin 3/metabolism ; Recurrence ; Aged, 80 and over ; Neoplasm Recurrence, Local/drug therapy/pathology ; Dose-Response Relationship, Drug ; Cytokine Release Syndrome/etiology ; }, abstract = {AMG 330, a bispecific T-cell engager (BiTE®) that binds CD33 and CD3 on T cells facilitates T-cell-mediated cytotoxicity against CD33+ cells. This first-in-human, open-label, dose-escalation study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of AMG 330 in adults with relapsed/refractory acute myeloid leukemia (R/R AML). Amongst 77 patients treated with AMG 330 (0.5 µg/day-1.6 mg/day) on 14-day or 28-day cycles, maximum tolerated dose was not reached; median duration of treatment was 29 days. The most frequent treatment-related adverse events were cytokine release syndrome (CRS; 78%) and rash (30%); 10% of patients experienced grade 3/4 CRS. CRS was mitigated with stepwise dosing of AMG 330, prophylactic dexamethasone, and early treatment with tocilizumab. Among 60 evaluable patients, eight achieved complete remission or morphologic leukemia-free state; of the 52 non-responders, 37% had ≥50% reduction in AML bone marrow blasts. AMG 330 is a promising CD33-targeted therapeutic strategy for R/R AML.}, }
@article {pmid38712512, year = {2024}, author = {Magee, AF and Holbrook, AJ and Pekar, JE and Caviedes-Solis, IW and Matsen Iv, FA and Baele, G and Wertheim, JO and Ji, X and Lemey, P and Suchard, MA}, title = {Random-Effects Substitution Models for Phylogenetics via Scalable Gradient Approximations.}, journal = {Systematic biology}, volume = {73}, number = {3}, pages = {562-578}, pmid = {38712512}, issn = {1076-836X}, support = {K25 AI153816/AI/NIAID NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; 725422-ReservoirDOCS/ERC_/European Research Council/International ; C14/18/094//KU Leuven/ ; }, mesh = {*Phylogeny ; *Classification/methods ; SARS-CoV-2/genetics/classification ; Influenza A Virus, H3N2 Subtype/genetics/classification ; Models, Genetic ; Markov Chains ; Bayes Theorem ; }, abstract = {Phylogenetic and discrete-trait evolutionary inference depend heavily on an appropriate characterization of the underlying character substitution process. In this paper, we present random-effects substitution models that extend common continuous-time Markov chain models into a richer class of processes capable of capturing a wider variety of substitution dynamics. As these random-effects substitution models often require many more parameters than their usual counterparts, inference can be both statistically and computationally challenging. Thus, we also propose an efficient approach to compute an approximation to the gradient of the data likelihood with respect to all unknown substitution model parameters. We demonstrate that this approximate gradient enables scaling of sampling-based inference, namely Bayesian inference via Hamiltonian Monte Carlo, under random-effects substitution models across large trees and state-spaces. Applied to a dataset of 583 SARS-CoV-2 sequences, an HKY model with random-effects shows strong signals of nonreversibility in the substitution process, and posterior predictive model checks clearly show that it is a more adequate model than a reversible model. When analyzing the pattern of phylogeographic spread of 1441 influenza A virus (H3N2) sequences between 14 regions, a random-effects phylogeographic substitution model infers that air travel volume adequately predicts almost all dispersal rates. A random-effects state-dependent substitution model reveals no evidence for an effect of arboreality on the swimming mode in the tree frog subfamily Hylinae. Simulations reveal that random-effects substitution models can accommodate both negligible and radical departures from the underlying base substitution model. We show that our gradient-based inference approach is over an order of magnitude more time efficient than conventional approaches.}, }
@article {pmid38712232, year = {2024}, author = {Crook, ZR and Sevilla, GP and Young, P and Girard, EJ and Phi, TD and Howard, M and Price, J and Olson, JM and Nairn, NW}, title = {CYpHER: Catalytic extracellular targeted protein degradation with high potency and durable effect.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38712232}, issn = {2692-8205}, support = {R01 CA223674/CA/NCI NIH HHS/United States ; }, abstract = {Many disease-causing proteins have multiple pathogenic mechanisms, and conventional inhibitors struggle to reliably disrupt more than one. Targeted protein degradation (TPD) can eliminate the protein, and thus all its functions, by directing a cell's protein turnover machinery towards it. Two established strategies either engage catalytic E3 ligases or drive uptake towards the endolysosomal pathway. Here we describe CYpHER (CatalYtic pH-dependent Endolysosomal delivery with Recycling) technology with potency and durability from a novel catalytic mechanism that shares the specificity and straightforward modular design of endolysosomal uptake. By bestowing pH-dependent release on the target engager and using the rapid-cycling transferrin receptor as the uptake receptor, CYpHER induces endolysosomal target delivery while re-using drug, potentially yielding increased potency and reduced off-target tissue exposure risks. The TfR-based approach allows targeting to tumors that overexpress this receptor and offers the potential for transport to the CNS. CYpHER function was demonstrated in vitro with EGFR and PD-L1, and in vivo with EGFR in a model of EGFR-driven non-small cell lung cancer.}, }
@article {pmid38712102, year = {2024}, author = {Belmont, L and Contreras, M and Cartwright-Acar, CH and Marceau, CD and Agrawal, A and Levoir, LM and Lubow, J and Goo, L}, title = {Functional genomics screens reveal a role for TBC1D24 and SV2B in antibody-dependent enhancement of dengue virus infection.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38712102}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; T32 AI083203/AI/NIAID NIH HHS/United States ; }, abstract = {Dengue virus (DENV) can hijack non-neutralizing IgG antibodies to facilitate its uptake into target cells expressing Fc gamma receptors (FcgR) - a process known as antibody-dependent enhancement (ADE) of infection. Beyond a requirement for FcgR, host dependency factors for this non-canonical infection route remain unknown. To identify cellular factors exclusively required for ADE, here, we performed CRISPR knockout screens in an in vitro system permissive to infection only in the presence of IgG antibodies. Validating our approach, a top hit was FcgRIIa, which facilitates binding and internalization of IgG-bound DENV but is not required for canonical infection. Additionally, we identified host factors with no previously described role in DENV infection, including TBC1D24 and SV2B, both of which have known functions in regulated secretion. Using genetic knockout and trans-complemented cells, we validated a functional requirement for these host factors in ADE assays performed with monoclonal antibodies and polyclonal sera in multiple cell lines and using all four DENV serotypes. We show that knockout of TBC1D24 or SV2B impaired binding of IgG-DENV complexes to cells without affecting FcgRIIa expression levels. Thus, we identify cellular factors beyond FcgR that are required for ADE of DENV infection. Our findings represent a first step towards advancing fundamental knowledge behind the biology of ADE that can ultimately be exploited to inform vaccination and therapeutic approaches.}, }
@article {pmid38712065, year = {2024}, author = {Jones, DC and Elz, AE and Hadadianpour, A and Ryu, H and Glass, DR and Newell, EW}, title = {Cell Simulation as Cell Segmentation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38712065}, issn = {2692-8205}, support = {P01 CA225517/CA/NCI NIH HHS/United States ; R01 CA264646/CA/NCI NIH HHS/United States ; U19 AI128914/AI/NIAID NIH HHS/United States ; }, abstract = {Single-cell spatial transcriptomics promises a highly detailed view of a cell's transcriptional state and microenvironment, yet inaccurate cell segmentation can render this data murky by misattributing large numbers of transcripts to nearby cells or conjuring nonexistent cells. We adopt methods from ab initio cell simulation to rapidly infer morphologically plausible cell boundaries that preserve cell type heterogeneity. Benchmarking applied to datasets generated by three commercial platforms show superior performance and computational efficiency of this approach compared with existing methods. We show that improved accuracy in cell segmentation aids greatly in detection of difficult to accurately segment tumor infiltrating immune cells such as neutrophils and T cells. Lastly, through improvements in our ability to delineate subsets of tumor infiltrating T cells, we show that CXCL13-expressing CD8+ T cells tend to be more closely associated with tumor cells than their CXCL13-negative counterparts in data generated from renal cell carcinoma patient samples.}, }
@article {pmid38711498, year = {2024}, author = {Schreiber, S and Dressler, LS and Loffredo-Verde, E and Asen, T and Färber, S and Wang, W and Groll, T and Chakraborty, A and Kolbe, F and Kreer, C and Kosinska, AD and Simon, S and Urban, S and Klein, F and Riddell, SR and Protzer, U}, title = {CARs derived from broadly neutralizing, human monoclonal antibodies identified by single B cell sorting target hepatitis B virus-positive cells.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1340619}, pmid = {38711498}, issn = {1664-3224}, mesh = {Humans ; *Hepatitis B virus/immunology/genetics ; Animals ; Mice ; *Hepatitis B Surface Antigens/immunology ; Receptors, Chimeric Antigen/immunology/genetics/metabolism ; Antibodies, Monoclonal/immunology ; Immunotherapy, Adoptive ; Hepatitis B/immunology/virology ; Broadly Neutralizing Antibodies/immunology ; B-Lymphocytes/immunology ; T-Lymphocytes/immunology ; }, abstract = {To design new CARs targeting hepatitis B virus (HBV), we isolated human monoclonal antibodies recognizing the HBV envelope proteins from single B cells of a patient with a resolved infection. HBV-specific memory B cells were isolated by incubating peripheral blood mononuclear cells with biotinylated hepatitis B surface antigen (HBsAg), followed by single-cell flow cytometry-based sorting of live, CD19[+] IgG[+] HBsAg[+] cells. Amplification and sequencing of immunoglobulin genes from single memory B cells identified variable heavy and light chain sequences. Corresponding immunoglobulin chains were cloned into IgG1 expression vectors and expressed in mammalian cells. Two antibodies named 4D06 and 4D08 were found to be highly specific for HBsAg, recognized a conformational and a linear epitope, respectively, and showed broad reactivity and neutralization capacity against all major HBV genotypes. 4D06 and 4D08 variable chain fragments were cloned into a 2[nd] generation CAR format with CD28 and CD3zeta intracellular signaling domains. The new CAR constructs displayed a high functional avidity when expressed on primary human T cells. CAR-grafted T cells proved to be polyfunctional regarding cytokine secretion and killed HBV-positive target cells. Interestingly, background activation of the 4D08-CAR recognizing a linear instead of a conformational epitope was consistently low. In a preclinical model of chronic HBV infection, murine T cells grafted with the 4D06 and the 4D08 CAR showed on target activity indicated by a transient increase in serum transaminases, and a lower number of HBV-positive hepatocytes in the mice treated. This study demonstrates an efficient and fast approach to identifying pathogen-specific monoclonal human antibodies from small donor cell numbers for the subsequent generation of new CARs.}, }
@article {pmid38710906, year = {2024}, author = {Prentice, RL}, title = {Competing risks and multivariate outcomes in epidemiological and clinical trial research.}, journal = {Lifetime data analysis}, volume = {30}, number = {3}, pages = {531-548}, pmid = {38710906}, issn = {1572-9249}, support = {P30CA015704/CA/NCI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; P30CA015704/CA/NCI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Clinical Trials as Topic ; Female ; Proportional Hazards Models ; Computer Simulation ; Survival Analysis ; Multivariate Analysis ; Models, Statistical ; }, abstract = {Data analysis methods for the study of treatments or exposures in relation to a clinical outcome in the presence of competing risks have a long history, often with inference targets that are hypothetical, thereby requiring strong assumptions for identifiability with available data. Here data analysis methods are considered that are based on single and higher dimensional marginal hazard rates, quantities that are identifiable under standard independent censoring assumptions. These lead naturally to joint survival function estimators for outcomes of interest, including competing risk outcomes, and provide the basis for addressing a variety of data analysis questions. These methods will be illustrated using simulations and Women's Health Initiative cohort and clinical trial data sets, and additional research needs will be described.}, }
@article {pmid38710483, year = {2024}, author = {Li, CI and Rogers, SC and Bult, CJ and Guerra, CE and Talton, A and Williams, LB and Law, W}, title = {Executing plans to enhance diversity across cancer centers in the United States: opportunities and challenges.}, journal = {Journal of the National Cancer Institute}, volume = {116}, number = {8}, pages = {1198-1205}, pmid = {38710483}, issn = {1460-2105}, support = {//Fred Hutchinson Cancer Center/ ; }, mesh = {Humans ; United States ; Cross-Sectional Studies ; *Cancer Care Facilities/organization &amp; administration/statistics &amp; numerical data ; *Cultural Diversity ; *National Cancer Institute (U.S.) ; Surveys and Questionnaires ; Leadership ; Neoplasms/epidemiology ; Male ; Female ; Biomedical Research/organization &amp; administration ; }, abstract = {BACKGROUND: Lack of diversity in the cancer research workforce persists, which the new requirement for all National Cancer Institute (NCI)-designated cancer centers to have a Plan to Enhance Diversity (PED) seeks to address. However, it is not well understood how different cancer centers are approaching the development and execution of these plans. Our objective was to assess how cancer centers are establishing and pursuing their PED.<br><br>METHODS: We conducted a cross-sectional survey of members of the Cancer Center Diversity, Equity and Inclusion Network, which includes all NCI-designated cancer centers and several emerging centers. A total of 62 cancer centers (75% of those invited), including 58 NCI-designated cancer centers (81% of those with this designation), participated and completed a questionnaire that assessed PED leadership, major challenges, implementation strategies, and approach to evaluate PED progress.<br><br>RESULTS: The most common PED challenge identified is recruiting diverse faculty (68% of centers), and the most common strategy currently used to address this is reviewing and revising faculty recruitment practices (67%). The most common approach centers are using to measure PED progress is shifts in demographics (68%), and data on the demographics of faculty, leadership, and trainees are available at 79%, 81%, and 75% of centers, respectively.<br><br>CONCLUSIONS: Almost all centers have established a PED leadership structure, however, there is considerable variation in the approaches used to realize PED goals and in the resources provided to support PED work. Realizing opportunities to share and implement common best practices and exemplar programs has the potential to elevate the impact of PED efforts nationally.}, }
@article {pmid38710302, year = {2024}, author = {Kopmar, NE and Othus, M and Quach, K and Rasmussen, A and Schonhoff, K and Becker, PS and Walter, RB and Halpern, AB and Salit, R and Cassaday, RD and Shustov, A and Stewart, FM and Oehler, VG and Scott, BL and Sandmaier, BM and Lee, SJ and Estey, EH and Percival, MM}, title = {Intensive Reinduction Chemotherapy Followed by Early Allogeneic Hematopoietic Cell Transplantation for Relapsed/Refractory High-Grade Myeloid Neoplasms.}, journal = {Transplantation and cellular therapy}, volume = {30}, number = {7}, pages = {727.e1-727.e8}, pmid = {38710302}, issn = {2666-6367}, support = {T32 HL007093/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/methods ; Middle Aged ; Male ; Adult ; Female ; Aged ; *Transplantation, Homologous ; Transplantation Conditioning/methods ; Cytarabine/therapeutic use/administration &amp; dosage ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Feasibility Studies ; Young Adult ; Cladribine/therapeutic use/administration &amp; dosage ; Mitoxantrone/therapeutic use/administration &amp; dosage ; Recurrence ; Adolescent ; }, abstract = {Outcomes for adults with relapsed/refractory (R/R) high-grade myeloid neoplasms remain poor, with allogeneic hematopoietic cell transplantation (HCT) the sole therapy likely to result in cure. We conducted the present study to determine the feasibility of early HCT-within 60 days of beginning reinduction chemotherapy-to see whether getting patients to HCT in an expeditious manner would expand the number of patients being offered this curative option. In this proof-of-principle feasibility study, we included adults age 18 to 75 years with R/R myeloid malignancies with ≥10% blood/marrow blasts at diagnosis who were eligible for a reduced-intensity HCT. Subjects received reinduction chemotherapy with cladribine, cytarabine, mitoxantrone, and filgrastim (CLAG-M) and proceeded to HCT with reduced-intensity conditioning (fludarabine/ melphalan). We enrolled 30 subjects, all of whom received CLAG-M reinduction, although only 9 underwent HCT within 60 days (<15, the predetermined threshold for feasibility "success"), with a median time to HCT of 48 days (range, 42 to 60 days). Eleven additional subjects received HCT beyond the target 60 days (off-study), with a median time to transplantation of 83 days (range, 53 to 367 days). Barriers to early HCT included infection, physician preference, lack of an HLA-matched donor, logistical delays, and disease progression, all of which may limit the real-world uptake of such early-to-transplantation protocols.}, }
@article {pmid38709898, year = {2024}, author = {Guo, H and Malone, KE and Heckbert, SR and Li, CI}, title = {Statin use and risks of breast cancer recurrence and mortality.}, journal = {Cancer}, volume = {130}, number = {18}, pages = {3106-3114}, doi = {10.1002/cncr.35362}, pmid = {38709898}, issn = {1097-0142}, support = {T32CA09168/CA/NCI NIH HHS/United States ; T32CA09168/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Breast Neoplasms/mortality/pathology/drug therapy ; Female ; *Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ; Aged ; *Neoplasm Recurrence, Local/prevention &amp; control/epidemiology ; Retrospective Studies ; Aged, 80 and over ; United States/epidemiology ; SEER Program ; Proportional Hazards Models ; Risk Factors ; }, abstract = {BACKGROUND: Preclinical evidence suggests improved breast cancer survival associated with statin use, but findings from observational studies are conflicting and remain inconclusive. The objective of this study was to assess the association between statin use after cancer diagnosis and cancer outcomes among breast cancer patients.<br><br>METHODS: In this retrospective cohort study, 38,858 women aged &#x2265;66 years who were diagnosed with localized and regional stage breast cancer from 2008 through 2017 were identified from the linked Surveillance, Epidemiology, and End Results Medicare database. Statin use was ascertained from Medicare Part D pharmacy claims data. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between post-diagnosis statin use and risks of breast cancer recurrence and breast cancer-specific mortality.<br><br>RESULTS: Over a median follow-up of 2.9 years for recurrence and 3.7 years for mortality, 1446 women experienced a recurrence, and 2215 died from breast cancer. The mean duration of post-diagnosis statin use was 2.2 years. Statin use post-diagnosis was not associated with recurrence risk (HR, 1.05; 95% CI, 0.91-1.21), but was associated with a reduced risk of cancer-specific mortality (HR, 0.85; 95% CI, 0.75-0.96). The reduction was more pronounced in women with hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer (HR, 0.71; 95% CI, 0.57-0.88).<br><br>CONCLUSIONS: These findings suggest that post-diagnosis statin use is associated with improved cancer-specific survival in women with breast cancer and should be confirmed in randomized trials of statin therapy in breast cancer patients.}, }
@article {pmid38709726, year = {2024}, author = {Balasingam, S and Dheda, K and Fortune, S and Gordon, SB and Hoft, D and Kublin, JG and Loynachan, CN and McShane, H and Morton, B and Nambiar, S and Sharma, NR and Robertson, B and Schrager, LK and Weller, CL}, title = {Review of Current Tuberculosis Human Infection Studies for Use in Accelerating Tuberculosis Vaccine Development: A Meeting Report.}, journal = {The Journal of infectious diseases}, volume = {230}, number = {2}, pages = {e457-e464}, pmid = {38709726}, issn = {1537-6613}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Tuberculosis/prevention &amp; control/immunology ; *Tuberculosis Vaccines/immunology/administration &amp; dosage ; Vaccine Development ; BCG Vaccine/immunology/administration &amp; dosage ; Mycobacterium tuberculosis/immunology ; Animals ; }, abstract = {Tools to evaluate and accelerate tuberculosis (TB) vaccine development are needed to advance global TB control strategies. Validated human infection studies for TB have the potential to facilitate breakthroughs in understanding disease pathogenesis, identify correlates of protection, develop diagnostic tools, and accelerate and de-risk vaccine and drug development. However, key challenges remain for realizing the clinical utility of these models, which require further discussion and alignment among key stakeholders. In March 2023, the Wellcome Trust and the International AIDS Vaccine Initiative convened international experts involved in developing both TB and bacillus Calmette-Guérin (BCG) human infection studies (including mucosal and intradermal challenge routes) to discuss the status of each of the models and the key enablers to move the field forward. This report provides a summary of the presentations and discussion from the meeting. Discussions identified key issues, including demonstrating model validity, to provide confidence for vaccine developers, which may be addressed through demonstration of known vaccine effects (eg, BCG vaccination in specific populations), and by comparing results from field efficacy and human infection studies. The workshop underscored the importance of establishing safe and acceptable studies in high-burden settings, and the need to validate >1 model to allow for different scientific questions to be addressed as well as to provide confidence to vaccine developers and regulators around use of human infection study data in vaccine development and licensure pathways.}, }
@article {pmid38709069, year = {2024}, author = {Sinicrope, FA and Nelson, GD and Saberzadeh-Ardestani, B and Segovia, DI and Graham, RP and Wu, C and Hagen, CE and Shivji, S and Savage, P and Buchanan, DD and Jenkins, MA and Phipps, AI and Swallow, C and LeMarchand, L and Gallinger, S and Grant, RC and Pai, RK and Sinicrope, SN and Yan, D and Shanmugam, K and Conner, J and Cyr, DP and Kirsch, R and Banerjee, I and Alberts, SR and Shi, Q and Pai, RK}, title = {Use of Deep Learning to Evaluate Tumor Microenvironmental Features for Prediction of Colon Cancer Recurrence.}, journal = {Cancer research communications}, volume = {4}, number = {5}, pages = {1344-1350}, pmid = {38709069}, issn = {2767-9764}, support = {U10 CA180821/CA/NCI NIH HHS/United States ; R01 CA210509/CA/NCI NIH HHS/United States ; Departments Engaging Research for InnoVation (DERIVE) award//Mayo Clinic (The Mayo Clinic)/ ; U01 CA167551/CA/NCI NIH HHS/United States ; U10 CA180882/CA/NCI NIH HHS/United States ; U10CA180821, U10CA180882, U24CA196171//HHS | NIH | NCI | Center for Cancer Research (CCR)/ ; U24 CA196171/CA/NCI NIH HHS/United States ; //Sanofi (Sanofi US)/ ; }, mesh = {Humans ; *Deep Learning ; *Colonic Neoplasms/pathology/genetics ; Male ; *Neoplasm Recurrence, Local/pathology ; Female ; *Tumor Microenvironment ; Middle Aged ; Aged ; *DNA Mismatch Repair ; Prognosis ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Fluorouracil/therapeutic use ; Leucovorin/therapeutic use ; Organoplatinum Compounds/therapeutic use ; Chemotherapy, Adjuvant ; }, abstract = {UNLABELLED: Deep learning may detect biologically important signals embedded in tumor morphologic features that confer distinct prognoses. Tumor morphologic features were quantified to enhance patient risk stratification within DNA mismatch repair (MMR) groups using deep learning. Using a quantitative segmentation algorithm (QuantCRC) that identifies 15 distinct morphologic features, we analyzed 402 resected stage III colon carcinomas [191 deficient (d)-MMR; 189 proficient (p)-MMR] from participants in a phase III trial of FOLFOX-based adjuvant chemotherapy. Results were validated in an independent cohort (176 d-MMR; 1,094 p-MMR). Association of morphologic features with clinicopathologic variables, MMR, KRAS, BRAFV600E, and time-to-recurrence (TTR) was determined. Multivariable Cox proportional hazards models were developed to predict TTR. Tumor morphologic features differed significantly by MMR status. Cancers with p-MMR had more immature desmoplastic stroma. Tumors with d-MMR had increased inflammatory stroma, epithelial tumor-infiltrating lymphocytes (TIL), high-grade histology, mucin, and signet ring cells. Stromal subtype did not differ by BRAFV600E or KRAS status. In p-MMR tumors, multivariable analysis identified tumor-stroma ratio (TSR) as the strongest feature associated with TTR [HRadj 2.02; 95% confidence interval (CI), 1.14-3.57; P = 0.018; 3-year recurrence: 40.2% vs. 20.4%; Q1 vs. Q2-4]. Among d-MMR tumors, extent of inflammatory stroma (continuous HRadj 0.98; 95% CI, 0.96-0.99; P = 0.028; 3-year recurrence: 13.3% vs. 33.4%, Q4 vs. Q1) and N stage were the most robust prognostically. Association of TSR with TTR was independently validated. In conclusion, QuantCRC can quantify morphologic differences within MMR groups in routine tumor sections to determine their relative contributions to patient prognosis, and may elucidate relevant pathophysiologic mechanisms driving prognosis.<br><br>SIGNIFICANCE: A deep learning algorithm can quantify tumor morphologic features that may reflect underlying mechanisms driving prognosis within MMR groups. TSR was the most robust morphologic feature associated with TTR in p-MMR colon cancers. Extent of inflammatory stroma and N stage were the strongest prognostic features in d-MMR tumors. TIL density was not independently prognostic in either MMR group.}, }
@article {pmid38704119, year = {2024}, author = {Crew, KD and Anderson, GL and Arnold, KB and Stieb, AP and Amenta, JN and Collins, N and Law, CW and Pruthi, S and Sandoval-Leon, A and Bertoni, D and Grosse Perdekamp, MT and Colonna, S and Krisher, S and King, T and Yee, LD and Ballinger, TJ and Braun-Inglis, C and Mangino, D and Wisinski, KB and DeYoung, CA and Ross, M and Floyd, J and Kaster, A and Vander Walde, L and Saphner, T and Zarwan, C and Lo, S and Graham, C and Conlin, A and Yost, K and Agnese, D and Jernigan, C and Hershman, DL and Neuhouser, ML and Arun, B and Kukafka, R}, title = {Making Informed Choices On Incorporating Chemoprevention into carE (MiCHOICE, SWOG 1904): Design and methods of a cluster randomized controlled trial.}, journal = {Contemporary clinical trials}, volume = {142}, number = {}, pages = {107564}, pmid = {38704119}, issn = {1559-2030}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; R01 CA226060/CA/NCI NIH HHS/United States ; UG1 CA189974/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Female ; Humans ; Middle Aged ; *Breast Neoplasms/prevention &amp; control ; *Chemoprevention/methods ; Decision Making ; Decision Support Techniques ; Estrogen Antagonists/therapeutic use/administration &amp; dosage ; Health Knowledge, Attitudes, Practice ; Patient Education as Topic/methods ; Patient Reported Outcome Measures ; Research Design ; Risk Reduction Behavior ; }, abstract = {INTRODUCTION: Women with atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS) have a significantly increased risk of breast cancer, which can be substantially reduced with antiestrogen therapy for chemoprevention. However, antiestrogen therapy for breast cancer risk reduction remains underutilized. Improving knowledge about breast cancer risk and chemoprevention among high-risk patients and their healthcare providers may enhance informed decision-making about this critical breast cancer risk reduction strategy.<br><br>METHODS/DESIGN: We are conducting a cluster randomized controlled trial to evaluate the effectiveness and implementation of patient and provider decision support tools to improve informed choice about chemoprevention among women with AH or LCIS. We have cluster randomized 26 sites across the U.S. through the SWOG Cancer Research Network. A total of 415 patients and 200 healthcare providers are being recruited. They are assigned to standard educational materials alone or combined with the web-based decision support tools. Patient-reported and clinical outcomes are assessed at baseline, after a follow-up visit at 6&#xa0;months, and yearly for 5&#xa0;years. The primary outcome is chemoprevention informed choice after the follow-up visit. Secondary endpoints include other patient-reported outcomes, such as chemoprevention knowledge, decision conflict and regret, and self-reported chemoprevention usage. Barriers and facilitators to implementing decision support into clinic workflow are assessed through patient and provider interviews at baseline and mid-implementation.<br><br>RESULTS/DISCUSSION: With this hybrid effectiveness/implementation study, we seek to evaluate if a multi-level intervention effectively promotes informed decision-making about chemoprevention and provide valuable insights on how the intervention is implemented in U.S.<br><br>TRIAL REGISTRATION: NCT04496739.}, }
@article {pmid38703890, year = {2024}, author = {Zhang, X and Schenk, JM and Perrigue, M and Drewnowski, A and Wang, CY and Beatty, SJ and Neuhouser, ML}, title = {No Effect of High Eating Frequency Compared with Low Eating Frequency on Appetite and Inflammation Biomarkers: Results from a Randomized Crossover Clinical Trial.}, journal = {The Journal of nutrition}, volume = {154}, number = {8}, pages = {2422-2430}, pmid = {38703890}, issn = {1541-6100}, mesh = {Humans ; *Cross-Over Studies ; Female ; *Biomarkers/blood ; Adult ; Male ; *Inflammation/blood ; *Ghrelin/blood ; *C-Reactive Protein/metabolism ; Appetite ; Young Adult ; Feeding Behavior ; Adiponectin/blood ; Leptin/blood ; Middle Aged ; }, abstract = {BACKGROUND: Eating frequency (EF) focuses on the total number of eating occasions per day and may influence metabolic health.<br><br>OBJECTIVES: We sought to examine the effect of high compared with low EF on appetite regulation and inflammatory biomarkers among healthy adults.<br><br>METHODS: Data are from a randomized, crossover trial (the Frequency of Eating and Satiety Hormones study). Participants (n = 50) completed 2 isocaloric 21-d study periods of low EF (3 eating occasions/d) and high EF (6 eating occasions/d) in random order with a 14-d washout period in between. Participants were free-living and consumed their own food, using study-directed, structured meal plans with identical foods and total energy in both study periods. On days 1 and 21 of each EF period, fasting blood was collected during in-person clinic visits to assess plasma concentrations of ghrelin, leptin, adiponectin, and high-sensitivity C-reactive protein (hs-CRP). Linear mixed models with EF, diet sequence, and period as fixed effects and participant as random effect were used to estimate the intervention effect. Interaction effects between EF and body fat percentage were examined.<br><br>RESULTS: Among the 50 participants who completed the trial, 39 (78%) were women, 30 (60%) were Non-Hispanic White, and 40 (80%) had a body mass index of <25 kg/m[2], and the mean age was 32.1 y. The differences between high and low EF in fasting ghrelin (geometric mean difference: 17.76 ng/mL; P = 0.60), leptin (geometric mean difference: 2.09 ng/mL; P = 0.14), adiponectin (geometric mean difference: 381.7 ng/mL; P = 0.32), and hs-CRP (geometric mean difference: -0.018 mg/dL; P = 0.08) were not statistically significant. No significant interaction was observed between EF and body fat percentage on appetite regulation and inflammatory biomarkers.<br><br>CONCLUSIONS: No differences was observed in fasting ghrelin, leptin, adiponectin, and hs-CRP comparing high and low EF. Future studies are needed to understand the physiology of EF and appetite as they relate to metabolic health. This trial was registered at clinicaltrials.gov as NCT02392897.}, }
@article {pmid38703776, year = {2024}, author = {Rupert, PB and Buerger, M and Friend, DJ and Strong, RK}, title = {Structural elucidation of the mesothelin-mucin-16/CA125 interaction.}, journal = {Structure (London, England : 1993)}, volume = {32}, number = {8}, pages = {1049-1054.e2}, pmid = {38703776}, issn = {1878-4186}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 AI176563/AI/NIAID NIH HHS/United States ; }, mesh = {*Mesothelin/metabolism ; Humans ; *CA-125 Antigen/metabolism/chemistry ; *Protein Binding ; *GPI-Linked Proteins/metabolism/chemistry/genetics ; Crystallography, X-Ray ; Binding Sites ; *Models, Molecular ; Recombinant Proteins/metabolism/chemistry/genetics ; Amino Acid Sequence ; Protein Engineering ; Membrane Proteins ; }, abstract = {Mesothelin (MSLN) is a cell-surface glycoprotein expressed at low levels on normal mesothelium but overexpressed in many cancers. Mesothelin has been implicated to play role/s in cell adhesion and multiple signaling pathways. Mucin-16/CA125 is an enormous cell-surface glycoprotein, also normally expressed on mesothelium and implicated in the progression and metastasis of several cancers, and directly binds mesothelin. However, the precise biological function/s of mesothelin and mucin-16/CA125 remain mysterious. We report protein engineering and recombinant production, qualitative and quantitative binding studies, and a crystal structure determination elucidating the molecular-level details governing recognition of mesothelin by mucin-16/CA125. The interface is small, consistent with the ∼micromolar binding constant and is free of glycan-mediated interactions. Sequence comparisons and modeling suggest that multiple mucin-16/CA125 modules can interact with mesothelin through comparable interactions, potentially generating a high degree of avidity at the cell surface to overcome the weak affinity, with implications for functioning and therapeutic interventions.}, }
@article {pmid38703010, year = {2024}, author = {Loggers, ET and Chugh, R and Federman, N and Hartner, L and Riedel, RF and Cho, S and Hyslop, D and Lim, A and Oton, AB and Oktay, KH}, title = {Onset and resolution of ovarian toxicity with nirogacestat treatment in females with desmoid tumors: Updated safety analyses from the DeFi phase 3 study.}, journal = {Cancer}, volume = {130}, number = {16}, pages = {2812-2821}, doi = {10.1002/cncr.35324}, pmid = {38703010}, issn = {1097-0142}, support = {//Springworks Therapeutics, Inc/ ; }, mesh = {Humans ; Female ; Adult ; Middle Aged ; *Fibromatosis, Aggressive/drug therapy ; Ovary/drug effects ; Young Adult ; Double-Blind Method ; Follicle Stimulating Hormone ; Aged ; Adolescent ; }, abstract = {INTRODUCTION: Nirogacestat is a targeted gamma secretase inhibitor approved in the United States for adults with progressing desmoid tumors. In the phase 3 DeFi study (NCT03785964) of nirogacestat, ovarian toxicity (OT) was identified as a safety signal among females of reproductive potential (FORP). This analysis further describes the incidence, presentation, and resolution of OT.<br><br>METHODS: Patients were randomized to twice-daily oral nirogacestat (150 mg) or placebo, taken in continuous 28-day cycles. Investigator-identified OT in FORP was based on abnormal reproductive hormone values or perimenopausal symptoms (or both). Adverse event follow-up was conducted to assess OT resolution. Post hoc analyses included return of menstruation and return of follicle-stimulating hormone (FSH) to within normal limits (WNL) (&#x2264;20.4 mIU/mL).<br><br>RESULTS: Of 92 randomized females, 73 in the safety population were FORP (n&#xa0;=&#xa0;36 nirogacestat, n&#xa0;=&#xa0;37 placebo). OT was identified in 75% (27 of 36) receiving nirogacestat and 0% (0 of 37) receiving placebo. As of October 24, 2022, investigators reported OT resolution in 78% (21 of 27) of patients, with median OT duration of 19.1 weeks. Off-treatment resolution was reported in all 11 patients (100%) who stopped nirogacestat treatment; of these, all nine with available menstruation information experienced return of menstruation and eight had FSH WNL at last reported assessment. Resolution was reported in 10 of 14 (71%) while on nirogacestat; of these, all 10 experienced return of menstruation and seven had FSH WNL. Two patients were lost to follow-up.<br><br>CONCLUSION: Most FORP treated with nirogacestat experienced OT, with the majority resolving, including all who stopped treatment, suggesting that OT is transient.}, }
@article {pmid38702775, year = {2024}, author = {Tian, X and Janes, HE and Kublin, JG}, title = {Statistical design and analysis of controlled human malaria infection trials.}, journal = {Malaria journal}, volume = {23}, number = {1}, pages = {133}, pmid = {38702775}, issn = {1475-2875}, support = {R01CA15208/NH/NIH HHS/United States ; }, mesh = {Humans ; *Malaria/prevention &amp; control ; Animals ; Research Design ; Controlled Clinical Trials as Topic ; Models, Statistical ; Anopheles/parasitology ; }, abstract = {BACKGROUND: Malaria is a potentially life-threatening disease caused by Plasmodium protozoa transmitted by infected Anopheles mosquitoes. Controlled human malaria infection (CHMI) trials are used to assess the efficacy of interventions for malaria elimination. The operating characteristics of statistical methods for assessing the ability of interventions to protect individuals from malaria is uncertain in small CHMI studies. This paper presents simulation studies comparing the performance of a variety of statistical methods for assessing efficacy of intervention in CHMI trials.<br><br>METHODS: Two types of CHMI designs were investigated: the commonly used single high-dose design (SHD) and the repeated low-dose design (RLD), motivated by simian immunodeficiency virus (SIV) challenge studies. In the context of SHD, the primary efficacy endpoint is typically time to infection. Using a continuous time survival model, five statistical tests for assessing the extent to which an intervention confers partial or full protection under single dose CHMI designs were evaluated. For RLD, the primary efficacy endpoint is typically the binary infection status after a specific number of challenges. A discrete time survival model was used to study the characteristics of RLD versus SHD challenge studies.<br><br>RESULTS: In a SHD study with the continuous time survival model, log-rank test and t-test are the most powerful and provide more interpretable results than Wilcoxon rank-sum tests and Lachenbruch tests, while the likelihood ratio test is uniformly most powerful but requires knowledge of the underlying probability model. In the discrete time survival model setting, SHDs are more powerful for assessing the efficacy of an intervention to prevent infection than RLDs. However, additional information can be inferred from RLD challenge designs, particularly using a likelihood ratio test.<br><br>CONCLUSIONS: Different statistical methods can be used to analyze controlled human malaria infection (CHMI) experiments, and the choice of method depends on the specific characteristics of the experiment, such as the sample size allocation between the control and intervention groups, and the nature of the intervention. The simulation results provide guidance for the trade off in statistical power when choosing between different statistical methods and study designs.}, }
@article {pmid38701912, year = {2024}, author = {Donlan, AN and Leslie, JL and Simpson, ME and Petri, WA and Allen, JE and Petri, WA}, title = {IL-13 protects from Clostridioides difficile colitis.}, journal = {Anaerobe}, volume = {88}, number = {}, pages = {102860}, pmid = {38701912}, issn = {1095-8274}, support = {R01 AI124214/AI/NIAID NIH HHS/United States ; R01 AI152477/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Clostridioides difficile/immunology ; *Clostridium Infections/prevention &amp; control/immunology/microbiology ; Colitis/immunology/prevention &amp; control/microbiology ; *Disease Models, Animal ; *Interleukin-13/metabolism/immunology ; Mice, Inbred C57BL ; Male ; }, abstract = {OBJECTIVES: Clostridioides difficile infection (CDI) is the leading hospital-acquired infection in North America. We have previously discovered that antibiotic disruption of the gut microbiota decreases intestinal IL-33 and IL-25 and increases susceptibility to CDI. We further found that IL-33 promotes protection through type 2 Innate Lymphoid Cells (ILC2s), which produce IL-13. However, the contribution of IL-13 to disease has never been explored.<br><br>METHODS: We used a validated model of CDI in mice, in which we neutralized via blocking antibodies, or administered recombinant protein, IL-13 to assess the role of this cytokine during infection using weight and clinical scores. Fluorescent activated cell sorting (FACS) was used to characterize myeloid cell population changes in response to IL-13 manipulation.<br><br>RESULTS: We found that administration of IL-13 protected, and anti-IL-13 exacerbated CDI. Additionally, we observed alterations to the monocyte/macrophage cells following neutralization of IL-13 as early as day three post infection. We also observed elevated accumulation of myeloid cells by day four post-infection following IL-13 neutralization. Neutralization of the decoy receptor, IL-13R&#x3b1;2, resulted in protection from disease, likely through increased available endogenous IL-13.<br><br>CONCLUSIONS: Our data highlight the protective role of IL-13 in protecting from more severe CDI and the association of poor responses with a dysregulated monocyte-macrophage compartment. These results increase our understanding of type 2 immunity in CDI and may have implications for treating disease in patients.}, }
@article {pmid38701405, year = {2024}, author = {Ahmed, G and Alsouqi, A and Szabo, A and Samples, L and Shadman, M and Awan, FT and Rojek, AE and Riedell, PA and Iqbal, M and Fenske, TS and Kharfan-Dabaja, MA and Ito, S and Hamadani, M}, title = {CAR T-cell therapy in mantle cell lymphoma with secondary CNS involvement: a multicenter experience.}, journal = {Blood advances}, volume = {8}, number = {13}, pages = {3528-3531}, pmid = {38701405}, issn = {2473-9537}, mesh = {Humans ; *Lymphoma, Mantle-Cell/therapy/pathology ; *Immunotherapy, Adoptive/methods ; *Central Nervous System Neoplasms/therapy ; Male ; Middle Aged ; Aged ; Female ; Receptors, Chimeric Antigen ; Treatment Outcome ; }, }
@article {pmid38700798, year = {2024}, author = {Mogal, H and Shen, P}, title = {Top Peritoneal Surface Malignancy Articles from 2022 to Inform your Cancer Practice.}, journal = {Annals of surgical oncology}, volume = {31}, number = {8}, pages = {5361-5369}, pmid = {38700798}, issn = {1534-4681}, mesh = {Humans ; *Peritoneal Neoplasms/therapy/secondary ; *Cytoreduction Surgical Procedures ; *Hyperthermic Intraperitoneal Chemotherapy ; Combined Modality Therapy ; Prognosis ; }, abstract = {Over the last few decades, the role of cytoreductive surgery (CRS) with or without regional-based peritoneal therapies such as hyperthermic intraperitoneal chemotherapy (HIPEC) has evolved in the management of patients with peritoneal surface malignances (PSMs). Despite the benefit of CRS in improving oncologic outcomes, significant challenges remain in the treatment of patients with advanced PSMs, and the role of HIPEC continues to be questioned. Additionally, while there has been improvement in perioperative outcomes, long-term survival remains poor. As a result, there is much need to improve our understanding of the processes that drive tumor biology, thereby improving patient selection for various treatment approaches. Additionally, newer therapies are needed for patients who remain poor surgical candidates and who progress on systemic therapy. This article highlights recently published studies that we consider impactful in the care of patients with PSMs.}, }
@article {pmid38700620, year = {2024}, author = {Merkel, EC and Vandeleur, DM and Cheng, X and Littman, AJ and Baker, KS}, title = {Association between adverse childhood experiences and health related quality of life in adult cancer survivors in the United States.}, journal = {Journal of cancer survivorship : research and practice}, volume = {}, number = {}, pages = {}, pmid = {38700620}, issn = {1932-2267}, support = {T32 CA009351/CA/NCI NIH HHS/United States ; T32 GM086270/GM/NIGMS NIH HHS/United States ; GM086270/NH/NIH HHS/United States ; CA009351/NH/NIH HHS/United States ; }, abstract = {PURPOSE: The impact of adverse childhood experiences (ACEs) on health-related quality of life (HRQOL) is increasingly recognized, however, this has not been studied in cancer survivors in the United States. This study investigates if ACEs are associated with HRQOL in cancer survivors.<br><br>METHODS: We conducted a cross-sectional analysis of the 2020 Behavioral Risk Factor Surveillance System from states that administered ACEs and Cancer Survivorship modules. Eligibility criteria included being a cancer survivor and not currently receiving cancer treatment. Primary exposure was number of ACEs (categorized as 0, 1-2, 3, or &#x2265;&#x2009;4). Primary outcomes were self-reported measures of HRQOL including worse overall health and &#x2265;&#x2009;14 unhealthy days (mentally or physically) per month. Mantel-Haenszel stratified analyses were performed and prevalence ratios were adjusted for age.<br><br>RESULTS: Of 5,780 participants, 62.0% were female and 67.8% were &#x2265;&#x2009;65&#x2009;years. Prevalence of worse overall health was 22.5% for individuals with no ACEs compared to 30.2% for 2-3 ACEs (aPR&#x2009;=&#x2009;1.4, 95% CI 1.2, 1.5) and 38.5% for &#x2265;&#x2009;4 ACEs (aPR&#x2009;=&#x2009;1.7, 95% CI 1.5, 2.0). Prevalence of &#x2265;&#x2009;14 unhealthy days was 18.1% with no ACEs compared to 21.0% for 1 ACE (aPR&#x2009;=&#x2009;1.3, 95% CI 1, 1.3), 29.0% for 2-3 ACEs (aPR&#x2009;=&#x2009;1.6, 95% CI 1.4, 1.8), and 44.8% for &#x2265;&#x2009;4 ACEs (aPR&#x2009;=&#x2009;2.2, 95% CI 2.0, 2.5).<br><br>CONCLUSIONS: Our study provides novel evidence of the association of multiple ACEs with higher prevalence of poor HRQOL in cancer survivors.<br><br>Screening for ACEs is warranted in all patients to guide targeted interventions to improve HRQOL and mitigate the impact of ACEs on HRQoL in cancer survivors.}, }
@article {pmid38700521, year = {2024}, author = {Gulleen, EA and Lubwama, M}, title = {How Should We Manage Antimicrobial Resistance in Resource-Limited Settings?.}, journal = {AMA journal of ethics}, volume = {26}, number = {5}, pages = {E373-379}, doi = {10.1001/amajethics.2024.373}, pmid = {38700521}, issn = {2376-6980}, mesh = {Humans ; Anti-Bacterial Agents/therapeutic use ; Anti-Infective Agents/therapeutic use ; *Developing Countries ; Drug Resistance, Bacterial ; *Drug Resistance, Microbial ; Health Services Accessibility ; *Resource-Limited Settings ; }, abstract = {Patients living in low- and middle-income countries (LMICs) shoulder the greatest burden of infections caused by antimicrobial-resistant pathogens. Speedy access to appropriate broad-spectrum antimicrobials significantly improves health outcomes and reduces transmission of antimicrobial-resistant pathogens, but persons living in LMICs have compromised access to these antimicrobials. This article considers how inequities in microbiology diagnostics, antimicrobial access, and antimicrobial affordability influence outcomes for patients infected with antimicrobial-resistant pathogens who live in resource-limited settings.}, }
@article {pmid38700354, year = {2024}, author = {Ouwendijk, WJD and Roychoudhury, P and Cunningham, AL and Jerome, KR and Koelle, DM and Kinchington, PR and Mohr, I and Wilson, AC and Verjans, GMGM and Depledge, DP}, title = {Reply to Wang et al., "Ample evidence for the presence of HSV-1 LAT in non-neuronal ganglionic cells of mice and humans".}, journal = {Journal of virology}, volume = {98}, number = {6}, pages = {e0052024}, pmid = {38700354}, issn = {1098-5514}, support = {APP1177942//DHAC | National Health and Medical Research Council (NHMRC)/ ; R01-AI176335//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; R01-AI151290//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; R01 GM056927/GM/NIGMS NIH HHS/United States ; 75N93019C00063/AI/NIAID NIH HHS/United States ; R01 AI176335/AI/NIAID NIH HHS/United States ; R01 AI132599/AI/NIAID NIH HHS/United States ; R01 AI151290/AI/NIAID NIH HHS/United States ; R01-AI073898, R01-GM056927//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; P30 EY08098//HHS | NIH | National Eye Institute (NEI)/ ; R01-AI132599//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; R01-AI152543//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; R01 AG064800/AG/NIA NIH HHS/United States ; R01 AI170583/AI/NIAID NIH HHS/United States ; R01 AI152543/AI/NIAID NIH HHS/United States ; R01 AI073898/AI/NIAID NIH HHS/United States ; P30 EY008098/EY/NEI NIH HHS/United States ; 75N93019C00063, R01-AG064800//HHS | National Institutes of Health (NIH)/ ; R01-AI170583//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; }, mesh = {Animals ; *Herpesvirus 1, Human/physiology ; Humans ; Mice ; Viral Proteins/metabolism/genetics ; Herpes Simplex/virology ; }, }
@article {pmid38699999, year = {2024}, author = {Schumacher, BT and LaMonte, MJ and Di, C and Parada, H and Hooker, SP and Bellettiere, J and Simonsick, EM and Liles, S and LaCroix, AZ}, title = {Associations of Relative Intensity of Physical Activity With Incident Cardiovascular Events and All-Cause Mortality.}, journal = {The journals of gerontology. Series A, Biological sciences and medical sciences}, volume = {79}, number = {8}, pages = {}, pmid = {38699999}, issn = {1758-535X}, support = {P30 AG059299/AG/NIA NIH HHS/United States ; HHSN268201600018C/NR/NINR NIH HHS/United States ; U54 CA132379/CA/NCI NIH HHS/United States ; K01 CA234317/CA/NCI NIH HHS/United States ; /NH/NIH HHS/United States ; R01HL105065/HL/NHLBI NIH HHS/United States ; R01 HL153462/HL/NHLBI NIH HHS/United States ; U54 CA132384/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Cardiovascular Diseases/mortality/prevention &amp; control/epidemiology ; Aged ; *Exercise ; *Accelerometry ; Incidence ; Cause of Death ; Proportional Hazards Models ; Aged, 80 and over ; }, abstract = {BACKGROUND: The relative intensity of physical activity (PA) can be estimated as the percent of one's maximal effort required.<br><br>METHODS: We compared associations of relative and absolute intensity PA with incident major cardiovascular disease (CVD) and all-cause mortality in 5&#xa0;633 women from the Objective Physical Activity and Cardiovascular Health Study (mean age 78.5&#x2005;&#xb1;&#x2005;6.7). Absolute intensity was measured by accelerometry. Relative intensity was estimated by dividing accelerometer-estimated metabolic equivalents (METs) by maximal MET capacity. Both were aggregated into mean daily hours of light intensity PA (LPA) and moderate-to-vigorous PA (MVPA). Cox proportional hazard models estimated hazard ratios (HRs) for 1-hour higher amounts of PA on outcomes.<br><br>RESULTS: During follow-up (median&#x2005;=&#x2005;7.4 years), there were 748 incident CVD events and 1&#xa0;312 deaths. Greater LPA and MVPA, on either scale, were associated with reduced risk of both outcomes. HRs for a 1-hour increment of absolute LPA were 0.88 (95% CI: 0.83-0.93) and 0.88 (95% CI: 0.84-0.92) for incident CVD and mortality, respectively. HRs for a 1-hour increment of absolute MPVA were 0.73 (95% CI: 0.61-0.87) and 0.55 (95% CI: 0.48-0.64) for the same outcomes. HRs for a 1-hour increment of relative LPA were 0.70 (95% CI: 0.59-0.84) and 0.78 (95% CI: 0.68-0.89) for incident CVD and mortality, respectively. HRs for a 1-hour increment of relative MPVA were 0.89 (95% CI: 0.83-0.96) and 0.82 (95% CI: 0.77-0.87) for the same outcomes. On the relative scale, LPA was more strongly, and inversely associated with both outcomes than relative MVPA. Absolute MVPA was more strongly inversely associated with the outcomes than relative MVPA.<br><br>CONCLUSIONS: Findings support the continued shift in the PA intensity paradigm toward recommendation of more movement, regardless of intensity. Relative LPA--a modifiable, more easily achieved behavioral target, particularly among ambulatory older adults--was associated with reduced risk of incident major CVD and death.}, }
@article {pmid38699359, year = {2024}, author = {Žuštra, A and Leonard, VR and Holland, LA and Hu, JC and Mu, T and Holland, SC and Wu, LI and Begnel, ER and Ojee, E and Chohan, BH and Richardson, BA and Kinuthia, J and Wamalwa, D and Slyker, J and Lehman, DA and Gantt, S and Lim, ES}, title = {Longitudinal dynamics of the nasopharyngal microbiome in response to SARS-CoV-2 Omicron variant and HIV infection in Kenyan women and their infants.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {38699359}, issn = {2693-5015}, support = {R01 HD092311/HD/NICHD NIH HHS/United States ; }, abstract = {The nasopharynx and its microbiota are implicated in respiratory health and disease. The interplay between viral infection and the nasopharyngeal microbiome is an area of increased interest and of clinical relevance. The impact of SARS-CoV-2, the etiological agent of the Coronavirus Disease 2019 (COVID-19) pandemic, on the nasopharyngeal microbiome, particularly among individuals living with HIV, is not fully characterized. Here we describe the nasopharyngeal microbiome before, during and after SARS-CoV-2 infection in a longitudinal cohort of Kenyan women (21 living with HIV and 14 HIV-uninfected) and their infants (18 HIV-exposed, uninfected and 18 HIV-unexposed, uninfected), followed between September 2021 through March 2022. We show using genomic epidemiology that mother and infant dyads were infected with the same strain of the SARS-CoV-2 Omicron variant that spread rapidly across Kenya. Additionally, we used metagenomic sequencing to characterize the nasopharyngeal microbiome of 20 women and infants infected with SARS-CoV-2, 6 infants negative for SARS-CoV-2 but experiencing respiratory symptoms, and 34 timepoint matched SARS-CoV-2 negative mothers and infants. Since individuals were sampled longitudinally before and after SARS-CoV-2 infection, we could characterize the short- and long-term impact of SARS-CoV-2 infection on the nasopharyngeal microbiome. We found that mothers and infants had significantly different microbiome composition and bacterial load (p-values <.0001). However, in both mothers and infants, the nasopharyngeal microbiome did not differ before and after SARS-CoV-2 infection, regardless of HIV-exposure status. Our results indicate that the nasopharyngeal microbiome is resilient to SARS-CoV-2 infection and was not significantly modified by HIV.}, }
@article {pmid38699315, year = {2024}, author = {Langelier, C and Chu, V and Glascock, A and Donnell, D and Grabow, C and Brown, C and Ward, R and Love, C and Kalantar, K and Cohen, S and Cannon, C and Woodworth, M and Kelley, C and Celum, C and Luetkemeyer, A}, title = {Doxycycline post-exposure prophylaxis for sexually transmitted infections impacts the gut antimicrobial resistome.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {38699315}, issn = {2693-5015}, support = {K23 AI144036/AI/NIAID NIH HHS/United States ; R01 AI143439/AI/NIAID NIH HHS/United States ; }, abstract = {Doxycycline post-exposure prophylaxis (doxy-PEP) reduces bacterial sexually transmitted infections (STIs) among men who have sex with men and transgender women. While poised for widespread clinical implementation, the impact of doxy-PEP on antimicrobial resistance remains a primary concern as its effects on the gut microbiome and resistome, or the antimicrobial resistance genes (ARGs) present in the gut microbiome, are unknown. To investigate these effects, we studied participants from a randomized clinical trial who either received doxy-PEP as a one-time doxycycline 200 mg taken after condomless sex (DP arm, n = 100) or standard of care treatment (SOC arm, n = 50). From self-collected rectal swabs at enrollment (day-0) and after 6 months (month-6), we performed metagenomic DNA sequencing (DNA-seq) or metatranscriptomic RNA sequencing (RNA-seq). DNA-seq data was analyzable from 127 samples derived from 89 participants, and RNA-seq data from 86 samples derived from 70 participants. We compared the bacterial microbiome and resistome between the two study arms and over time. Tetracycline ARGs were detected in all day-0 DNA-seq samples and 85% of day-0 RNA-seq samples. The proportional mass of tetracycline ARGs in the resistome increased between day-0 and month-6 in DP participants from 46-51% in the metagenome (p = 0.02) and 4-15% in the metatranscriptome (p < 0.01), but no changes in other ARG classes were observed. Exposure to a higher number of doxycycline doses correlated with proportional enrichment of tetracycline ARGs in the metagenome (Spearman's ρ = 0.23, p < 0.01) and metatranscriptome (Spearman's ρ = 0.55, p < 0.01). Bacterial microbiome alpha diversity, beta diversity, and total bacterial mass did not differ between day-0 and month-6 samples from DP participants when assessed by either DNA-seq or RNA-seq. In an abundance-based correlation analysis, we observed an increase over time in the strength of the correlation between tetracycline ARGs and specific bacterial taxa, including some common human pathogens. In sum, doxy-PEP use over a 6-month period was associated with an increase in the proportion of tetracycline ARGs comprising the gut resistome, and an increase in the expression of tetracycline ARGs. Notably, doxy-PEP did not significantly alter alpha diversity or taxonomic composition of the gut microbiome, and did not demonstrate significant increases in non-tetracycline ARG classes. Further studies and population level surveillance are needed to understand the implications of these findings as doxy-PEP is implemented as a public health strategy.}, }
@article {pmid38699305, year = {2024}, author = {Maqsood, R and Holland, LA and Wu, LI and Begnel, ER and Adhiambo, J and Owiti, P and Chohan, BH and Gantt, S and Kinuthia, J and Wamalwa, D and Ojee, E and Richardson, BA and Slyker, J and Lehman, DA and Lim, ES}, title = {Gut virome and microbiome dynamics before and after SARS-CoV-2 infection in women living with HIV and their infants.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {38699305}, issn = {2693-5015}, support = {R01 HD092311/HD/NICHD NIH HHS/United States ; }, abstract = {Microbiome perturbations can have long-term effects on health. The dynamics of the gut microbiome and virome in women living with HIV (WLHIV) and their newborn infants is poorly understood. Here, we performed metagenomic sequencing analyses on longitudinal stool samples including 23 mothers (13 WLHIV, 10 HIV-negative) and 12 infants that experienced SARS-CoV-2 infection with mild disease, as well as 40 mothers (18 WLHIV, 22 HIV-negative) and 60 infants that remained SARS-CoV-2 seronegative throughout the study follow-up. Regardless of HIV or SARS-CoV-2 status, maternal bacterial and viral profiles were distinct from infants. Using linear mixed effects models, we showed that while the microbiome alpha diversity trajectory was not significantly different between SARS-CoV-2 seropositive and seronegative women. However, seropositive women's positive trajectory while uninfected was abruptly reversed after SARS-CoV-2 infection (p = 0.015). However, gut virome signatures of women were not associated with SARS-CoV-2. Alterations in infant microbiome and virome diversities were generally not impacted by SARS-CoV-2 but were rather driven by development. We did not find statistically significant interactions between HIV and SARS-CoV-2 on the gut microbiome and virome. Overall, our study provides insights into the complex interplay between maternal and infant bacterial microbiome, virome, and the influence of SARS-CoV-2 and HIV status.}, }
@article {pmid38698683, year = {2024}, author = {Kuczmarski, TM and Lynch, RC}, title = {Managing common toxicities associated with checkpoint inhibitor and chemotherapy combinations for untreated classic Hodgkin lymphoma.}, journal = {British journal of haematology}, volume = {205}, number = {1}, pages = {100-108}, doi = {10.1111/bjh.19478}, pmid = {38698683}, issn = {1365-2141}, mesh = {Humans ; *Hodgkin Disease/drug therapy ; *Antineoplastic Combined Chemotherapy Protocols/adverse effects/therapeutic use ; *Immune Checkpoint Inhibitors/adverse effects/administration &amp; dosage ; Male ; Female ; Adult ; *Doxorubicin/adverse effects/administration &amp; dosage ; Vinblastine/administration &amp; dosage/adverse effects/therapeutic use ; Middle Aged ; Dacarbazine/adverse effects/administration &amp; dosage ; Neutropenia/chemically induced ; }, abstract = {Combination checkpoint inhibitor (CPI) and chemotherapy is an effective and safe treatment strategy for patients with untreated classic Hodgkin lymphoma. Recent studies of programmed cell death protein 1 inhibitors combined with doxorubicin, vinblastine and dacarbazine have demonstrated high overall and complete response rates. This combination has a unique toxicity profile that should be managed appropriately so as not to compromise treatment efficacy. Common toxicities include rash, hepatoxicity, neutropenia and thyroid dysfunction. Here, we present four cases and the management strategies around such toxicities. In addition, we highlight key clinical decision-making around the administration of subsequent doses of CPI and chemotherapy.}, }
@article {pmid38698170, year = {2024}, author = {Baik, C and Cheng, ML and Dietrich, M and Gray, JE and Karim, NA}, title = {A Practical Review of Encorafenib and Binimetinib Therapy Management in Patients with BRAF V600E-Mutant Metastatic Non-Small Cell Lung Cancer.}, journal = {Advances in therapy}, volume = {41}, number = {7}, pages = {2586-2605}, pmid = {38698170}, issn = {1865-8652}, mesh = {Humans ; *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics ; *Carbamates/therapeutic use/adverse effects/administration &amp; dosage ; *Benzimidazoles/therapeutic use/administration &amp; dosage/adverse effects ; *Lung Neoplasms/drug therapy/genetics ; *Sulfonamides/therapeutic use/administration &amp; dosage/adverse effects ; *Proto-Oncogene Proteins B-raf/genetics ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Mutation ; }, abstract = {According to current guidelines, targeted therapy with a combination of BRAF plus MEK inhibitors is the preferred first-line treatment for patients with BRAF V600E-mutant metastatic non-small cell lung cancer (NSCLC). In the open-label, single-arm, phase 2 PHAROS trial (NCT03915951), the combination of encorafenib, a potent BRAF inhibitor, and binimetinib, a potent MEK inhibitor, demonstrated durable antitumor activity with a manageable safety profile in this patient population. On the basis of the results of this study, the combination of encorafenib plus binimetinib was approved by the US Food and Drug Administration on October 11, 2023, for patients with BRAF V600E-mutant metastatic NSCLC. In this review, we summarize the efficacy and safety of encorafenib plus binimetinib from the PHAROS study. In addition, we discuss strategies to manage adverse reactions with this combination therapy with the intent of minimizing unnecessary treatment discontinuations in these patients.}, }
@article {pmid38698071, year = {2024}, author = {Ramdial, J and Kebriaei, P and Champlin, RE and Popat, U and Rezvani, K and Shpall, EJ and Mehta, RS}, title = {Improved survival with younger HLA-matched unrelated donors versus older matched sibling donor HCT with PTCy-prophylaxis.}, journal = {Leukemia}, volume = {38}, number = {6}, pages = {1432-1434}, pmid = {38698071}, issn = {1476-5551}, mesh = {Humans ; *Siblings ; *Hematopoietic Stem Cell Transplantation/methods/mortality ; *Unrelated Donors ; Adult ; Middle Aged ; Female ; Male ; HLA Antigens/immunology ; Young Adult ; Age Factors ; Adolescent ; Histocompatibility Testing ; Survival Rate ; Aged ; }, }
@article {pmid38697998, year = {2024}, author = {Ping, J and Jia, G and Cai, Q and Guo, X and Tao, R and Ambrosone, C and Huo, D and Ambs, S and Barnard, ME and Chen, Y and Garcia-Closas, M and Gu, J and Hu, JJ and John, EM and Li, CI and Nathanson, K and Nemesure, B and Olopade, OI and Pal, T and Press, MF and Sanderson, M and Sandler, DP and Yoshimatsu, T and Adejumo, PO and Ahearn, T and Brewster, AM and Hennis, AJM and Makumbi, T and Ndom, P and O'Brien, KM and Olshan, AF and Oluwasanu, MM and Reid, S and Yao, S and Butler, EN and Huang, M and Ntekim, A and Li, B and Troester, MA and Palmer, JR and Haiman, CA and Long, J and Zheng, W}, title = {Using genome and transcriptome data from African-ancestry female participants to identify putative breast cancer susceptibility genes.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {3718}, pmid = {38697998}, issn = {2041-1723}, support = {P30 ES010126/ES/NIEHS NIH HHS/United States ; U01 CA164974/CA/NCI NIH HHS/United States ; R01 CA235553/CA/NCI NIH HHS/United States ; R01 CA242929/CA/NCI NIH HHS/United States ; R01 MD013452/MD/NIMHD NIH HHS/United States ; S10 OD023680/OD/NIH HHS/United States ; P30 CA068485/CA/NCI NIH HHS/United States ; R01 CA202981/CA/NCI NIH HHS/United States ; R01 CA228198/CA/NCI NIH HHS/United States ; P20 CA233307/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Middle Aged ; Black People/genetics ; *Breast Neoplasms/genetics ; Case-Control Studies ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; *Genetic Predisposition to Disease ; Genome-Wide Association Study ; Polymorphism, Single Nucleotide ; Receptors, Estrogen/genetics/metabolism ; *Transcriptome ; Black or African American ; United States ; }, abstract = {African-ancestry (AA) participants are underrepresented in genetics research. Here, we conducted a transcriptome-wide association study (TWAS) in AA female participants to identify putative breast cancer susceptibility genes. We built genetic models to predict levels of gene expression, exon junction, and 3' UTR alternative polyadenylation using genomic and transcriptomic data generated in normal breast tissues from 150 AA participants and then used these models to perform association analyses using genomic data from 18,034 cases and 22,104 controls. At Bonferroni-corrected P < 0.05, we identified six genes associated with breast cancer risk, including four genes not previously reported (CTD-3080P12.3, EN1, LINC01956 and NUP210L). Most of these genes showed a stronger association with risk of estrogen-receptor (ER) negative or triple-negative than ER-positive breast cancer. We also replicated the associations with 29 genes reported in previous TWAS at P < 0.05 (one-sided), providing further support for an association of these genes with breast cancer risk. Our study sheds new light on the genetic basis of breast cancer and highlights the value of conducting research in AA populations.}, }
@article {pmid38697986, year = {2024}, author = {Shadman, M and Tedeschi, A and Mohseninejad, L and Yang, K and Lamanna, N and Xu, S and Cohen, A and Challagulla, S and Xue, M and Williams, R and O'Brien, SM and Brown, JR and Tam, C}, title = {Similar efficacy of ibrutinib arms across ALPINE and ELEVATE-RR trials in relapsed/refractory chronic lymphocytic leukemia: a matching-adjusted indirect comparison.}, journal = {Blood cancer journal}, volume = {14}, number = {1}, pages = {77}, pmid = {38697986}, issn = {2044-5385}, mesh = {Humans ; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/mortality ; *Adenine/*analogs &amp; derivatives/therapeutic use ; *Piperidines/therapeutic use ; Male ; Pyrazoles/therapeutic use ; Female ; Pyrimidines/therapeutic use ; Aged ; Treatment Outcome ; Middle Aged ; }, }
@article {pmid38697164, year = {2024}, author = {Webb, AB and Berg, CD and Castle, PE and Crosby, D and Etzioni, R and Kessler, LG and Menon, U and Parmar, M and Steele, RJC and Sasieni, PD}, title = {Considerations for using potential surrogate endpoints in cancer screening trials.}, journal = {The Lancet. Oncology}, volume = {25}, number = {5}, pages = {e183-e192}, pmid = {38697164}, issn = {1474-5488}, support = {MC_UU_00004/01/MRC_/Medical Research Council/United Kingdom ; MC_UU_00004/02/MRC_/Medical Research Council/United Kingdom ; R35 CA274442/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Early Detection of Cancer/methods ; *Neoplasms/diagnosis ; Biomarkers, Tumor/analysis ; Clinical Trials as Topic ; Research Design/standards ; Biomarkers/analysis ; Endpoint Determination ; }, abstract = {The requirement of large-scale expensive cancer screening trials spanning decades creates considerable barriers to the development, commercialisation, and implementation of novel screening tests. One way to address these problems is to use surrogate endpoints for the ultimate endpoint of interest, cancer mortality, at an earlier timepoint. This Review aims to highlight the issues underlying the choice and use of surrogate endpoints for cancer screening trials, to propose criteria for when and how we might use such endpoints, and to suggest possible candidates. We present the current landscape and challenges, and discuss lessons and shortcomings from the therapeutic trial setting. It is hugely challenging to validate a surrogate endpoint, even with carefully designed clinical studies. Nevertheless, we consider whether there are candidates that might satisfy the requirements defined by research and regulatory bodies.}, }
@article {pmid38695668, year = {2024}, author = {Lyman, GH and Kuderer, NM}, title = {Artificial Intelligence in Cancer Clinical Research: I. Introduction.}, journal = {Cancer investigation}, volume = {42}, number = {6}, pages = {443-446}, doi = {10.1080/07357907.2024.2347784}, pmid = {38695668}, issn = {1532-4192}, mesh = {Humans ; *Artificial Intelligence ; *Neoplasms/therapy ; *Biomedical Research/methods ; }, }
@article {pmid38695123, year = {2024}, author = {Cortes, JE and Jiang, Q and Wang, J and Weng, J and Zhu, H and Liu, X and Hochhaus, A and Kim, DW and Radich, J and Savona, M and Martin-Regueira, P and Sy, O and Saglio, G}, title = {Treatment of chronic-phase chronic myeloid leukemia in patients randomized to dasatinib or imatinib after suboptimal responses to 3 months of imatinib therapy: final 5-year results from DASCERN.}, journal = {Haematologica}, volume = {109}, number = {10}, pages = {3251-3260}, pmid = {38695123}, issn = {1592-8721}, mesh = {Humans ; *Dasatinib/therapeutic use/administration &amp; dosage ; *Imatinib Mesylate/therapeutic use/administration &amp; dosage ; Male ; Female ; Middle Aged ; Aged ; *Leukemia, Myeloid, Chronic-Phase/drug therapy/mortality ; Adult ; Treatment Outcome ; Follow-Up Studies ; Protein Kinase Inhibitors/therapeutic use/adverse effects/administration &amp; dosage ; Antineoplastic Agents/therapeutic use ; Aged, 80 and over ; Young Adult ; }, abstract = {Early molecular response at 3 months is predictive of improved overall survival and progression-free survival in patients with chronic myeloid leukemia in the chronic phase. Although about one-third of patients treated with first-line imatinib do not achieve an early molecular response, long-term overall survival and progression-free survival are still observed in most patients. DASCERN (NCT01593254) is a prospective, phase IIb, randomized trial evaluating a switch to dasatinib in patients who have not achieved an early molecular response after 3 months of treatment with first-line imatinib. Early analysis demonstrated an improved major molecular response (MMR) rate at 12 months with dasatinib versus imatinib (29% vs. 13%, P=0.005). Here, we report results from the final 5-year follow-up. In total, 174 patients were randomized to dasatinib and 86 to remain on imatinib. Forty-six (53%) patients who remained on imatinib but subsequently experienced failure were allowed to cross over to dasatinib per protocol. At a minimum follow-up of 60 months, the cumulative MMR rate was significantly higher in patients randomized to dasatinib than those randomized to imatinib (77% vs. 44%, P<0.001). The median time to MMR was 13.9 months with dasatinib versus 19.7 months with imatinib. The safety profile was consistent with previous reports. These results demonstrate that switching to dasatinib after a suboptimal response to imatinib at 3 months leads to faster MMR, provides earlier deep molecular responses, and improves some outcomes in patients with chronic myeloid leukemia in the chronic phase.}, }
@article {pmid38692824, year = {2024}, author = {Frank, I and Li, SS and Grunenberg, N and Overton, ET and Robinson, ST and Zheng, H and Seaton, KE and Heptinstall, JR and Allen, MA and Mayer, KH and Culver, DA and Keefer, MC and Edupuganti, S and Pensiero, MN and Mehra, VL and De Rosa, SC and Morris, DE and Wang, S and Seaman, MS and Montefiori, DC and Ferrari, G and Tomaras, GD and Kublin, JG and Corey, L and Lu, S and , }, title = {Safety and immunogenicity of a polyvalent DNA-protein HIV vaccine with matched Env immunogens delivered as a prime-boost regimen or coadministered in HIV-uninfected adults in the USA (HVTN 124): a phase 1, placebo-controlled, double-blind randomised controlled trial.}, journal = {The lancet. HIV}, volume = {11}, number = {5}, pages = {e285-e299}, pmid = {38692824}, issn = {2352-3018}, support = {UM1 AI069534/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; U19 AI082676/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; P30 AI064518/AI/NIAID NIH HHS/United States ; P30 AI045008/AI/NIAID NIH HHS/United States ; UM1 AI069412/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *AIDS Vaccines/administration &amp; dosage/immunology/adverse effects ; Adult ; Male ; Female ; Double-Blind Method ; *Vaccines, DNA/administration &amp; dosage/immunology/adverse effects ; *HIV Infections/prevention &amp; control/immunology ; Middle Aged ; Young Adult ; *HIV Antibodies/blood ; Adolescent ; *HIV-1/immunology ; United States ; Immunization, Secondary ; Immunogenicity, Vaccine ; HIV Envelope Protein gp120/immunology/genetics ; Antibodies, Neutralizing/blood ; }, abstract = {BACKGROUND: An effective HIV vaccine will most likely need to have potent immunogenicity and broad cross-subtype coverage. The aim of the HIV Vaccine Trials Network (HVTN) 124 was to evaluate safety and immunogenicity of a unique polyvalent DNA-protein HIV vaccine with matching envelope (Env) immunogens.<br><br>METHODS: HVTN 124 was a randomised, phase 1, placebo-controlled, double-blind study, including participants who were HIV seronegative and aged 18-50 years at low risk for infection. The DNA vaccine comprised five plasmids: four copies expressing Env gp120 (clades A, B, C, and AE) and one gag p55 (clade C). The protein vaccine included four DNA vaccine-matched GLA-SE-adjuvanted recombinant gp120 proteins. Participants were enrolled across six clinical sites in the USA and were randomly assigned to placebo or one of two vaccine groups (ie, prime-boost or coadministration) in a 5:1 ratio in part A and a 7:1 ratio in part B. Vaccines were delivered via intramuscular needle injection. The primary outcomes were safety and tolerability, assessed via frequency, severity, and attributability of local and systemic reactogenicity and adverse events, laboratory safety measures, and early discontinuations. Part A evaluated safety. Part B evaluated safety and immunogenicity of two regimens: DNA prime (administered at months 0, 1, and 3) with protein boost (months 6 and 8), and DNA-protein coadministration (months 0, 1, 3, 6, and 8). All randomly assigned participants who received at least one dose were included in the safety analysis. The study is registered with ClinicalTrials.gov (NCT03409276) and is closed to new participants.<br><br>FINDINGS: Between April 19, 2018 and Feb 13, 2019, 60 participants (12 in part A [five men and seven women] and 48 in part B [21 men and 27 women]) were enrolled. All 60 participants received at least one dose, and 14 did not complete follow-up (six of 21 in the prime-boost group and eight of 21 in the coadminstration group). 11 clinical adverse events deemed by investigators as study-related occurred in seven of 48 participants in part B (eight of 21 in the prime-boost group and three of 21 in the coadministration group). Local reactogenicity in the vaccine groups was common, but the frequency and severity of reactogenicity signs or symptoms did not differ between the prime-boost and coadministration groups (eg, 20 [95%] of 21 in the prime-boost group vs 21 [100%] of 21 in the coadministration group had either local pain or tenderness of any severity [p=1&#xb7;00], and seven [33%] vs nine [43%] had either erythema or induration [p=0&#xb7;97]), nor did laboratory safety measures. There were no delayed-type hypersensitivity reactions or vasculitis or any severe clinical adverse events related to vaccination. The most frequently reported systemic reactogenicity symptoms in the active vaccine groups were malaise or fatigue (five [50%] of ten in part A and 17 [81%] of 21 in the prime-boost group vs 15 [71%] of 21 in the coadministration group in part B), headache (five [50%] and 18 [86%] vs 12 [57%]), and myalgia (four [40%] and 13 [62%] vs ten [48%]), mostly of mild or moderate severity.<br><br>INTERPRETATION: Both vaccine regimens were safe, warranting evaluation in larger trials.<br><br>FUNDING: US National Institutes of Health and US National Institute of Allergy and Infectious Diseases.}, }
@article {pmid38692470, year = {2024}, author = {Dougan, MM and Fest, S and Cushing-Haugen, K and Farland, LV and Chavarro, J and Harris, HR and Missmer, SA}, title = {A prospective study of dietary patterns and the incidence of endometriosis diagnosis.}, journal = {American journal of obstetrics and gynecology}, volume = {231}, number = {4}, pages = {443.e1-443.e10}, pmid = {38692470}, issn = {1097-6868}, support = {U01 HL145386/HL/NHLBI NIH HHS/United States ; P30 ES006694/ES/NIEHS NIH HHS/United States ; U01 CA176726/CA/NCI NIH HHS/United States ; P30 DK046200/DK/NIDDK NIH HHS/United States ; R01 HD057210/HD/NICHD NIH HHS/United States ; R03 HD048544/HD/NICHD NIH HHS/United States ; R01 HD052473/HD/NICHD NIH HHS/United States ; }, mesh = {Female ; *Endometriosis/epidemiology/diagnosis ; Humans ; Prospective Studies ; Adult ; Incidence ; Proportional Hazards Models ; Diet ; Diet, Healthy ; Dietary Approaches To Stop Hypertension ; Cohort Studies ; Feeding Behavior ; Premenopause ; Diet, Western/adverse effects ; Middle Aged ; United States/epidemiology ; Dietary Patterns ; }, abstract = {BACKGROUND: Although endometriosis is a common condition-affecting ∼10% of premenopausal individuals-its etiology is unknown. Diet receives a lot of attention from patients, but studies of the role of diet are limited. Examining dietary patterns is essential to provide new insight.<br><br>OBJECTIVE: We sought to determine whether dietary patterns are associated with laparoscopically-confirmed endometriosis diagnosis.<br><br>STUDY DESIGN: We conducted a prospective cohort study among 81,997 premenopausal participants of the Nurses' Health Study II, who were followed from 1991-2015. Diet was assessed with validated food frequency questionnaires every 4 years. We examined 6 dietary patterns: Western, Prudent, Alternative Healthy Eating Index, Dietary Approaches to Stop Hypertension, an estrogen-associated pattern, and a proinflammatory pattern. Cox proportional hazard ratios and 95% confidence intervals were used to quantify the association between each of these patterns and laparoscopically-confirmed endometriosis diagnosis.<br><br>RESULTS: Three thousand eight hundred ten incident cases of endometriosis were diagnosed during 24 years of follow-up. Adherence to the Alternative Healthy Eating Index, reflecting a healthier dietary pattern, was associated with a 13% lower risk of endometriosis diagnosis (fifth vs first quintile 95% confidence interval, 0.78-0.96; Ptrend=.02). Participants in the highest quintile of the Western dietary pattern, characterized by high intake of red meat, processed meat, refined grains, and desserts, had a 27% higher risk of endometriosis diagnosis than those in the lowest quintile (95% confidence interval, 1.09-1.47; Ptrend=.004). The Prudent, Dietary Approaches to Stop Hypertension, and estrogen-associated dietary patterns did not demonstrate clear associations with endometriosis risk, and there was the suggestion of a higher risk of endometriosis diagnosis among those with a higher proinflammatory diet score (hazard ratio for fifth vs first quintile, 1.10 [95% confidence interval, 0.99-1.23]; Ptrend=.01).<br><br>CONCLUSION: Our results suggest that consuming a dietary pattern that adheres to the Alternative Healthy Eating Index-2010 recommendations lowers the risk of endometriosis diagnosis, potentially through a beneficial impact on pelvic pain. In addition, consuming a less healthy diet high in red/processed meats and refined grains may have a detrimental impact on endometriosis symptoms.}, }
@article {pmid38691368, year = {2024}, author = {Manson, JE and Crandall, CJ and Rossouw, JE and Chlebowski, RT and Anderson, GL and Stefanick, ML and Aragaki, AK and Cauley, JA and Wells, GL and LaCroix, AZ and Thomson, CA and Neuhouser, ML and Van Horn, L and Kooperberg, C and Howard, BV and Tinker, LF and Wactawski-Wende, J and Shumaker, SA and Prentice, RL}, title = {The Women's Health Initiative Randomized Trials and Clinical Practice: A Review.}, journal = {JAMA}, volume = {331}, number = {20}, pages = {1748-1760}, doi = {10.1001/jama.2024.6542}, pmid = {38691368}, issn = {1538-3598}, mesh = {Aged ; Female ; Humans ; Middle Aged ; *Breast Neoplasms/prevention &amp; control ; Calcium/therapeutic use/administration &amp; dosage ; Calcium, Dietary/administration &amp; dosage ; *Cardiovascular Diseases/prevention &amp; control ; Diet, Fat-Restricted ; *Dietary Supplements ; *Estrogen Replacement Therapy/adverse effects ; Estrogens, Conjugated (USP)/therapeutic use/administration &amp; dosage/adverse effects ; Hot Flashes/drug therapy ; Medroxyprogesterone Acetate/administration &amp; dosage/therapeutic use/adverse effects ; Osteoporosis, Postmenopausal/prevention &amp; control/drug therapy ; Postmenopause ; Randomized Controlled Trials as Topic ; Vitamin D/therapeutic use/administration &amp; dosage ; *Women's Health ; United States ; }, abstract = {IMPORTANCE: Approximately 55 million people in the US and approximately 1.1 billion people worldwide are postmenopausal women. To inform clinical practice about the health effects of menopausal hormone therapy, calcium plus vitamin D supplementation, and a low-fat dietary pattern, the Women's Health Initiative (WHI) enrolled 161 808 postmenopausal US women (N = 68 132 in the clinical trials) aged 50 to 79 years at baseline from 1993 to 1998, and followed them up for up to 20 years.<br><br>OBSERVATIONS: The WHI clinical trial results do not support hormone therapy with oral conjugated equine estrogens plus medroxyprogesterone acetate for postmenopausal women or conjugated equine estrogens alone for those with prior hysterectomy to prevent cardiovascular disease, dementia, or other chronic diseases. However, hormone therapy is effective for treating moderate to severe vasomotor and other menopausal symptoms. These benefits of hormone therapy in early menopause, combined with lower rates of adverse effects of hormone therapy in early compared with later menopause, support initiation of hormone therapy before age 60 years for women without contraindications to hormone therapy who have bothersome menopausal symptoms. The WHI results do not support routinely recommending calcium plus vitamin D supplementation for fracture prevention in all postmenopausal women. However, calcium and vitamin D are appropriate for women who do not meet national guidelines for recommended intakes of these nutrients through diet. A low-fat dietary pattern with increased fruit, vegetable, and grain consumption did not prevent the primary outcomes of breast or colorectal cancer but was associated with lower rates of the secondary outcome of breast cancer mortality during long-term follow-up.<br><br>CONCLUSIONS AND RELEVANCE: For postmenopausal women, the WHI randomized clinical trials do not support menopausal hormone therapy to prevent cardiovascular disease or other chronic diseases. Menopausal hormone therapy is appropriate to treat bothersome vasomotor symptoms among women in early menopause, without contraindications, who are interested in taking hormone therapy. The WHI evidence does not support routine supplementation with calcium plus vitamin D for menopausal women to prevent fractures or a low-fat diet with increased fruits, vegetables, and grains to prevent breast or colorectal cancer. A potential role of a low-fat dietary pattern in reducing breast cancer mortality, a secondary outcome, warrants further study.}, }
@article {pmid38689544, year = {2024}, author = {Yun, J and Baek, G and Indorf, A and Duong, A}, title = {Incidence of port site complications in relation to timing of bevacizumab infusion.}, journal = {Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners}, volume = {}, number = {}, pages = {10781552241245037}, doi = {10.1177/10781552241245037}, pmid = {38689544}, issn = {1477-092X}, abstract = {INTRODUCTION: Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor, with a serious complication of wound healing complications. The package insert currently does not have recommendations on the management of bevacizumab administration around minor procedures, including port placements. Currently, there are only two trials that have examined the optimal timing of bevacizumab after port placement.<br><br>METHODS: This is a single-center retrospective trial aiming to evaluate the rate of wound dehiscence and other port site complications depending on the time between port placement and bevacizumab infusion. Eligible patients who have had at least one port place and have received bevacizumab for an oncologic indication were identified in a study period of 1/1/2016-3/31/2021. The primary outcome of this study was the incidence of wound dehiscence in relation to the timing of bevacizumab infusion.<br><br>RESULTS: A total of 243 patients met the inclusion criteria, and 116 port placements had a port site complication. For wound dehiscence, 6% was observed 0 days from port placement, 10% was observed 1 day from port placement, 0% was observed 2 days from port placement, 0% was observed 3-7 days from port placement, 3% was observed 8-14 days from port placement, and 3% was observed 15-30 days from port placement.<br><br>CONCLUSIONS: The results of this study show an inverse relationship between the risk of wound dehiscence and port site complication and the timing of bevacizumab infusion to port placement, with an increase in absolute risk of wound dehiscence when bevacizumab is given within 2 days of port placement.}, }
@article {pmid38689480, year = {2024}, author = {Chambers, M and Andre, AT and Wright, JL and Vakar-Lopez, F and Tretiakova, M and Reder, NP and Haffner, MC and True, LD}, title = {Outcome Analysis of a Series of Mixed-Grade, Non-muscle Invasive, Papillary Carcinomas of the Bladder.}, journal = {International journal of surgical pathology}, volume = {}, number = {}, pages = {10668969241246492}, doi = {10.1177/10668969241246492}, pmid = {38689480}, issn = {1940-2465}, abstract = {Introduction. Papillary urothelial carcinomas are currently graded as either low- or high-grade tumors based on World Health Organization (WHO) 2022 guidelines for genitourinary tumors. However, a minority of tumors are mixed-grade tumors, composed predominantly of low-grade cancer with a minor high-grade component. In the 2022 WHO these cancers are recognized as having outcomes comparable to low-grade cancers, although data to date has been limited. Methods. The pathology records of a large academic institution were searched for mixed-grade, non-muscle invasive papillary carcinomas of the bladder and ureter in order to characterize prognosis of these cancers. Results. Of 136 cancers, the majority (n = 104, 76.5%) were solitary, mixed-grade tumors, while 21 (15.4%) had a concurrent low-grade cancer and 11 (8.1%) had multiple mixed-grade tumors at the time of diagnosis. At follow-up (median 48.3 months, range = 1.3 months-18.1 years), 71 cancers recurred (52.2%): 52 (38.2%) as low- or mixed-grade cancers and 18 (13.2%) as high-grade cancers. There were no instances of stage-progression to >pT2. Conclusions. The clinical outcome of mixed-grade carcinomas was similar to what has been reported for low-grade carcinomas. Based on our results, and prior congruent studies of mixed-grade lesions, these lesions may be regarded as a distinct sub-category with a better prognosis than high-grade tumors.}, }
@article {pmid38688309, year = {2024}, author = {Cloyd, JM and Colby, S and Guthrie, KA and Lowy, AM and Chiorean, EG and Philip, P and Sohal, D and Ahmad, S}, title = {Failure to Undergo Resection Following Neoadjuvant Therapy for Resectable Pancreatic Cancer: A Secondary Analysis of SWOG S1505.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {4}, pages = {}, doi = {10.6004/jnccn.2023.7099}, pmid = {38688309}, issn = {1540-1413}, support = {U10 CA180888/CA/NCI NIH HHS/United States ; U10 CA180819/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Neoadjuvant Therapy/methods/statistics &amp; numerical data ; Female ; Male ; *Pancreatic Neoplasms/therapy/mortality/pathology ; Middle Aged ; Aged ; *Pancreatectomy/methods ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Leucovorin/therapeutic use/administration &amp; dosage ; Carcinoma, Pancreatic Ductal/therapy/mortality/pathology ; Paclitaxel/therapeutic use/administration &amp; dosage ; Fluorouracil/therapeutic use/administration &amp; dosage ; Irinotecan/therapeutic use/administration &amp; dosage ; Oxaliplatin/therapeutic use/administration &amp; dosage ; Deoxycytidine/analogs &amp; derivatives/therapeutic use ; Gemcitabine ; Adult ; Albumins ; }, abstract = {BACKGROUND: Neoadjuvant therapy (NT) is increasingly used for patients with pancreatic ductal adenocarcinoma (PDAC), and yet reasons for not undergoing subsequent pancreatectomy are poorly understood. Given the importance of completing multimodality therapy, we investigated factors associated with failure to undergo surgical resection following NT for PDAC.<br><br>METHODS: SWOG S1505 was a multicenter phase II randomized trial of preoperative mFOLFIRINOX or gemcitabine/nab-paclitaxel prior to planned pancreatectomy for patients with potentially resectable PDAC. Associations between clinical, demographic, and hospital-level characteristics and receipt of surgical resection were estimated via multiple logistic regression. Differences in overall survival from 18 weeks postrandomization (scheduled time of surgery) according to resection status were assessed via Cox regression models.<br><br>RESULTS: Among 102 eligible patients, 73 (71.6%) underwent successful pancreatectomy, whereas 29 (28.4%) did not, primarily because of progression (n=11; 10.8%) or toxicity during NT (n=9; 8.8%). Weight loss during NT (odds ratio [OR], 0.34; 95% CI, 0.11-0.93) and the hospital's city size (small: OR, 0.24 [95% CI, 0.07-0.80] and large: OR, 0.28 [95% CI, 0.10-0.79] compared with midsize) were significantly associated with a lower probability of surgical resection in adjusted models, whereas age, sex, race, body mass index, performance status, insurance type, geographic region, treatment arm, tumor location, chemotherapy delays/modifications, and hospital characteristics were not. Surgical resection following NT was associated with improved overall survival (median, 23.8 vs 10.8 months; P<.01) even after adjusting for grade 3-5 adverse events during NT, performance status, and body mass index (hazard ratio, 0.55; 95% CI, 0.32-0.95).<br><br>CONCLUSIONS: Failure to undergo resection following NT was relatively common among patients with potentially resectable PDAC and associated with worse survival. Although few predictive factors were identified in this secondary analysis of the SWOG S1505 randomized trial, further research must focus on risk factors for severe toxicities during NT that preclude surgical resection so that patient-centered interventions can be delivered or alternate treatment sequencing can be recommended.}, }
@article {pmid38688280, year = {2024}, author = {Benbarche, S and Pineda, JMB and Galvis, LB and Biswas, J and Liu, B and Wang, E and Zhang, Q and Hogg, SJ and Lyttle, K and Dahi, A and Lewis, AM and Sarchi, M and Rahman, J and Fox, N and Ai, Y and Mehta, S and Garippa, R and Ortiz-Pacheco, J and Li, Z and Monetti, M and Stanley, RF and Doulatov, S and Bradley, RK and Abdel-Wahab, O}, title = {GPATCH8 modulates mutant SF3B1 mis-splicing and pathogenicity in hematologic malignancies.}, journal = {Molecular cell}, volume = {84}, number = {10}, pages = {1886-1903.e10}, pmid = {38688280}, issn = {1097-4164}, support = {R01 HL169156/HL/NHLBI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; P50 CA254838/CA/NCI NIH HHS/United States ; R01 HL128239/HL/NHLBI NIH HHS/United States ; R01 HL151651/HL/NHLBI NIH HHS/United States ; R01 CA251138/CA/NCI NIH HHS/United States ; R01 CA242020/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; R01 CA283364/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; DEAD-box RNA Helicases/genetics/metabolism ; HEK293 Cells ; *Hematologic Neoplasms/genetics/pathology/metabolism ; Hematopoiesis/genetics ; Introns ; *Mutation ; *Phosphoproteins/genetics/metabolism ; RNA Helicases/genetics/metabolism ; RNA Splicing ; *RNA Splicing Factors/genetics/metabolism ; RNA-Binding Proteins/genetics/metabolism ; *Muscle Proteins/genetics/metabolism ; }, abstract = {Mutations in the RNA splicing factor gene SF3B1 are common across hematologic and solid cancers and result in widespread alterations in splicing, yet there is currently no therapeutic means to correct this mis-splicing. Here, we utilize synthetic introns uniquely responsive to mutant SF3B1 to identify trans factors required for aberrant mutant SF3B1 splicing activity. This revealed the G-patch domain-containing protein GPATCH8 as required for mutant SF3B1-induced splicing alterations and impaired hematopoiesis. GPATCH8 is involved in quality control of branchpoint selection, interacts with the RNA helicase DHX15, and functionally opposes SURP and G-patch domain containing 1 (SUGP1), a G-patch protein recently implicated in SF3B1-mutant diseases. Silencing of GPATCH8 corrected one-third of mutant SF3B1-dependent splicing defects and was sufficient to improve dysfunctional hematopoiesis in SF3B1-mutant mice and primary human progenitors. These data identify GPATCH8 as a novel splicing factor required for mis-splicing by mutant SF3B1 and highlight the therapeutic impact of correcting aberrant splicing in SF3B1-mutant cancers.}, }
@article {pmid38687617, year = {2024}, author = {Han, D and Labaf, M and Zhao, Y and Owiredu, J and Zhang, S and Patel, K and Venkataramani, K and Steinfeld, JS and Han, W and Li, M and Liu, M and Wang, Z and Besschetnova, A and Patalano, S and Mulhearn, MJ and Macoska, JA and Yuan, X and Balk, SP and Nelson, PS and Plymate, SR and Gao, S and Siegfried, KR and Liu, R and Stangis, MM and Foxa, G and Czernik, PJ and Williams, BO and Zarringhalam, K and Li, X and Cai, C}, title = {Androgen receptor splice variants drive castration-resistant prostate cancer metastasis by activating distinct transcriptional programs.}, journal = {The Journal of clinical investigation}, volume = {134}, number = {11}, pages = {}, pmid = {38687617}, issn = {1558-8238}, support = {R01 CA211350/CA/NCI NIH HHS/United States ; P50 CA090381/CA/NCI NIH HHS/United States ; R21 CA277368/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; I01 BX003324/BX/BLRD VA/United States ; R01 CA234715/CA/NCI NIH HHS/United States ; R01 CA230744/CA/NCI NIH HHS/United States ; R01 AI167570/AI/NIAID NIH HHS/United States ; U54 CA156734/CA/NCI NIH HHS/United States ; P01 CA163227/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Humans ; Male ; Mice ; Alternative Splicing ; Bone Neoplasms/secondary/genetics/metabolism/pathology ; Cell Line, Tumor ; Epithelial-Mesenchymal Transition/genetics ; *Gene Expression Regulation, Neoplastic ; Neoplasm Metastasis ; *Prostatic Neoplasms, Castration-Resistant/genetics/pathology/metabolism ; Protein Isoforms/genetics/metabolism ; *Receptors, Androgen/genetics/metabolism ; SOX9 Transcription Factor/genetics/metabolism ; Transcription, Genetic ; }, abstract = {One critical mechanism through which prostate cancer (PCa) adapts to treatments targeting androgen receptor (AR) signaling is the emergence of ligand-binding domain-truncated and constitutively active AR splice variants, particularly AR-V7. While AR-V7 has been intensively studied, its ability to activate distinct biological functions compared with the full-length AR (AR-FL), and its role in regulating the metastatic progression of castration-resistant PCa (CRPC), remain unclear. Our study found that, under castrated conditions, AR-V7 strongly induced osteoblastic bone lesions, a response not observed with AR-FL overexpression. Through combined ChIP-seq, ATAC-seq, and RNA-seq analyses, we demonstrated that AR-V7 uniquely accesses the androgen-responsive elements in compact chromatin regions, activating a distinct transcription program. This program was highly enriched for genes involved in epithelial-mesenchymal transition and metastasis. Notably, we discovered that SOX9, a critical metastasis driver gene, was a direct target and downstream effector of AR-V7. Its protein expression was dramatically upregulated in AR-V7-induced bone lesions. Moreover, we found that Ser81 phosphorylation enhanced AR-V7's pro-metastasis function by selectively altering its specific transcription program. Blocking this phosphorylation with CDK9 inhibitors impaired the AR-V7-mediated metastasis program. Overall, our study has provided molecular insights into the role of AR splice variants in driving the metastatic progression of CRPC.}, }
@article {pmid38687474, year = {2024}, author = {Elmore, JG and Lee, CI}, title = {Toward More Equitable Breast Cancer Outcomes.}, journal = {JAMA}, volume = {331}, number = {22}, pages = {1896-1897}, doi = {10.1001/jama.2024.6052}, pmid = {38687474}, issn = {1538-3598}, support = {P01 CA154292/CA/NCI NIH HHS/United States ; R37 CA240403/CA/NCI NIH HHS/United States ; R01 CA266377/CA/NCI NIH HHS/United States ; R01 CA262023/CA/NCI NIH HHS/United States ; }, mesh = {Female ; Humans ; *Breast Neoplasms/diagnosis/epidemiology/mortality/therapy ; *Healthcare Disparities/statistics &amp; numerical data ; United States/epidemiology ; *Health Equity ; Mass Screening ; Adult ; Middle Aged ; *Mammography/methods/statistics &amp; numerical data ; Black or African American/statistics &amp; numerical data ; White/statistics &amp; numerical data ; Computer Simulation ; Hispanic or Latino/statistics &amp; numerical data ; Biopsy ; }, }
@article {pmid38687020, year = {2024}, author = {Crawford, KHD and Selke, S and Pepper, G and Goecker, E and Sobel, A and Wald, A and Johnston, C and Greninger, AL}, title = {Performance characteristics of highly automated HSV-1 and HSV-2 IgG testing.}, journal = {Journal of clinical microbiology}, volume = {62}, number = {6}, pages = {e0026324}, pmid = {38687020}, issn = {1098-660X}, mesh = {Humans ; *Immunoglobulin G/blood ; *Herpesvirus 1, Human/immunology ; *Herpesvirus 2, Human/immunology/isolation &amp; purification ; *Antibodies, Viral/blood ; *Sensitivity and Specificity ; *Herpes Simplex/diagnosis/virology ; Male ; Female ; Adult ; Middle Aged ; Adolescent ; Young Adult ; Aged ; Automation, Laboratory ; Child ; Aged, 80 and over ; Immunoassay/methods ; Child, Preschool ; }, abstract = {Herpes simplex virus (HSV) infections are one of the most common and stigmatized infections of humankind, affecting more than 4 billion people around the world and more than 100 million Americans. Yet, most people do not know their infection status, and antibody testing is not recommended, partly due to poor test performance. Here, we compared the test performance of the Roche Elecsys HSV-1 IgG and HSV-2 IgG, DiaSorin LIAISON HSV-1/2 IgG, and Bio-Rad BioPlex 2200 HSV-1 and HSV-2 IgG assays with the gold-standard HSV western blot in 1,994 persons, including 1,017 persons with PCR or culture-confirmed HSV-1 and/or HSV-2 infection. Across all samples, the Bio-Rad and Roche assays had similar performance metrics with low sensitivity (<85%) but high specificity (>97%) for detecting HSV-1 IgG and both high sensitivity (>97%) and high specificity (>98%) for detecting HSV-2 IgG. The DiaSorin assay had a higher sensitivity (92.1%) but much lower specificity (88.7%) for detecting HSV-1 IgG and comparatively poor sensitivity (94.5%) and specificity (94.2%) for detecting HSV-2 IgG. The DiaSorin assay performed poorly at low-positive index values with 60.9% of DiaSorin HSV-1 results and 20.8% of DiaSorin HSV-2 results with positive index values <3.0 yielding false positive results. Based on an estimated HSV-2 seroprevalence of 12% in the United States, positive predictive values for HSV-2 IgG were 96.1% for Roche, 87.4% for Bio-Rad, and 69.0% for DiaSorin, meaning nearly one of every three positive DiaSorin HSV-2 IgG results would be falsely positive. Further development in HSV antibody diagnostics is needed to provide appropriate patient care.IMPORTANCESerological screening for HSV infections is currently not recommended in part due to the poor performance metrics of widely used commercial HSV-1 and HSV-2 IgG assays. Here, we compare three Food and Drug Administration (FDA)-cleared automated HSV-1 and HSV-2 IgG assays to the gold-standard western blot across nearly 2,000 samples. We find that not all commercially available HSV assays are created equal, with comparably low sensitivities for HSV-1 IgG across platforms and high false positivity rates for DiaSorin on HSV-2 IgG. This study is the first large-scale comparison of performance metrics for the Bio-Rad and Roche assays in over 10 years. Our study confirms that there remains room for improvement in HSV serological diagnostic testing-especially in regard to low sensitivities for HSV-1 IgG detection-and highlights that some previously less-studied assays may have better performance metrics than previously considered typical of commercially available HSV-2 IgG assays.}, }
@article {pmid38686922, year = {2024}, author = {Singal, AG and Parikh, ND and Shetty, K and Han, SH and Xie, C and Ning, J and Rinaudo, JA and Arvind, A and Lok, AS and Kanwal, F and , }, title = {Natural History of Indeterminate Liver Nodules in Patients With Advanced Liver Disease: A Multicenter Retrospective Cohort Study.}, journal = {The American journal of gastroenterology}, volume = {119}, number = {11}, pages = {2251-2258}, pmid = {38686922}, issn = {1572-0241}, support = {U24 CA230144/CA/NCI NIH HHS/United States ; U01 CA230694/CA/NCI NIH HHS/United States ; U01 CA230690/CA/NCI NIH HHS/United States ; U01 CA230997/CA/NCI NIH HHS/United States ; U01 CA271887/CA/NCI NIH HHS/United States ; U01 CA230669/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; Retrospective Studies ; *Liver Neoplasms/pathology/epidemiology ; Middle Aged ; *Carcinoma, Hepatocellular/pathology/epidemiology/diagnostic imaging ; Aged ; Risk Factors ; Tomography, X-Ray Computed ; Magnetic Resonance Imaging ; Incidence ; Disease Progression ; }, abstract = {INTRODUCTION: Indeterminate liver nodules (ILNs) are frequently encountered on diagnostic imaging after positive hepatocellular carcinoma (HCC) surveillance results, but their natural history remains unclear.<br><br>METHODS: We conducted a multicenter retrospective cohort study among patients with &#x2265;1 newly detected LI-RADS 3 (LR-3) lesion &#x2265;1 cm or LI-RADS 4 (LR-4) lesion of any size (per LI-RADS v2018) between January 2018 and December 2019. Patients were followed with repeat imaging at each site per institutional standard of care. Multivariable Fine-Gray models were used to evaluate associations between potential risk factors and patient-level time-to-HCC diagnosis, with death and liver transplantation as competing risks.<br><br>RESULTS: Of 307 patients with ILNs, 208 had LR-3 lesions, 83 had LR-4 lesions, and 16 had both LR-3 and LR-4 lesions. HCC incidence rates for patients with LR-3 and LR-4 lesions were 110 (95% CI 70-150) and 420 (95% CI 310-560) per 1,000 person-year, respectively. In multivariable analysis, incident HCC among patients with LR-3 lesions was associated with older age, thrombocytopenia (platelet count &#x2264;150 &#xd7;10 9 /L), and elevated serum alpha-fetoprotein levels. Among those with LR-4 lesions, incident HCC was associated with a maximum lesion diameter >1 cm. Although most patients had follow-up computed tomography or magnetic resonance imaging, 13.7% had no follow-up imaging and another 14.3% had follow-up ultrasound only.<br><br>DISCUSSION: ILNs have a high but variable risk of HCC, with 4-fold higher risk in patients with LR-4 lesions than those with LR-3 lesions, highlighting a need for accurate risk stratification tools and close follow-up in this population.}, }
@article {pmid38685481, year = {2024}, author = {Rowell, S and Meier, EN and Hoyos Gomez, T and Fleming, M and Jui, J and Morrison, L and Bulger, E and Sopko, G and Weisfeldt, M and Christenson, J and Klotz, P and McMullan, J and Callum, J and Sheehan, K and Tibbs, B and Aufderheide, T and Cotton, B and Gandhi, R and Idris, A and Frascone, RJ and Ferrara, M and Richmond, N and Kannas, D and Schlamp, R and Robinson, B and Dries, D and Tallon, J and Hendrickson, A and Gamber, M and Garrett, J and Simonson, R and McKinley, WI and Schreiber, M}, title = {The effects of prehospital TXA on mortality and neurologic outcomes in patients with traumatic intracranial hemorrhage: A subgroup analysis from the prehospital TXA for TBI trial.}, journal = {The journal of trauma and acute care surgery}, volume = {97}, number = {4}, pages = {572-580}, doi = {10.1097/TA.0000000000004354}, pmid = {38685481}, issn = {2163-0763}, mesh = {Humans ; Male ; Female ; *Tranexamic Acid/administration &amp; dosage/therapeutic use ; Middle Aged ; *Intracranial Hemorrhage, Traumatic/drug therapy/mortality ; *Antifibrinolytic Agents/administration &amp; dosage/therapeutic use ; Adult ; *Emergency Medical Services/methods ; *Glasgow Coma Scale ; *Tomography, X-Ray Computed ; Brain Injuries, Traumatic/mortality/complications/drug therapy ; Treatment Outcome ; }, abstract = {BACKGROUND: In the prehospital tranexamic acid (TXA) for traumatic brain injury (TBI) trial, TXA administered within 2 hours of injury in the out-of-hospital setting did not reduce mortality in all patients with moderate/severe traumatic brain injury (TBI). We examined the association between TXA dosing arms, neurologic outcome, and mortality in patients with intracranial hemorrhage (ICH) on computed tomography (CT).<br><br>METHODS: This was a secondary analysis of the Prehospital Tranexamic Acid for TBI Trial (ClinicalTrials.gov [NCT01990768]) that randomized adults with moderate/severe TBI (Glasgow Coma Scale score < 13) and systolic blood pressure &#x2265; 90 mm Hg within 2 hours of injury to a 2-g out-of-hospital TXA bolus followed by an in-hospital saline infusion, a 1-g out-of-hospital TXA bolus/1-g in-hospital TXA infusion, or an out-of-hospital saline bolus/in-hospital saline infusion (placebo). This analysis included the subgroup with ICH on initial CT. Primary outcomes included 28-day mortality, 6-month Glasgow Outcome Scale-Extended (GOSE) &#x2264; 4, and 6-month Disability Rating Scale (DRS). Outcomes were modeled using linear regression with robust standard errors.<br><br>RESULTS: The primary trial included 966 patients. Among 541 participants with ICH, 28-day mortality was lower in the 2-g TXA bolus group (17%) compared with the other two groups (1-g bolus/1-g infusion 26%, placebo 27%). The estimated adjusted difference between the 2-g bolus and placebo groups was -8&#xb7;5 percentage points (95% confidence interval [CI], -15.9 to -1.0) and between the 2-g bolus and 1-g bolus/1-g infusion groups was -10.2 percentage points (95% CI, -17.6 to -2.9). Disability Rating Scale at 6 months was lower in the 2-g TXA bolus group than the 1-g bolus/1-g infusion (estimated difference - 2.1 [95% CI, -4.2 to -0.02]) and placebo groups (-2.2 [95% CI, -4.3, -0.2]). Six-month GOSE did not differ among groups.<br><br>CONCLUSION: A 2-g out-of-hospital TXA bolus in patients with moderate/severe TBI and ICH resulted in lower 28-day mortality and lower 6-month DRS than placebo and standard TXA dosing.<br><br>LEVEL OF EVIDENCE: Therapeutic/Care Management; Level II.}, }
@article {pmid38684898, year = {2024}, author = {Madden, EB and Hindorff, LA and Bonham, VL and Akintobi, TH and Burchard, EG and Baker, KE and Begay, RL and Carpten, JD and Cox, NJ and Di Francesco, V and Dillard, DA and Fletcher, FE and Fullerton, SM and Garrison, NA and Hammack-Aviran, CM and Hiratsuka, VY and Hildreth, JEK and Horowitz, CR and Hughes Halbert, CA and Inouye, M and Jackson, A and Landry, LG and Kittles, RA and Leek, JT and Limdi, NA and Lockhart, NC and Ofili, EO and Pérez-Stable, EJ and Sabatello, M and Saulsberry, L and Schools, LE and Troyer, JL and Wilfond, BS and Wojcik, GL and Cho, JH and Lee, SS and Green, ED}, title = {Advancing genomics to improve health equity.}, journal = {Nature genetics}, volume = {56}, number = {5}, pages = {752-757}, pmid = {38684898}, issn = {1546-1718}, support = {K08 HG011505/HG/NHGRI NIH HHS/United States ; P30 DK092949/DK/NIDDK NIH HHS/United States ; Z99 HG999999/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Humans ; *Genomics/methods ; *Health Equity ; United States ; Genome, Human ; National Human Genome Research Institute (U.S.) ; }, abstract = {Health equity is the state in which everyone has fair and just opportunities to attain their highest level of health. The field of human genomics has fallen short in increasing health equity, largely because the diversity of the human population has been inadequately reflected among participants of genomics research. This lack of diversity leads to disparities that can have scientific and clinical consequences. Achieving health equity related to genomics will require greater effort in addressing inequities within the field. As part of the commitment of the National Human Genome Research Institute (NHGRI) to advancing health equity, it convened experts in genomics and health equity research to make recommendations and performed a review of current literature to identify the landscape of gaps and opportunities at the interface between human genomics and health equity research. This Perspective describes these findings and examines health equity within the context of human genomics and genomic medicine.}, }
@article {pmid38684813, year = {2024}, author = {Radko-Juettner, S and Yue, H and Myers, JA and Carter, RD and Robertson, AN and Mittal, P and Zhu, Z and Hansen, BS and Donovan, KA and Hunkeler, M and Rosikiewicz, W and Wu, Z and McReynolds, MG and Roy Burman, SS and Schmoker, AM and Mageed, N and Brown, SA and Mobley, RJ and Partridge, JF and Stewart, EA and Pruett-Miller, SM and Nabet, B and Peng, J and Gray, NS and Fischer, ES and Roberts, CWM}, title = {Author Correction: Targeting DCAF5 suppresses SMARCB1-mutant cancer by stabilizing SWI/SNF.}, journal = {Nature}, volume = {629}, number = {8012}, pages = {E12}, doi = {10.1038/s41586-024-07402-3}, pmid = {38684813}, issn = {1476-4687}, }
@article {pmid38684704, year = {2024}, author = {King, DF and Groves, H and Weller, C and Jones, I and Cramer, JP and Gilbert, PB and Goldblatt, D and Gruber, MF and Kampmann, B and Maïga, D and Pasetti, MF and Plotkin, SA and Precioso, A and Wassie, L and Wittke, F and Kaslow, DC}, title = {Realising the potential of correlates of protection for vaccine development, licensure and use: short summary.}, journal = {NPJ vaccines}, volume = {9}, number = {1}, pages = {82}, pmid = {38684704}, issn = {2059-0105}, support = {/WT_/Wellcome Trust/United Kingdom ; 001/WHO_/World Health Organization/International ; }, abstract = {On 27–29[th] of September 2022, Wellcome convened an international multi-stakeholder workshop to discuss the use of Correlates of Protection (CoP) to accelerate vaccine development, the hybrid format meeting was attended by 80 delegates including developers, manufacturers, regulators, public health officials and policy-makers from 17 countries, including 7 LMIC’s.}, }
@article {pmid38684633, year = {2024}, author = {Greywoode, R and Larson, J and Peraza, J and Clark, R and Allison, MA and Chaudhry, NA and Schnatz, PF and Shadyab, AH and Wallace, RB and Wassertheil-Smoller, S}, title = {Risk of Adverse Cardiovascular Outcomes in Postmenopausal Women with Inflammatory Bowel Disease.}, journal = {Digestive diseases and sciences}, volume = {69}, number = {7}, pages = {2586-2594}, pmid = {38684633}, issn = {1573-2568}, support = {UL1 TR001073/TR/NCATS NIH HHS/United States ; UL1TR001073/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; Female ; Middle Aged ; *Postmenopause ; *Inflammatory Bowel Diseases/complications/epidemiology ; *Cardiovascular Diseases/epidemiology/etiology ; Aged ; Proportional Hazards Models ; Ischemic Stroke/epidemiology/etiology ; Risk Factors ; United States/epidemiology ; Heart Disease Risk Factors ; Coronary Disease/epidemiology ; }, abstract = {BACKGROUND: Individuals with inflammatory bowel disease (IBD) who lack traditional cardiovascular disease (CVD) risk factors, such as young females, are observed to experience adverse CVD outcomes. Whether women with IBD have increased CVD risk after the menopause transition is unclear.<br><br>METHODS: We conducted a survival analysis of Women's Health Initiative (WHI) participants and excluded those with missing IBD diagnosis, model covariate data, follow-up data, or a baseline history of the following CVD outcomes: coronary heart disease (CHD), ischemic stroke, venous thromboembolism (VTE), peripheral arterial disease (PAD). Risk of outcomes between IBD and non-IBD women was performed using Cox proportional hazard models, stratified by WHI trial and follow-up. Models were adjusted for age, socio-demographics, comorbidities (e.g., hypertension, diabetes, hypercholesterolemia, etc.), family history, and lifestyle factors (e.g., smoking, alcohol, physical activity, body mass index, etc.).<br><br>RESULTS: Of 134,022 WHI participants meeting inclusion criteria, 1367 (1.0%) reported IBD at baseline. Mean baseline age was 63.4 years. After adjusting for age and other confounders, no significant difference was observed between IBD and non-IBD women for the risk of CHD (HR 0.96, 95% CI 0.73-1.24), VTE (HR 1.11, 95% CI 0.81-1.52) or PAD (HR 0.64, 95% CI 0.28-1.42). After adjusting for age, risk of ischemic stroke was significantly higher (HR 1.41, 95% CI 1.06-1.88) in IBD than non-IBD women. With further adjustment, the excess risk of ischemic stroke among IBD women was attenuated and no longer statistically significant (HR 1.31, 95% CI 0.98-1.76).<br><br>CONCLUSIONS: Among postmenopausal women with IBD, risk of ischemic stroke may be higher than in non-IBD women.}, }
@article {pmid38684115, year = {2024}, author = {Kelnhofer-Millevolte, LE and Arnold, EA and Nguyen, DH and Avgousti, DC}, title = {Controlling Much? Viral Control of Host Chromatin Dynamics.}, journal = {Annual review of virology}, volume = {11}, number = {1}, pages = {171-191}, doi = {10.1146/annurev-virology-100422-011616}, pmid = {38684115}, issn = {2327-0578}, mesh = {*Chromatin/metabolism/genetics ; Humans ; *Host-Pathogen Interactions ; Virus Replication ; Cell Nucleus/virology/metabolism ; Herpesviridae/genetics/physiology ; Animals ; Adenoviridae/physiology/genetics ; }, abstract = {Viruses are exemplary molecular biologists and have been integral to scientific discovery for generations. It is therefore no surprise that nuclear replicating viruses have evolved to systematically take over host cell function through astoundingly specific nuclear and chromatin hijacking. In this review, we focus on nuclear replicating DNA viruses-herpesviruses and adenoviruses-as key examples of viral invasion in the nucleus. We concentrate on critical features of nuclear architecture, such as chromatin and the nucleolus, to illustrate the complexity of the virus-host battle for resources in the nucleus. We conclude with a discussion of the technological advances that have enabled the discoveries we describe and upcoming steps in this burgeoning field.}, }
@article {pmid38683966, year = {2024}, author = {Krakow, EF and Brault, M and Summers, C and Cunningham, TM and Biernacki, MA and Black, RG and Woodward, KB and Vartanian, N and Kanaan, SB and Yeh, AC and Dossa, RG and Bar, M and Cassaday, RD and Dahlberg, A and Till, BG and Denker, AE and Yeung, CCS and Gooley, TA and Maloney, DG and Riddell, SR and Greenberg, PD and Chapuis, AG and Newell, EW and Furlan, SN and Bleakley, M}, title = {HA-1-targeted T-cell receptor T-cell therapy for recurrent leukemia after hematopoietic stem cell transplantation.}, journal = {Blood}, volume = {144}, number = {10}, pages = {1069-1082}, pmid = {38683966}, issn = {1528-0020}, support = {K23 CA154532/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/methods ; Female ; Male ; Adult ; Middle Aged ; *Leukemia/therapy ; *Receptors, Antigen, T-Cell/genetics/immunology ; Minor Histocompatibility Antigens/genetics/immunology ; Immunotherapy, Adoptive/methods/adverse effects ; Recurrence ; Aged ; Receptors, Chimeric Antigen/immunology ; Oligopeptides ; }, abstract = {Relapse is the leading cause of death after allogeneic hematopoietic stem cell transplantation (HCT) for leukemia. T cells engineered by gene transfer to express T cell receptors (TCR; TCR-T) specific for hematopoietic-restricted minor histocompatibility (H) antigens may provide a potent selective antileukemic effect post-HCT. We conducted a phase 1 clinical trial using a novel TCR-T product targeting the minor H antigen, HA-1, to treat or consolidate treatment of persistent or recurrent leukemia and myeloid neoplasms. The primary objective was to evaluate the feasibility and safety of administration of HA-1 TCR-T after HCT. CD8+ and CD4+ T cells expressing the HA-1 TCR and a CD8 coreceptor were successfully manufactured from HA-1-disparate HCT donors. One or more infusions of HA-1 TCR-T following lymphodepleting chemotherapy were administered to 9 HCT recipients who had developed disease recurrence after HCT. TCR-T cells expanded and persisted in vivo after adoptive transfer. No dose-limiting toxicities occurred. Although the study was not designed to assess efficacy, 4 patients achieved or maintained complete remissions following lymphodepletion and HA-1 TCR-T, with 1 patient still in remission at >2 years. Single-cell RNA sequencing of relapsing/progressive leukemia after TCR-T therapy identified upregulated molecules associated with T-cell dysfunction or cancer cell survival. HA-1 TCR-T therapy appears feasible and safe and shows preliminary signals of efficacy. This clinical trial was registered at ClinicalTrials.gov as #NCT03326921.}, }
@article {pmid38682560, year = {2024}, author = {Loriot, Y and Kalebasty, AR and Fléchon, A and Jain, RK and Gupta, S and Bupathi, M and Beuzeboc, P and Palmbos, P and Balar, AV and Kyriakopoulos, CE and Pouessel, D and Sternberg, CN and Tonelli, J and Sierecki, M and Zhou, H and Grivas, P and Barthélémy, P and Bangs, R and Tagawa, ST}, title = {A plain language summary of the TROPHY-U-01 study: sacituzumab govitecan use in people with locally advanced or metastatic urothelial cancer.}, journal = {Future oncology (London, England)}, volume = {20}, number = {23}, pages = {1621-1631}, doi = {10.2217/fon-2023-1030}, pmid = {38682560}, issn = {1744-8301}, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects/administration &amp; dosage ; *Camptothecin/analogs &amp; derivatives/therapeutic use/adverse effects ; Carcinoma, Transitional Cell/drug therapy/pathology ; Immunoconjugates ; Neoplasm Metastasis ; Neoplasm Staging ; Urinary Bladder Neoplasms/drug therapy/pathology ; }, abstract = {WHAT IS THIS SUMMARY ABOUT?: Sacituzumab govitecan (brand name: TRODELVY[®]) is a new treatment being studied for people with a type of bladder cancer, called urothelial cancer, that has progressed to a locally advanced or metastatic stage. Locally advanced and metastatic urothelial cancer are usually treated with platinum-based chemotherapy. Metastatic urothelial cancer is also treated with immune checkpoint inhibitors. There are few treatment options for people whose cancer gets worse after receiving these treatments. Sacituzumab govitecan is a suitable treatment option for most people with urothelial cancer because it aims to deliver an anti-cancer drug directly to the cancer in an attempt to limit the potential harmful side effects on healthy cells. This is a summary of a clinical study called TROPHY-U-01, focusing on the first group of participants, referred to as Cohort 1. All participants in Cohort 1 received sacituzumab govitecan.<br><br>WHAT ARE THE KEY TAKEAWAYS?: All participants received previous treatments for their metastatic urothelial cancer, including a platinum-based chemotherapy and a checkpoint inhibitor. The tumor in 31 of 113 participants became significantly smaller or could not be seen on scans after sacituzumab govitecan treatment; an effect that lasted for a median of 7.2&#xa0;months. Half of the participants were still alive 5.4&#xa0;months after starting treatment, without their tumor getting bigger or spreading further. Half of them were still alive 10.9&#xa0;months after starting treatment regardless of tumor size changes. Most participants experienced side effects. These side effects included lower levels of certain types of blood cells, sometimes with a fever, and loose or watery stools (diarrhea). Side effects led 7 of 113 participants to stop taking sacituzumab govitecan.<br><br>The study showed that sacituzumab govitecan had significant anti-cancer activity. Though most participants who received sacituzumab govitecan experienced side effects, these did not usually stop participants from continuing sacituzumab govitecan. Doctors can help control these side effects using treatment guidelines, but these side effects can be serious.Clinical Trial Registration: NCT03547973 (ClinicalTrials.gov) (TROPHY-U-1).}, }
@article {pmid38681192, year = {2024}, author = {Gundle, KR and Rajasekaran, K and Houlton, J and Deutsch, GB and Ow, TJ and Maki, RG and Pang, J and Nathan, CO and Clayburgh, D and Newman, JG and Brinkmann, E and Wagner, MJ and Pollack, SM and Thompson, MJ and Li, RJ and Mehta, V and Schiff, BA and Wenig, BI and Swiecicki, PL and Tang, AL and Davis, JL and van Zante, A and Bertout, JA and Jenkins, W and Turner, A and Grenley, M and Burns, C and Frazier, JP and Merrell, A and Sottero, KHW and Derry, JMJ and Gillespie, KC and Mills, B and Klinghoffer, RA}, title = {Early, precise, and safe clinical evaluation of the pharmacodynamic effects of novel agents in the intact human tumor microenvironment.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1367581}, pmid = {38681192}, issn = {1663-9812}, abstract = {Introduction: Drug development is systemically inefficient. Research and development costs for novel therapeutics average hundreds of millions to billions of dollars, with the overall likelihood of approval estimated to be as low as 6.7% for oncology drugs. Over half of these failures are due to a lack of drug efficacy. This pervasive and repeated low rate of success exemplifies how preclinical models fail to adequately replicate the complexity and heterogeneity of human cancer. Therefore, new methods of evaluation, early in the development trajectory, are essential both to rule-in and rule-out novel agents with more rigor and speed, but also to spare clinical trial patients from the potentially toxic sequelae (high risk) of testing investigational agents that have a low likelihood of producing a response (low benefit). Methods: The clinical in vivo oncology (CIVO[®]) platform was designed to change this drug development paradigm. CIVO precisely delivers microdose quantities of up to 8 drugs or combinations directly into patient tumors 4-96 h prior to planned surgical resection. Resected tissue is then analyzed for responses at each site of intratumoral drug exposure. Results: To date, CIVO has been used safely in 6 clinical trials, including 68 subjects, with 5 investigational and 17 approved agents. Resected tissues were analyzed initially using immunohistochemistry and in situ hybridization assays (115 biomarkers). As technology advanced, the platform was paired with spatial biology analysis platforms, to successfully track anti-neoplastic and immune-modulating activity of the injected agents in the intact tumor microenvironment. Discussion: Herein we provide a report of the use of CIVO technology in patients, a depiction of the robust analysis methods enabled by this platform, and a description of the operational and regulatory mechanisms used to deploy this approach in synergistic partnership with pharmaceutical partners. We further detail how use of the CIVO platform is a clinically safe and scientifically precise alternative or complement to preclinical efficacy modeling, with outputs that inform, streamline, and de-risk drug development.}, }
@article {pmid38680611, year = {2024}, author = {Anidi, IU and Sakai, S and Brooks, K and Fling, SP and Wagner, MJ and Lurain, K and Lindestam Arlehamn, CS and Sette, A and Knox, KS and Brenchley, JM and Uldrick, TS and Sharon, E and Barber, DL}, title = {Exacerbation of CMV and Nontuberculous Mycobacterial Infections Following PD-1 Blockade for HIV-Associated Kaposi Sarcoma.}, journal = {Open forum infectious diseases}, volume = {11}, number = {5}, pages = {ofae183}, pmid = {38680611}, issn = {2328-8957}, abstract = {Blockade of the co-inhibitory receptor PD-1 enhances antitumor responses by boosting the function of antigen-specific T cells. Although rare, PD-1 blockade in patients with cancer can lead to exacerbation of infection-associated pathology. Here, we detail the case of a 38-year-old man who was enrolled in a clinical trial for assessment of the safety and activity of anti-PD-1 therapy for Kaposi sarcoma in people with HIV well-controlled on antiretroviral therapy. Less than a week after receiving the first dose of anti-PD-1 antibody (pembrolizumab), he presented with severe abdominal pain associated with sudden exacerbations of preexisting cytomegalovirus (CMV) enteritis and nontuberculous mycobacterial mesenteric lymphadenitis. Plasma biomarkers of gastrointestinal tract damage were highly elevated compared with healthy controls, consistent with HIV-associated loss of gut epithelial barrier integrity. Moreover, CMV-specific CD8 T cells expressed high levels of PD-1, and 7 days following PD-1 blockade, there was an increase in the frequency of activated CD38[+] Ki67[+] CMV-specific CD8 T cells. This case highlights the potential for PD-1 blockade to drive rapid exacerbations of inflammatory symptoms when administered to individuals harboring multiple unresolved infections.}, }
@article {pmid38680292, year = {2024}, author = {Alkassis, S and Fitzsimmons, K and Hurvitz, S}, title = {Pembrolizumab-induced nephrotoxicity in a patient with breast cancer.}, journal = {Therapeutic advances in medical oncology}, volume = {16}, number = {}, pages = {17588359241248362}, pmid = {38680292}, issn = {1758-8340}, abstract = {The introduction of immunotherapy has revolutionized the treatment and improved outcomes of multiple types of cancer. Although breast cancer is a less immune-responsive tumor type, the incorporation of pembrolizumab into chemotherapy regimens in the neoadjuvant and first-line metastatic setting for the triple-negative disease has improved outcomes. However, the use of this type of treatment is associated with a spectrum of adverse events. Although rarely affected, kidneys can be a target for immunotherapy, leading to irreversible injury if not recognized and addressed early. A 52-year-old woman presented with clinical stage II right breast cancer diagnosed at an outside facility. Neoadjuvant docetaxel/carboplatin/pembrolizumab every 3 weeks was started. Given the partial response on MRI after the 4th cycle, treatment was switched to doxorubicin/cyclophosphamide. However, pembrolizumab was held in cycle 2 due to the rash and then resumed in cycle 3 after the resolution of symptoms. Elevated creatinine was noted 3 weeks after the last dose of pembrolizumab without improvement despite adequate fluid resuscitation. Diagnostic workup was unremarkable except for pyuria and minimal albuminuria on urinalysis. In the absence of other risk factors and the temporal relationship between pembrolizumab administration and the onset of acute kidney injury (AKI), immune-related nephrotoxicity was the underlying diagnosis. After initiation of corticosteroids, creatinine decreased back to baseline without the need for kidney biopsy. An addendum to the original pathology report from the outside facility surfaced 5 months after starting treatment, revealing that the second breast lesion had a Fluorescence in situ hybridization (FISH) test performed that was positive. Given this fact, therapy was changed to two cycles of neoadjuvant paclitaxel/carboplatin/trastuzumab/pertuzumab, with approximately 8 weeks between the last pembrolizumab dose and the first dose of trastuzumab. Thereafter, she underwent a right breast mastectomy which showed residual invasive carcinoma with negative margins and lymph nodes. She completed 1 year of trastuzumab. Immune-related AKI is a rare, but potentially serious complication associated with an increase in mortality. Further research is needed in the development and early detection. There is promising research in the development of noninvasive biomarkers which has the added benefit of identifying patients who can be re-challenged with immunotherapy.}, }
@article {pmid38677728, year = {2024}, author = {Amery, T and Tabatabaei, S and Sonpatki, M and Yu, EY and Beer, TM}, title = {MAOA Inhibitor Plus Docetaxel in Patients Receiving and Progressing on Docetaxel Therapy.}, journal = {Anticancer research}, volume = {44}, number = {5}, pages = {2247-2248}, doi = {10.21873/anticanres.17033}, pmid = {38677728}, issn = {1791-7530}, mesh = {Humans ; Male ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Disease Progression ; *Docetaxel/therapeutic use/administration &amp; dosage ; }, }
@article {pmid38677524, year = {2024}, author = {Inamdar, VV and Hao, S and Stephan, SB and Stephan, MT}, title = {Biomaterial-based scaffolds for direct in situ programming of tumor-infiltrating T lymphocytes.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {370}, number = {}, pages = {310-317}, doi = {10.1016/j.jconrel.2024.04.040}, pmid = {38677524}, issn = {1873-4995}, mesh = {Animals ; *Lymphocytes, Tumor-Infiltrating/immunology ; Female ; *Tissue Scaffolds ; *Biocompatible Materials/chemistry ; Mice ; Cell Line, Tumor ; Immunotherapy, Adoptive/methods ; T-Lymphocytes/immunology ; Breast Neoplasms/immunology/pathology/therapy ; Mice, Inbred C57BL ; Mice, Inbred BALB C ; }, abstract = {Adoptive cell therapy with tumor-infiltrating T cells (TILs) has generated exciting clinical trial results for the treatment of unresectable solid tumors. However, solid tumors remain difficult targets for adoptively transferred T cells, due in part to poor migration of TILs to the tumor, physical barriers to infiltration, and active suppression of TILs by the tumor. Furthermore, a highly skilled team is required to obtain tumor tissue, isolate and expand the TILs ex vivo, and reinfuse them into the patient, which drives up costs and limits patient access. Here, we describe a cell-free polymer implant designed to recruit, genetically reprogram and expand host T cells at tumor lesions in situ. Importantly, the scaffold can be fabricated on a large scale and is stable to lyophilization. Using a mouse breast cancer model, we show that the implants quickly and efficiently amass cancer-specific host lymphocytes at the tumor site in quantities sufficient to bring about long-term tumor regression. Given that surgical care is the mainstay of cancer treatment for many patients, this technology could be easily implemented in a clinical setting as an add-on to surgery for solid tumors. Furthermore, the approach could be broadened to recruit and genetically reprogram other therapeutically desirable host cells, such as macrophages, natural killer cells or dendritic cells, potentially boosting the antitumor effectiveness of the implant even more.}, }
@article {pmid38677521, year = {2024}, author = {Zhang, Y and Li, Y and Peila, R and Wang, T and Xue, X and Kaplan, RC and Dannenberg, AJ and Qi, Q and Rohan, TE}, title = {Associations of Lifestyle and Genetic Risks with Obesity and Related Chronic Diseases in the UK Biobank: A Prospective Cohort Study.}, journal = {The American journal of clinical nutrition}, volume = {119}, number = {6}, pages = {1514-1522}, pmid = {38677521}, issn = {1938-3207}, support = {R01 DK119268/DK/NIDDK NIH HHS/United States ; R01 DK120870/DK/NIDDK NIH HHS/United States ; R01 DK126698/DK/NIDDK NIH HHS/United States ; R01 HL060712/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Obesity/epidemiology/genetics ; United Kingdom/epidemiology ; Middle Aged ; Female ; Prospective Studies ; Male ; *Life Style ; Chronic Disease/epidemiology ; *Biological Specimen Banks ; Risk Factors ; Cardiovascular Diseases/epidemiology ; Genetic Predisposition to Disease ; Cohort Studies ; Aged ; Neoplasms/epidemiology/genetics ; Adult ; Body Mass Index ; Diabetes Mellitus/epidemiology/genetics ; UK Biobank ; }, abstract = {BACKGROUND: Interplay between lifestyle risk scores (LRSs) and genetic risk scores (GRSs) on obesity and related chronic diseases are underinvestigated and necessary for understanding obesity causes and developing prevention strategies.<br><br>OBJECTIVES: This study aimed to investigate independent and joint associations and interactions of LRS and GRS with obesity prevalence and risks of diabetes, cardiovascular disease (CVD), and obesity-related cancer.<br><br>METHODS: In this cohort study of 444,957 UK Biobank participants [age: 56.5 &#xb1; 8.1 y; BMI (in kg/m[2]): 27.4 &#xb1; 4.7], LRS included physical activity, dietary score, sedentary behavior, sleep duration, and smoking (range: 0-20, each factor had 5 levels). GRS was calculated based on 941 genetic variants related to BMI. Both scores were categorized into quintiles. Obesity (n = 106,301) was defined as baseline BMI &#x2265;30. Incident diabetes (n = 16,311), CVD (n = 18,076), and obesity-related cancer (n = 17,325) were ascertained through linkage to registries over a median of 12-y follow-up.<br><br>RESULTS: The LRS and GRS were independently positively associated with all outcomes. Additive interactions of LRS and GRS were observed for all outcomes (P < 0.021). Comparing the top with bottom LRS quintile, prevalence differences (95% CIs) for obesity were 17.8% (15.9%, 19.7%) in the top GRS quintile and 10.7% (8.3%, 13.1%) in the bottom GRS quintile; for diabetes, CVD, and obesity-related cancer, incidence rate differences associated with per SD increase in LRS were greater in the top than that in the bottom GRS quintile. Participants from top quintiles of both LRS and GRS had 6.16-fold, 3.81-fold, 1.56-fold, and 1.44-fold higher odds/risks of obesity, diabetes, CVD, and obesity-related cancer, respectively, than those from bottom quintiles of both scores.<br><br>CONCLUSIONS: Higher LRS was associated with higher obesity prevalence and risks of related chronic diseases regardless of GRS, highlighting the broad benefits of healthy lifestyles. Additive gene-lifestyle interactions emphasize the public health importance of lifestyle interventions among people with high genetic risks.}, }
@article {pmid38676662, year = {2024}, author = {Fauer, AJ and Qiu, W and Huang, IC and Ganz, PA and Casillas, JN and Yabroff, KR and Armstrong, GT and Leisenring, W and Howell, R and Howell, CR and Kirchhoff, AC and Yasui, Y and Nathan, PC}, title = {Financial hardship and neighborhood socioeconomic disadvantage in long-term childhood cancer survivors.}, journal = {JNCI cancer spectrum}, volume = {8}, number = {3}, pages = {}, pmid = {38676662}, issn = {2515-5091}, support = {5K12-CA138464/NH/NIH HHS/United States ; P30 CA021765/CA/NCI NIH HHS/United States ; K12 CA138464/CA/NCI NIH HHS/United States ; CA55727/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; P30 CA093373/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Cancer Survivors/psychology/statistics &amp; numerical data ; Male ; Female ; Cross-Sectional Studies ; Adult ; Middle Aged ; *Financial Stress ; Child ; Neoplasms/economics/psychology ; Neighborhood Characteristics ; Siblings ; Socioeconomic Factors ; Residence Characteristics ; Social Class ; Adolescent ; Poverty ; Self Report ; Socioeconomic Disparities in Health ; }, abstract = {BACKGROUND: Long-term survivors of childhood cancer face elevated risk for financial hardship. We evaluate whether childhood cancer survivors live in areas of greater deprivation and the association with self-reported financial hardships.<br><br>METHODS: We performed a cross-sectional analysis of data from the Childhood Cancer Survivor Study between 1970 and 1999 and self-reported financial information from 2017 to 2019. We measured neighborhood deprivation with the Area Deprivation Index (ADI) based on current zip code. Financial hardship was measured with validated surveys that captured behavioral, material and financial sacrifice, and psychological hardship. Bivariate analyses described neighborhood differences between survivors and siblings. Generalized linear models estimated effect sizes between ADI and financial hardship adjusting for clinical factors and personal socioeconomic status.<br><br>RESULTS: Analysis was restricted to 3475 long-term childhood cancer survivors and 923 sibling controls. Median ages at time of evaluation was 39 years (interquartile range [IQR] = 33-46 years and 47 years (IQR = 39-59 years), respectively. Survivors resided in areas with greater deprivation (ADI &#x2265; 50: 38.7% survivors vs 31.8% siblings; P < .001). One quintile increases in deprivation were associated with small increases in behavioral (second quintile, P = .017) and psychological financial hardship (second quintile, P = .009; third quintile, P = .014). Lower psychological financial hardship was associated with individual factors including greater household income (&#x2265;$60&#x200a;000 income, P < .001) and being single (P = .048).<br><br>CONCLUSIONS: Childhood cancer survivors were more likely to live in areas with socioeconomic deprivation. Neighborhood-level disadvantage and personal socioeconomic circumstances should be evaluated when trying to assist childhood cancer survivors with financial hardships.}, }
@article {pmid38676439, year = {2024}, author = {Zhang, Y and Win, AK and Makalic, E and Buchanan, DD and Pai, RK and Phipps, AI and Rosty, C and Boussioutas, A and Karahalios, A and Jenkins, MA}, title = {Associations between pathological features and risk of metachronous colorectal cancer.}, journal = {International journal of cancer}, volume = {155}, number = {6}, pages = {1023-1032}, doi = {10.1002/ijc.34979}, pmid = {38676439}, issn = {1097-0215}, support = {U01 CA167551/CA/NCI NIH HHS/United States ; //University of Melbourne/ ; //China Scholarship Council/ ; 1195099//National Health and Medical Research Council (NHMRC)/ ; 1194392//National Health and Medical Research Council (NHMRC)/ ; 1194896//National Health and Medical Research Council (NHMRC)/ ; //National Cancer Institute (NCI)/ ; U01 CA167551/CA/NCI NIH HHS/United States ; //Surveillance, Epidemiology, and End Results (SEER) Program/ ; //Victoria Cancer Registry (Australia)/ ; //Ontario Cancer Registry (Canada)/ ; }, mesh = {Humans ; Male ; *Neoplasms, Second Primary/epidemiology/pathology/genetics ; Female ; *Colorectal Neoplasms/pathology/genetics/epidemiology ; Middle Aged ; Aged ; Australia/epidemiology ; Canada/epidemiology ; Risk Factors ; Adult ; Prospective Studies ; Incidence ; United States/epidemiology ; Registries ; Proportional Hazards Models ; }, abstract = {Survivors of colorectal cancer (CRC) are at risk of developing another primary colorectal cancer - metachronous CRC. Understanding which pathological features of the first tumour are associated with risk of metachronous CRC might help tailor existing surveillance guidelines. Population-based CRC cases were recruited from the United States, Canada and Australia between 1997 and 2012 and followed prospectively until 2022 by the Colon Cancer Family Registry. Metachronous CRC was defined as a new primary CRC diagnosed at least 1 year after the initial CRC. Those with the genetic cancer predisposition Lynch syndrome or MUTYH mutation carriers were excluded. Cox regression models were fitted to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the associations. Of 6085 CRC cases, 138 (2.3%) were diagnosed with a metachronous CRC over a median follow-up time of 12 years (incidence: 2.0 per 1000 person-years). CRC cases with a synchronous CRC were 3.4-fold more likely to develop a metachronous CRC (adjusted HR: 3.36, 95% CI: 1.89-5.98) than those without a synchronous tumour. CRC cases with MMR-deficient tumours had a 72% increased risk of metachronous CRC (adjusted HR: 1.72, 95% CI: 1.11-2.64) compared to those with MMR-proficient tumours. Compared to cases who had an adenocarcinoma histologic type, those with an undifferentiated histologic type were 77% less likely to develop a metachronous CRC (adjusted HR: 0.23, 95% CI: 0.06-0.94). Existing surveillance guidelines for CRC survivors could be updated to include increased surveillance for those whose first CRC was diagnosed with a synchronous CRC or was MMR-deficient.}, }
@article {pmid38675841, year = {2024}, author = {Kampouri, E and Handley, G and Hill, JA}, title = {Human Herpes Virus-6 (HHV-6) Reactivation after Hematopoietic Cell Transplant and Chimeric Antigen Receptor (CAR)- T Cell Therapy: A Shifting Landscape.}, journal = {Viruses}, volume = {16}, number = {4}, pages = {}, pmid = {38675841}, issn = {1999-4915}, mesh = {*Herpesvirus 6, Human/immunology/genetics/physiology ; Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects ; *Virus Activation ; *Roseolovirus Infections/virology/immunology/therapy ; *Receptors, Chimeric Antigen/immunology/genetics ; Immunotherapy, Adoptive/methods/adverse effects ; Graft vs Host Disease/immunology/etiology ; }, abstract = {HHV-6B reactivation affects approximately half of all allogeneic hematopoietic cell transplant (HCT) recipients. HHV-6B is the most frequent infectious cause of encephalitis following HCT and is associated with pleiotropic manifestations in this setting, including graft-versus-host disease, myelosuppression, pneumonitis, and CMV reactivation, although the causal link is not always clear. When the virus inserts its genome in chromosomes of germ cells, the chromosomally integrated form (ciHHV6) is inherited by offspring. The condition of ciHHV6 is characterized by the persistent detection of HHV-6 DNA, often confounding diagnosis of reactivation and disease-this has also been associated with adverse outcomes. Recent changes in clinical practice in the field of cellular therapies, including a wider use of post-HCT cyclophosphamide, the advent of letermovir for CMV prophylaxis, and the rapid expansion of novel cellular therapies require contemporary epidemiological studies to determine the pathogenic role and spectrum of disease of HHV-6B in the current era. Research into the epidemiology and clinical significance of HHV-6B in chimeric antigen receptor T cell (CAR-T cell) therapy recipients is in its infancy. No controlled trials have determined the optimal treatment for HHV-6B. Treatment is reserved for end-organ disease, and the choice of antiviral agent is influenced by expected toxicities. Virus-specific T cells may provide a novel, less toxic therapeutic modality but is more logistically challenging. Preventive strategies are hindered by the high toxicity of current antivirals. Ongoing study is needed to keep up with the evolving epidemiology and impact of HHV-6 in diverse and expanding immunocompromised patient populations.}, }
@article {pmid38672531, year = {2024}, author = {van Dijk, AD and Hoff, FW and Qiu, Y and Hubner, SE and Go, RL and Ruvolo, VR and Leonti, AR and Gerbing, RB and Gamis, AS and Aplenc, R and Kolb, EA and Alonzo, TA and Meshinchi, S and de Bont, ESJM and Horton, TM and Kornblau, SM}, title = {Chromatin Profiles Are Prognostic of Clinical Response to Bortezomib-Containing Chemotherapy in Pediatric Acute Myeloid Leukemia: Results from the COG AAML1031 Trial.}, journal = {Cancers}, volume = {16}, number = {8}, pages = {}, pmid = {38672531}, issn = {2072-6694}, support = {U10 CA180886/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; }, abstract = {The addition of the proteasome inhibitor bortezomib to standard chemotherapy did not improve survival in pediatric acute myeloid leukemia (AML) when all patients were analyzed as a group in the Children's Oncology Group phase 3 trial AAML1031 (NCT01371981). Proteasome inhibition influences the chromatin landscape and proteostasis, and we hypothesized that baseline proteomic analysis of histone- and chromatin-modifying enzymes (HMEs) would identify AML subgroups that benefitted from bortezomib addition. A proteomic profile of 483 patients treated with AAML1031 chemotherapy was generated using a reverse-phase protein array. A relatively high expression of 16 HME was associated with lower EFS and higher 3-year relapse risk after AML standard treatment compared to low expressions (52% vs. 29%, p = 0.005). The high-HME profile correlated with more transposase-accessible chromatin, as demonstrated via ATAC-sequencing, and the bortezomib addition improved the 3-year overall survival compared with standard therapy (62% vs. 75%, p = 0.033). These data suggest that there are pediatric AML populations that respond well to bortezomib-containing chemotherapy.}, }
@article {pmid38671485, year = {2024}, author = {Zablocki, RW and Hartman, SJ and Di, C and Zou, J and Carlson, JA and Hibbing, PR and Rosenberg, DE and Greenwood-Hickman, MA and Dillon, L and LaCroix, AZ and Natarajan, L}, title = {Using functional principal component analysis (FPCA) to quantify sitting patterns derived from wearable sensors.}, journal = {The international journal of behavioral nutrition and physical activity}, volume = {21}, number = {1}, pages = {48}, pmid = {38671485}, issn = {1479-5868}, support = {R01DK114945/DK/NIDDK NIH HHS/United States ; R01 DK114945/DK/NIDDK NIH HHS/United States ; P01 AG052352/AG/NIA NIH HHS/United States ; P01AG052352/AG/NIA NIH HHS/United States ; R01HL130483/HL/NHLBI NIH HHS/United States ; R01 HL130483/HL/NHLBI NIH HHS/United States ; }, mesh = {Aged ; Female ; Humans ; Middle Aged ; Accelerometry/instrumentation/methods ; Actigraphy/instrumentation/methods ; Blood Pressure/physiology ; Exercise/physiology ; Movement ; Overweight ; Postmenopause/physiology ; *Principal Component Analysis ; *Sedentary Behavior ; *Sitting Position ; *Wearable Electronic Devices ; }, abstract = {BACKGROUND: Sedentary behavior (SB) is a recognized risk factor for many chronic diseases. ActiGraph and activPAL are two commonly used wearable accelerometers in SB research. The former measures body movement and the latter measures body posture. The goal of the current study is to quantify the pattern and variation of movement (by ActiGraph activity counts) during activPAL-identified sitting events, and examine associations between patterns and health-related outcomes, such as systolic and diastolic blood pressure (SBP and DBP).<br><br>METHODS: The current study included 314 overweight postmenopausal women, who were instructed to wear an activPAL (at thigh) and ActiGraph (at waist) simultaneously for 24 hours a day for a week under free-living conditions. ActiGraph and activPAL data were processed to obtain minute-level time-series outputs. Multilevel functional principal component analysis (MFPCA) was applied to minute-level ActiGraph activity counts within activPAL-identified sitting bouts to investigate variation in movement while sitting across subjects and days. The multilevel approach accounted for the nesting of days within subjects.<br><br>RESULTS: At least 90% of the overall variation of activity counts was explained by two subject-level principal components (PC) and six day-level PCs, hence dramatically reducing the dimensions from the original minute-level scale. The first subject-level PC captured patterns of fluctuation in movement during sitting, whereas the second subject-level PC delineated variation in movement during different lengths of sitting bouts: shorter (< 30 minutes), medium (30 -39 minutes) or longer (> 39 minute). The first subject-level PC scores showed positive association with DBP (standardized &#x3b2; ^ : 2.041, standard error: 0.607, adjusted p = 0.007), which implied that lower activity counts (during sitting) were associated with higher DBP.<br><br>CONCLUSION: In this work we implemented MFPCA to identify variation in movement patterns during sitting bouts, and showed that these patterns were associated with cardiovascular health. Unlike existing methods, MFPCA does not require pre-specified cut-points to define activity intensity, and thus offers a novel powerful statistical tool to elucidate variation in SB patterns and health.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT03473145; Registered 22 March 2018; https://clinicaltrials.gov/ct2/show/NCT03473145 ; International Registered Report Identifier (IRRID): DERR1-10.2196/28684.}, }
@article {pmid38670944, year = {2024}, author = {Chen, Z and Guo, X and Tao, R and Huyghe, JR and Law, PJ and Fernandez-Rozadilla, C and Ping, J and Jia, G and Long, J and Li, C and Shen, Q and Xie, Y and Timofeeva, MN and Thomas, M and Schmit, SL and Díez-Obrero, V and Devall, M and Moratalla-Navarro, F and Fernandez-Tajes, J and Palles, C and Sherwood, K and Briggs, SEW and Svinti, V and Donnelly, K and Farrington, SM and Blackmur, J and Vaughan-Shaw, PG and Shu, XO and Lu, Y and Broderick, P and Studd, J and Harrison, TA and Conti, DV and Schumacher, FR and Melas, M and Rennert, G and Obón-Santacana, M and Martín-Sánchez, V and Oh, JH and Kim, J and Jee, SH and Jung, KJ and Kweon, SS and Shin, MH and Shin, A and Ahn, YO and Kim, DH and Oze, I and Wen, W and Matsuo, K and Matsuda, K and Tanikawa, C and Ren, Z and Gao, YT and Jia, WH and Hopper, JL and Jenkins, MA and Win, AK and Pai, RK and Figueiredo, JC and Haile, RW and Gallinger, S and Woods, MO and Newcomb, PA and Duggan, D and Cheadle, JP and Kaplan, R and Kerr, R and Kerr, D and Kirac, I and Böhm, J and Mecklin, JP and Jousilahti, P and Knekt, P and Aaltonen, LA and Rissanen, H and Pukkala, E and Eriksson, JG and Cajuso, T and Hänninen, U and Kondelin, J and Palin, K and Tanskanen, T and Renkonen-Sinisalo, L and Männistö, S and Albanes, D and Weinstein, SJ and Ruiz-Narvaez, E and Palmer, JR and Buchanan, DD and Platz, EA and Visvanathan, K and Ulrich, CM and Siegel, E and Brezina, S and Gsur, A and Campbell, PT and Chang-Claude, J and Hoffmeister, M and Brenner, H and Slattery, ML and Potter, JD and Tsilidis, KK and Schulze, MB and Gunter, MJ and Murphy, N and Castells, A and Castellví-Bel, S and Moreira, L and Arndt, V and Shcherbina, A and Bishop, DT and Giles, GG and Southey, MC and Idos, GE and McDonnell, KJ and Abu-Ful, Z and Greenson, JK and Shulman, K and Lejbkowicz, F and Offit, K and Su, YR and Steinfelder, R and Keku, TO and van Guelpen, B and Hudson, TJ and Hampel, H and Pearlman, R and Berndt, SI and Hayes, RB and Martinez, ME and Thomas, SS and Pharoah, PDP and Larsson, SC and Yen, Y and Lenz, HJ and White, E and Li, L and Doheny, KF and Pugh, E and Shelford, T and Chan, AT and Cruz-Correa, M and Lindblom, A and Hunter, DJ and Joshi, AD and Schafmayer, C and Scacheri, PC and Kundaje, A and Schoen, RE and Hampe, J and Stadler, ZK and Vodicka, P and Vodickova, L and Vymetalkova, V and Edlund, CK and Gauderman, WJ and Shibata, D and Toland, A and Markowitz, S and Kim, A and Chanock, SJ and van Duijnhoven, F and Feskens, EJM and Sakoda, LC and Gago-Dominguez, M and Wolk, A and Pardini, B and FitzGerald, LM and Lee, SC and Ogino, S and Bien, SA and Kooperberg, C and Li, CI and Lin, Y and Prentice, R and Qu, C and Bézieau, S and Yamaji, T and Sawada, N and Iwasaki, M and Le Marchand, L and Wu, AH and Qu, C and McNeil, CE and Coetzee, G and Hayward, C and Deary, IJ and Harris, SE and Theodoratou, E and Reid, S and Walker, M and Ooi, LY and Lau, KS and Zhao, H and Hsu, L and Cai, Q and Dunlop, MG and Gruber, SB and Houlston, RS and Moreno, V and Casey, G and Peters, U and Tomlinson, I and Zheng, W}, title = {Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {3557}, pmid = {38670944}, issn = {2041-1723}, support = {U01 CA206110/CA/NCI NIH HHS/United States ; R01 CA263318/CA/NCI NIH HHS/United States ; P01 CA196569/CA/NCI NIH HHS/United States ; 001/WHO_/World Health Organization/International ; R37CA227130//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01CA188214//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; P30 CA008748/CA/NCI NIH HHS/United States ; U01 CA272529/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Colorectal Neoplasms/genetics ; *Genetic Predisposition to Disease ; *Genome-Wide Association Study ; *Asian People/genetics ; *White People/genetics ; *Polymorphism, Single Nucleotide ; *Quantitative Trait Loci ; Exome Sequencing ; Case-Control Studies ; Transcriptome ; Chromosome Mapping ; Male ; Female ; East Asian People ; }, abstract = {Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.}, }
@article {pmid38670103, year = {2024}, author = {Martin, CG and Bent, JS and Hill, T and Topalidou, I and Singhvi, A}, title = {Epithelial UNC-23 limits mechanical stress to maintain glia-neuron architecture in C. elegans.}, journal = {Developmental cell}, volume = {59}, number = {13}, pages = {1668-1688.e7}, pmid = {38670103}, issn = {1878-1551}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 NS114222/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Caenorhabditis elegans/metabolism ; *Caenorhabditis elegans Proteins/metabolism/genetics ; Cell Shape ; Cytoskeleton/metabolism ; Epithelial Cells/metabolism/cytology ; *Neuroglia/metabolism ; *Neurons/metabolism ; Receptors, Fibroblast Growth Factor/metabolism/genetics ; Stress, Mechanical ; }, abstract = {For an organ to maintain correct architecture and function, its diverse cellular components must coordinate their size and shape. Although cell-intrinsic mechanisms driving homotypic cell-cell coordination are known, it is unclear how cell shape is regulated across heterotypic cells. We find that epithelial cells maintain the shape of neighboring sense-organ glia-neuron units in adult Caenorhabditis elegans (C. elegans). Hsp co-chaperone UNC-23/BAG2 prevents epithelial cell shape from deforming, and its loss causes head epithelia to stretch aberrantly during animal movement. In the sense-organ glia, amphid sheath (AMsh), this causes progressive fibroblast growth factor receptor (FGFR)-dependent disruption of the glial apical cytoskeleton. Resultant glial cell shape alteration causes concomitant shape change in glia-associated neuron endings. Epithelial UNC-23 maintenance of glia-neuron shape is specific both spatially, within a defined anatomical zone, and temporally, in a developmentally critical period. As all molecular components uncovered are broadly conserved across central and peripheral nervous systems, we posit that epithelia may similarly regulate glia-neuron architecture cross-species.}, }
@article {pmid38670099, year = {2024}, author = {Glass, DR and Mayer-Blackwell, K and Ramchurren, N and Parks, KR and Duran, GE and Wright, AK and Bastidas Torres, AN and Islas, L and Kim, YH and Fling, SP and Khodadoust, MS and Newell, EW}, title = {Multi-omic profiling reveals the endogenous and neoplastic responses to immunotherapies in cutaneous T cell lymphoma.}, journal = {Cell reports. Medicine}, volume = {5}, number = {5}, pages = {101527}, pmid = {38670099}, issn = {2666-3791}, support = {L30 CA284435/CA/NCI NIH HHS/United States ; R01 CA264646/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Lymphoma, T-Cell, Cutaneous/immunology/therapy/pathology ; *Immunotherapy/methods ; Interferon-gamma/metabolism/immunology ; Skin Neoplasms/immunology/therapy/pathology/drug therapy ; Male ; Female ; Programmed Cell Death 1 Receptor/immunology/antagonists &amp; inhibitors/metabolism ; Immune Checkpoint Inhibitors/therapeutic use/pharmacology ; Multiomics ; }, abstract = {Cutaneous T cell lymphomas (CTCLs) are skin cancers with poor survival rates and limited treatments. While immunotherapies have shown some efficacy, the immunological consequences of administering immune-activating agents to CTCL patients have not been systematically characterized. We apply a suite of high-dimensional technologies to investigate the local, cellular, and systemic responses in CTCL patients receiving either mono- or combination anti-PD-1 plus interferon-gamma (IFN-γ) therapy. Neoplastic T cells display no evidence of activation after immunotherapy. IFN-γ induces muted endogenous immunological responses, while anti-PD-1 elicits broader changes, including increased abundance of CLA[+]CD39[+] T cells. We develop an unbiased multi-omic profiling approach enabling discovery of immune modules stratifying patients. We identify an enrichment of activated regulatory CLA[+]CD39[+] T cells in non-responders and activated cytotoxic CLA[+]CD39[+] T cells in leukemic patients. Our results provide insights into the effects of immunotherapy in CTCL patients and a generalizable framework for multi-omic analysis of clinical trials.}, }
@article {pmid38669515, year = {2024}, author = {Beichman, AC and Zhu, L and Harris, K}, title = {The Evolutionary Interplay of Somatic and Germline Mutation Rates.}, journal = {Annual review of biomedical data science}, volume = {7}, number = {1}, pages = {83-105}, doi = {10.1146/annurev-biodatasci-102523-104225}, pmid = {38669515}, issn = {2574-3414}, mesh = {Humans ; *Germ-Line Mutation/genetics ; *Mutation Rate ; Evolution, Molecular ; Animals ; Germ Cells/metabolism ; Mutation ; Neoplasms/genetics ; }, abstract = {Novel sequencing technologies are making it increasingly possible to measure the mutation rates of somatic cell lineages. Accurate germline mutation rate measurement technologies have also been available for a decade, making it possible to assess how this fundamental evolutionary parameter varies across the tree of life. Here, we review some classical theories about germline and somatic mutation rate evolution that were formulated using principles of population genetics and the biology of aging and cancer. We find that somatic mutation rate measurements, while still limited in phylogenetic diversity, seem consistent with the theory that selection to preserve the soma is proportional to life span. However, germline and somatic theories make conflicting predictions regarding which species should have the most accurate DNA repair. Resolving this conflict will require carefully measuring how mutation rates scale with time and cell division and achieving a better understanding of mutation rate pleiotropy among cell types.}, }
@article {pmid38669341, year = {2024}, author = {Babushok, DV and DeZern, AE and de Castro, CM and Rogers, ZR and Beenhouwer, D and Broder, MS and Fanning, SR and Gibbs, SN and Hanna, R and Maciejewski, JP and Scott, BL and Tantravahi, SK and Wlodarski, MW and Yermilov, I and Patel, BJ}, title = {Modified Delphi panel consensus recommendations for management of severe aplastic anemia.}, journal = {Blood advances}, volume = {8}, number = {15}, pages = {3946-3960}, pmid = {38669341}, issn = {2473-9537}, mesh = {*Anemia, Aplastic/therapy/diagnosis ; Humans ; *Consensus ; *Delphi Technique ; *Disease Management ; }, abstract = {Severe aplastic anemia (SAA) is a rare hematologic condition for which there is no clear management algorithm. A panel of 11 experts on adult and pediatric aplastic anemia was assembled and, using the RAND/University of California, Los Angeles modified Delphi panel method, evaluated >600 varying patient care scenarios to develop clinical recommendations for the initial and subsequent management of patients of all ages with SAA. Here, we present the panel's recommendations to rule out inherited bone marrow failure syndromes, on supportive care before and during first-line therapy, and on first-line (initial management) and second-line (subsequent management) therapy of acquired SAA, focusing on when transplant vs medical therapy is most appropriate. These recommendations represent the consensus of 11 experts informed by published literature and experience. They are intended only as general guidance for experienced clinicians who treat patients with SAA and are in no way intended to supersede individual physician and patient decision making. Current and future research should validate this consensus using clinical data. Once validated, we hope these expert panel recommendations will improve outcomes for patients with SAA.}, }
@article {pmid38669315, year = {2024}, author = {Holtzman, NG and Curtis, LM and Salit, RB and Shaffer, BC and Pirsl, F and Ostojic, A and Steinberg, SM and Schulz, E and Wilder, JS and Hughes, TE and Rose, J and Memon, S and Korngold, R and Gea-Banacloche, JC and Fowler, DH and Hakim, FT and Gress, RE and Bishop, MR and Pavletic, SZ}, title = {High-dose alemtuzumab and cyclosporine vs tacrolimus, methotrexate, and sirolimus for chronic graft-versus-host disease prevention.}, journal = {Blood advances}, volume = {8}, number = {16}, pages = {4294-4310}, pmid = {38669315}, issn = {2473-9537}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Alemtuzumab/therapeutic use/administration &amp; dosage ; Chronic Disease/prevention &amp; control ; *Cyclosporine/therapeutic use/administration &amp; dosage ; *Graft vs Host Disease/epidemiology/etiology/prevention &amp; control ; Hematologic Neoplasms/therapy ; Hematopoietic Stem Cell Transplantation/adverse effects ; *Immunosuppressive Agents/administration &amp; dosage/therapeutic use ; *Methotrexate/therapeutic use/administration &amp; dosage ; *Sirolimus/administration &amp; dosage/therapeutic use ; *Tacrolimus/administration &amp; dosage/therapeutic use ; Transplantation Conditioning/methods ; Transplantation, Homologous/adverse effects ; }, abstract = {Chronic graft-versus-host disease (cGVHD) remains a significant problem for patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although in vivo lymphodepletion for cGVHD prophylaxis has been explored in the myeloablative setting, its effects after reduced-intensity conditioning (RIC) are not well described. Patients (N = 83) with hematologic malignancies underwent targeted lymphodepletion chemotherapy followed by a RIC allo-HSCT using peripheral blood stem cells from unrelated donors. Patients were randomized to 2 GVHD prophylaxis arms: alemtuzumab and cyclosporine (AC; n = 44) or tacrolimus, methotrexate, and sirolimus (TMS; n = 39), with the primary end point of cumulative incidence of severe cGVHD. The incidence of severe cGVHD was lower with AC vs TMS prophylaxis at 1- and 5-years (0% vs 10.3% and 4.5% vs 28.5%; overall, P = .0002), as well as any grade (P = .003) and moderate-severe (P < .0001) cGVHD. AC was associated with higher rates of grade 3 to 4 infections (P = .02) and relapse (52% vs 21%; P = .003) with no difference in 5-year GVHD-free-, relapse-free-, or overall survival. AC severely depleted naïve T-cell reconstitution, resulting in reduced T-cell receptor repertoire diversity, smaller populations of CD4Treg and CD8Tscm, but a higher ratio of Treg to naïve T-cells at 6 months. In summary, an alemtuzumab-based regimen successfully reduced the rate and severity of cGVHD after RIC allo-HSCT and resulted in a distinct immunomodulatory profile, which may have reduced cGVHD incidence and severity. However, increased infections and relapse resulted in a lack of survival benefit after long-term follow-up. This trial was registered at www.ClinicalTrials.gov as #NCT00520130.}, }
@article {pmid38667288, year = {2024}, author = {Turnham, DJ and Mullen, MS and Bullock, NP and Gilroy, KL and Richards, AE and Patel, R and Quintela, M and Meniel, VS and Seaton, G and Kynaston, H and Clarkson, RWE and Phesse, TJ and Nelson, PS and Haffner, MC and Staffurth, JN and Pearson, HB}, title = {Development and Characterisation of a New Patient-Derived Xenograft Model of AR-Negative Metastatic Castration-Resistant Prostate Cancer.}, journal = {Cells}, volume = {13}, number = {8}, pages = {}, pmid = {38667288}, issn = {2073-4409}, support = {R01 CA234715/CA/NCI NIH HHS/United States ; R01 CA266452/CA/NCI NIH HHS/United States ; A27894/CRUK_/Cancer Research UK/United Kingdom ; }, mesh = {Male ; Humans ; *Prostatic Neoplasms, Castration-Resistant/pathology/genetics/metabolism/drug therapy ; Animals ; *Receptors, Androgen/metabolism/genetics ; Mice ; Xenograft Model Antitumor Assays ; Phenylthiohydantoin/pharmacology/analogs &amp; derivatives/therapeutic use ; Neoplasm Metastasis ; Nitriles/pharmacology ; Disease Models, Animal ; Benzamides/pharmacology ; Phthalazines/pharmacology/therapeutic use ; *Piperazines ; }, abstract = {As the treatment landscape for prostate cancer gradually evolves, the frequency of treatment-induced neuroendocrine prostate cancer (NEPC) and double-negative prostate cancer (DNPC) that is deficient for androgen receptor (AR) and neuroendocrine (NE) markers has increased. These prostate cancer subtypes are typically refractory to AR-directed therapies and exhibit poor clinical outcomes. Only a small range of NEPC/DNPC models exist, limiting our molecular understanding of this disease and hindering our ability to perform preclinical trials exploring novel therapies to treat NEPC/DNPC that are urgently needed in the clinic. Here, we report the development of the CU-PC01 PDX model that represents AR-negative mCRPC with PTEN/RB/PSMA loss and CTNN1B/TP53/BRCA2 genetic variants. The CU-PC01 model lacks classic NE markers, with only focal and/or weak expression of chromogranin A, INSM1 and CD56. Collectively, these findings are most consistent with a DNPC phenotype. Ex vivo and in vivo preclinical studies revealed that CU-PC01 PDX tumours are resistant to mCRPC standard-of-care treatments enzalutamide and docetaxel, mirroring the donor patient's treatment response. Furthermore, short-term CU-PC01 tumour explant cultures indicate this model is initially sensitive to PARP inhibition with olaparib. Thus, the CU-PC01 PDX model provides a valuable opportunity to study AR-negative mCRPC biology and to discover new treatment avenues for this hard-to-treat disease.}, }
@article {pmid38666501, year = {2024}, author = {Kim, SR and Nordlander, A and Xie, H and Kim, YJ and Ogimi, C and Thakar, MS and Leisenring, W and Englund, JA and Boeckh, M and Waghmare, A}, title = {The Impact of Pretransplant Respiratory Virus Detection on Posttransplant Outcomes in Children Undergoing Hematopoietic Cell Transplantation.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {79}, number = {3}, pages = {761-771}, pmid = {38666501}, issn = {1537-6591}, support = {T32 HD007233/HD/NICHD NIH HHS/United States ; NICHD 2T32HD007233/NH/NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Male ; Female ; Retrospective Studies ; *Respiratory Tract Infections/virology ; Child, Preschool ; Child ; Infant ; Adolescent ; Risk Factors ; }, abstract = {BACKGROUND: Pretransplant respiratory virus (RV) infections have been associated with negative transplant outcomes in adult hematopoietic cell transplantation (HCT) recipients. In the era of HCT delay because of high-risk RVs, we examined the impact of pretransplant RV detection on transplant outcomes in pediatric HCT recipients.<br><br>METHODS: This retrospective cohort study included pediatric myeloablative allogeneic HCT recipients from 2010 to 2019. All patients were screened for RV at least once within 90 days before HCT using reverse transcriptase polymerase chain reaction (PCR), regardless of symptoms. Posttransplant outcomes included days alive and out of hospital and progression to lower respiratory tract infection (LRTI).<br><br>RESULTS: Among 310 patients, 134 had an RV detected in the 90 days before HCT. In univariable analysis, transplant factors including younger age, total body irradiation, umbilical cord blood transplantation, lymphocyte count <100/mm3, HCT comorbidity index score &#x2265;3, and viral factors including symptomatic infection, human rhinovirus as a virus type, and symptomatic pretransplant upper respiratory tract infection were associated with fewer days alive and out of hospital. In multivariable analysis, transplant factors remained significant, but not viral factors. There was a higher incidence of progression to posttransplant LRTI with the same pretransplant RV if the last positive PCR before HCT was &#x2264;30 days compared with >30 days (P = .007).<br><br>CONCLUSIONS: In the setting of recommending HCT delay for high-risk RVs, symptomatic upper respiratory tract infection, including human rhinovirus infections, may lead to increased duration of hospitalization and early progression to LRTI when transplantation is performed within 30 days of the last positive PCR test.}, }
@article {pmid38666065, year = {2024}, author = {Poston, JN and Brown, SP and Ilich, A and Ginsburg, AS and Herren, H and El Kassar, N and Jensen, CE and Triulzi, DJ and Key, NS and May, S and Gernsheimer, TB}, title = {Fewer severe infections with tranexamic acid in patients with hematologic malignancies.}, journal = {Research and practice in thrombosis and haemostasis}, volume = {8}, number = {2}, pages = {102358}, pmid = {38666065}, issn = {2475-0379}, abstract = {BACKGROUND: Tranexamic acid (TXA) is an antifibrinolytic agent that reduces bleeding in a multitude of clinical settings from postpartum hemorrhage to trauma. TXA may have clinical effects unrelated to bleeding; plasminogen, the target of TXA, alters immune responses, and TXA appears to decrease the risk of infection in patients undergoing cardiac surgery, as well as joint arthroplasty.<br><br>OBJECTIVES: To address whether TXA alters rates of infection and inflammatory outcomes in patients with hematologic malignancies.<br><br>METHODS: We performed a post hoc analysis of outcomes of patients randomized to receive either TXA or placebo in the double-blinded, multicenter American Trial to Evaluate Tranexamic Acid Therapy in Thrombocytopenia (Clinicaltrials.gov identifier: NCT02578901).<br><br>RESULTS: TXA did not change the overall rate of infections, but the rate of severe infections (Common Toxicology Criteria for Adverse Events grade 3+) was lower in patients who received TXA compared with the placebo group. Patients who experienced grade 3+ infections had higher rates of World Health Organization grade 2+ bleeding and red blood cell transfusion requirements than patients who did not experience a grade 3+ infection, irrespective of treatment group. TXA did not impact other inflammatory outcomes such as mucositis, rash, or graft vs host disease.<br><br>CONCLUSION: Patients with hematologic malignancies who received TXA had less severe infections than those who received placebo with no difference in overall rate of infection or other inflammatory outcomes. Further investigation is needed on the impact of TXA on infections in this population.}, }
@article {pmid38664404, year = {2024}, author = {Hurvitz, SA and Bardia, A and Punie, K and Kalinsky, K and Carey, LA and Rugo, HS and Diéras, V and Phan, S and Delaney, R and Zhu, Y and Tolaney, SM}, title = {Subgroup analyses from the phase 3 ASCENT study of sacituzumab govitecan in metastatic triple-negative breast cancer.}, journal = {NPJ breast cancer}, volume = {10}, number = {1}, pages = {33}, pmid = {38664404}, issn = {2374-4677}, abstract = {In this post hoc analysis of the ASCENT study, we compared outcomes with sacituzumab govitecan (SG) vs single-agent chemotherapy in clinically important subgroups of patients with metastatic triple-negative breast cancer (mTNBC). Patients with mTNBC refractory to/relapsing after ≥2 prior chemotherapies (≥1 in the metastatic setting) were randomized 1:1 to receive SG or treatment of physician's choice (TPC) until unacceptable toxicity/progression. The primary endpoint was progression-free survival (PFS) per RECIST 1.1 by central review in patients without brain metastases. Patients with brain metastases were allowed if metastases were stable ≥4 weeks. In the intention-to-treat (ITT) population, 19% of patients were age ≥65 years; 12% were Black, and 12% had brain metastases. SG improved PFS and overall survival (OS), respectively, vs TPC in patients age ≥65 years (7.1 vs 2.4 months and 14.7 vs 8.9 months), or of Black race (5.4 vs 2.2 months and 13.8 vs 8.5 months), consistent with outcomes in the ITT population. Patients with brain metastases had numerically higher median PFS with SG vs TPC, but median OS was similar between treatment groups. SG was well tolerated and had a manageable safety profile consistent with the full safety population across all subgroups; neutropenia and diarrhea were the most common treatment-emergent adverse events. These findings confirm the meaningful clinical benefit of SG vs standard chemotherapy in patient subgroups with high unmet needs. SG should be considered an effective and safe treatment option for patients with mTNBC eligible for second-line or later therapy. ClinicalTrials.gov Number: NCT02574455.}, }
@article {pmid38663768, year = {2024}, author = {Meyers, G and Bubalo, J and Eckstrom, E and Winsnes, K and Carpenter, PA and Artz, A and Lin, RJ}, title = {Transplantation-Associated Altered Mentation and Encephalopathy: A New Classification for Acute Neurocognitive Changes Associated with Hematopoietic Cell Transplantation from the ASTCT Committee on Practice Guidelines.}, journal = {Transplantation and cellular therapy}, volume = {30}, number = {7}, pages = {646-662}, doi = {10.1016/j.jtct.2024.04.009}, pmid = {38663768}, issn = {2666-6367}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Brain Diseases/diagnosis/therapy ; Delirium/diagnosis/etiology/classification/therapy ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Transplantation Conditioning/adverse effects ; }, abstract = {Acute encephalopathy, manifesting clinically as delirium, is a common but often unrecognized complication of hematopoietic cell transplantation (HCT). Delirium can occur in patients of any age and is observed after autologous or allogeneic HCT. Although delirium has been studied primarily during initial HCT hospitalizations in recipients of myeloablative conditioning, recent investigations have identified delirium later post-transplantation and in recipients of reduced-intensity conditioning. Acute encephalopathy can be driven by infectious complications, medications, tissue damage, and/or organ dysfunction. Altered consciousness, either mild or profound, is often its only clinical manifestation. Identifying delirium is essential to overall HCT care, because patients who experience delirium have longer hospitalization and recovery times and are at risk for other poor post-HCT outcomes. Given the critical nature of this common complication and the ongoing expansion of HCT for more vulnerable populations, the American Society of Transplantation and Cellular Therapy (ASTCT) recommends intensifying research into post-HCT cognitive changes and establishing standardized definitions that encompass the full spectrum of altered consciousness for clinical care purposes and to provide benchmark endpoints for future research studies. To capture a range of acute neurocognitive changes specifically found in HCT patients (often referred to as acute encephalopathy), the ASTCT proposes a new diagnosis, transplantation-associated altered mentation and encephalopathy (TAME). The TAME diagnosis includes HCT patients who meet Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for delirium and those with acute neurocognitive changes who do not meet all the DSM-5 criteria for delirium (subsyndromal delirium). Early TAME is defined as occurring during conditioning or ≤100 days post-HCT, whereas late TAME occurs >100 days post-HCT in patients with additional HCT-related complications. This manuscript establishes clear diagnostic criteria and discusses factors that can potentially impact the development of TAME, as well as the workup and management of TAME.}, }
@article {pmid38662984, year = {2024}, author = {Raychaudhuri, R and Mo, G and Tuchayi, AM and Graham, L and Gulati, R and Pritchard, CC and Haffner, MC and Yezefski, T and Hawley, JE and Cheng, HH and Yu, EY and Grivas, P and Montgomery, RB and Nelson, PS and Chen, DL and Hope, T and Iravani, A and Schweizer, MT}, title = {Genomic Correlates of Prostate-Specific Membrane Antigen Expression and Response to [177]Lu-PSMA-617: A Retrospective Multicenter Cohort Study.}, journal = {JCO precision oncology}, volume = {8}, number = {}, pages = {e2300634}, pmid = {38662984}, issn = {2473-4284}, support = {R50 CA221836/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; T32 CA009515/CA/NCI NIH HHS/United States ; R37 CA286450/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; Retrospective Studies ; Aged ; *Prostatic Neoplasms, Castration-Resistant/genetics/pathology/blood/drug therapy ; *Lutetium/therapeutic use ; *Dipeptides/therapeutic use ; Heterocyclic Compounds, 1-Ring/therapeutic use ; Prostate-Specific Antigen/blood ; Antigens, Surface/genetics ; Cohort Studies ; Glutamate Carboxypeptidase II/genetics ; }, abstract = {PURPOSE: While [177]Lu-PSMA-617 (LuPSMA) is an effective therapy for many patients with metastatic castration-resistant prostate cancer (mCRPC), biomarkers associated with outcomes are not well defined. We hypothesized that prostate cancer mutational profile may associate with clinical activity of LuPSMA. We devised a study to evaluate associations between mCRPC mutational profile with LuPSMA clinical outcomes.<br><br>METHODS: This was a multicenter retrospective analysis of patients with mCRPC with next-generation sequencing (NGS) who received LuPSMA. PSA50 response (ie, &#x2265;50% decline in prostate-specific antigen [PSA]) rate, PSA progression free survival (PSA PFS), and overall survival (OS) were compared between genetically defined subgroups.<br><br>RESULTS: One hundred twenty-six patients with NGS results who received at least one cycle of LuPSMA were identified. The median age was 73 (IQR, 68-78) years, 124 (98.4%) received &#x2265;1 prior androgen receptor-signaling inhibitor, and 121 (96%) received &#x2265;1 taxane-based chemotherapy regimen. Fifty-eight (46%) patients with a DNA damage repair gene mutation (DNA damage response group) and 59 (46.8%) with a mutation in TP53, RB1, or PTEN tumor suppressor genes (TSG group) were identified. After adjusting for relevant confounders, the presence of &#x2265;1 TSG mutation was associated with shorter PSA PFS (hazard ratio [HR], 1.93 [95% CI, 1.05 to 3.54]; P = .034) and OS (HR, 2.65 [95% CI, 1.15 to 6.11]; P = .023). There was improved OS favoring the DNA damage response group (HR, 0.37 [95% CI, 0.14 to 0.97]; P = .044) on multivariable analysis. Univariate analysis of patients with ATM mutations had significantly higher rates of PSA50 response, PSA PFS, and OS.<br><br>CONCLUSION: Outcomes on LuPSMA varied on the basis of mutational profile. Prospective studies to define the clinical activity of LuPSMA in predefined genomic subgroups are justified.}, }
@article {pmid38661372, year = {2024}, author = {Khera, N and Ailawadhi, S and Brazauskas, R and Patel, J and Jacobs, B and Ustun, C and Ballen, K and Abid, MB and Diaz Perez, MA and Al-Homsi, AS and Hashem, H and Hong, S and Munker, R and Schears, RM and Lazarus, HM and Ciurea, S and Badawy, SM and Savani, BN and Wirk, B and LeMaistre, CF and Bhatt, NS and Beitinjaneh, A and Aljurf, M and Sharma, A and Cerny, J and Knight, JM and Kelkar, AH and Yared, JA and Kindwall-Keller, T and Winestone, LE and Steinberg, A and Arnold, SD and Seo, S and Preussler, JM and Hossain, NM and Fingrut, WB and Agrawal, V and Hashmi, S and Lehmann, LE and Wood, WA and Rangarajan, HG and Saber, W and Hahn, T}, title = {Trends in volumes and survival after hematopoietic cell transplantation in racial/ethnic minorities.}, journal = {Blood advances}, volume = {8}, number = {13}, pages = {3497-3506}, pmid = {38661372}, issn = {2473-9537}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation ; Male ; Female ; Adult ; Middle Aged ; Ethnic and Racial Minorities ; Adolescent ; Child ; Aged ; Young Adult ; Child, Preschool ; }, abstract = {There has been an increase in volume as well as an improvement in overall survival (OS) after hematopoietic cell transplantation (HCT) for hematologic disorders. It is unknown if these changes have affected racial/ethnic minorities equally. In this observational study from the Center for International Blood and Marrow Transplant Research of 79 904 autologous (auto) and 65 662 allogeneic (allo) HCTs, we examined the volume and rates of change of autoHCT and alloHCT over time and trends in OS in 4 racial/ethnic groups: non-Hispanic Whites (NHWs), non-Hispanic African Americans (NHAAs), and Hispanics across 5 2-year cohorts from 2009 to 2018. Rates of change were compared using Poisson model. Adjusted and unadjusted Cox proportional hazards models examined trends in mortality in the 4 racial/ethnic groups over 5 study time periods. The rates of increase in volume were significantly higher for Hispanics and NHAAs vs NHW for both autoHCT and alloHCT. Adjusted overall mortality after autoHCT was comparable across all racial/ethnic groups. NHAA adults (hazard ratio [HR] 1.13; 95% confidence interval [CI] 1.04-1.22; P = .004) and pediatric patients (HR 1.62; 95% CI 1.3-2.03; P < .001) had a higher risk of mortality after alloHCT than NHWs. Improvement in OS over time was seen in all 4 groups after both autoHCT and alloHCT. Our study shows the rate of change for the use of autoHCT and alloHCT is higher in NHAAs and Hispanics than in NHWs. Survival after autoHCT and alloHCT improved over time; however, NHAAs have worse OS after alloHCT, which has persisted. Continued efforts are needed to mitigate disparities for patients requiring alloHCT.}, }
@article {pmid38661186, year = {2024}, author = {Aitken, SL and Pierce, VM and Pogue, JM and Kline, EG and Tverdek, FP and Shields, RK}, title = {The Growing Threat of NDM-Producing Escherichia coli With Penicillin-Binding Protein 3 Mutations in the United States-Is There a Potential Role for Durlobactam?.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {79}, number = {4}, pages = {834-837}, doi = {10.1093/cid/ciae229}, pmid = {38661186}, issn = {1537-6591}, support = {//Innoviva Specialty Therapeutics/ ; }, mesh = {Humans ; *Escherichia coli/genetics/drug effects/enzymology ; *beta-Lactamases/genetics/metabolism ; *Microbial Sensitivity Tests ; *Anti-Bacterial Agents/pharmacology/therapeutic use ; *Escherichia coli Infections/microbiology/drug therapy ; *Penicillin-Binding Proteins/genetics/metabolism ; *Mutation ; United States ; *Azabicyclo Compounds/pharmacology/therapeutic use ; Male ; Female ; beta-Lactamase Inhibitors/pharmacology/therapeutic use ; Middle Aged ; Aztreonam/pharmacology ; Cephalosporins/pharmacology/therapeutic use ; Drug Combinations ; Aged ; Cefiderocol ; Escherichia coli Proteins/genetics/metabolism ; }, abstract = {We report identification of 5 patients with infections caused by NDM-5-producing Escherichia coli harboring PBP3 mutations that showed reduced susceptibility to aztreonam-avibactam and cefiderocol. Durlobactam, a novel diazabicyclooctane β-lactamase inhibitor, demonstrated minimum inhibitory concentrations ranging from 0.5 to 2 µg/mL supporting future investigations into a potential role in clinical management.}, }
@article {pmid38659968, year = {2024}, author = {Valint, DJ and Fiedler, TL and Liu, C and Srinivasan, S and Fredricks, DN}, title = {Effect of Metronidazole on Concentrations of Vaginal Bacteria Associated with Risk of HIV Acquisition.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {38659968}, issn = {2693-5015}, support = {R01 AI061628/AI/NIAID NIH HHS/United States ; }, abstract = {Several bacterial vaginosis (BV)-associated bacteria have been associated with elevated risk of HIV acquisition, however susceptibility of these bacteria to antibiotics is poorly understood. Vaginal samples were collected from 22 persons daily for two weeks following BV diagnosis. Metronidazole treatment was prescribed for 5-7 days. Changes in bacterial concentrations were measured with taxon-specific 16S rRNA gene quantitative PCR (qPCR) assays. A culture-based antimicrobial assay confirmed presence of antibiotics in vaginal swab samples. Bacterial DNA concentrations decreased during antibiotic administration for all thirteen bacterial taxa tested. Comparison of bacterial DNA concentrations in samples before administration of antibiotics to samples taken on the last day of antimicrobial assay-confirmed antibiotic presence showed a 2.3-4.5 log10-fold decrease across all taxa. Concentrations were frequently reduced to the qPCR assay's limit of detection, suggesting eradication of bacteria. Mean clearance time varied across taxa (1.2-8.6 days), with several bacteria (e.g., Gemella asaccharolytica, Sneathia spp., Eggerthella-like sp.) taking >7 days to suppress. Metronidazole reduces quantities of bacterial taxa associated with increased HIV acquisition risk. Eradication of high-risk vaginal bacteria using metronidazole is one promising avenue for reducing HIV acquisition risk. A 5-7-day treatment course may not be sufficient to suppress all bacteria.}, }
@article {pmid38659959, year = {2024}, author = {Larsen, BB and McMahon, T and Brown, JT and Wang, Z and Radford, CE and Crowe, JE and Veesler, D and Bloom, JD}, title = {Functional and antigenic landscape of the Nipah virus receptor binding protein.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38659959}, issn = {2692-8205}, support = {DP1 AI158186/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; U19 AI142764/AI/NIAID NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; R01 AI141707/AI/NIAID NIH HHS/United States ; 75N93022C00036/AI/NIAID NIH HHS/United States ; }, abstract = {Nipah virus recurrently spills over to humans, causing fatal infections. The viral receptor-binding protein (RBP or G) attaches to host receptors and is a major target of neutralizing antibodies. Here we use deep mutational scanning to measure how all amino-acid mutations to the RBP affect cell entry, receptor binding, and escape from neutralizing antibodies. We identify functionally constrained regions of the RBP, including sites involved in oligomerization, along with mutations that differentially modulate RBP binding to its two ephrin receptors. We map escape mutations for six anti-RBP antibodies, and find that few antigenic mutations are present in natural Nipah strains. Our findings offer insights into the potential for functional and antigenic evolution of the RBP that can inform the development of antibody therapies and vaccines.}, }
@article {pmid38659935, year = {2024}, author = {Denos, M and Sun, YQ and Brumpton, B and Li, Y and Albanes, D and Burnett-Hartman, A and Campbell, PT and Küry, S and Li, CI and White, E and Samadder, JN and Jenkins, M and Mai, XM}, title = {Sex hormones and risk of lung and colorectal cancers in women: a Mendelian randomization study.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {38659935}, issn = {2693-5015}, support = {R01 CA067941/CA/NCI NIH HHS/United States ; U01 HG004438/HG/NHGRI NIH HHS/United States ; U01 HG004446/HG/NHGRI NIH HHS/United States ; K05 CA154337/CA/NCI NIH HHS/United States ; P30 DK034987/DK/NIDDK NIH HHS/United States ; R21 CA235464/CA/NCI NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; P30 CA076292/CA/NCI NIH HHS/United States ; R01 CA042182/CA/NCI NIH HHS/United States ; P01 CA196569/CA/NCI NIH HHS/United States ; R01 CA097325/CA/NCI NIH HHS/United States ; U01 CA067941/CA/NCI NIH HHS/United States ; R01 CA059045/CA/NCI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; R01 CA197350/CA/NCI NIH HHS/United States ; R01 CA076366/CA/NCI NIH HHS/United States ; R35 CA197735/CA/NCI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; U10 CA037429/CA/NCI NIH HHS/United States ; R01 CA072520/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P30 CA006973/CA/NCI NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; R01 CA151993/CA/NCI NIH HHS/United States ; U01 CA152753/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R01 CA048998/CA/NCI NIH HHS/United States ; U01 CA137088/CA/NCI NIH HHS/United States ; R01 CA189184/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; Z01 CP010200/ImNIH/Intramural NIH HHS/United States ; U24 CA074794/CA/NCI NIH HHS/United States ; R01 CA066635/CA/NCI NIH HHS/United States ; U01 CA206110/CA/NCI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; R01 CA137178/CA/NCI NIH HHS/United States ; U01 CA074794/CA/NCI NIH HHS/United States ; HHSN268201200008C/HL/NHLBI NIH HHS/United States ; R01 CA242218/CA/NCI NIH HHS/United States ; P30 CA014089/CA/NCI NIH HHS/United States ; R01 CA081488/CA/NCI NIH HHS/United States ; R01 CA143237/CA/NCI NIH HHS/United States ; R01 CA201407/CA/NCI NIH HHS/United States ; R01 CA063464/CA/NCI NIH HHS/United States ; P01 CA033619/CA/NCI NIH HHS/United States ; U01 CA086308/CA/NCI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; R01 CA207371/CA/NCI NIH HHS/United States ; R03 CA153323/CA/NCI NIH HHS/United States ; R01 CA060987/CA/NCI NIH HHS/United States ; T32 ES013678/ES/NIEHS NIH HHS/United States ; R01 CA136726/CA/NCI NIH HHS/United States ; P30 CA016058/CA/NCI NIH HHS/United States ; UM1 CA167552/CA/NCI NIH HHS/United States ; K05 CA152715/CA/NCI NIH HHS/United States ; U01 CA122839/CA/NCI NIH HHS/United States ; U01 CA074783/CA/NCI NIH HHS/United States ; KL2 TR000421/TR/NCATS NIH HHS/United States ; UM1 CA182883/CA/NCI NIH HHS/United States ; HHSN268201200008I/HL/NHLBI NIH HHS/United States ; R37 CA054281/CA/NCI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; U19 CA148107/CA/NCI NIH HHS/United States ; U01 AG018033/AG/NIA NIH HHS/United States ; }, abstract = {The roles of sex hormones such as estradiol, testosterone, and sex hormone-binding globulin (SHBG) in the etiology of lung and colorectal cancers in women, among the most common cancers after breast cancer, are unclear. This Mendelian randomization (MR) study evaluated such potential causal associations in women of European ancestry. We used summary statistics data from genome-wide association studies (GWASs) on sex hormones and from the Trøndelag Health (HUNT) Study and large consortia on cancers. There was suggestive evidence of genetically predicted 1-standard deviation increase in total testosterone levels being associated with a lower risk of lung non-adenocarcinoma (hazard ratio (HR) 0.60, 95% CI 0.37-0.98) in the HUNT Study. However, this was not confirmed by using data from a larger consortium. In general, we did not find convincing evidence to support a causal role of sex hormones on risk of lung and colorectal cancers in women of European ancestry.}, }
@article {pmid38659838, year = {2024}, author = {O'Connor, SA and Garcia, L and Patel, AP and Bartelle, BB and Hugnot, JP and Paddison, PJ and Plaisier, CL}, title = {Classifying cell cycle states and a quiescent-like G0 state using single-cell transcriptomics.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38659838}, issn = {2692-8205}, support = {R01 CA190957/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 NS123038/NS/NINDS NIH HHS/United States ; R01 NS119650/NS/NINDS NIH HHS/United States ; R21 CA170722/CA/NCI NIH HHS/United States ; }, abstract = {Single-cell transcriptomics has unveiled a vast landscape of cellular heterogeneity in which the cell cycle is a significant component. We trained a high-resolution cell cycle classifier (ccAFv2) using single cell RNA-seq (scRNA-seq) characterized human neural stem cells. The ccAFv2 classifies six cell cycle states (G1, Late G1, S, S/G2, G2/M, and M/Early G1) and a quiescent-like G0 state (qG0), and it incorporates a tunable parameter to filter out less certain classifications. The ccAFv2 classifier performed better than or equivalent to other state-of-the-art methods even while classifying more cell cycle states, including G0. We demonstrate that the ccAFv2 classifier is generalizable across cell types and all three germ layers by applying it to developing fetal cells. We showcased the versatility of ccAFv2 by successfully applying it to classify cells, nuclei, and spatial transcriptomics data in humans and mice, using various normalization methods and gene identifiers. We provide methods to regress the cell cycle expression patterns out of single cell or nuclei data to uncover underlying biological signals. The classifier can be used either as an R package integrated with Seurat or a PyPI package integrated with scanpy. We proved that ccAFv2 has enhanced accuracy, flexibility, and adaptability across various experimental conditions, establishing ccAFv2 as a powerful tool for dissecting complex biological systems, unraveling cellular heterogeneity, and deciphering the molecular mechanisms by which proliferation and quiescence affect cellular processes.}, }
@article {pmid38657269, year = {2024}, author = {McCune, JM and Kiem, HP}, title = {Extending Gene Medicines to All in Need.}, journal = {The New England journal of medicine}, volume = {390}, number = {18}, pages = {1721-1722}, doi = {10.1056/NEJMe2403104}, pmid = {38657269}, issn = {1533-4406}, mesh = {Humans ; *Genetic Therapy/methods ; United States ; Hematopoietic Stem Cells/physiology ; *Gene Editing/methods ; Anemia, Sickle Cell/genetics/therapy ; beta-Thalassemia/genetics/therapy ; *Hematopoietic Stem Cell Transplantation/methods ; *Hemoglobinopathies/genetics/therapy ; *Health Services Accessibility ; }, }
@article {pmid38657020, year = {2024}, author = {Till, C and Goodman, PJ and Tangen, C and Lucia, MS and Thompson, IM}, title = {Letter: Survival After Selenium and Vitamin E Supplementation: Long-Term Followup of the Selenium and Vitamin E Cancer Prevention Trial.}, journal = {The Journal of urology}, volume = {212}, number = {1}, pages = {228-229}, pmid = {38657020}, issn = {1527-3792}, support = {U10 CA037429/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Selenium/administration &amp; dosage/therapeutic use ; *Vitamin E/administration &amp; dosage/therapeutic use ; *Dietary Supplements ; Male ; Follow-Up Studies ; Survival Rate ; Time Factors ; Prostatic Neoplasms/prevention &amp; control/mortality ; Antioxidants/administration &amp; dosage/therapeutic use ; }, }
@article {pmid38657001, year = {2024}, author = {Singh, K and Rubenstein, K and Callier, V and Shaw-Saliba, K and Rupert, A and Dewar, R and Laverdure, S and Highbarger, H and Lallemand, P and Huang, ML and Jerome, KR and Sampoleo, R and Mills, MG and Greninger, AL and Juneja, K and Porter, D and Benson, CA and Dempsey, W and El Sahly, HM and Focht, C and Jilg, N and Paules, CI and Rapaka, RR and Uyeki, TM and Clifford Lane, H and Beigel, J and Dodd, LE and , }, title = {SARS-CoV-2 RNA and Nucleocapsid Antigen Are Blood Biomarkers Associated With Severe Disease Outcomes That Improve in Response to Remdesivir.}, journal = {The Journal of infectious diseases}, volume = {230}, number = {3}, pages = {624-634}, pmid = {38657001}, issn = {1537-6613}, support = {K08 AI143923/AI/NIAID NIH HHS/United States ; UM1 AI148685/AI/NIAID NIH HHS/United States ; HHSN261200800001E 75N910D00024/CA/NCI NIH HHS/United States ; //London International Coordinating Centre/ ; UM1 AI148689/AI/NIAID NIH HHS/United States ; UM1 AI148450/AI/NIAID NIH HHS/United States ; //National Institute of Allergy and Infectious Diseases/ ; UM1 AI148576/AI/NIAID NIH HHS/United States ; //Seoul National University Hospital/ ; I01 CX002688/CX/CSRD VA/United States ; MRC_UU_12023/23/MRC_/Medical Research Council/United Kingdom ; /NH/NIH HHS/United States ; }, mesh = {Humans ; *Adenosine Monophosphate/analogs &amp; derivatives/therapeutic use ; *Alanine/analogs &amp; derivatives/therapeutic use ; *SARS-CoV-2/immunology ; *Antiviral Agents/therapeutic use ; *COVID-19 Drug Treatment ; *RNA, Viral/blood ; *COVID-19/blood/virology/immunology ; Male ; Female ; *Biomarkers/blood ; Middle Aged ; *Viral Load ; Treatment Outcome ; Adult ; Coronavirus Nucleocapsid Proteins/immunology ; Aged ; Antigens, Viral/blood ; }, abstract = {BACKGROUND: Although antivirals remain important for the treatment COVID-19, methods to assess treatment efficacy are lacking. Here, we investigated the impact of remdesivir on viral dynamics and their contribution to understanding antiviral efficacy in the multicenter Adaptive COVID-19 Treatment Trial 1, which randomized patients to remdesivir or placebo.<br><br>METHODS: Longitudinal specimens collected during hospitalization from a substudy of 642 patients with COVID-19 were measured for viral RNA (upper respiratory tract and plasma), viral nucleocapsid antigen (serum), and host immunologic markers. Associations with clinical outcomes and response to therapy were assessed.<br><br>RESULTS: Higher baseline plasma viral loads were associated with poorer clinical outcomes, and decreases in viral RNA and antigen in blood but not the upper respiratory tract correlated with enhanced benefit from remdesivir. The treatment effect of remdesivir was most pronounced in patients with elevated baseline nucleocapsid antigen levels: the recovery rate ratio was 1.95 (95% CI, 1.40-2.71) for levels >245&#x2005;pg/mL vs 1.04 (95% CI, .76-1.42) for levels <245&#x2005;pg/mL. Remdesivir also accelerated the rate of viral RNA and antigen clearance in blood, and patients whose blood levels decreased were more likely to recover and survive.<br><br>CONCLUSIONS: Reductions in SARS-CoV-2 RNA and antigen levels in blood correlated with clinical benefit from antiviral therapy.<br><br>CLINICAL TRIAL REGISTRATION: NCT04280705 (ClinicalTrials.gov).}, }
@article {pmid38656285, year = {2024}, author = {Chen, J and Hart, JE and VoPham, T and Elliott, EG and Birmann, BM and Laden, F}, title = {Association of Residential Exposure to Hazardous Air Pollutants with Risk of Non-Hodgkin Lymphoma and Multiple Myeloma.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {33}, number = {7}, pages = {961-964}, pmid = {38656285}, issn = {1538-7755}, support = {R01 CA098122/CA/NCI NIH HHS/United States ; U01 HL145386/HL/NHLBI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; UM1 CA167552/CA/NCI NIH HHS/United States ; R01 CA149445/CA/NCI NIH HHS/United States ; P30 ES000002/ES/NIEHS NIH HHS/United States ; U01 CA176726/CA/NCI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; U01 HL145386/HL/NHLBI NIH HHS/United States ; P30 ES000002/ES/NIEHS NIH HHS/United States ; R01 CA149445/CA/NCI NIH HHS/United States ; R01 CA09812//National Cancer Institute (NCI)/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Middle Aged ; *Air Pollutants/adverse effects/analysis ; *Environmental Exposure/adverse effects/statistics &amp; numerical data ; *Lymphoma, Non-Hodgkin/epidemiology/etiology ; *Multiple Myeloma/epidemiology/etiology ; Prospective Studies ; Risk Factors ; United States/epidemiology ; }, abstract = {BACKGROUND: Certain hazardous air pollutants (HAP) are known or suspected to pose immunological or cancer risk to humans, but evidence is limited from the general population.<br><br>METHODS: We assessed associations between residential exposure to HAPs at the census tract level and incident non-Hodgkin lymphoma (NHL) and multiple myeloma in the Nurses' Health Study (NHS, 1986-2012) and NHSII (1989-2019). We used the covariate-adjusted proportional hazards model to estimate hazard ratios (HR) of NHL, major NHL subtypes, and multiple myeloma per interquartile range increase in exposure to a given HAP and pooled the cohort-specific estimates using fixed-effects meta-analyses.<br><br>RESULTS: There were 810 NHL and 158 multiple myeloma cases in NHS (1,700,707 person-years) and 379 NHL and 59 multiple myeloma cases in NHSII (2,820,772 person-years). Most HRs approximated unity. Meta-analyses did not show consistent evidence of associations between any HAP exposure and risk of NHL or multiple myeloma.<br><br>CONCLUSIONS: Exposure to HAPs was not consistently associated with risks of NHL or multiple myeloma in these nationwide prospective cohorts of women.<br><br>IMPACT: This is the first nationwide study assessing associations between residential HAP exposures and risk of lymphoid malignances in prospective cohorts and focuses on women, who have frequently been underrepresented in (primarily occupational) studies of exposure to HAPs.}, }
@article {pmid38655842, year = {2024}, author = {Riddler, SA and Kelly, CW and Hoesley, CJ and Ho, KS and Piper, JM and Edick, S and Heard, F and Doncel, GF and Johnson, S and Anderson, PL and Brand, RM and Kunjara Na Ayudhya, RP and Bauermeister, JA and Hillier, SL and Hendrix, CW}, title = {A Phase 1 Clinical Trial to Assess the Safety and Pharmacokinetics of a Tenofovir Alafenamide/Elvitegravir Insert Administered Rectally for HIV Prevention.}, journal = {The Journal of infectious diseases}, volume = {230}, number = {3}, pages = {696-705}, pmid = {38655842}, issn = {1537-6613}, support = {UM1 AI069494/AI/NIAID NIH HHS/United States ; AID-OAA-A-14-00010//Eastern Virginia Medical School/ ; UM1AI069494/GF/NIH HHS/United States ; //USAID/ ; /MH/NIMH NIH HHS/United States ; UM1 AI106707/AI/NIAID NIH HHS/United States ; UM1AI068633//National Institute of Allergy and Infectious Diseases/ ; //Gilead Sciences/ ; UM1 AI069452/AI/NIAID NIH HHS/United States ; //Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; //US President's Emergency Plan for AIDS Relief/ ; }, mesh = {Humans ; *Tenofovir/pharmacokinetics/administration &amp; dosage/analogs &amp; derivatives ; *HIV Infections/prevention &amp; control/drug therapy ; Male ; *Quinolones/pharmacokinetics/administration &amp; dosage/adverse effects ; Adult ; *Anti-HIV Agents/pharmacokinetics/administration &amp; dosage/adverse effects ; Female ; *Alanine/pharmacokinetics/administration &amp; dosage ; Middle Aged ; *Adenine/analogs &amp; derivatives/pharmacokinetics/administration &amp; dosage/adverse effects ; *Administration, Rectal ; Rectum/virology ; Young Adult ; HIV-1/drug effects ; Drug Combinations ; }, abstract = {BACKGROUND: On-demand topical products could be an important tool for human immunodeficiency virus (HIV) prevention. We evaluated the safety, pharmacokinetics, and ex vivo pharmacodynamics of a tenofovir alafenamide/elvitegravir (TAF/EVG, 20 mg/16 mg) insert administered rectally.<br><br>METHODS: MTN-039 was a phase 1, open-label, single-arm, 2-dose study. Blood, rectal fluid, and rectal tissue were collected over 72&#x2005;hours following rectal administration of 1 and 2 TAF/EVG inserts for each participant.<br><br>RESULTS: TAF/EVG inserts were safe and well tolerated. EVG and tenofovir (TFV) were detected in blood plasma at low concentrations: median peak concentrations after 2 inserts were EVG 2.4&#x2005;ng/mL and TFV 4.4&#x2005;ng/mL. Rectal tissue EVG peaked at 2 hours (median, 2 inserts = 9&#x2005;ng/mg) but declined to below limit of quantification in the majority of samples at 24 hours, whereas tenofovir diphosphate (TFV-DP) remained high >2000&#x2005;fmol/million cells for 72 hours with 2 inserts. Compared to baseline, median cumulative log10 HIV p24 antigen of ex vivo rectal tissue HIV infection was reduced at each time point for both 1 and 2 inserts (P < .065 and P < .039, respectively).<br><br>DISCUSSION: Rectal administration of TAF/EVG inserts achieved high rectal tissue concentrations of EVG and TFV-DP with low systemic drug exposure and demonstrable ex vivo inhibition of HIV infection for 72&#x2005;hours. Clinical Trials Registration . NCT04047420.}, }
@article {pmid38653906, year = {2024}, author = {Haas, CB and Chen, H and Harrison, T and Fan, S and Gago-Dominguez, M and Castelao, JE and Bolla, MK and Wang, Q and Dennis, J and Michailidou, K and Dunning, AM and Easton, DF and Antoniou, AC and Hall, P and Czene, K and Andrulis, IL and Mulligan, AM and Milne, RL and Fasching, PA and Haeberle, L and Garcia-Closas, M and Ahearn, T and Gierach, GL and Haiman, C and Maskarinec, G and Couch, FJ and Olson, JE and John, EM and Chenevix-Trench, G and Berrington de Gonzalez, A and Jones, M and Stone, J and Murphy, R and Aronson, KJ and Wernli, KJ and Hsu, L and Vachon, C and Tamimi, RM and Lindström, S}, title = {Disentangling the relationships of body mass index and circulating sex hormone concentrations in mammographic density using Mendelian randomization.}, journal = {Breast cancer research and treatment}, volume = {206}, number = {2}, pages = {295-305}, pmid = {38653906}, issn = {1573-7217}, support = {CA244670//Division of Cancer Epidemiology and Genetics, National Cancer Institute/ ; }, mesh = {Humans ; *Breast Density ; Female ; *Mendelian Randomization Analysis ; *Body Mass Index ; *Breast Neoplasms/genetics/blood/diagnostic imaging ; *Genome-Wide Association Study ; *Gonadal Steroid Hormones/blood ; Sex Hormone-Binding Globulin/analysis/metabolism/genetics ; Middle Aged ; Polymorphism, Single Nucleotide ; Mammography ; Estradiol/blood ; Testosterone/blood ; Phenotype ; }, abstract = {PURPOSE: Mammographic density phenotypes, adjusted for age and body mass index (BMI), are strong predictors of breast cancer risk. BMI is associated with mammographic density measures, but the role of circulating sex hormone concentrations is less clear. We investigated the relationship between BMI, circulating sex hormone concentrations, and mammographic density phenotypes using Mendelian randomization (MR).<br><br>METHODS: We applied two-sample MR approaches to assess the association between genetically predicted circulating concentrations of sex hormones [estradiol, testosterone, sex hormone-binding globulin (SHBG)], BMI, and mammographic density phenotypes (dense and non-dense area). We created instrumental variables from large European ancestry-based genome-wide association studies and applied estimates to mammographic density phenotypes in up to 14,000 women of European ancestry. We performed analyses overall and by menopausal status.<br><br>RESULTS: Genetically predicted BMI was positively associated with non-dense area (IVW: &#x3b2;&#x2009;=&#x2009;1.79; 95% CI&#x2009;=&#x2009;1.58, 2.00; p&#x2009;=&#x2009;9.57&#x2009;&#xd7;&#x2009;10[-63]) and inversely associated with dense area (IVW: &#x3b2;&#x2009;=&#x2009;-&#x2009;0.37; 95% CI&#x2009;=&#x2009;-&#x2009;0.51,-&#x2009;0.23; p&#x2009;=&#x2009;4.7&#x2009;&#xd7;&#x2009;10[-7]). We observed weak evidence for an association of circulating sex hormone concentrations with mammographic density phenotypes, specifically inverse associations between genetically predicted testosterone concentration and dense area (&#x3b2;&#x2009;=&#x2009;-&#x2009;0.22; 95% CI&#x2009;=&#x2009;-&#x2009;0.38,&#x2009;-&#x2009;0.053; p&#x2009;=&#x2009;0.009) and between genetically predicted estradiol concentration and non-dense area (&#x3b2;&#x2009;=&#x2009;&#x2009;-&#x2009;3.32; 95% CI&#x2009;=&#x2009;-&#x2009;5.83,&#x2009;-&#x2009;0.82; p&#x2009;=&#x2009;0.009), although results were not consistent across a range of MR approaches.<br><br>CONCLUSION: Our findings support a positive causal association between BMI and mammographic non-dense area and an inverse association between BMI and dense area. Evidence was weaker and inconsistent for a causal effect of circulating sex hormone concentrations on mammographic density phenotypes. Based on our findings, associations between circulating sex hormone concentrations and mammographic density phenotypes are weak at best.}, }
@article {pmid38653905, year = {2024}, author = {Chlebowski, RT and Aragaki, AK and Pan, K and Mortimer, JE and Johnson, KC and Wactawski-Wende, J and LeBoff, MS and Lavasani, S and Lane, D and Nelson, RA and Manson, JE}, title = {Randomized trials of estrogen-alone and breast cancer incidence: a meta-analysis.}, journal = {Breast cancer research and treatment}, volume = {206}, number = {1}, pages = {177-184}, pmid = {38653905}, issn = {1573-7217}, support = {R01 CA119171 and R01 CA10921/CA/NCI NIH HHS/United States ; R01 CA119171 and R01 CA10921/CA/NCI NIH HHS/United States ; HHSN268201600018C, HHSN268201600001C//National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services/ ; }, mesh = {Humans ; *Breast Neoplasms/epidemiology ; Female ; *Randomized Controlled Trials as Topic ; Incidence ; *Estrogens/therapeutic use ; Estrogen Replacement Therapy/adverse effects ; Estrogens, Conjugated (USP)/therapeutic use/adverse effects/administration &amp; dosage ; }, abstract = {PURPOSE: In the Women's Health initiative (WHI) randomized clinical trial, conjugated equine estrogen (CEE)-alone significantly reduced breast cancer incidence (P = 0.005). As cohort studies had opposite findings, other randomized clinical trials were identified to conduct a meta-analysis of estrogen-alone influence on breast cancer incidence.<br><br>METHODS: We conducted literature searches on randomized trials and: estrogen, hormone therapy, and breast cancer, and searches from a prior meta-analysis and reviews. In the meta-analysis, for trials with published relative risks (RR) and 95% confidence intervals (CI), each log-RR was multiplied by weight&#x2009;=&#x2009;1/V, where V&#x2009;=&#x2009;variance of the log-RR, and V was derived from the corresponding 95% CI. For smaller trials with only breast cancer numbers, the corresponding log-RR&#x2009;=&#x2009;(O - E)/weight, where O is the observed case number in the oestrogen-alone group and E the corresponding expected case number, E&#x2009;=&#x2009;nP.<br><br>RESULTS: Findings from 10 randomized trials included 14,282 participants and 591 incident breast cancers. In 9 smaller trials, with 1.2% (24 of 2029) vs 2.2% (33 of 1514) randomized to estrogen-alone vs placebo (open label, one trial) (RR 0.65 95% CI 0.38-1.11, P&#x2009;=&#x2009;0.12). For 5 trials evaluating estradiol formulations, RR&#x2009;=&#x2009;0.63 95% CI 0.34-1.16, P&#x2009;=&#x2009;0.15. Combining the 10 trials, 3.6% (262 of 7339) vs 4.7% (329 of 6943) randomized to estrogen-alone vs placebo (overall RR 0.77 95% CI 0.65-0.91, P&#x2009;=&#x2009;0.002).<br><br>CONCLUSION: The totality of randomized clinical trial evidence supports a conclusion that estrogen-alone use significantly reduces breast cancer incidence.}, }
@article {pmid38653648, year = {2024}, author = {Chen, EX and Kavan, P and Tehfe, M and Kortmansky, JS and Sawyer, MB and Chiorean, EG and Lieu, CH and Polite, B and Wong, L and Fakih, M and Spencer, K and Chaves, J and Li, C and Leconte, P and Adelberg, D and Kim, R}, title = {Pembrolizumab Plus Binimetinib With or Without Chemotherapy for MSS/pMMR Metastatic Colorectal Cancer: Outcomes From KEYNOTE-651 Cohorts A, C, and E.}, journal = {Clinical colorectal cancer}, volume = {23}, number = {2}, pages = {183-193}, doi = {10.1016/j.clcc.2024.03.002}, pmid = {38653648}, issn = {1938-0674}, mesh = {Humans ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects/administration &amp; dosage ; Female ; Male ; *Colorectal Neoplasms/drug therapy/pathology ; Middle Aged ; *Antibodies, Monoclonal, Humanized/administration &amp; dosage/adverse effects/therapeutic use ; Aged ; Adult ; *Benzimidazoles/administration &amp; dosage/adverse effects/therapeutic use ; Fluorouracil/administration &amp; dosage/therapeutic use ; Irinotecan/administration &amp; dosage/therapeutic use ; Oxaliplatin/administration &amp; dosage ; DNA Mismatch Repair ; Leucovorin/administration &amp; dosage/therapeutic use/adverse effects ; Microsatellite Instability ; Aged, 80 and over ; }, abstract = {BACKGROUND: Cohorts A, C, and E of the phase Ib KEYNOTE-651 study evaluated pembrolizumab + binimetinib ± chemotherapy in microsatellite stable/mismatch repair-proficient metastatic colorectal cancer.<br><br>PATIENTS AND METHODS: Patients received pembrolizumab 200 mg every 3 weeks plus binimetinib 30 mg twice daily alone (cohort A; previously treated with any chemotherapy) or with 5-fluorouracil, leucovorin, oxaliplatin (cohort C; previously untreated) or 5-fluorouracil, leucovorin, irinotecan (cohort E; previously treated with 1 line of therapy including fluoropyrimidine + oxaliplatin-based regimen) every 2 weeks. Binimetinib dose-escalation to 45 mg twice daily was planned in all cohorts using a modified toxicity probability interval design (target dose-limiting toxicity [DLT], 30%). The primary endpoint was safety; investigator-assessed objective response rate was secondary.<br><br>RESULTS: In cohort A, 1/6 patients (17%) had DLTs with binimetinib 30 mg; none occurred in 14 patients with 45 mg. In cohort C, 3/9 patients (33%) had DLTs with binimetinib 30 mg; dose was not escalated to 45 mg. In cohort E, 1/5 patients (20%) had DLTs with binimetinib 30 mg; 5/10 patients (50%) had DLTs with 45 mg. Enrollment was stopped in cohort E binimetinib 45 mg and deescalated to 30 mg; 2/4 additional patients (50%) had DLTs with binimetinib 30 mg (total 3/9 [33%] had DLTs with binimetinib 30 mg). Objective response rate was 0% in cohort A, 9% in cohort C, and 15% in cohort E.<br><br>CONCLUSION: Per DLT criteria, binimetinib + pembrolizumab (cohort A) was tolerable, binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, oxaliplatin (cohort C) did not qualify for binimetinib dose escalation to 45 mg, and binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, irinotecan (cohort E) required binimetinib dose reduction from 45 to 30 mg. No new safety findings were observed across cohorts. There was no apparent additive efficacy when binimetinib + pembrolizumab was added to chemotherapy. Data did not support continued enrollment in cohorts C and E.}, }
@article {pmid38653622, year = {2024}, author = {Psutka, SP and Veleber, S and Siman, J and Holt, SK and Jannat, S and Wright, JL and Lin, DW and Gore, JL and Schade, GR and Annen, Z and Greenlee, H}, title = {Phase 1/2 Randomized Clinical Trial of In-clinic acupuncture Prior to Bacillus Calmette-Guérin in Patients with High-risk Non-muscle-invasive Bladder Cancer.}, journal = {European urology oncology}, volume = {7}, number = {6}, pages = {1431-1440}, pmid = {38653622}, issn = {2588-9311}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Urinary Bladder Neoplasms/therapy/pathology ; Male ; *BCG Vaccine/therapeutic use ; Female ; Aged ; *Acupuncture Therapy/methods ; Middle Aged ; Administration, Intravesical ; Adjuvants, Immunologic/therapeutic use ; Neoplasm Invasiveness ; Feasibility Studies ; Quality of Life ; Non-Muscle Invasive Bladder Neoplasms ; }, abstract = {BACKGROUND: Treatment-related dose-limiting dysuria and irritative bladder symptoms are common in patients receiving intravesical bacillus Calmette-Guérin (BCG) to treat non-muscle-invasive bladder cancer (NMIBC). Acupuncture has been shown to reduce pain and urinary urgency/frequency in other patient populations.<br><br>OBJECTIVE: To evaluate the feasibility, safety, and tolerability of weekly in-clinic preprocedural acupuncture among patients receiving induction BCG.<br><br>Patients with high-risk NMIBC undergoing induction BCG were randomized 2:1 to a standardized acupuncture protocol (acupuncture) versus the standard-of-care control arm.<br><br>INTERVENTION: In-office acupuncture prior to each BCG instillation.<br><br>Feasibility was assessed via recruitment, retention, and intervention adherence. Acupuncture safety and tolerability were assessed via physician-reported Common Terminology Criteria for Adverse Events version 5.0 and adverse events (AEs). Secondary endpoints included BCG treatment adherence, patient-reported BCG-related toxicity, and bladder cancer-specific and generic (European Organisation for Research and Treatment of Cancer [EORTC]-QLQ-NMIBC-24 and EORTC-QLQ-NMIBC-C30) quality of life (QOL). Subjective assessments of acupuncture acceptability were performed through patient surveys.<br><br>RESULTS AND LIMITATIONS: A total of 43 individuals were randomized 2:1 to the acupuncture (n&#xa0;=&#xa0;28) versus control (n&#xa0;=&#xa0;15) group. The median age was 70.3 yr, and 76% were male. Week 7 follow-up surveys were completed by 93%; six participants withdrew early due to disease progression, refractory gross hematuria, or preference. Acupuncture was delivered successfully prior to each BCG treatment, with no acupuncture-related AEs or interruptions to induction BCG. BCG-attributed AEs were reported by 91% acupuncture and 100% control individuals, including pain (28% vs 43%, p&#xa0;=&#xa0;0.34) and urinary symptoms (62% vs 79%, p&#xa0;=&#xa0;0.31). Comparing acupuncture patients with controls, change in QOL over the study period demonstrated greater improvements in median urinary symptoms (9.5, interquartile range [IQR] 0.0-19.0 vs 0.0, IQR -14.3 to 7.1; p&#xa0;=&#xa0;0.02) among patients in the acupuncture arm. Of the acupuncture patients, 96% reported that acupuncture was "very/extremely helpful," and 91% would recommend acupuncture to other patients. Limitations include modest sample size and single-institution design.<br><br>CONCLUSIONS: Acupuncture prior to induction BCG treatments is feasible and safe. In this phase 1/2 trial, improved urinary function scores were observed among patients undergoing acupuncture. Patients receiving acupuncture reported high degrees of satisfaction with treatments.<br><br>PATIENT SUMMARY: We evaluated the safety and feasibility of delivering acupuncture in a urology clinic prior to weekly intravesical bladder cancer treatments with bacillus Calmette-Gu&#xe9;rin (BCG) in a randomized controlled trial. We found that acupuncture could be delivered safely prior to weekly BCG instillations and that the use of acupuncture was associated with high patient satisfaction and a decrease in patient-reported urinary symptoms compared with usual care.}, }
@article {pmid38652878, year = {2024}, author = {Im, C and Neupane, A and Baedke, JL and Lenny, B and Delaney, A and Dixon, SB and Chow, EJ and Mostoufi-Moab, S and Yang, T and Richard, MA and Gramatges, MM and Lupo, PJ and Sharafeldin, N and Bhatia, S and Armstrong, GT and Hudson, MM and Ness, KK and Robison, LL and Yasui, Y and Wilson, CL and Sapkota, Y}, title = {Trans-Ancestral Genetic Risk Factors for Treatment-Related Type 2 Diabetes Mellitus in Survivors of Childhood Cancer.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {42}, number = {19}, pages = {2306-2316}, pmid = {38652878}, issn = {1527-7755}, support = {U24 CA055727/CA/NCI NIH HHS/United States ; R01 HL173881/HL/NHLBI NIH HHS/United States ; R01 CA261898/CA/NCI NIH HHS/United States ; R21 CA261833/CA/NCI NIH HHS/United States ; P30 CA021765/CA/NCI NIH HHS/United States ; U01 CA195547/CA/NCI NIH HHS/United States ; R01 CA216354/CA/NCI NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Child ; Female ; Humans ; Male ; *Cancer Survivors ; *Diabetes Mellitus, Type 2/genetics/drug therapy ; Genetic Predisposition to Disease ; *Genome-Wide Association Study ; *Neoplasms/genetics/drug therapy ; Risk Factors ; White People/genetics ; Black People ; }, abstract = {PURPOSE: Type 2 diabetes mellitus (T2D) is a prevalent long-term complication of treatment in survivors of childhood cancer, with marked racial/ethnic differences in burden. In this study, we investigated trans-ancestral genetic risks for treatment-related T2D.<br><br>PATIENTS AND METHODS: Leveraging whole-genome sequencing data from the St Jude Lifetime Cohort (N = 3,676, 304 clinically ascertained cases), we conducted ancestry-specific genome-wide association studies among survivors of African and European genetic ancestry (AFR and EUR, respectively) followed by trans-ancestry meta-analysis. Trans-/within-ancestry replication including data from the Childhood Cancer Survivor Study (N = 5,965) was required for prioritization. Three external general population T2D polygenic risk scores (PRSs) were assessed, including multiancestry PRSs. Treatment risk effect modification was evaluated for prioritized loci.<br><br>RESULTS: Four novel T2D risk loci showing trans-/within-ancestry replication evidence were identified, with three loci achieving genome-wide significance (P < 5 &#xd7; 10[-8]). Among these, common variants at 5p15.2 (LINC02112), 2p25.3 (MYT1L), and 19p12 (ZNF492) showed evidence of modifying alkylating agent-related T2D risk in both ancestral groups, but showed disproportionately greater risk in AFR survivors (AFR odds ratios [ORs], 3.95-17.81; EUR ORs, 2.37-3.32). In survivor-specific RNA-sequencing data (N = 207), the 19p12 locus variant was associated with greater ZNF492 expression dysregulation after exposures to alkylators. Elevated T2D risks across ancestry groups were only observed with increasing values for multiancestry T2D PRSs and were especially increased among survivors treated with alkylators (top v bottom quintiles: ORAFR, 20.18; P = .023; OREUR, 13.44; P = 1.3 &#xd7; 10[-9]).<br><br>CONCLUSION: Our findings suggest therapy-related genetic risks contribute to the increased T2D burden among non-Hispanic Black childhood cancer survivors. Additional study of how therapy-related genetic susceptibility contributes to this disparity is needed.}, }
@article {pmid38652672, year = {2024}, author = {Kwak, SH and Hernandez-Cancela, RB and DiCorpo, DA and Condon, DE and Merino, J and Wu, P and Brody, JA and Yao, J and Guo, X and Ahmadizar, F and Meyer, M and Sincan, M and Mercader, JM and Lee, S and Haessler, J and Vy, HMT and Lin, Z and Armstrong, ND and Gu, S and Tsao, NL and Lange, LA and Wang, N and Wiggins, KL and Trompet, S and Liu, S and Loos, RJF and Judy, R and Schroeder, PH and Hasbani, NR and Bos, MM and Morrison, AC and Jackson, RD and Reiner, AP and Manson, JE and Chaudhary, NS and Carmichael, LK and Chen, YI and Taylor, KD and Ghanbari, M and van Meurs, J and Pitsillides, AN and Psaty, BM and Noordam, R and Do, R and Park, KS and Jukema, JW and Kavousi, M and Correa, A and Rich, SS and Damrauer, SM and Hajek, C and Cho, NH and Irvin, MR and Pankow, JS and Nadkarni, GN and Sladek, R and Goodarzi, MO and Florez, JC and Chasman, DI and Heckbert, SR and Kooperberg, C and Dupuis, J and Malhotra, R and de Vries, PS and Liu, CT and Rotter, JI and Meigs, JB and , }, title = {Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People With Type 2 Diabetes.}, journal = {Diabetes care}, volume = {47}, number = {6}, pages = {1042-1047}, pmid = {38652672}, issn = {1935-5548}, support = {1-19-ICTS-068//American Diabetes Association/ ; 75N92021D00005/WH/WHI NIH HHS/United States ; R01 HL087652/HL/NHLBI NIH HHS/United States ; R01 HL159514/HL/NHLBI NIH HHS/United States ; R01 DK125403/DK/NIDDK NIH HHS/United States ; N01HC85081/HL/NHLBI NIH HHS/United States ; R01 HL103612/HL/NHLBI NIH HHS/United States ; 75N92020D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; HHSN268201500003C/HL/NHLBI NIH HHS/United States ; HHSN268201800012C/HL/NHLBI NIH HHS/United States ; 75N92020D00005/HL/NHLBI NIH HHS/United States ; N01HC95160/HL/NHLBI NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; N01HC95163/HL/NHLBI NIH HHS/United States ; U01 HL080295/HL/NHLBI NIH HHS/United States ; HHSN268201500001C/HL/NHLBI NIH HHS/United States ; UL1 TR001079/TR/NCATS NIH HHS/United States ; UL1 TR001878/TR/NCATS NIH HHS/United States ; HHSN268201800014I/HB/NHLBI NIH HHS/United States ; R01 HL043851/HL/NHLBI NIH HHS/United States ; U01 HL130114/HL/NHLBI NIH HHS/United States ; HHSN268200800007C/HL/NHLBI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R01 HL085251/HL/NHLBI NIH HHS/United States ; 75N92020D00001/HL/NHLBI NIH HHS/United States ; N01HC95169/HL/NHLBI NIH HHS/United States ; N01HC95164/HL/NHLBI NIH HHS/United States ; N01HC55222/HL/NHLBI NIH HHS/United States ; N02HL64278/HL/NHLBI NIH HHS/United States ; T32 HL007457/HL/NHLBI NIH HHS/United States ; HHSN268201800014C/HL/NHLBI NIH HHS/United States ; N01HC95162/HL/NHLBI NIH HHS/United States ; S10 OD026880/OD/NIH HHS/United States ; R01 HL136666/HL/NHLBI NIH HHS/United States ; N01HC85086/HL/NHLBI NIH HHS/United States ; 75N92020D00003/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; N01HC95168/HL/NHLBI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; P30 DK063491/DK/NIDDK NIH HHS/United States ; R01 DK109588/DK/NIDDK NIH HHS/United States ; R01 HL146860/HL/NHLBI NIH HHS/United States ; U01HG011723/HG/NHGRI NIH HHS/United States ; HHSN268201200036C/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; RS-2023-00262002//Korean Minstry of Science and ICT/ ; HHSN268201800013I/MD/NIMHD NIH HHS/United States ; IK2 CX001780/CX/CSRD VA/United States ; P30-DK063491/DK/NIDDK NIH HHS/United States ; N01HC95165/HL/NHLBI NIH HHS/United States ; U01 NS041588/NS/NINDS NIH HHS/United States ; N01HC95159/HL/NHLBI NIH HHS/United States ; HHSN268201500001I/HL/NHLBI NIH HHS/United States ; HHSN268201800012I/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; U01 HG011723/HG/NHGRI NIH HHS/United States ; N01HC95161/HL/NHLBI NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; 75N92020D00004/HL/NHLBI NIH HHS/United States ; UL1TR001420/TR/NCATS NIH HHS/United States ; UM1 CA182913/CA/NCI NIH HHS/United States ; HHSN268201800011C/HL/NHLBI NIH HHS/United States ; 75N92020D00007/HL/NHLBI NIH HHS/United States ; T32 GM100842/GM/NIGMS NIH HHS/United States ; R01 CA047988/CA/NCI NIH HHS/United States ; HHSN268201500003I/HL/NHLBI NIH HHS/United States ; 75N92021D00006/HL/NHLBI NIH HHS/United States ; S10 OD030463/OD/NIH HHS/United States ; R01 HL080467/HL/NHLBI NIH HHS/United States ; N01HC85082/HL/NHLBI NIH HHS/United States ; N01HC95167/HL/NHLBI NIH HHS/United States ; N01HC85083/HL/NHLBI NIH HHS/United States ; N01HC25195/HL/NHLBI NIH HHS/United States ; HHSN268201800015I/HB/NHLBI NIH HHS/United States ; 75N92019D00031/HL/NHLBI NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; R01 HL151855/HL/NHLBI NIH HHS/United States ; HHSN268201800010I/HB/NHLBI NIH HHS/United States ; UM1 DK078616/DK/NIDDK NIH HHS/United States ; 75N92020D00006/HL/NHLBI NIH HHS/United States ; N01HC85079/HL/NHLBI NIH HHS/United States ; N01HC95166/HL/NHLBI NIH HHS/United States ; R01 AG023629/AG/NIA NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; HHSN268201800011I/HB/NHLBI NIH HHS/United States ; N01HC85080/HL/NHLBI NIH HHS/United States ; R01 HL142809/HL/NHLBI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; }, mesh = {Humans ; *Diabetes Mellitus, Type 2/genetics/epidemiology/complications ; *Genome-Wide Association Study ; *Cardiovascular Diseases/genetics/epidemiology ; Female ; Male ; Middle Aged ; Aged ; Polymorphism, Single Nucleotide ; }, abstract = {OBJECTIVE: To identify genetic risk factors for incident cardiovascular disease (CVD) among people with type 2 diabetes (T2D).<br><br>RESEARCH DESIGN AND METHODS: We conducted a multiancestry time-to-event genome-wide association study for incident CVD among people with T2D. We also tested 204 known coronary artery disease (CAD) variants for association with incident CVD.<br><br>RESULTS: Among 49,230 participants with T2D, 8,956 had incident CVD events (event rate 18.2%). We identified three novel genetic loci for incident CVD: rs147138607 (near CACNA1E/ZNF648, hazard ratio [HR] 1.23, P = 3.6 &#xd7; 10-9), rs77142250 (near HS3ST1, HR 1.89, P = 9.9 &#xd7; 10-9), and rs335407 (near TFB1M/NOX3, HR 1.25, P = 1.5 &#xd7; 10-8). Among 204 known CAD loci, 5 were associated with incident CVD in T2D (multiple comparison-adjusted P < 0.00024, 0.05/204). A standardized polygenic score of these 204 variants was associated with incident CVD with HR 1.14 (P = 1.0 &#xd7; 10-16).<br><br>CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.}, }
@article {pmid38652659, year = {2024}, author = {Blest, HTW and Redmond, A and Avissar, J and Barker, J and Bridgeman, A and Fowler, G and Chauveau, L and Hertzog, J and Vendrell, I and Fischer, R and Iversen, MB and Jing, L and Koelle, DM and Paludan, SR and Kessler, BM and Crump, CM and Rehwinkel, J}, title = {HSV-1 employs UL56 to antagonize expression and function of cGAMP channels.}, journal = {Cell reports}, volume = {43}, number = {5}, pages = {114122}, doi = {10.1016/j.celrep.2024.114122}, pmid = {38652659}, issn = {2211-1247}, support = {R01 AI094019/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Humans ; HEK293 Cells ; Herpes Simplex/virology/metabolism/immunology ; *Herpesvirus 1, Human/physiology ; *Nucleotides, Cyclic/metabolism ; Viral Proteins/metabolism ; }, abstract = {DNA sensing is important for antiviral immunity. The DNA sensor cGAS synthesizes 2'3'-cyclic GMP-AMP (cGAMP), a second messenger that activates STING, which induces innate immunity. cGAMP not only activates STING in the cell where it is produced but cGAMP also transfers to other cells. Transporters, channels, and pores (including SLC19A1, SLC46A2, P2X7, ABCC1, and volume-regulated anion channels (VRACs)) release cGAMP into the extracellular space and/or import cGAMP. We report that infection with multiple human viruses depletes some of these cGAMP conduits. This includes herpes simplex virus 1 (HSV-1) that targets SLC46A2, P2X7, and the VRAC subunits LRRC8A and LRRC8C for degradation. The HSV-1 protein UL56 is necessary and sufficient for these effects that are mediated at least partially by proteasomal turnover. UL56 thereby inhibits cGAMP uptake via VRAC, SLC46A2, and P2X7. Taken together, HSV-1 antagonizes intercellular cGAMP transfer. We propose that this limits innate immunity by reducing cell-to-cell communication via the immunotransmitter cGAMP.}, }
@article {pmid38652484, year = {2024}, author = {Martin, PJ}, title = {Steroid tapering after GVHD Rx: not too fast, not too slow.}, journal = {Blood advances}, volume = {8}, number = {8}, pages = {2044-2046}, pmid = {38652484}, issn = {2473-9537}, mesh = {*Graft vs Host Disease/drug therapy/etiology ; Humans ; Steroids/therapeutic use/administration &amp; dosage ; Hematopoietic Stem Cell Transplantation/adverse effects ; }, }
@article {pmid38651213, year = {2024}, author = {Lockhart, EJ and Horowitz, LF and Rodríguez, A and Zhu, S and Nguyen, T and Mehrabi, M and Gujral, TS and Folch, A}, title = {Drug testing of monodisperse arrays of live microdissected tumors using a valved multiwell microfluidic platform.}, journal = {Lab on a chip}, volume = {24}, number = {10}, pages = {2683-2699}, doi = {10.1039/d4lc00016a}, pmid = {38651213}, issn = {1473-0189}, support = {R01 CA272677/CA/NCI NIH HHS/United States ; R01 CA181445/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Animals ; *Lab-On-A-Chip Devices ; *Antineoplastic Agents/pharmacology ; *Drug Screening Assays, Antitumor/instrumentation ; Mice ; Tumor Microenvironment/drug effects ; Microfluidic Analytical Techniques/instrumentation ; Equipment Design ; Cell Line, Tumor ; Neoplasms/drug therapy ; }, abstract = {Cancer drug testing in animals is an extremely poor predictor of the drug's safety and efficacy observed in humans. Hence there is a pressing need for functional testing platforms that better predict traditional and immunotherapy responses in human, live tumor tissue or tissue constructs, and at the same time are compatible with the use of mouse tumor tissue to facilitate building more accurate disease models. Since many cancer drug actions rely on mechanisms that depend on the tumor microenvironment (TME), such platforms should also retain as much of the native TME as possible. Additionally, platforms based on miniaturization technologies are desirable to reduce animal use and sensitivity to human tissue scarcity. Present high-throughput testing platforms that have some of these features, e.g. based on patient-derived tumor organoids, require a growth step that alters the TME. On the other hand, microdissected tumors (μDTs) or "spheroids" that retain an intact TME have shown promising responses to immunomodulators acting on native immune cells. However, difficult tissue handling after microdissection has reduced the throughput of drug testing on μDTs, thereby constraining the inherent advantages of producing numerous TME-preserving units of tissue for drug testing. Here we demonstrate a microfluidic 96-well platform designed for drug treatment of hundreds of similarly-sized, cuboidal μDTs ("cuboids") produced from a single tumor sample. The platform organizes a monodisperse array of four cuboids per well in 384 hydrodynamic traps. The microfluidic device, entirely fabricated in thermoplastics, features 96 microvalves that fluidically isolate each well after the cuboid loading step for straightforward multi-drug testing. Since our platform makes the most of scarce tumor tissue, it can potentially be applied to human biopsies that preserve the human TME while minimizing animal testing.}, }
@article {pmid38647375, year = {2024}, author = {Dirican, CD and Nelson, PS}, title = {Y Chromosome Loss and Implications for Oncology.}, journal = {Molecular cancer research : MCR}, volume = {22}, number = {7}, pages = {603-612}, pmid = {38647375}, issn = {1557-3125}, support = {P50 CA097186/CA/NCI NIH HHS/United States ; R21 CA277368/CA/NCI NIH HHS/United States ; PC200262//DOD Prostate Cancer Research Program (PCRP)/ ; CA097186//National Cancer Institute (NCI)/ ; }, mesh = {Humans ; *Chromosomes, Human, Y/genetics ; *Neoplasms/genetics ; Male ; Female ; Chromosome Deletion ; }, abstract = {The Y chromosome has recognized functions in promoting male sex determination and regulating aspects of fertility. However, recent work has demonstrated important roles for the Y chromosome and Y-encoded genes in multiple domains of male health, including cancer. It is well established that males experience shorter lifespans than females, and this sex bias on overall mortality is accentuated in populations with longer life expectancy, in part related to elevated rates of cancer. The majority of human malignancies exhibit a sex bias with elevated frequencies in males. For many of these cancer types, the disparity has not been explained by environmental risk factors such as tobacco use. Notably, loss of the Y chromosome (LOY) detected in blood cells, termed mosaic LOY, is a common event that is related to advancing age and is associated with a shortened lifespan. Mosaic LOY is linked to increased incidence and mortality across a range of malignancies. Furthermore, tumors arising in different anatomic sites exhibit different frequencies of partial or complete Y chromosome loss. Causal oncogenic or tumor-suppressive roles have been documented for several Y-encoded genes, such as lysine-specific demethylase 5 D, that exert pleiotropic effects on cellular functions by virtue of genome-wide regulation of gene activity. In this review, we discuss aspects of the Y chromosome relevant to oncology. The recent completion of the entire human Y-chromosome sequence provides a reference map of Y-encoded genes and regulatory elements to enable causal molecular studies that may explain and exploit the marked disparity in male cancer risk and mortality.}, }
@article {pmid38647082, year = {2024}, author = {Chen, KY and Park, H and Subramaniam, AR}, title = {Massively parallel identification of sequence motifs triggering ribosome-associated mRNA quality control.}, journal = {Nucleic acids research}, volume = {52}, number = {12}, pages = {7171-7187}, pmid = {38647082}, issn = {1362-4962}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; S10-OD-020069//Fred Hutchinson Cancer Center/ ; R35 GM119835/NH/NIH HHS/United States ; MCB 1846521//National Science Foundation/ ; R35 GM119835/GM/NIGMS NIH HHS/United States ; }, mesh = {*Ribosomes/metabolism/genetics ; *Saccharomyces cerevisiae/genetics/metabolism ; *RNA, Messenger/genetics/metabolism ; *RNA Stability/genetics ; Codon/genetics ; Protein Biosynthesis ; Nucleotide Motifs ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Dipeptides/genetics/metabolism ; }, abstract = {Decay of mRNAs can be triggered by ribosome slowdown at stretches of rare codons or positively charged amino acids. However, the full diversity of sequences that trigger co-translational mRNA decay is poorly understood. To comprehensively identify sequence motifs that trigger mRNA decay, we use a massively parallel reporter assay to measure the effect of all possible combinations of codon pairs on mRNA levels in S. cerevisiae. In addition to known mRNA-destabilizing sequences, we identify several dipeptide repeats whose translation reduces mRNA levels. These include combinations of positively charged and bulky residues, as well as proline-glycine and proline-aspartate dipeptide repeats. Genetic deletion of the ribosome collision sensor Hel2 rescues the mRNA effects of these motifs, suggesting that they trigger ribosome slowdown and activate the ribosome-associated quality control (RQC) pathway. Deep mutational scanning of an mRNA-destabilizing dipeptide repeat reveals a complex interplay between the charge, bulkiness, and location of amino acid residues in conferring mRNA instability. Finally, we show that the mRNA effects of codon pairs are predictive of the effects of endogenous sequences. Our work highlights the complexity of sequence motifs driving co-translational mRNA decay in eukaryotes, and presents a high throughput approach to dissect their requirements at the codon level.}, }
@article {pmid38645152, year = {2024}, author = {Luecken, MD and Gigante, S and Burkhardt, DB and Cannoodt, R and Strobl, DC and Markov, NS and Zappia, L and Palla, G and Lewis, W and Dimitrov, D and Vinyard, ME and Magruder, DS and Andersson, A and Dann, E and Qin, Q and Otto, DJ and Klein, M and Botvinnik, OB and Deconinck, L and Waldrant, K and ,  and Bloom, JM and Pisco, AO and Saez-Rodriguez, J and Wulsin, D and Pinello, L and Saeys, Y and Theis, FJ and Krishnaswamy, S}, title = {Defining and benchmarking open problems in single-cell analysis.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {38645152}, issn = {2693-5015}, support = {/WT_/Wellcome Trust/United Kingdom ; F31 CA257625/CA/NCI NIH HHS/United States ; U24 CA180996/CA/NCI NIH HHS/United States ; }, abstract = {With the growing number of single-cell analysis tools, benchmarks are increasingly important to guide analysis and method development. However, a lack of standardisation and extensibility in current benchmarks limits their usability, longevity, and relevance to the community. We present Open Problems, a living, extensible, community-guided benchmarking platform including 10 current single-cell tasks that we envision will raise standards for the selection, evaluation, and development of methods in single-cell analysis.}, }
@article {pmid38645034, year = {2024}, author = {Zaidi, S and Park, J and Chan, JM and Roudier, MP and Zhao, JL and Gopalan, A and Wadosky, KM and Patel, RA and Sayar, E and Karthaus, WR and Henry Kates, D and Chaudhary, O and Xu, T and Masilionis, I and Mazutis, L and Chaligné, R and Obradovic, A and Linkov, I and Barlas, A and Jungbluth, A and Rekhtman, N and Silber, J and Manova-Todorova, K and Watson, PA and True, LD and Morrissey, CM and Scher, HI and Rathkopf, D and Morris, MJ and Goodrich, DW and Choi, J and Nelson, PS and Haffner, MC and Sawyers, CL}, title = {Single Cell Analysis of Treatment-Resistant Prostate Cancer: Implications of Cell State Changes for Cell Surface Antigen Targeted Therapies.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38645034}, issn = {2692-8205}, support = {R21 CA277368/CA/NCI NIH HHS/United States ; R01 CA193837/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; R01 CA155169/CA/NCI NIH HHS/United States ; P01 CA265768/CA/NCI NIH HHS/United States ; U54 CA224079/CA/NCI NIH HHS/United States ; K08 CA282978/CA/NCI NIH HHS/United States ; R01 CA266452/CA/NCI NIH HHS/United States ; R01 CA234715/CA/NCI NIH HHS/United States ; P50 CA092629/CA/NCI NIH HHS/United States ; }, abstract = {Targeting cell surface molecules using radioligand and antibody-based therapies has yielded considerable success across cancers. However, it remains unclear how the expression of putative lineage markers, particularly cell surface molecules, varies in the process of lineage plasticity, wherein tumor cells alter their identity and acquire new oncogenic properties. A notable example of lineage plasticity is the transformation of prostate adenocarcinoma (PRAD) to neuroendocrine prostate cancer (NEPC)--a growing resistance mechanism that results in the loss of responsiveness to androgen blockade and portends dismal patient survival. To understand how lineage markers vary across the evolution of lineage plasticity in prostate cancer, we applied single cell analyses to 21 human prostate tumor biopsies and two genetically engineered mouse models, together with tissue microarray analysis (TMA) on 131 tumor samples. Not only did we observe a higher degree of phenotypic heterogeneity in castrate-resistant PRAD and NEPC than previously anticipated, but also found that the expression of molecules targeted therapeutically, namely PSMA, STEAP1, STEAP2, TROP2, CEACAM5, and DLL3, varied within a subset of gene-regulatory networks (GRNs). We also noted that NEPC and small cell lung cancer (SCLC) subtypes shared a set of GRNs, indicative of conserved biologic pathways that may be exploited therapeutically across tumor types. While this extreme level of transcriptional heterogeneity, particularly in cell surface marker expression, may mitigate the durability of clinical responses to novel antigen-directed therapies, its delineation may yield signatures for patient selection in clinical trials, potentially across distinct cancer types.}, }
@article {pmid38643749, year = {2024}, author = {Morgenstern, C and Lastres-Becker, I and Demirdöğen, BC and Costa, VM and Daiber, A and Foresti, R and Motterlini, R and Kalyoncu, S and Arioz, BI and Genc, S and Jakubowska, M and Trougakos, IP and Piechota-Polanczyk, A and Mickael, M and Santos, M and Kensler, TW and Cuadrado, A and Copple, IM}, title = {Biomarkers of NRF2 signalling: Current status and future challenges.}, journal = {Redox biology}, volume = {72}, number = {}, pages = {103134}, pmid = {38643749}, issn = {2213-2317}, mesh = {*NF-E2-Related Factor 2/metabolism/genetics ; Humans ; *Signal Transduction ; *Biomarkers ; *Oxidative Stress ; Animals ; Gene Expression Regulation ; }, abstract = {The cytoprotective transcription factor NRF2 regulates the expression of several hundred genes in mammalian cells and is a promising therapeutic target in a number of diseases associated with oxidative stress and inflammation. Hence, an ability to monitor basal and inducible NRF2 signalling is vital for mechanistic understanding in translational studies. Due to some caveats related to the direct measurement of NRF2 levels, the modulation of NRF2 activity is typically determined by measuring changes in the expression of one or more of its target genes and/or the associated protein products. However, there is a lack of consensus regarding the most relevant set of these genes/proteins that best represents NRF2 activity across cell types and species. We present the findings of a comprehensive literature search that according to stringent criteria identifies GCLC, GCLM, HMOX1, NQO1, SRXN1 and TXNRD1 as a robust panel of markers that are directly regulated by NRF2 in multiple cell and tissue types. We assess the relevance of these markers in clinically accessible biofluids and highlight future challenges in the development and use of NRF2 biomarkers in humans.}, }
@article {pmid38643547, year = {2024}, author = {Moore, M and Zhu, Y and Hirsch, I and White, T and Reiner, RC and Barber, RM and Pigott, D and Collins, JK and Santoni, S and Sobieszczyk, ME and Janes, H}, title = {Estimating vaccine efficacy during open-label follow-up of COVID-19 vaccine trials based on population-level surveillance data.}, journal = {Epidemics}, volume = {47}, number = {}, pages = {100768}, pmid = {38643547}, issn = {1878-0067}, support = {U01 AI069470/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI069470/AI/NIAID NIH HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *COVID-19/prevention &amp; control/epidemiology ; *COVID-19 Vaccines/administration &amp; dosage/therapeutic use ; Follow-Up Studies ; Incidence ; Population Surveillance/methods ; *SARS-CoV-2/immunology ; United States/epidemiology ; *Vaccine Efficacy/statistics &amp; numerical data ; }, abstract = {While rapid development and roll out of COVID-19 vaccines is necessary in a pandemic, the process limits the ability of clinical trials to assess longer-term vaccine efficacy. We leveraged COVID-19 surveillance data in the U.S. to evaluate vaccine efficacy in U.S. Government-funded COVID-19 vaccine efficacy trials with a three-step estimation process. First, we used a compartmental epidemiological model informed by county-level surveillance data, a "population model", to estimate SARS-CoV-2 incidence among the unvaccinated. Second, a "cohort model" was used to adjust the population SARS-CoV-2 incidence to the vaccine trial cohort, taking into account individual participant characteristics and the difference between SARS-CoV-2 infection and COVID-19 disease. Third, we fit a regression model estimating the offset between the cohort-model-based COVID-19 incidence in the unvaccinated with the placebo-group COVID-19 incidence in the trial during blinded follow-up. Counterfactual placebo COVID-19 incidence was estimated during open-label follow-up by adjusting the cohort-model-based incidence rate by the estimated offset. Vaccine efficacy during open-label follow-up was estimated by contrasting the vaccine group COVID-19 incidence with the counterfactual placebo COVID-19 incidence. We documented good performance of the methodology in a simulation study. We also applied the methodology to estimate vaccine efficacy for the two-dose AZD1222 COVID-19 vaccine using data from the phase 3 U.S. trial (ClinicalTrials.gov # NCT04516746). We estimated AZD1222 vaccine efficacy of 59.1% (95% uncertainty interval (UI): 40.4%-74.3%) in April, 2021 (mean 106 days post-second dose), which reduced to 35.7% (95% UI: 15.0%-51.7%) in July, 2021 (mean 198 days post-second-dose). We developed and evaluated a methodology for estimating longer-term vaccine efficacy. This methodology could be applied to estimating counterfactual placebo incidence for future placebo-controlled vaccine efficacy trials of emerging pathogens with early termination of blinded follow-up, to active-controlled or uncontrolled COVID-19 vaccine efficacy trials, and to other clinical endpoints influenced by vaccination.}, }
@article {pmid38643166, year = {2024}, author = {Luo, K and Peters, BA and Moon, JY and Xue, X and Wang, Z and Usyk, M and Hanna, DB and Landay, AL and Schneider, MF and Gustafson, D and Weber, KM and French, A and Sharma, A and Anastos, K and Wang, T and Brown, T and Clish, CB and Kaplan, RC and Knight, R and Burk, RD and Qi, Q}, title = {Metabolic and inflammatory perturbation of diabetes associated gut dysbiosis in people living with and without HIV infection.}, journal = {Genome medicine}, volume = {16}, number = {1}, pages = {59}, pmid = {38643166}, issn = {1756-994X}, support = {R01HL140976/HL/NHLBI NIH HHS/United States ; U01 AI035004/AI/NIAID NIH HHS/United States ; U01 HL146208/HL/NHLBI NIH HHS/United States ; R01 HL126543/HL/NHLBI NIH HHS/United States ; U01 HL146192/HL/NHLBI NIH HHS/United States ; R01DK119268/DK/NIDDK NIH HHS/United States ; P30 AI124414/AI/NIAID NIH HHS/United States ; U01 HL146194/HL/NHLBI NIH HHS/United States ; U01 HL146241/HL/NHLBI NIH HHS/United States ; P30 AI027767/AI/NIAID NIH HHS/United States ; P30 AI050409/AI/NIAID NIH HHS/United States ; U01 HL146333/HL/NHLBI NIH HHS/United States ; R01 DK126698/DK/NIDDK NIH HHS/United States ; U01 HL146245/HL/NHLBI NIH HHS/United States ; R01 MD011389/MD/NIMHD NIH HHS/United States ; R01 DK119268/DK/NIDDK NIH HHS/United States ; U01 HL146205/HL/NHLBI NIH HHS/United States ; R01 HL095140/HL/NHLBI NIH HHS/United States ; P30 MH116867/MH/NIMH NIH HHS/United States ; R01 HL083760/HL/NHLBI NIH HHS/United States ; R01 HL132794/HL/NHLBI NIH HHS/United States ; K01 HL169019/HL/NHLBI NIH HHS/United States ; U01 HL146242/HL/NHLBI NIH HHS/United States ; K01 HL129892/HL/NHLBI NIH HHS/United States ; R01 HL170904/HL/NHLBI NIH HHS/United States ; P30 AI073961/AI/NIAID NIH HHS/United States ; U01 HL146201/HL/NHLBI NIH HHS/United States ; U01 HL146193/HL/NHLBI NIH HHS/United States ; R01 HL140976/HL/NHLBI NIH HHS/United States ; U01 HL146204/HL/NHLBI NIH HHS/United States ; U01 HL146202/HL/NHLBI NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; P30 CA013330/CA/NCI NIH HHS/United States ; UL1 TR000004/TR/NCATS NIH HHS/United States ; U01 HL146240/HL/NHLBI NIH HHS/United States ; U01 HL146203/HL/NHLBI NIH HHS/United States ; K01 HL137557/HL/NHLBI NIH HHS/United States ; UL1 TR003098/TR/NCATS NIH HHS/United States ; P30 AI050410/AI/NIAID NIH HHS/United States ; }, mesh = {Male ; Humans ; Female ; *HIV Infections/drug therapy ; Prospective Studies ; Cohort Studies ; Dysbiosis/complications ; Cross-Sectional Studies ; *Diabetes Mellitus ; Bacteria ; }, abstract = {BACKGROUND: Gut dysbiosis has been linked with both HIV infection and diabetes, but its interplay with metabolic and inflammatory responses in diabetes, particularly in the context of HIV infection, remains unclear.<br><br>METHODS: We first conducted a cross-sectional association analysis to characterize the gut microbial, circulating metabolite, and immune/inflammatory protein features associated with diabetes in up to 493 women (~&#x2009;146 with prevalent diabetes with 69.9% HIV&#x2009;+) of the Women's Interagency HIV Study. Prospective analyses were then conducted to determine associations of identified metabolites with incident diabetes over 12 years of follow-up in 694 participants (391 women from WIHS and 303 men from the Multicenter AIDS Cohort Study; 166 incident cases were recorded) with and without HIV infection. Mediation analyses were conducted to explore whether gut bacteria-diabetes associations are explained by altered metabolites and proteins.<br><br>RESULTS: Seven gut bacterial genera were identified to be associated with diabetes (FDR-q&#x2009;<&#x2009; 0.1), with positive associations for Shigella, Escherichia, Megasphaera, and Lactobacillus, and inverse associations for Adlercreutzia, Ruminococcus, and Intestinibacter. Importantly, the associations of most species, especially Adlercreutzia and Ruminococcus, were largely independent of antidiabetic medications use. Meanwhile, 18 proteins and 76 metabolites, including 3 microbially derived metabolites (trimethylamine N-oxide, phenylacetylglutamine (PAGln), imidazolepropionic acid (IMP)), 50 lipids (e.g., diradylglycerols (DGs) and triradylglycerols (TGs)) and 23 non-lipid metabolites, were associated with diabetes (FDR-q&#x2009;<&#x2009; 0.1), with the majority showing positive associations and more than half of them (59/76) associated with incident diabetes. In mediation analyses, several proteins, especially interleukin-18 receptor 1 and osteoprotegerin, IMP and PAGln partially mediate the observed bacterial genera-diabetes associations, particularly for those of Adlercreutzia and Escherichia. Many diabetes-associated metabolites and proteins were altered in HIV, but no effect modification on their associations with diabetes was observed by HIV.<br><br>CONCLUSION: Among individuals with and without HIV, multiple gut bacterial genera, blood metabolites, and proinflammatory proteins were associated with diabetes. The observed mediated effects by metabolites and proteins in genera-diabetes associations highlighted the potential involvement of inflammatory and metabolic perturbations in the link between gut dysbiosis and diabetes in the context of HIV infection.}, }
@article {pmid38642840, year = {2024}, author = {Murakami, MA and Connelly-Smith, L and Spitzer, T and Kassim, AA and Penza, SL and Al Malki, MM and Mason, J and Tourville, C and Magliocco, B and Barten, J and Guidry-Groves, H and Margolis, J and Devine, SM and Rennert, WP and Stefanski, HE}, title = {Bone Marrow Harvest: A White Paper of Best Practices by the NMDP Marrow Alliance.}, journal = {Transplantation and cellular therapy}, volume = {30}, number = {7}, pages = {663-680}, pmid = {38642840}, issn = {2666-6367}, support = {U24 CA076518/CA/NCI NIH HHS/United States ; 27307C0011/ES/NIEHS NIH HHS/United States ; 27398C0011/ES/NIEHS NIH HHS/United States ; UG1 HL174426/HL/NHLBI NIH HHS/United States ; 27305C0011/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Bone Marrow ; Bone Marrow Transplantation/standards/methods ; Practice Guidelines as Topic ; Bone Marrow Cells ; Tissue and Organ Harvesting/methods/standards ; }, abstract = {Data on recent bone marrow harvest (BMH) collections from the NMDP has shown that bone marrow (BM) quality has decreased based on total nucleated cell count in the product. To ensure that quality BM products are available to all recipients, the NMDP Marrow Alliance was formed in April 2021 to increase the capability of BM collection centers to safely deliver high-quality products consistently and to identify and disseminate guidelines for performing BMH. This white paper describes the best practices for BMH as defined by the NMDP Marrow Alliance.}, }
@article {pmid38642459, year = {2024}, author = {Crawford, DE and Albala, D and Garnick, MB and Hahn, AW and Maroni, P and McKay, RR and Miner, M and Orio Ⅲ, P and Pandit, K and Sellinger, S and Yu, EY and Eckel, RH}, title = {Optimizing outcomes in men with prostate cancer: the cardiovascular event lowering (CaELo) pathways.}, journal = {The Canadian journal of urology}, volume = {31}, number = {2}, pages = {11820-11825}, pmid = {38642459}, issn = {1195-9479}, mesh = {Male ; Humans ; *Prostatic Neoplasms/drug therapy ; Androgen Antagonists/adverse effects ; Androgens ; *Cardiovascular Diseases/etiology/prevention &amp; control ; }, abstract = {INTRODUCTION: Risk of cardiovascular disease is higher among men with prostate cancer than men without, and prostate cancer treatments (especially those that are hormonally based) are associated with increased cardiovascular risk.<br><br>MATERIALS AND METHODS: An 11-member panel of urologic, medical, and radiation oncologists (along with a men's health specialist and an endocrinologist/preventive cardiologist) met to discuss current practices and challenges in the management of cardiovascular risk in prostate cancer patients who are taking androgen deprivation therapies (ADT) including LHRH analogues, alone and in combination with androgen-targeted therapies (ATTs).<br><br>RESULTS: The panel developed an assessment algorithm to categorize patients by risk and deploy a risk-adapted management strategy, in collaboration with other healthcare providers (the patient's healthcare "village"), with the goal of preventing as well as reducing cardiovascular events. The panel also developed a patient questionnaire for cardiovascular risk as well as a checklist to ensure that all aspects of cardiovascular disease risk reduction are completed and monitored.<br><br>CONCLUSIONS: Prostate cancer patients receiving ADT with or without ATT need to be more zealously assessed for prevention and aggressively managed to reduce cardiovascular events. This can and should include participation from the entire multidisciplinary healthcare team.}, }
@article {pmid38640253, year = {2024}, author = {Minnie, SA and Waltner, OG and Zhang, P and Takahashi, S and Nemychenkov, NS and Ensbey, KS and Schmidt, CR and Legg, SRW and Comstock, M and Boiko, JR and Nelson, E and Bhise, SS and Wilkens, AB and Koyama, M and Dhodapkar, MV and Chesi, M and Riddell, SR and Green, DJ and Spencer, A and Furlan, SN and Hill, GR}, title = {TIM-3[+] CD8 T cells with a terminally exhausted phenotype retain functional capacity in hematological malignancies.}, journal = {Science immunology}, volume = {9}, number = {94}, pages = {eadg1094}, pmid = {38640253}, issn = {2470-9468}, support = {T32 CA009351/CA/NCI NIH HHS/United States ; U01 CA244291/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R01 CA234181/CA/NCI NIH HHS/United States ; P50 CA186781/CA/NCI NIH HHS/United States ; KL2 TR002317/TR/NCATS NIH HHS/United States ; P01 CA078902/CA/NCI NIH HHS/United States ; R01 CA272426/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Hepatitis A Virus Cellular Receptor 2 ; *Multiple Myeloma/metabolism ; CD8-Positive T-Lymphocytes ; Phenotype ; *Hematologic Neoplasms ; Tumor Microenvironment ; }, abstract = {Chronic antigen stimulation is thought to generate dysfunctional CD8 T cells. Here, we identify a CD8 T cell subset in the bone marrow tumor microenvironment that, despite an apparent terminally exhausted phenotype (TPHEX), expressed granzymes, perforin, and IFN-γ. Concurrent gene expression and DNA accessibility revealed that genes encoding these functional proteins correlated with BATF expression and motif accessibility. IFN-γ[+] TPHEX effectively killed myeloma with comparable efficacy to transitory effectors, and disease progression correlated with numerical deficits in IFN-γ[+] TPHEX. We also observed IFN-γ[+] TPHEX within CD19-targeted chimeric antigen receptor T cells, which killed CD19[+] leukemia cells. An IFN-γ[+] TPHEX gene signature was recapitulated in TEX cells from human cancers, including myeloma and lymphoma. Here, we characterize a TEX subset in hematological malignancies that paradoxically retains function and is distinct from dysfunctional TEX found in chronic viral infections. Thus, IFN-γ[+] TPHEX represent a potential target for immunotherapy of blood cancers.}, }
@article {pmid38639810, year = {2024}, author = {Oswald, LB and Bloomer, A and Li, X and Jean-Baptiste, E and Trujillo, G and Felder, S and Small, BJ and Ose, J and Hardikar, S and Strehli, I and Huang, LC and Mooney, K and Mutch, MG and Chao, D and Cohen, SA and Karchi, M and Wood, EH and Damerell, V and Loroña, NC and Gong, J and Toriola, AT and Li, CI and Shibata, D and Schneider, M and Gigic, B and Figueiredo, JC and Jim, HSL and Ulrich, CM and Siegel, EM}, title = {Functional quality of life among newly diagnosed young adult colorectal cancer survivors compared to older adults: results from the ColoCare Study.}, journal = {Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer}, volume = {32}, number = {5}, pages = {298}, pmid = {38639810}, issn = {1433-7339}, support = {U01 CA206110/CA/NCI NIH HHS/United States ; P30 CA076292/CA/NCI NIH HHS/United States ; R01 NR018762/NR/NINR NIH HHS/United States ; R01 CA207371/CA/NCI NIH HHS/United States ; R01 CA254108/CA/NCI NIH HHS/United States ; R01 CA189184/CA/NCI NIH HHS/United States ; }, mesh = {Aged ; Humans ; Young Adult ; *Cancer Survivors/psychology ; *Colorectal Neoplasms/therapy/psychology ; Emotions ; Quality of Life/psychology ; Survivors/psychology ; Adolescent ; Adult ; Middle Aged ; }, abstract = {PURPOSE: Colorectal cancer (CRC) incidence and mortality are increasing among young adults (YAs) aged 18-39. This study compared quality of life (QOL) between YA and older adult CRC survivors in the ColoCare Study.<br><br>METHODS: Participants were grouped by age (years) as follows: 18-39 (YA), 40-49, 50-64, and 65&#x2009;+&#x2009;. Functional QOL (physical, social, role, emotional, cognitive) and global QOL were assessed with the EORTC-QLQ-C30 at enrollment, 3, 6, and 12&#xa0;months. Average scores were compared between groups over time using longitudinal mixed-effect modeling. Proportions with clinically meaningful QOL impairment were calculated using age-relevant thresholds and compared between groups over time using logistic regression with mixed effects.<br><br>RESULTS: Participants (N&#x2009;=&#x2009;1590) were n&#x2009;=&#x2009;81 YAs, n&#x2009;=&#x2009;196 aged 40-49, n&#x2009;=&#x2009;627 aged 50-64, and n&#x2009;=&#x2009;686 aged 65&#x2009;+&#x2009;. Average physical function was better among YAs than participants aged 50-64 (p&#x2009;=&#x2009;0.010) and 65&#x2009;+&#x2009;(p&#x2009;<&#x2009;0.001), and average social function was worse among YAs than aged 65&#x2009;+&#x2009;(p&#x2009;=&#x2009;0.046). Relative to YAs, all age groups were less likely to report clinically meaningful social dysfunction (aged 40-49 OR&#x2009;=&#x2009;0.13, 95%CI&#x2009;=&#x2009;0.06-0.29; aged 50-64 OR&#x2009;=&#x2009;0.10, 95%CI&#x2009;=&#x2009;0.05-0.21; aged 65&#x2009;+&#x2009;OR&#x2009;=&#x2009;0.07, 95%CI&#x2009;=&#x2009;0.04-0.15) and role dysfunction (aged 40-49 OR&#x2009;=&#x2009;0.36, 95%CI&#x2009;=&#x2009;0.18-0.75; aged 50-64 OR&#x2009;=&#x2009;0.41, 95%CI&#x2009;=&#x2009;0.22-0.78; aged 65&#x2009;+&#x2009;OR&#x2009;=&#x2009;0.32, 95%CI&#x2009;=&#x2009;0.17-0.61). Participants aged 40-49 were also less likely to report physical dysfunction (OR&#x2009;=&#x2009;0.42, 95%CI&#x2009;=&#x2009;0.19-0.93).<br><br>CONCLUSION: YA CRC survivors reported better physical and worse social function compared to older CRC survivors, and YA CRC survivors were more likely to report clinically meaningful social, role, and physical disfunction. Future work should further investigate QOL using age-relevant benchmarks to inform best practices for CRC survivorship care.<br><br>TRIAL REGISTRATION: NCT02328677, registered December 2014.}, }
@article {pmid38638362, year = {2023}, author = {Harrison, J and Stokes, T and Hahne, J and Shen, M}, title = {Ca-HELP: Adaptation of a Communication Tool to Help Geriatric Cancer Patients in Rural Settings Talk to Their Doctors About Pain.}, journal = {Innovation in aging}, volume = {7}, number = {10}, pages = {igad087}, pmid = {38638362}, issn = {2399-5300}, support = {K07 CA207580/CA/NCI NIH HHS/United States ; P30 AG022845/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVES: Among the older adult population living in the rural United States, undertreated cancer pain is very common. The need for interventions targeting pain management communication between older adults with cancer in rural communities and their doctors outpaces the current evidence base. Adaptation of existing pain interventions may improve the speed at which clinicians can respond to pain in this vulnerable population.<br><br>RESEARCH DESIGN AND METHODS: The Cancer Health Empowerment for Living without Pain (Ca-HELP) is an evidence-based communication tool that coaches patients to communicate about pain by asking questions, making requests, and signaling distress to their physicians in order to achieve improved pain control. Guided by the Method for Program Adaptation through Community Engagement (M-PACE) model, which utilizes detailed stakeholder feedback to guide the adaptation of an intervention for an appropriate target audience, we proactively adapted the Ca-HELP and its delivery for use among geriatric cancer patients living in rural settings using qualitative feedback from patients, informal caregivers, and providers as a planned step in a multiphase pilot study.<br><br>RESULTS: All stakeholders agreed that the Ca-HELP was a promising candidate intervention to improve pain among older adults with cancer. They suggested modifications to the delivery, context, and content of the intervention. A multidisciplinary team of nurse leaders and researchers evaluated stakeholder feedback and recommendations before determining which adaptations were made. Adaptations were cataloged and reported using the Framework for Reporting Adaptations and Modifications-Enhanced model.<br><br>DISCUSSION AND IMPLICATIONS: Our multistakeholder team proactively modified the Ca-HELP intervention tool using end-user feedback with a goal to optimize fit for use by older adults with cancer in rural settings without compromising the active ingredients. Documenting and reporting modifications to interventions are critical to their implementation and will lay the groundwork for further testing of the efficacy of the adapted Ca-HELP intervention.}, }
@article {pmid38637498, year = {2024}, author = {Keller, MD and Hanley, PJ and Chi, YY and Aguayo-Hiraldo, P and Dvorak, CC and Verneris, MR and Kohn, DB and Pai, SY and Dávila Saldaña, BJ and Hanisch, B and Quigg, TC and Adams, RH and Dahlberg, A and Chandrakasan, S and Hasan, H and Malvar, J and Jensen-Wachspress, MA and Lazarski, CA and Sani, G and Idso, JM and Lang, H and Chansky, P and McCann, CD and Tanna, J and Abraham, AA and Webb, JL and Shibli, A and Keating, AK and Satwani, P and Muranski, P and Hall, E and Eckrich, MJ and Shereck, E and Miller, H and Mamcarz, E and Agarwal, R and De Oliveira, SN and Vander Lugt, MT and Ebens, CL and Aquino, VM and Bednarski, JJ and Chu, J and Parikh, S and Whangbo, J and Lionakis, M and Zambidis, ET and Gourdine, E and Bollard, CM and Pulsipher, MA}, title = {Antiviral cellular therapy for enhancing T-cell reconstitution before or after hematopoietic stem cell transplantation (ACES): a two-arm, open label phase II interventional trial of pediatric patients with risk factor assessment.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {3258}, pmid = {38637498}, issn = {2041-1723}, support = {R38 HL167247/HL/NHLBI NIH HHS/United States ; U01 AI126612/AI/NIAID NIH HHS/United States ; UL1 TR002494/TR/NCATS NIH HHS/United States ; KL2 TR002492/TR/NCATS NIH HHS/United States ; UG1 HL069254/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; Child ; *Epstein-Barr Virus Infections ; Herpesvirus 4, Human ; *Virus Diseases ; Risk Factors ; *Hematopoietic Stem Cell Transplantation/adverse effects ; }, abstract = {Viral infections remain a major risk in immunocompromised pediatric patients, and virus-specific T cell (VST) therapy has been successful for treatment of refractory viral infections in prior studies. We performed a phase II multicenter study (NCT03475212) for the treatment of pediatric patients with inborn errors of immunity and/or post allogeneic hematopoietic stem cell transplant with refractory viral infections using partially-HLA matched VSTs targeting cytomegalovirus, Epstein-Barr virus, or adenovirus. Primary endpoints were feasibility, safety, and clinical responses (>1 log reduction in viremia at 28 days). Secondary endpoints were reconstitution of antiviral immunity and persistence of the infused VSTs. Suitable VST products were identified for 75 of 77 clinical queries. Clinical responses were achieved in 29 of 47 (62%) of patients post-HSCT including 73% of patients evaluable at 1-month post-infusion, meeting the primary efficacy endpoint (>52%). Secondary graft rejection occurred in one child following VST infusion as described in a companion article. Corticosteroids, graft-versus-host disease, transplant-associated thrombotic microangiopathy, and eculizumab treatment correlated with poor response, while uptrending absolute lymphocyte and CD8 T cell counts correlated with good response. This study highlights key clinical factors that impact response to VSTs and demonstrates the feasibility and efficacy of this therapy in pediatric HSCT.}, }
@article {pmid38636793, year = {2024}, author = {Sidahmed, E and Freedland, SJ and Wang, M and Wu, K and Albanes, D and Barnett, M and van den Brandt, PA and Cook, MB and Giles, GG and Giovannucci, E and Haiman, CA and Larsson, SC and Key, TJ and Loftfield, E and Männistö, S and McCullough, ML and Milne, RL and Neuhouser, ML and Platz, EA and Perez-Cornago, A and Sawada, N and Schenk, JM and Sinha, R and Tsugane, S and Visvanathan, K and Wang, Y and White, KK and Willett, WC and Wolk, A and Ziegler, RG and Genkinger, JM and Smith-Warner, SA}, title = {Dietary Fiber Intake and Risk of Advanced and Aggressive Forms of Prostate Cancer: A Pooled Analysis of 15 Prospective Cohort Studies.}, journal = {Journal of the Academy of Nutrition and Dietetics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jand.2024.04.006}, pmid = {38636793}, issn = {2212-2672}, abstract = {BACKGROUND: Evidence of an association between dietary fiber intake and risk of advanced and aggressive forms of prostate cancer (PC) and PC mortality is limited.<br><br>OBJECTIVE: The aim of this study was to examine associations between intakes of dietary fiber overall and by food source and risk of advanced and aggressive forms of PC.<br><br>DESIGN: The study design was a pooled analysis of the primary data from 15 cohorts in 3 continents. Baseline dietary fiber intake was assessed using a validated food frequency questionnaire or diet history in each study.<br><br>PARTICIPANTS/SETTING: There were 842 149 men followed for up to 9 to 22 years between 1985 and 2009 across studies.<br><br>MAIN OUTCOME MEASURES: The primary outcome measures were advanced (stage T4, N1, or M1 or PC mortality), advanced restricted (excluded men with missing stage and those with localized PC who died of PC), and high-grade PC (Gleason score &#x2265;8 or poorly differentiated/undifferentiated) and PC mortality.<br><br>Study-specific multivariable hazard ratios (MVHR) were calculated using Cox proportional hazards regression and pooled using random effects models.<br><br>RESULTS: Intake of dietary fiber overall, from fruits, and from vegetables was not associated with risk of advanced (n&#xa0;= 4863), advanced restricted (n&#xa0;= 2978), or high-grade PC (n&#xa0;= 9673) or PC mortality (n&#xa0;= 3097). Dietary fiber intake from grains was inversely associated with advanced PC (comparing the highest vs lowest quintile, MVHR 0.84; 95% CI 0.76-0.93), advanced restricted PC (MVHR 0.85; 95% CI 0.74-0.97), and PC mortality (MVHR 0.78; 95% CI 0.68-0.89); statistically significant trends were noted for each of these associations (P &#x2264; .03), and a null association was observed for high-grade PC for the same comparison (MVHR 1.00; 95% CI 0.93-1.07). The comparable results were 1.06 (95% CI 1.01-1.10; P value, test for trend&#xa0;= .002) for localized PC (n&#xa0;= 35,199) and 1.05 (95% CI 0.99-1.11; P value, test for trend&#xa0;= .04) for low/intermediate grade PC (n&#xa0;= 34 366).<br><br>CONCLUSIONS: Weak nonsignificant associations were observed between total dietary fiber intake and risk of advanced forms of PC, high-grade PC, and PC mortality. High dietary fiber intake from grains was associated with a modestly lower risk of advanced forms of PC and PC mortality.}, }
@article {pmid38636510, year = {2024}, author = {Sun, Q and Yang, Y and Rosen, JD and Chen, J and Li, X and Guan, W and Jiang, MZ and Wen, J and Pace, RG and Blackman, SM and Bamshad, MJ and Gibson, RL and Cutting, GR and O'Neal, WK and Knowles, MR and Kooperberg, C and Reiner, AP and Raffield, LM and Carson, AP and Rich, SS and Rotter, JI and Loos, RJF and Kenny, E and Jaeger, BC and Min, YI and Fuchsberger, C and Li, Y}, title = {MagicalRsq-X: A cross-cohort transferable genotype imputation quality metric.}, journal = {American journal of human genetics}, volume = {111}, number = {5}, pages = {990-995}, pmid = {38636510}, issn = {1537-6605}, support = {T32 ES007018/ES/NIEHS NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; R01 MH123724/MH/NIMH NIH HHS/United States ; R01 HL146500/HL/NHLBI NIH HHS/United States ; U01 HG011720/HG/NHGRI NIH HHS/United States ; U24 AR076730/AR/NIAMS NIH HHS/United States ; }, mesh = {Humans ; *Polymorphism, Single Nucleotide ; *Software ; *Genotype ; *Gene Frequency ; Cohort Studies ; Linkage Disequilibrium ; Genome-Wide Association Study/methods ; Genome, Human ; Quality Control ; Machine Learning ; Whole Genome Sequencing/standards/methods ; }, abstract = {Since genotype imputation was introduced, researchers have been relying on the estimated imputation quality from imputation software to perform post-imputation quality control (QC). However, this quality estimate (denoted as Rsq) performs less well for lower-frequency variants. We recently published MagicalRsq, a machine-learning-based imputation quality calibration, which leverages additional typed markers from the same cohort and outperforms Rsq as a QC metric. In this work, we extended the original MagicalRsq to allow cross-cohort model training and named the new model MagicalRsq-X. We removed the cohort-specific estimated minor allele frequency and included linkage disequilibrium scores and recombination rates as additional features. Leveraging whole-genome sequencing data from TOPMed, specifically participants in the BioMe, JHS, WHI, and MESA studies, we performed comprehensive cross-cohort evaluations for predominantly European and African ancestral individuals based on their inferred global ancestry with the 1000 Genomes and Human Genome Diversity Project data as reference. Our results suggest MagicalRsq-X outperforms Rsq in almost every setting, with 7.3%-14.4% improvement in squared Pearson correlation with true R[2], corresponding to 85-218 K variant gains. We further developed a metric to quantify the genetic distances of a target cohort relative to a reference cohort and showed that such metric largely explained the performance of MagicalRsq-X models. Finally, we found MagicalRsq-X saved up to 53 known genome-wide significant variants in one of the largest blood cell trait GWASs that would be missed using the original Rsq for QC. In conclusion, MagicalRsq-X shows superiority for post-imputation QC and benefits genetic studies by distinguishing well and poorly imputed lower-frequency variants.}, }
@article {pmid38635788, year = {2024}, author = {Kampouri, E and Krantz, EM and Xie, H and Ibrahimi, SS and Kiem, ES and Sekhon, MK and Liang, EC and Cowan, AJ and Portuguese, A and Green, DJ and Albittar, A and Huang, JJ and Gauthier, J and Pérez-Osorio, AC and Jerome, KR and Zerr, DM and Boeckh, MJ and Hill, JA}, title = {Human herpesvirus 6 reactivation and disease are infrequent in chimeric antigen receptor T-cell therapy recipients.}, journal = {Blood}, volume = {144}, number = {5}, pages = {490-495}, pmid = {38635788}, issn = {1528-0020}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Herpesvirus 6, Human/immunology ; Male ; Female ; Middle Aged ; Adult ; *Roseolovirus Infections/immunology/virology/therapy/diagnosis ; *Receptors, Chimeric Antigen/immunology ; *Virus Activation/immunology ; *Immunotherapy, Adoptive/methods/adverse effects ; Aged ; Prospective Studies ; Retrospective Studies ; Young Adult ; Incidence ; }, abstract = {Human herpesvirus 6B (HHV-6B) reactivation and disease are increasingly reported after chimeric antigen receptor (CAR) T-cell therapy (CARTx). HHV-6 reactivation in the CAR T-cell product was recently reported, raising questions about product and patient management. Because of overlapping manifestations with immune effector cell-associated neurotoxicity syndrome, diagnosing HHV-6B encephalitis is challenging. We provide 2 lines of evidence assessing the incidence and outcomes of HHV-6B after CARTx. First, in a prospective study with weekly HHV-6B testing for up to 12 weeks after infusion, HHV-6B reactivation occurred in 8 of 89 participants; 3 had chromosomally integrated HHV-6 and were excluded, resulting in a cumulative incidence of HHV-6B reactivation of 6% (95% confidence interval [CI], 2.2-12.5). HHV-6B detection was low level (median peak, 435 copies per mL; interquartile range, 164-979) and did not require therapy. Second, we retrospectively analyzed HHV-6B detection in the blood and/or cerebrospinal fluid (CSF) within 12 weeks after infusion in CARTx recipients. Of 626 patients, 24 had symptom-driven plasma testing, with detection in 1. Among 34 patients with CSF HHV-6 testing, 1 patient had possible HHV-6 encephalitis for a cumulative incidence of 0.17% (95% CI, 0.02-0.94), although symptoms improved without treatment. Our data demonstrate that HHV-6B reactivation and disease are infrequent after CARTx. Routine HHV-6 monitoring is not warranted.}, }
@article {pmid38635762, year = {2024}, author = {Locke, FL and Siddiqi, T and Jacobson, CA and Ghobadi, A and Ahmed, S and Miklos, DB and Perales, MA and Munoz, J and Fingrut, WB and Pennisi, M and Gauthier, J and Shadman, M and Gowda, L and Mirza, AS and Abid, MB and Hong, S and Majhail, NS and Kharfan-Dabaja, MA and Khurana, A and Badar, T and Lin, Y and Bennani, NN and Herr, MM and Hu, ZH and Wang, HL and Baer, A and Baro, E and Miao, H and Spooner, C and Xu, H and Pasquini, MC}, title = {Real-world and clinical trial outcomes in large B-cell lymphoma with axicabtagene ciloleucel across race and ethnicity.}, journal = {Blood}, volume = {143}, number = {26}, pages = {2722-2734}, pmid = {38635762}, issn = {1528-0020}, support = {R01 CA152108/CA/NCI NIH HHS/United States ; R01 AI158861/AI/NIAID NIH HHS/United States ; U24 HL138660/HL/NHLBI NIH HHS/United States ; R01 HL155741/HL/NHLBI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; OT3 HL147741/HL/NHLBI NIH HHS/United States ; SC1 MH093181/MH/NIMH NIH HHS/United States ; U01 AI069197/AI/NIAID NIH HHS/United States ; U24 CA233032/CA/NCI NIH HHS/United States ; R01 CA218285/CA/NCI NIH HHS/United States ; UM1 CA121947/CA/NCI NIH HHS/United States ; R01 CA231838/CA/NCI NIH HHS/United States ; U01 HL128568/HL/NHLBI NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; R01 CA231141/CA/NCI NIH HHS/United States ; R01 CA100019/CA/NCI NIH HHS/United States ; UG1 HL069246/HL/NHLBI NIH HHS/United States ; R01 AI150999/AI/NIAID NIH HHS/United States ; R01 HL131731/HL/NHLBI NIH HHS/United States ; U01 AI126612/AI/NIAID NIH HHS/United States ; U24 HL157560/HL/NHLBI NIH HHS/United States ; R01 CA262899/CA/NCI NIH HHS/United States ; R01 AI128775/AI/NIAID NIH HHS/United States ; R01 CA244328/CA/NCI NIH HHS/United States ; P01 CA111412/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; Antigens, CD19/immunology/therapeutic use ; *Biological Products/therapeutic use ; Ethnicity ; *Immunotherapy, Adoptive ; *Lymphoma, Large B-Cell, Diffuse/therapy ; Treatment Outcome ; Black or African American ; White ; Asian ; Clinical Trials as Topic ; }, abstract = {Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Despite extensive data supporting its use, outcomes stratified by race and ethnicity groups are limited. Here, we report clinical outcomes with axi-cel in patients with R/R LBCL by race and ethnicity in both real-world and clinical trial settings. In the real-world setting, 1290 patients who received axi-cel between 2017 and 2020 were identified from the Center for International Blood and Marrow Transplant Research database; 106 and 169 patients were included from the ZUMA-1 and ZUMA-7 trials, respectively. Overall survival was consistent across race/ethnicity groups. However, non-Hispanic (NH) Black patients had lower overall response rate (OR, 0.37; 95% CI, 0.22-0.63) and lower complete response rate (OR, 0.57; 95% CI, 0.33-0.97) than NH White patients. NH Black patients also had a shorter progression-free survival vs NH White (HR, 1.41; 95% CI, 1.04-1.90) and NH Asian patients (HR, 1.67; 95% CI, 1.08-2.59). NH Asian patients had a longer duration of response than NH White (HR, 0.56; 95% CI, 0.33-0.94) and Hispanic patients (HR, 0.54; 95% CI, 0.30-0.97). There was no difference in cytokine release syndrome by race/ethnicity; however, higher rates of any-grade immune effector cell-associated neurotoxicity syndrome were observed in NH White patients than in other patients. These results provide important context when treating patients with R/R LBCL with CAR T-cell therapy across different racial and ethnic groups. ZUMA-1 and ZUMA-7 (ClinicalTrials.gov identifiers: #NCT02348216 and #NCT03391466, respectively) are registered on ClinicalTrials.gov.}, }
@article {pmid38635416, year = {2024}, author = {Larouche, JD and Laumont, CM and Trofimov, A and Vincent, K and Hesnard, L and Brochu, S and Côté, C and Humeau, JF and Bonneil, &#xc9; and Lanoix, J and Durette, C and Gendron, P and Laverdure, JP and Richie, ER and Lemieux, S and Thibault, P and Perreault, C}, title = {Transposable elements regulate thymus development and function.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, pmid = {38635416}, issn = {2050-084X}, support = {FDN 148400/CAPMC/CIHR/Canada ; }, mesh = {Mice ; Humans ; Animals ; *DNA Transposable Elements ; *AIRE Protein ; Thymus Gland/metabolism ; Transcription Factors/genetics/metabolism ; Thymocytes/metabolism ; Epithelial Cells/metabolism ; Cell Differentiation/genetics ; Mice, Inbred C57BL ; }, abstract = {Transposable elements (TEs) are repetitive sequences representing ~45% of the human and mouse genomes and are highly expressed by medullary thymic epithelial cells (mTECs). In this study, we investigated the role of TEs on T-cell development in the thymus. We performed multiomic analyses of TEs in human and mouse thymic cells to elucidate their role in T-cell development. We report that TE expression in the human thymus is high and shows extensive age- and cell lineage-related variations. TE expression correlates with multiple transcription factors in all cell types of the human thymus. Two cell types express particularly broad TE repertoires: mTECs and plasmacytoid dendritic cells (pDCs). In mTECs, transcriptomic data suggest that TEs interact with transcription factors essential for mTEC development and function (e.g., PAX1 and REL), and immunopeptidomic data showed that TEs generate MHC-I-associated peptides implicated in thymocyte education. Notably, AIRE, FEZF2, and CHD4 regulate small yet non-redundant sets of TEs in murine mTECs. Human thymic pDCs homogenously express large numbers of TEs that likely form dsRNA, which can activate innate immune receptors, potentially explaining why thymic pDCs constitutively secrete IFN ɑ/β. This study highlights the diversity of interactions between TEs and the adaptive immune system. TEs are genetic parasites, and the two thymic cell types most affected by TEs (mTEcs and pDCs) are essential to establishing central T-cell tolerance. Therefore, we propose that orchestrating TE expression in thymic cells is critical to prevent autoimmunity in vertebrates.}, }
@article {pmid38635241, year = {2024}, author = {Tosoian, JJ and Zhang, Y and Xiao, L and Xie, C and Samora, NL and Niknafs, YS and Chopra, Z and Siddiqui, J and Zheng, H and Herron, G and Vaishampayan, N and Robinson, HS and Arivoli, K and Trock, BJ and Ross, AE and Morgan, TM and Palapattu, GS and Salami, SS and Kunju, LP and Tomlins, SA and Sokoll, LJ and Chan, DW and Srivastava, S and Feng, Z and Sanda, MG and Zheng, Y and Wei, JT and Chinnaiyan, AM and , }, title = {Development and Validation of an 18-Gene Urine Test for High-Grade Prostate Cancer.}, journal = {JAMA oncology}, volume = {10}, number = {6}, pages = {726-736}, pmid = {38635241}, issn = {2374-2445}, support = {P50 CA186786/CA/NCI NIH HHS/United States ; R01 CA236558/CA/NCI NIH HHS/United States ; R35 CA231996/CA/NCI NIH HHS/United States ; U2C CA271854/CA/NCI NIH HHS/United States ; }, mesh = {Male ; Humans ; *Prostatic Neoplasms/genetics/urine/diagnosis/pathology ; Aged ; *Biomarkers, Tumor/urine/genetics ; Middle Aged ; *Neoplasm Grading ; Prostate-Specific Antigen/blood ; Early Detection of Cancer/methods ; }, abstract = {IMPORTANCE: Benefits of prostate cancer (PCa) screening with prostate-specific antigen (PSA) alone are largely offset by excess negative biopsies and overdetection of indolent cancers resulting from the poor specificity of PSA for high-grade PCa (ie, grade group [GG] 2 or greater).<br><br>OBJECTIVE: To develop a multiplex urinary panel for high-grade PCa and validate its external performance relative to current guideline-endorsed biomarkers.<br><br>RNA sequencing analysis of 58&#x202f;724 genes identified 54 markers of PCa, including 17 markers uniquely overexpressed by high-grade cancers. Gene expression and clinical factors were modeled in a new urinary test for high-grade PCa (MyProstateScore 2.0 [MPS2]). Optimal models were developed in parallel without prostate volume (MPS2) and with prostate volume (MPS2+). The locked models underwent blinded external validation in a prospective National Cancer Institute trial cohort. Data were collected from January 2008 to December 2020, and data were analyzed from November 2022 to November 2023.<br><br>EXPOSURE: Protocolized blood and urine collection and transrectal ultrasound-guided systematic prostate biopsy.<br><br>MAIN OUTCOMES AND MEASURES: Multiple biomarker tests were assessed in the validation cohort, including serum PSA alone, the Prostate Cancer Prevention Trial risk calculator, and the Prostate Health Index (PHI) as well as derived multiplex 2-gene and 3-gene models, the original 2-gene MPS test, and the 18-gene MPS2 models. Under a testing approach with 95% sensitivity for PCa of GG 2 or greater, measures of diagnostic accuracy and clinical consequences of testing were calculated. Cancers of GG 3 or greater were assessed secondarily.<br><br>RESULTS: Of 761 men included in the development cohort, the median (IQR) age was 63 (58-68) years, and the median (IQR) PSA level was 5.6 (4.6-7.2) ng/mL; of 743 men included in the validation cohort, the median (IQR) age was 62 (57-68) years, and the median (IQR) PSA level was 5.6 (4.1-8.0) ng/mL. In the validation cohort, 151 (20.3%) had high-grade PCa on biopsy. Area under the receiver operating characteristic curve values were 0.60 using PSA alone, 0.66 using the risk calculator, 0.77 using PHI, 0.76 using the derived multiplex 2-gene model, 0.72 using the derived multiplex 3-gene model, and 0.74 using the original MPS model compared with 0.81 using the MPS2 model and 0.82 using the MPS2+ model. At 95% sensitivity, the MPS2 model would have reduced unnecessary biopsies performed in the initial biopsy population (range for other tests, 15% to 30%; range for MPS2, 35% to 42%) and repeat biopsy population (range for other tests, 9% to 21%; range for MPS2, 46% to 51%). Across pertinent subgroups, the MPS2 models had negative predictive values of 95% to 99% for cancers of GG 2 or greater and of 99% for cancers of GG 3 or greater.<br><br>CONCLUSIONS AND RELEVANCE: In this study, a new 18-gene PCa test had higher diagnostic accuracy for high-grade PCa relative to existing biomarker tests. Clinically, use of this test would have meaningfully reduced unnecessary biopsies performed while maintaining highly sensitive detection of high-grade cancers. These data support use of this new PCa biomarker test in patients with elevated PSA levels to reduce the potential harms of PCa screening while preserving its long-term benefits.}, }
@article {pmid38634730, year = {2024}, author = {Konecny, AJ and Mage, PL and Tyznik, AJ and Prlic, M and Mair, F}, title = {OMIP-102: 50-color phenotyping of the human immune system with in-depth assessment of T cells and dendritic cells.}, journal = {Cytometry. Part A : the journal of the International Society for Analytical Cytology}, volume = {105}, number = {6}, pages = {430-436}, pmid = {38634730}, issn = {1552-4930}, support = {R01 AI123323/AI/NIAID NIH HHS/United States ; R56 DE032009/DE/NIDCR NIH HHS/United States ; }, mesh = {Humans ; *Dendritic Cells/immunology/cytology ; *Flow Cytometry/methods ; *Immunophenotyping/methods ; *T-Lymphocytes/immunology/cytology ; Leukocytes, Mononuclear/immunology/cytology ; Immune System/cytology ; Phenotype ; Biomarkers ; }, abstract = {We report the development of an optimized 50-color spectral flow cytometry panel designed for the in-depth analysis of the immune system in human blood and tissues, with the goal of maximizing the amount of information that can be collected using currently available flow cytometry platforms. We established and tested this panel using peripheral blood mononuclear cells (PBMCs), but included CD45 to enable its future use for the analysis of human tissue samples. The panel contains lineage markers for all major immune cell subsets, and an extensive set of phenotyping markers focused on the activation and differentiation status of the T cell and dendritic cell (DC) compartment. We outline the biological insight that can be gained from the simultaneous measurement of such a large number of proteins and propose that this approach provides a unique opportunity for the comprehensive exploration of the immune status in human samples with a limited number of cells. Of note, we tested the panel to be compatible with cell sorting for further downstream applications. Furthermore, to facilitate the wide-spread implementation of such a panel across different cohorts and samples, we established a trimmed-down 45-color version which can be used with different spectral cytometry platforms. Finally, to generate this panel, we utilized not only existing panel design guidelines, but also developed new metrics to systematically identify the optimal combination of 50 fluorochromes and evaluate fluorochrome-specific resolution in the context of a 50-color unmixing matrix.}, }
@article {pmid38634655, year = {2024}, author = {De Rosa, SC and Mahnke, YD}, title = {Setting the gold standard: Commentary on designing and optimizing high-parameter flow cytometry panels.}, journal = {Cytometry. Part A : the journal of the International Society for Analytical Cytology}, volume = {105}, number = {6}, pages = {428-429}, doi = {10.1002/cyto.a.24844}, pmid = {38634655}, issn = {1552-4930}, support = {/NH/NIH HHS/United States ; /NH/NIH HHS/United States ; }, mesh = {*Flow Cytometry/methods/standards ; Humans ; Reference Standards ; }, }
@article {pmid38633776, year = {2024}, author = {Zhang, Y and Lindström, S and Kraft, P and Liu, Y}, title = {Genetic Risk, Health-Associated Lifestyle, and Risk of Early-onset Total Cancer and Breast Cancer.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {38633776}, support = {/WT_/Wellcome Trust/United Kingdom ; R01 CA194393/CA/NCI NIH HHS/United States ; R01 CA260352/CA/NCI NIH HHS/United States ; U01 CA249866/CA/NCI NIH HHS/United States ; }, abstract = {IMPORTANCE: Early-onset cancer (diagnosed under 50 years of age) is associated with aggressive disease characteristics and its rising incidence is a global concern. The association between healthy lifestyle and early-onset cancer and whether it varies by common genetic variants is unknown.<br><br>OBJECTIVE: To examine the associations between genetic risk, lifestyle, and risk of early-onset cancers.<br><br>We analyzed a prospective cohort of 66,308 white British participants who were under age 50 and free of cancer at baseline in the UK Biobank.<br><br>EXPOSURES: Sex-specific composite total cancer polygenic risk scores (PRSs), a breast cancer-specific PRS, and sex-specific health-associated lifestyle scores (HLSs, which summarize smoking status, body mass index [males only], physical activity, alcohol consumption, and diet).<br><br>MAIN OUTCOMES AND MEASURES: Hazard ratios (HRs) and 95% confidence intervals (CIs) for early-onset total and breast cancer.<br><br>RESULTS: A total of 1,247 incident invasive early-onset cancer cases (female: 820, male: 427, breast: 386) were documented. In multivariable-adjusted analyses with 2-year latency, higher genetic risk (highest vs. lowest tertile of PRS) was associated with significantly increased risks of early-onset total cancer in females (HR, 95% CI: 1.85, 1.50-2.29) and males (1.94, 1.45-2.59) as well as early-onset breast cancer in females (3.06, 2.20-4.25). An unfavorable lifestyle (highest vs. lowest category of HLS) was associated with higher risk of total cancer and breast cancer in females across genetic risk categories; the association with total cancer was stronger in the highest genetic risk category than the lowest: HRs in females and men were 1.85 (1.02, 3.36), 3.27 (0.78, 13.72) in the highest genetic risk category and 1.15 (0.44, 2.98), 1.16 (0.39, 3.40) in the lowest.<br><br>CONCLUSIONS AND RELEVANCE: Both genetic and lifestyle factors were independently associated with early-onset total and breast cancer risk. Compared to those with low genetic risk, individuals with a high genetic risk may benefit more from adopting a healthy lifestyle in preventing early-onset cancer.}, }
@article {pmid38633407, year = {2024}, author = {Webster, AP and Ecker, S and Moghul, I and Liu, X and Dhami, P and Marzi, S and Paul, DS and Kuxhausen, M and Lee, SJ and Spellman, SR and Wang, T and Feber, A and Rakyan, V and Peggs, KS and Beck, S}, title = {Donor whole blood DNA methylation is not a strong predictor of acute graft versus host disease in unrelated donor allogeneic haematopoietic cell transplantation.}, journal = {Frontiers in genetics}, volume = {15}, number = {}, pages = {1242636}, pmid = {38633407}, issn = {1664-8021}, support = {U24 CA076518/CA/NCI NIH HHS/United States ; C0000008/CL/CLC NIH HHS/United States ; 27307C0011/ES/NIEHS NIH HHS/United States ; 27398C0011/ES/NIEHS NIH HHS/United States ; 27307C0009/ES/NIEHS NIH HHS/United States ; 27305C0011/ES/NIEHS NIH HHS/United States ; }, abstract = {Allogeneic hematopoietic cell transplantation (HCT) is used to treat many blood-based disorders and malignancies, however it can also result in serious adverse events, such as the development of acute graft-versus-host disease (aGVHD). This study aimed to develop a donor-specific epigenetic classifier to reduce incidence of aGVHD by improving donor selection. Genome-wide DNA methylation was assessed in a discovery cohort of 288 HCT donors selected based on recipient aGVHD outcome; this cohort consisted of 144 cases with aGVHD grades III-IV and 144 controls with no aGVHD. We applied a machine learning algorithm to identify CpG sites predictive of aGVHD. Receiver operating characteristic (ROC) curve analysis of these sites resulted in a classifier with an encouraging area under the ROC curve (AUC) of 0.91. To test this classifier, we used an independent validation cohort (n = 288) selected using the same criteria as the discovery cohort. Attempts to validate the classifier failed with the AUC falling to 0.51. These results indicate that donor DNA methylation may not be a suitable predictor of aGVHD in an HCT setting involving unrelated donors, despite the initial promising results in the discovery cohort. Our work highlights the importance of independent validation of machine learning classifiers, particularly when developing classifiers intended for clinical use.}, }
@article {pmid38632891, year = {2024}, author = {Patterson, JG and McQuoid, J and Heffner, JL and Ye, Q and Ennis, AC and Ganz, O and Tan, ASL}, title = {Resonating With Pride: Considerations for Tailoring Tobacco Interventions for LGBTQ+ Communities.}, journal = {Nicotine &amp; tobacco research : official journal of the Society for Research on Nicotine and Tobacco}, volume = {26}, number = {10}, pages = {1438-1441}, pmid = {38632891}, issn = {1469-994X}, support = {R01 DA054236/DA/NIDA NIH HHS/United States ; R01 CA237670/CA/NCI NIH HHS/United States ; K99CA260718//U.S. Food and Drug Administration Center for Tobacco Products/ ; K99 CA260718/CA/NCI NIH HHS/United States ; F32 CA260118/CA/NCI NIH HHS/United States ; //Safeway Early Career Award in Cancer Research/ ; R00 CA260718/CA/NCI NIH HHS/United States ; L60 CA264533/CA/NCI NIH HHS/United States ; STCST00400_FY24//Oklahoma Tobacco Settlement Endowment Trust Grant/ ; P30 CA225520/CA/NCI NIH HHS/United States ; R01CA237670/DA/NIDA NIH HHS/United States ; }, mesh = {Humans ; *Sexual and Gender Minorities/psychology ; Male ; Female ; Smoking Cessation/methods ; }, }
@article {pmid38630732, year = {2024}, author = {Banack, HR and Wactawski-Wende, J and Ochs-Balcom, HM and Feliciano, EMC and Caan, B and Lee, C and Anderson, G and Shankaran, M and Evans, WJ}, title = {A protocol for remote collection of skeletal muscle mass via D3-creatine dilution in community-dwelling postmenopausal women from the Women's Health Initiative.}, journal = {PloS one}, volume = {19}, number = {4}, pages = {e0300140}, pmid = {38630732}, issn = {1932-6203}, support = {R37 CA258761/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; Aged ; Aged, 80 and over ; *Creatine ; Independent Living ; Postmenopause ; *Neoplasms ; Muscle, Skeletal ; Women's Health ; }, abstract = {BACKGROUND: There is emerging evidence that cancer and its treatments may accelerate the normal aging process, increasing the magnitude and rate of decline in functional capacity. This accelerated aging process is hypothesized to hasten the occurrence of common adverse age-related outcomes in cancer survivors, including loss of muscle mass and decrease in physical function. However, there is no data describing age-related loss of muscle mass and its relation to physical function in the long-term in cancer survivors.<br><br>METHODS: This study protocol describes the use of a novel method of muscle mass measurement, D3-creatine dilution method (D3Cr), in a large sample (n~6000) of community dwelling postmenopausal women from the Women's Health Initiative (WHI). D3Cr will be used to obtain a direct measure of muscle mass remotely. Participants will be drawn from two sub-cohorts embedded within the WHI that have recently completed an in-home visit. Cancer survivors will be drawn from the Life and Longevity After Cancer (LILAC) cohort, and cancer-free controls will be drawn from the WHI Long Life Study 2. The overall objective of this study is to examine the antecedents and consequences of low muscle mass in cancer survivors. The study aims are to: 1) create age-standardized muscle mass percentile curves and z-scores to characterize the distribution of D3- muscle mass in cancer survivors and non-cancer controls, 2) compare muscle mass, physical function, and functional decline in cancer survivors and non- cancer controls, and 3) use machine learning approaches to generate multivariate risk-prediction algorithms to detect low muscle mass.<br><br>DISCUSSION: The D3Cr method will transform our ability to measure muscle mass in large-scale epidemiologic research. This study is an opportunity to advance our understanding of a key source of morbidity among older and long-term female cancer survivors. This project will fill knowledge gaps, including the antecedents and consequences of low muscle mass, and use innovative methods to overcome common sources of bias in cancer research. The results of this study will be used to develop interventions to mitigate the harmful effects of low muscle mass in older adults and promote healthy survivorship in cancer survivors in the old (>65) and oldest-old (>85) age groups.}, }
@article {pmid38629238, year = {2024}, author = {Greteman, BB and Del Vecchio, NJ and Garcia-Auguste, CJ and Kahl, AR and Gryzlak, BM and Chrischilles, EA and Charlton, ME and Nash, SH}, title = {Identifying predictors of COVID-related delays in cancer-specific medical care.}, journal = {Cancer medicine}, volume = {13}, number = {8}, pages = {e7183}, pmid = {38629238}, issn = {2045-7634}, support = {P30 CA086862/CA/NCI NIH HHS/United States ; COVID-19 Supplement Grant 3P30CA086862-19S5/CA/NCI NIH HHS/United States ; HHSN261201800012I/HHSN26100001/3P30CA086862/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *COVID-19/epidemiology ; *Delayed Diagnosis ; Delivery of Health Care ; *Health Services Accessibility ; Iowa ; *Neoplasms/prevention &amp; control ; Pandemics ; Time-to-Treatment ; Male ; Female ; Adolescent ; Adult ; Middle Aged ; Aged ; Aged, 80 and over ; }, abstract = {PURPOSE: Evidence of the impact of the COVID-19 pandemic on cancer prevention and control is growing, but little is known about patient-level factors associated with delayed care. We analyzed data from a survey focused on Iowan cancer patients' COVID-19 experiences in the early part of the pandemic.<br><br>METHODS: Participants were recruited from the University of Iowa Holden Comprehensive Cancer Center's Patients Enhancing Research Collaborations at Holden (PERCH) program. We surveyed respondents on demographic characteristics, COVID-19 experiences and reactions, and delays in any cancer-related health care appointment, or cancer-related treatment appointments. Two-sided significance tests assessed differences in COVID-19 experiences and reactions between those who experienced delays and those who did not.<br><br>RESULTS: There were 780 respondents (26% response), with breast, prostate, kidney, skin, and colorectal cancers representing the majority of respondents. Delays in cancer care were reported by 29% of respondents. In multivariable-adjusted models, rural residents (OR 1.47; 95% CI 1.03, 2.11) and those experiencing feelings of isolation (OR 2.18; 95% CI 1.37, 3.47) were more likely to report any delay, where experiencing financial difficulties predicted delays in treatment appointments (OR 5.72; 95% CI 1.96, 16.67). Health insurance coverage and concern about the pandemic were not statistically significantly associated with delays.<br><br>CONCLUSION: These findings may inform cancer care delivery during periods of instability when treatment may be disrupted by informing clinicians about concerns that patients have during the treatment process. Future research should assess whether delays in cancer care impact long-term cancer outcomes and whether delays exacerbate existing disparities in cancer outcomes.}, }
@article {pmid38627946, year = {2024}, author = {Ergas, IJ and Cheng, RK and Roh, JM and Kushi, LH and Kresovich, JK and Iribarren, C and Nguyen-Huynh, M and Rana, JS and Rillamas-Sun, E and Laurent, CA and Lee, VS and Quesenberry, CP and Greenlee, H and Kwan, ML}, title = {Diet quality and cardiovascular disease risk among breast cancer survivors in the Pathways Study.}, journal = {JNCI cancer spectrum}, volume = {8}, number = {2}, pages = {}, pmid = {38627946}, issn = {2515-5091}, support = {U01 CA195565/CA/NCI NIH HHS/United States ; R01CA214057/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Breast Neoplasms/epidemiology ; *Cardiovascular Diseases/epidemiology ; Prospective Studies ; *Cancer Survivors ; Diet/adverse effects ; *Heart Failure ; Arrhythmias, Cardiac ; }, abstract = {BACKGROUND: Women with breast cancer are at higher risk of cardiovascular disease (CVD) compared with women without breast cancer. Whether higher diet quality at breast cancer diagnosis lowers this risk remains unknown. We set out to determine if higher diet quality at breast cancer diagnosis was related to lower risk of CVD and CVD-related death.<br><br>METHODS: This analysis included 3415 participants from the Pathway Study, a prospective cohort of women diagnosed with invasive breast cancer at Kaiser Permanente Northern California between 2005 and 2013 and followed through December 31, 2021. Scores from 5 diet quality indices consistent with healthy eating were obtained at the time of breast cancer diagnosis. Scores were categorized into ascending quartiles of concordance for each diet quality index, and multivariable adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated. P values were 2-sided.<br><br>RESULTS: The Dietary Approaches to Stop Hypertension diet quality index was associated with lower risk of heart failure (HR&#x2009;=&#x2009;0.53, 95% CI = 0.33 to 0.87; Ptrend&#x2009;=&#x2009;.03), arrhythmia (HR&#x2009;=&#x2009;0.77, 95% CI = 0.62 to 0.94; Ptrend&#x2009;=&#x2009;.008), cardiac arrest (HR&#x2009;=&#x2009;0.77, 95% CI = 0.61 to 0.96; Ptrend&#x2009;=&#x2009;.02), valvular heart disease (HR&#x2009;=&#x2009;0.79, 95% CI = 0.64 to 0.98; Ptrend&#x2009;=&#x2009;.046), venous thromboembolic disease (HR&#x2009;=&#x2009;0.75, 95% CI = 0.60 to 0.93; Ptrend&#x2009;=&#x2009;.01), and CVD-related death (HR&#x2009;=&#x2009;0.70, 95% CI = 0.50 to 0.99; Ptrend&#x2009;=&#x2009;.04), when comparing the highest with lowest quartiles. Inverse associations were also found between the healthy plant-based dietary index and heart failure (HR&#x2009;=&#x2009;0.60, 95% CI = 0.39 to 0.94; Ptrend&#x2009;=&#x2009;.02), as well as the alternate Mediterranean dietary index and arrhythmia (HR&#x2009;=&#x2009;0.74, 95% CI = 0.60 to 0.93; Ptrend&#x2009;=&#x2009;.02).<br><br>CONCLUSION: Among newly diagnosed breast cancer patients, higher diet quality at diagnosis was associated with lower risk of CVD events and death.}, }
@article {pmid38627450, year = {2024}, author = {Liang, EC and Rejeski, K and Fei, T and Albittar, A and Huang, JJ and Portuguese, AJ and Wu, Q and Raj, S and Subklewe, M and Shouval, R and Gauthier, J}, title = {Development and validation of an automated computational approach to grade immune effector cell-associated hematotoxicity.}, journal = {Bone marrow transplantation}, volume = {59}, number = {7}, pages = {910-917}, pmid = {38627450}, issn = {1476-5365}, support = {T32 HL007093/HL/NHLBI NIH HHS/United States ; 5T32CA951539//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; P30 CA015704/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; K08 CA282987/CA/NCI NIH HHS/United States ; 5T32HL007093//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; P30 CA15704//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; }, mesh = {Humans ; *Immunotherapy, Adoptive/methods/adverse effects ; }, abstract = {Hematologic toxicity frequently complicates chimeric antigen receptor (CAR) T-cell therapy, resulting in significant morbidity and mortality. In an effort to standardize reporting, the European Hematology Association (EHA) and European Society of Blood and Marrow Transplantation (EBMT) devised the immune effector cell-associated hematotoxicity (ICAHT) grading system, distinguishing between early (day 0-30) and late (after day +30) events based on neutropenia depth and duration. However, manual implementation of ICAHT grading criteria is time-consuming and susceptible to subjectivity and error. To address these challenges, we introduce a novel computational approach, utilizing the R programming language, to automate early and late ICAHT grading. Given the complexities of early ICAHT grading, we benchmarked our approach both manually and computationally in two independent cohorts totaling 1251 patients. Our computational approach offers significant implications by streamlining grading processes, reducing manual time and effort, and promoting standardization across varied clinical settings. We provide this tool to the scientific community alongside a comprehensive implementation guide, fostering its widespread adoption and enhancing reporting consistency for ICAHT.}, }
@article {pmid38623592, year = {2024}, author = {Wang, L and Slaughter, F and Nguyen, AT and Smith, S and Prabhu, S and Beima-Sofie, K and Wallace, S and Crane, HM and Simoni, JM and Graham, SM}, title = {Impact of the COVID-19 pandemic on mental health and viral suppression among persons living with HIV in western Washington.}, journal = {AIDS care}, volume = {36}, number = {7}, pages = {885-898}, doi = {10.1080/09540121.2024.2341220}, pmid = {38623592}, issn = {1360-0451}, support = {P30 AI027757/AI/NIAID NIH HHS/United States ; P30 MH123248/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; *COVID-19/psychology/epidemiology ; Male ; Female ; Washington/epidemiology ; Middle Aged ; *Social Support ; *HIV Infections/psychology/epidemiology ; *Adaptation, Psychological ; *Mental Health ; Adult ; *Depression/epidemiology/psychology ; *SARS-CoV-2 ; *Stress, Psychological/epidemiology/psychology ; *Anxiety/epidemiology/psychology ; *Self Efficacy ; Pandemics ; Viral Load ; Surveys and Questionnaires ; }, abstract = {The COVID-19 pandemic and social distancing measures elevated stress levels globally, exacerbating mental health challenges for people with HIV (PWH). We examined the effect of COVID-19-related stress on mental health among PWH in western Washington, exploring whether social support and coping self-efficacy were protective. Data on COVID-19-related stress, mental health, social support, and coping self-efficacy were collected using online surveys during the pandemic. Pre-COVID-19 mental health data were available for a subset of participants and were linked with the survey data. In the total sample (N = 373), COVID-19-stress was associated with elevated depression (PHQ-8, β = 0.21, 95%CI [0.10, 0.32]) and anxiety (GAD-7, β = 0.28, 95%CI [0.17, 0.39]). Among the subset of respondents with pre-pandemic mental health data (N = 103), COVID-19-related stress was associated with elevated PHQ-8 scores (β = 0.35, 95%CI [0.15, 0.56]) and GAD-7 scores (β = 0.35, 95%CI [0.16, 0.54]), adjusted for baseline mental health and other confounders. Coping self-efficacy was negatively associated with GAD-7 scores (β = -0.01, 95%CI [-0.01, 0.00]), while social support was negatively associated with PHQ-8 scores (β = -0.06, 95%CI [-0.12, -0.01]). Viral suppression before and during the pandemic did not differ among participants with available data. While COVID-19-related stress predicted elevated depression and anxiety symptoms among PWH, social support and coping self-efficacy were protective.}, }
@article {pmid38623380, year = {2024}, author = {Persky, V and Abasilim, C and Tsintsifas, K and Day, T and Sargis, RM and Daviglus, M and Cai, J and Freels, S and Kaplan, R and Isasi, CR and Pirzada, A and Meyer, ML and Talavera, GA and Thyagarajan, B and Agarwal, S and Chavez, N and Grieco, A and Turyk, ME}, title = {Thyroid Hormones and Diabetes in Euthyroid Hispanic/Latino Adults of Diverse Backgrounds: HCHS/SOL.}, journal = {Journal of the Endocrine Society}, volume = {8}, number = {6}, pages = {bvae039}, pmid = {38623380}, issn = {2472-1972}, support = {HHSN268201300005C/HL/NHLBI NIH HHS/United States ; HHSN268201300003I/HL/NHLBI NIH HHS/United States ; N01HC65236/HL/NHLBI NIH HHS/United States ; N01HC65235/HL/NHLBI NIH HHS/United States ; N01HC65234/HL/NHLBI NIH HHS/United States ; N01HC65237/HL/NHLBI NIH HHS/United States ; R01 ES025159/ES/NIEHS NIH HHS/United States ; T42OH008672/ACL/ACL HHS/United States ; T42 OH008672/OH/NIOSH CDC HHS/United States ; HHSN268201300004C/HL/NHLBI NIH HHS/United States ; P30 DK111022/DK/NIDDK NIH HHS/United States ; N01HC65233/HL/NHLBI NIH HHS/United States ; HHSN268201300003C/HL/NHLBI NIH HHS/United States ; P30 ES027792/ES/NIEHS NIH HHS/United States ; }, abstract = {CONTEXT: Previous studies have demonstrated associations of endogenous thyroid hormones with diabetes; less is known about stages of diabetes development at which they are operative, mechanisms of associations, and the role of the hypothalamic-pituitary-thyroid axis.<br><br>OBJECTIVE: This study examined associations of thyroid hormones with incident prediabetes and diabetes and with changes in glycemic traits in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), the largest cohort of Hispanic/Latino adults with diverse backgrounds in the United States.<br><br>METHODS: The study includes 592 postmenopausal euthyroid women and 868 euthyroid men aged 45 to 74 years without diabetes at baseline participating in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Baseline hormones included thyrotropin (TSH), free thyroxine (FT4), total triiodothyronine (T3), and indices calculated from thyroid hormones evaluating pituitary sensitivity to thyroid hormone. Transitions to diabetes and prediabetes, and changes in glycemic traits determined at the 6-year follow-up visit, were examined using multivariable Poisson and linear regressions.<br><br>RESULTS: Among women, T3 (incident rate ratio [IRR] = 1.65; 95% CI, 1.22-2.24; P = .001) and TSH (IRR = 2.09; 95% CI, 1.01-4.33; P = .047) were positively, while FT4 (IRR = 0.59; 95% CI, 0.39-0.88; P = .011) was inversely, associated with transition from prediabetes to diabetes. Among men, the T3/FT4 ratio was positively associated with transition from normoglycemia to prediabetes but not from prediabetes to diabetes. Indices measuring sensitivity of the pituitary to thyroid hormone suggested increased sensitivity in men who transitioned from prediabetes to diabetes.<br><br>CONCLUSION: Positive associations in women of T3 and TSH and inverse associations of FT4, as well as inverse associations of thyroid indices in men with transition from prediabetes to diabetes, but not from normoglycemia to diabetes, suggest decreased pituitary sensitivity to thyroid hormones in women and increased sensitivity in men later in the development of diabetes.}, }
@article {pmid38622850, year = {2024}, author = {Lim, JJ and Chen, EY and Schaub, SK and Wagner, MJ}, title = {Reclassification of a spindle cell sarcoma after identification of a TFG-ROS1 fusion: A case demonstrating the clinical benefit of next-generation sequencing in sarcoma.}, journal = {Molecular genetics &amp; genomic medicine}, volume = {12}, number = {4}, pages = {e2423}, pmid = {38622850}, issn = {2324-9269}, mesh = {Female ; Humans ; Adult ; *Protein-Tyrosine Kinases/genetics ; Anaplastic Lymphoma Kinase/genetics ; In Situ Hybridization, Fluorescence ; Proto-Oncogene Proteins/genetics ; *Sarcoma/drug therapy/genetics/pathology ; High-Throughput Nucleotide Sequencing ; Ubiquitin Thiolesterase/genetics ; Vesicular Transport Proteins/genetics ; }, abstract = {BACKGROUND: Inflammatory myofibroblastic tumors (IMTs) are rare mesenchymal soft tissue sarcomas that often present diagnostic challenges due to their wide and varied morphology. A subset of IMTs have fusions involving ALK or ROS1. The role of next-generation sequencing (NGS) for classification of unselected sarcomas remains controversial.<br><br>METHODS AND RESULTS: We report a case of a metastatic sarcoma in a 34-year-old female originally diagnosed as an unclassified spindle cell sarcoma with myofibroblastic differentiation and later reclassified as IMT after NGS revealed a TFG-ROS1 rearrangement. Histologically, the neoplasm had spindle cell morphology with a lobulated to focally infiltrative growth pattern with scant inflammatory cell infiltrate. Immunohistochemistry demonstrated focal desmin and variable smooth muscle actin staining but was negative for SOX10, S100, and CD34. Fluorescence in&#xa0;situ hybridization was negative for USP6 or ALK gene rearrangements. NGS revealed a TFG-ROS1 rearrangement and the patient was treated with crizotinib with clinical benefit.<br><br>CONCLUSIONS: We discuss the role of NGS as well as its potential benefit in patients with unresectable, ALK-negative metastatic disease. Considering this case and previous literature, we support the use of NGS for patients requiring systemic treatment.}, }
@article {pmid38618958, year = {2024}, author = {Hansen, UK and Church, CD and Carnaz Simões, AM and Frej, MS and Bentzen, AK and Tvingsholm, SA and Becker, JC and Fling, SP and Ramchurren, N and Topalian, SL and Nghiem, PT and Hadrup, SR}, title = {T antigen-specific CD8+ T cells associate with PD-1 blockade response in virus-positive Merkel cell carcinoma.}, journal = {The Journal of clinical investigation}, volume = {134}, number = {8}, pages = {}, pmid = {38618958}, issn = {1558-8238}, support = {P01 CA225517/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Antigens, Viral, Tumor ; *Carcinoma, Merkel Cell/drug therapy/genetics ; Programmed Cell Death 1 Receptor/genetics ; CD8-Positive T-Lymphocytes ; *Skin Neoplasms/drug therapy/genetics ; }, abstract = {Merkel cell carcinoma (MCC) is a highly immunogenic skin cancer primarily induced by Merkel cell polyomavirus, which is driven by the expression of the oncogenic T antigens (T-Ags). Blockade of the programmed cell death protein-1 (PD-1) pathway has shown remarkable response rates, but evidence for therapy-associated T-Ag-specific immune response and therapeutic strategies for the nonresponding fraction are both limited. We tracked T-Ag-reactive CD8+ T cells in peripheral blood of 26 MCC patients under anti-PD1 therapy, using DNA-barcoded pMHC multimers, displaying all peptides from the predicted HLA ligandome of the oncoproteins, covering 33 class I haplotypes. We observed a broad T cell recognition of T-Ags, including identification of 20 T-Ag-derived epitopes we believe to be novel. Broadening of the T-Ag recognition profile and increased T cell frequencies during therapy were strongly associated with clinical response and prolonged progression-free survival. T-Ag-specific T cells could be further boosted and expanded directly from peripheral blood using artificial antigen-presenting scaffolds, even in patients with no detectable T-Ag-specific T cells. These T cells provided strong tumor-rejection capacity while retaining a favorable phenotype for adoptive cell transfer. These findings demonstrate that T-Ag-specific T cells are associated with the clinical outcome to PD-1 blockade and that Ag-presenting scaffolds can be used to boost such responses.}, }
@article {pmid38617425, year = {2024}, author = {VoPham, T and Ton, M and Weaver, MD}, title = {Spatiotemporal light exposure modeling for environmental circadian misalignment and solar jetlag.}, journal = {Environmental epidemiology (Philadelphia, Pa.)}, volume = {8}, number = {2}, pages = {e301}, pmid = {38617425}, issn = {2474-7882}, abstract = {BACKGROUND: Light exposure is the most powerful resetting signal for circadian rhythms. The objective of this study was to develop and validate a high-resolution geospatial light exposure model that measures environmental circadian misalignment (or solar jetlag) as the mismatch between the social clock and sun clock, which occurs from geographic variation in light exposure leading to delayed circadian phase from relatively less morning light exposure and greater evening light exposure with increasing westward position within a time zone.<br><br>METHODS: The light exposure model (30 m[2] spatial resolution) incorporated geospatial data across the United States on time zones, elevation (using Google Earth Engine), sunrise time, and sunset time to estimate solar jetlag scores (higher values indicate higher environmental circadian misalignment). The validation study compared the light exposure model in 2022, which was linked with geocoded residential addresses of n = 20 participants in Boston, MA (eastern time zone position) and Seattle, WA (western time zone position) using a geographic information system, with illuminance values captured from wearable LYS light sensors and with sun times from the Solar Calculator.<br><br>RESULTS: Western versus eastern positions within a time zone were associated with higher solar jetlag scores from the light exposure model (P < 0.01) and relatively larger differences in sunset time measured using light sensors (social clock) and the Solar Calculator (sun clock) (P = 0.04).<br><br>CONCLUSION: We developed and validated a geospatial light exposure model, enabling high spatiotemporal resolution and comprehensive characterization of geographic variation in light exposure potentially impacting circadian phase in epidemiologic studies.}, }
@article {pmid38617337, year = {2024}, author = {Grinde, KE and Browning, BL and Reiner, AP and Thornton, TA and Browning, SR}, title = {Adjusting for principal components can induce spurious associations in genome-wide association studies in admixed populations.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38617337}, issn = {2692-8205}, support = {HHSN268201100037C/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; HHSN268201300048C/HL/NHLBI NIH HHS/United States ; HHSN268201300049C/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; HHSN268201300046C/HL/NHLBI NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; U01 HL089897/HL/NHLBI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; U01 HL089856/HL/NHLBI NIH HHS/United States ; R01 HG010869/HG/NHGRI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; HHSN268201300047C/HL/NHLBI NIH HHS/United States ; HHSN268201300050C/HL/NHLBI NIH HHS/United States ; }, abstract = {Principal component analysis (PCA) is widely used to control for population structure in genome-wide association studies (GWAS). Top principal components (PCs) typically reflect population structure, but challenges arise in deciding how many PCs are needed and ensuring that PCs do not capture other artifacts such as regions with atypical linkage disequilibrium (LD). In response to the latter, many groups suggest performing LD pruning or excluding known high LD regions prior to PCA. However, these suggestions are not universally implemented and the implications for GWAS are not fully understood, especially in the context of admixed populations. In this paper, we investigate the impact of pre-processing and the number of PCs included in GWAS models in African American samples from the Women's Women's Health Initiative SNP Health Association Resource and two Trans-Omics for Precision Medicine Whole Genome Sequencing Project contributing studies (Jackson Heart Study and Genetic Epidemiology of Chronic Obstructive Pulmonary Disease Study). In all three samples, we find the first PC is highly correlated with genome-wide ancestry whereas later PCs often capture local genomic features. The pattern of which, and how many, genetic variants are highly correlated with individual PCs differs from what has been observed in prior studies focused on European populations and leads to distinct downstream consequences: adjusting for such PCs yields biased effect size estimates and elevated rates of spurious associations due to the phenomenon of collider bias. Excluding high LD regions identified in previous studies does not resolve these issues. LD pruning proves more effective, but the optimal choice of thresholds varies across datasets. Altogether, our work highlights unique issues that arise when using PCA to control for ancestral heterogeneity in admixed populations and demonstrates the importance of careful pre-processing and diagnostics to ensure that PCs capturing multiple local genomic features are not included in GWAS models.}, }
@article {pmid38617334, year = {2024}, author = {Lane, DD and Gottimukkala, KSV and Cunningham, RA and Jwa, S and Cassidy, ME and Castelli, JMP and Adair, JE}, title = {Cas9 RNP Physiochemical Analysis for Enhanced CRISPR-AuNP Assembly and Function.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38617334}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 AI158728/AI/NIAID NIH HHS/United States ; R01 AI167009/AI/NIAID NIH HHS/United States ; U54 DK106829/DK/NIDDK NIH HHS/United States ; }, abstract = {CRISPR therapy for hematological disease has proven effective for transplant dependent beta thalassemia and sickle cell anemia, with additional disease targets in sight. The success of these therapies relies on high rates of CRISPR-induced double strand DNA breaks in hematopoietic stem and progenitor cells (HSPC). To achieve these levels, CRISPR complexes are typically delivered by electroporation ex vivo which is toxic to HSPCs. HSPCs are then cultured in stimulating conditions that promote error-prone DNA repair, requiring conditioning with chemotherapy to facilitate engraftment after reinfusion. In vivo delivery by nanocarriers of CRISPR gene editing tools has the potential to mitigate this complexity and toxicity and make this revolutionary therapy globally available. To achieve in vivo delivery, the inherent restriction factors against oligonucleotide delivery into HSPCs, that make ex vivo manipulation including electroporation and stimulation essential, must be overcome. To this end, our group developed a CRISPR carrying gold nanoparticle (CRISPR-AuNP) capable of delivering either Cas9 or Cas12a CRISPRs as ribonucleoprotein complexes (RNP) without compromising HSPC fitness. However, the most commonly used CRISPR, Cas9, demonstrated inconsistent activity in this delivery system, with lower activity relative to Cas12a. Investigation of Cas9 RNP biophysics relative to Cas12a revealed duplex RNA instability during the initial loading onto Au cores, resulting in undetectable Cas9 loading to the particle surface. Here we demonstrate preformation of RNP before loading, coupled with optimization of the loading chemistry and conditions, resulted in 39.6 ± 7.0 Cas9 RNP/AuNP without compromising RNP activity in both in vitro assays and primary human HSPC. The same alterations improved Cas12a RNP/AuNP loading 10-fold over previously reported levels. To achieve particle stability, the reported polyethyleneimine outer coating was altered to include PEGylation and the resulting 2[nd] generation CRISPR-AuNP demonstrates favorable nanoformulation characteristics for in vivo administration, with a hydrophilic, more neutral nanoparticle surface. Direct treatment of HSPC in vitro showed 72.5 ± 7.37% uptake of 2[nd] generation CRISPR-AuNP in primary human HSPC, but with endosomal accumulation and low rates of gene editing consistent with low levels of endosomal escape.}, }
@article {pmid38615031, year = {2024}, author = {Wagner, C and Kistler, KE and Perchetti, GA and Baker, N and Frisbie, LA and Torres, LM and Aragona, F and Yun, C and Figgins, M and Greninger, AL and Cox, A and Oltean, HN and Roychoudhury, P and Bedford, T}, title = {Positive selection underlies repeated knockout of ORF8 in SARS-CoV-2 evolution.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {3207}, pmid = {38615031}, issn = {2041-1723}, support = {S10 OD020069/OD/NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, mesh = {Humans ; *COVID-19 ; Phylogeny ; *SARS-CoV-2/genetics ; Viral Proteins/genetics ; *Selection, Genetic/genetics ; }, abstract = {Knockout of the ORF8 protein has repeatedly spread through the global viral population during SARS-CoV-2 evolution. Here we use both regional and global pathogen sequencing to explore the selection pressures underlying its loss. In Washington State, we identified transmission clusters with ORF8 knockout throughout SARS-CoV-2 evolution, not just on novel, high fitness viral backbones. Indeed, ORF8 is truncated more frequently and knockouts circulate for longer than for any other gene. Using a global phylogeny, we find evidence of positive selection to explain this phenomenon: nonsense mutations resulting in shortened protein products occur more frequently and are associated with faster clade growth rates than synonymous mutations in ORF8. Loss of ORF8 is also associated with reduced clinical severity, highlighting the diverse clinical impacts of SARS-CoV-2 evolution.}, }
@article {pmid38613330, year = {2024}, author = {Baek, G and Kim, M and Lee, M and O'Connor, S and Held, L and van der Laan, L and Cassaday, RD}, title = {Retrospective review of the toxicities and change in dosing patterns for pegaspargase in patients with acute lymphoblastic leukemia/lymphoma and T-cell lymphoma.}, journal = {Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners}, volume = {}, number = {}, pages = {10781552241246104}, doi = {10.1177/10781552241246104}, pmid = {38613330}, issn = {1477-092X}, abstract = {INTRODUCTION: Pegaspargase (PEG) is a key component of standard regimens for acute lymphoblastic leukemia/lymphoma (ALL) and extranodal natural killer/T-cell lymphoma (NKTCL). Emerging evidence suggests an opportunity to decrease incidence of PEG-associated toxicities with dose capping, but evidence is limited. This study aims to evaluate whether a significant difference in PEG-associated toxicities related to dosing strategy exists and to identify patient-specific or regimen-specific factors for PEG-related toxicity.<br><br>METHODS: A retrospective analysis of PEG-associated toxicities was completed in adult patients with ALL or NKTCL who received PEG within Cancer and Leukemia Group B (CALGB) 10403 or modified dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide (mSMILE) regimens at the UW Medical Center/Fred Hutchinson Cancer Center. PEG-associated toxicities that occurred through 8 weeks after PEG doses were noted.<br><br>RESULTS: Twenty-eight patients received dose-capped PEG, and 29 received noncapped PEG. Fewer all-grade and grade 3/4 toxicities were observed in the dose-capped cohort. Grade 3/4 toxicities observed were hepatotoxicity, hyperglycemia, hypersensitivity, and hypertriglyceridemia. In addition, fewer grade 3/4 pancreatitis and thrombosis events occurred in the dose-capped cohort. Hypertriglyceridemia and hepatotoxicity were associated with the highest cumulative incidence proportions among all toxicities.<br><br>CONCLUSION: Dose capping of PEG was associated with a similar or later median onset for most toxicities, a less heterogeneic toxicity profile, and a lower recurrence of most toxicities upon PEG rechallenge compared to the non-dose-capped cohort. Standardizing PEG dose capping in the CALGB 10403 and mSMILE regimens may translate to improved tolerance compared to a historical standard of no dose capping PEG.}, }
@article {pmid38607625, year = {2024}, author = {Wagner, MJ and Ravi, V and Schaub, SK and Kim, EY and Sharib, J and Mogal, H and Park, M and Tsai, M and Duarte-Bateman, D and Tufaro, A and Loggers, ET and Cranmer, LD and Chau, B and Hassett, MJ and Grilley-Olson, J and Paulson, KG}, title = {Incidence and Presenting Characteristics of Angiosarcoma in the US, 2001-2020.}, journal = {JAMA network open}, volume = {7}, number = {4}, pages = {e246235}, pmid = {38607625}, issn = {2574-3805}, mesh = {Male ; Humans ; Female ; Aged ; Incidence ; *Hemangiosarcoma/epidemiology ; Cross-Sectional Studies ; Retrospective Studies ; *Breast Neoplasms ; }, abstract = {IMPORTANCE: Angiosarcoma is an aggressive vascular malignant neoplasm presenting either as a primary or secondary cancer, often arising after radiotherapy or in the context of preexisting lymphedema. Comprehensive data describing its incidence and presentation patterns are needed.<br><br>OBJECTIVE: To describe the incidence, presenting characteristics, and change over time of angiosarcoma in the US.<br><br>This retrospective cross-sectional study used data from the US Cancer Statistics (USCS) National Program of Cancer Registries-Surveillance, Epidemiology, and End Results Combined Database, which captures more than 99% of newly diagnosed cancers in the US. The study included all 19&#x202f;289 patients in the US with a new diagnosis of angiosarcoma between 2001 and 2020 captured in the USCS database. Statistical analysis was performed from June to September 2023.<br><br>MAIN OUTCOMES AND MEASURES: Incidence of angiosarcoma, demographics of patients with angiosarcoma, and extent of disease at presentation.<br><br>RESULTS: The study included 19&#x202f;289 patients (median age, 71 years [IQR, 59-80 years]; 10&#x202f;506 women [54.5%]) with a new diagnosis of angiosarcoma. The US incidence of angiosarcoma doubled between 2001 (657 cases) and 2019 (1312 cases), reflecting both an increase in the adjusted incidence rate of 1.6% per year (P&#x2009;=&#x2009;.001), to 3.3 cases per 1&#x202f;000&#x202f;000 person-years (95% CI, 3.1-3.5 cases per 1&#x202f;000&#x202f;000 person-years), and an increase in the population at risk. In 2020, the reported incidence rate (3.0 cases per 1&#x202f;000&#x202f;000 person-years) and cases of angiosarcoma (n&#x2009;=&#x2009;1159) were modestly lower than in 2019. Overall, 72.3% of cases of angiosarcoma (n&#x2009;=&#x2009;13&#x202f;955) were cutaneous, subcutaneous, or breast angiosarcomas; 24.4% were visceral (n&#x2009;=&#x2009;4701); and 3.3% were located in unknown or rare primary sites (n&#x2009;=&#x2009;633). Secondary breast and chest wall angiosarcomas among women represented the largest contribution to increasing incidence. Among breast angiosarcomas, 99.2% (2684 of 2705) were in women and 71.9% (1944 of 2705) were secondary. A total of 80.4% of chest wall or thorax cases among women (1861 of 2316) were secondary vs 26.5% among men (112 of 422), and 63.9% of upper extremity cases among women (205 of 321) were secondary vs 26.8% (56 of 209) among men (P&#x2009;=&#x2009;.001). Rates of secondary angiosarcoma in the abdomen and lower extremities were similar between men and women. The incidence rate of visceral angiosarcoma was also found to be increasing (1.5% per year; P&#x2009;=&#x2009;.001).<br><br>CONCLUSIONS AND RELEVANCE: This cross-sectional study describes angiosarcoma presentation patterns and incidence rates in the US over a 20-year period and shows that the number of cases in men and women increased, with the greatest increase among women with secondary angiosarcoma of the chest, breast, and upper extremity. These data increase awareness of a rare but highly morbid disease and highlight the need for improved early detection of angiosarcoma among patients at high risk, such as women with a history of breast cancer.}, }
@article {pmid38607410, year = {2024}, author = {Zhao, Y and Laird, AD and Roberts, KG and Yafawi, R and Kantarjian, H and DeAngelo, DJ and Stelljes, M and Liedtke, M and Stock, W and Gökbuget, N and O'Brien, S and Jabbour, E and Cassaday, RD and Loyd, MR and Olsen, S and Neale, G and Liu, X and Vandendries, E and Advani, A and Mullighan, CG}, title = {Association of leukemic molecular profile with efficacy of inotuzumab ozogamicin in adults with relapsed/refractory ALL.}, journal = {Blood advances}, volume = {8}, number = {12}, pages = {3226-3236}, pmid = {38607410}, issn = {2473-9537}, support = {R35 CA197695/CA/NCI NIH HHS/United States ; P30 CA021765/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Inotuzumab Ozogamicin/therapeutic use ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/mortality ; Adult ; Female ; Male ; Middle Aged ; Treatment Outcome ; Aged ; Recurrence ; Antineoplastic Agents, Immunological/therapeutic use ; Young Adult ; Drug Resistance, Neoplasm ; Adolescent ; }, abstract = {The phase 3 INO-VATE trial demonstrated higher rates of remission, measurable residual disease negativity, and improved overall survival for patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) who received inotuzumab ozogamicin (InO) vs standard-of-care chemotherapy (SC). Here, we examined associations between genomic alterations and the efficacy of InO. Of 326 randomized patients, 91 (InO, n = 43; SC, n = 48) had samples evaluable for genomic analysis. The spectrum of gene fusions and other genomic alterations observed was comparable with prior studies of adult ALL. Responses to InO were observed in all leukemic subtypes, genomic alterations, and risk groups. Significantly higher rates of complete remission (CR)/CR with incomplete count recovery were observed with InO vs SC in patients with BCR::ABL1-like ALL (85.7% [6/7] vs 0% [0/5]; P = .0076), with TP53 alterations (100% [5/5] vs 12.5% [1/8]; P = .0047), and in the high-risk BCR::ABL1- (BCR::ABL1-like, low-hypodiploid, KMT2A-rearranged) group (83.3% [10/12] vs 10.5% [2/19]; P < .0001). This retrospective, exploratory analysis of the INO-VATE trial demonstrated potential for benefit with InO for patients with R/R ALL across leukemic subtypes, including BCR::ABL1-like ALL, and for those bearing diverse genomic alterations. Further confirmation of the efficacy of InO in patients with R/R ALL exhibiting the BCR::ABL1-like subtype or harboring TP53 alterations is warranted. This trial was registered at www.ClinicalTrials.gov as #NCT01564784.}, }
@article {pmid38606632, year = {2024}, author = {Liu, M and Su, YR and Liu, Y and Hsu, L and He, Q}, title = {Structured testing of genetic association with mixed clinical outcomes.}, journal = {Genetic epidemiology}, volume = {}, number = {}, pages = {}, pmid = {38606632}, issn = {1098-2272}, support = {R01CA189532/NH/NIH HHS/United States ; R01 GM105785/GM/NIGMS NIH HHS/United States ; R01 HL152439/HL/NHLBI NIH HHS/United States ; R01HL152439/NH/NIH HHS/United States ; R01CA223498/NH/NIH HHS/United States ; R01 CA223498/CA/NCI NIH HHS/United States ; R01 CA189532/CA/NCI NIH HHS/United States ; R01GM105785/NH/NIH HHS/United States ; }, abstract = {Genetic factors play a fundamental role in disease development. Studying the genetic association with clinical outcomes is critical for understanding disease biology and devising novel treatment targets. However, the frequencies of genetic variations are often low, making it difficult to examine the variants one-by-one. Moreover, the clinical outcomes are complex, including patients' survival time and other binary or continuous outcomes such as recurrences and lymph node count, and how to effectively analyze genetic association with these outcomes remains unclear. In this article, we proposed a structured test statistic for testing genetic association with mixed types of survival, binary, and continuous outcomes. The structured testing incorporates known biological information of variants while allowing for their heterogeneous effects and is a powerful strategy for analyzing infrequent genetic factors. Simulation studies show that the proposed test statistic has correct type I error and is highly effective in detecting significant genetic variants. We applied our approach to a uterine corpus endometrial carcinoma study and identified several genetic pathways associated with the clinical outcomes.}, }
@article {pmid38604173, year = {2024}, author = {Ahmad, K and Brahma, S and Henikoff, S}, title = {Response to "Learning from chromatin reconstitution: Pioneering factors enabling nucleosome remodelers".}, journal = {Molecular cell}, volume = {84}, number = {10}, pages = {1818}, doi = {10.1016/j.molcel.2024.03.020}, pmid = {38604173}, issn = {1097-4164}, mesh = {*Nucleosomes/metabolism/genetics ; *Chromatin Assembly and Disassembly ; *Chromatin/metabolism/genetics ; Humans ; Animals ; }, }
@article {pmid38604127, year = {2024}, author = {Jin, J and Zhan, J and Zhang, J and Zhao, R and O'Connell, J and Jiang, Y and ,  and Buyske, S and Gignoux, C and Haiman, C and Kenny, EE and Kooperberg, C and North, K and Koelsch, BL and Wojcik, G and Zhang, H and Chatterjee, N}, title = {MUSSEL: Enhanced Bayesian polygenic risk prediction leveraging information across multiple ancestry groups.}, journal = {Cell genomics}, volume = {4}, number = {4}, pages = {100539}, pmid = {38604127}, issn = {2666-979X}, support = {U01 HG007419/HG/NHGRI NIH HHS/United States ; R01 HG010480/HG/NHGRI NIH HHS/United States ; U2C OD023196/OD/NIH HHS/United States ; OT2 OD026551/OD/NIH HHS/United States ; U24 OD023121/OD/NIH HHS/United States ; OT2 OD026552/OD/NIH HHS/United States ; OT2 OD026549/OD/NIH HHS/United States ; OT2 OD025337/OD/NIH HHS/United States ; OT2 OD025277/OD/NIH HHS/United States ; OT2 OD026550/OD/NIH HHS/United States ; OT2 OD026553/OD/NIH HHS/United States ; OT2 OD023205/OD/NIH HHS/United States ; OT2 OD025276/OD/NIH HHS/United States ; OT2 OD026557/OD/NIH HHS/United States ; OT2 OD026554/OD/NIH HHS/United States ; U24 OD023163/OD/NIH HHS/United States ; R01 HG010297/HG/NHGRI NIH HHS/United States ; OT2 OD023206/OD/NIH HHS/United States ; R35 HG011944/HG/NHGRI NIH HHS/United States ; OT2 OD026556/OD/NIH HHS/United States ; R00 HG012223/HG/NHGRI NIH HHS/United States ; U24 OD023176/OD/NIH HHS/United States ; OT2 OD026548/OD/NIH HHS/United States ; OT2 OD025315/OD/NIH HHS/United States ; U01 CA249866/CA/NCI NIH HHS/United States ; K99 CA256513/CA/NCI NIH HHS/United States ; R01 HL151152/HL/NHLBI NIH HHS/United States ; OT2 OD026555/OD/NIH HHS/United States ; }, mesh = {Humans ; Animals ; *Multifactorial Inheritance/genetics ; Genome-Wide Association Study/methods ; Bayes Theorem ; Phenotype ; Genetic Risk Score ; *Bivalvia ; }, abstract = {Polygenic risk scores (PRSs) are now showing promising predictive performance on a wide variety of complex traits and diseases, but there exists a substantial performance gap across populations. We propose MUSSEL, a method for ancestry-specific polygenic prediction that borrows information in summary statistics from genome-wide association studies (GWASs) across multiple ancestry groups via Bayesian hierarchical modeling and ensemble learning. In our simulation studies and data analyses across four distinct studies, totaling 5.7 million participants with a substantial ancestral diversity, MUSSEL shows promising performance compared to alternatives. For example, MUSSEL has an average gain in prediction R[2] across 11 continuous traits of 40.2% and 49.3% compared to PRS-CSx and CT-SLEB, respectively, in the African ancestry population. The best-performing method, however, varies by GWAS sample size, target ancestry, trait architecture, and linkage disequilibrium reference samples; thus, ultimately a combination of methods may be needed to generate the most robust PRSs across diverse populations.}, }
@article {pmid38598658, year = {2024}, author = {Sherman, AC and Tuan, J and Cantos, VD and Adeyiga, O and Mahoney, S and Ortega-Villa, AM and Tillman, A and Whitaker, J and Woodward Davis, AS and Leav, B and Hirsch, I and Sadoff, J and Dunkle, LM and Gilbert, PB and Janes, HE and Kublin, JG and Goepfert, PA and Kotloff, K and Rouphael, N and Falsey, AR and El Sahly, HM and Sobieszczyk, ME and Huang, Y and Neuzil, KM and Corey, L and Grinsztejn, B and Gray, G and Nason, M and Baden, LR and Gay, CL}, title = {COVID-19 Vaccine Efficacy in Participants With Weakened Immune Systems From 4 Randomized Controlled Trials.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {79}, number = {2}, pages = {364-374}, pmid = {38598658}, issn = {1537-6591}, support = {UM1 AI069423/AI/NIAID NIH HHS/United States ; UM1 AI069476/AI/NIAID NIH HHS/United States ; U01 AI069470/AI/NIAID NIH HHS/United States ; //HIV Prevention Trials Network/ ; //Infectious Diseases Clinical Research Consortium/ ; UM1 AI068614/AI/NIAID NIH HHS/United States ; //US government/ ; UM1 AI068614/NH/NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI148689/AI/NIAID NIH HHS/United States ; UM1 AI148450/AI/NIAID NIH HHS/United States ; //National Institute of Allergy and Infectious Diseases/ ; UM1 AI148576/AI/NIAID NIH HHS/United States ; //AIDS Clinical Trials Group/ ; //Biomedical Advanced Research and Development Authority/ ; UM1 AI069412/AI/NIAID NIH HHS/United States ; UM1 AI069470/AI/NIAID NIH HHS/United States ; //HIV Vaccine Trials Network/ ; //Vaccine Treatment and Evaluation Units/ ; }, mesh = {Humans ; *COVID-19/prevention &amp; control/immunology ; *COVID-19 Vaccines/immunology/administration &amp; dosage ; Male ; Female ; *SARS-CoV-2/immunology ; *Vaccine Efficacy ; Middle Aged ; Adult ; Immunocompromised Host ; Aged ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Although the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are highly efficacious at preventing severe disease in the general population, current data are lacking regarding vaccine efficacy (VE) for individuals with mild immunocompromising conditions.<br><br>METHODS: A post hoc, cross-protocol analysis of participant-level data from the blinded phase of four randomized, placebo-controlled, coronavirus disease 2019 (COVID-19) vaccine phase 3 trials (Moderna, AstraZeneca, Janssen, and Novavax) was performed. We defined a "tempered immune system" (TIS) variable via a consensus panel based on medical history and medications to determine VE against symptomatic and severe COVID-19 cases in TIS participants versus non-TIS individuals starting at 14 days after completion of the primary series through the blinded phase for each of the 4 trials. An analysis of participants living with well-controlled human immunodeficiency virus was conducted using the same methods.<br><br>RESULTS: A total of 3852/30 351 (12.7%) Moderna participants, 3088/29 868 (10.3%) Novavax participants, 3549/32 380 (11.0%) AstraZeneca participants, and 5047/43 788 (11.5%) Janssen participants were identified as having a TIS. Most TIS conditions (73.9%) were due to metabolism and nutritional disorders. Vaccination (vs placebo) significantly reduced the likelihood of symptomatic and severe COVID-19 for all participants for each trial. VE was not significantly different for TIS participants versus non-TIS for either symptomatic or severe COVID-19 for each trial, nor was VE significantly different in the symptomatic endpoint for participants with human immunodeficiency virus.<br><br>CONCLUSIONS: For individuals with mildly immunocompromising conditions, there is no evidence of differences in VE against symptomatic or severe COVID-19 compared with those with non-TIS in the 4 COVID-19 vaccine randomized controlled efficacy trials.}, }
@article {pmid38598634, year = {2024}, author = {Hiatt, JB and Doebley, AL and Arnold, HU and Adil, M and Sandborg, H and Persse, TW and Ko, M and Wu, F and Quintanal Villalonga, A and Santana-Davila, R and Eaton, K and Dive, C and Rudin, CM and Thomas, A and Houghton, AM and Ha, G and MacPherson, D}, title = {Molecular phenotyping of small cell lung cancer using targeted cfDNA profiling of transcriptional regulatory regions.}, journal = {Science advances}, volume = {10}, number = {15}, pages = {eadk2082}, pmid = {38598634}, issn = {2375-2548}, support = {T32 HL007093/HL/NHLBI NIH HHS/United States ; K12 CA076930/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; K22 CA237746/CA/NCI NIH HHS/United States ; DP2 CA280624/CA/NCI NIH HHS/United States ; R21 CA264383/CA/NCI NIH HHS/United States ; P50 CA228944/CA/NCI NIH HHS/United States ; U24 CA213274/CA/NCI NIH HHS/United States ; R35 CA263816/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Small Cell Lung Carcinoma/metabolism ; *Lung Neoplasms/metabolism ; *Cell-Free Nucleic Acids ; *Carcinoma, Non-Small-Cell Lung/pathology ; Regulatory Sequences, Nucleic Acid ; Gene Expression Regulation, Neoplastic ; }, abstract = {We report an approach for cancer phenotyping based on targeted sequencing of cell-free DNA (cfDNA) for small cell lung cancer (SCLC). In SCLC, differential activation of transcription factors (TFs), such as ASCL1, NEUROD1, POU2F3, and REST defines molecular subtypes. We designed a targeted capture panel that identifies chromatin organization signatures at 1535 TF binding sites and 13,240 gene transcription start sites and detects exonic mutations in 842 genes. Sequencing of cfDNA from SCLC patient-derived xenograft models captured TF activity and gene expression and revealed individual highly informative loci. Prediction models of ASCL1 and NEUROD1 activity using informative loci achieved areas under the receiver operating characteristic curve (AUCs) from 0.84 to 0.88 in patients with SCLC. As non-SCLC (NSCLC) often transforms to SCLC following targeted therapy, we applied our framework to distinguish NSCLC from SCLC and achieved an AUC of 0.99. Our approach shows promising utility for SCLC subtyping and transformation monitoring, with potential applicability to diverse tumor types.}, }
@article {pmid38598511, year = {2024}, author = {Triplette, M and Kross, EK and Snidarich, M and Shahrir, S and Hippe, DS and Crothers, K}, title = {An alternating-intervention pilot trial on the impact of an informational handout on patient-reported outcomes and follow-up after lung cancer screening.}, journal = {PloS one}, volume = {19}, number = {4}, pages = {e0300352}, pmid = {38598511}, issn = {1932-6203}, mesh = {Humans ; *Lung Neoplasms/diagnosis ; Early Detection of Cancer ; Follow-Up Studies ; Prospective Studies ; Pilot Projects ; Patient Reported Outcome Measures ; Mass Screening/methods ; }, abstract = {INTRODUCTION: Lung cancer screening (LCS) can reduce lung cancer mortality; however, poor understanding of results may impact patient experience and follow-up. We sought to determine whether an informational handout accompanying LCS results can improve patient-reported outcomes and adherence to follow-up.<br><br>STUDY DESIGN: This was a prospective alternating intervention pilot trial of a handout to accompany LCS results delivery.<br><br>SETTING/PARTICIPANTS: Patients undergoing LCS in a multisite program over a 6-month period received a mailing containing either: 1) a standardized form letter of LCS results (control) or 2) the LCS results letter and the handout (intervention).<br><br>INTERVENTION: A two-sided informational handout on commonly asked questions after LCS created through iterative mixed-methods evaluation with both LCS patients and providers.<br><br>OUTCOME MEASURES: The primary outcomes of 1)patient understanding of LCS results, 2)correct identification of next steps in screening, and 3)patient distress were measured through survey. Adherence to recommended follow-up after LCS was determined through chart review. Outcomes were compared between the intervention and control group using generalized estimating equations.<br><br>RESULTS: 389 patients were eligible and enrolled with survey responses from 230 participants (59% response rate). We found no differences in understanding of results, identification of next steps in follow-up or distress but did find higher levels of knowledge and understanding on questions assessing individual components of LCS in the intervention group. Follow-up adherence was overall similar between the two arms, though was higher in the intervention group among those with positive findings (p = 0.007).<br><br>CONCLUSIONS: There were no differences in self-reported outcomes between the groups or overall follow-up adherence. Those receiving the intervention did report greater understanding and knowledge of key LCS components, and those with positive results had a higher rate of follow-up. This may represent a feasible component of a multi-level intervention to address knowledge and follow-up for LCS.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT05265897.}, }
@article {pmid38597608, year = {2024}, author = {Neal, JW and Minichiello, K and Brennick, R and Huang, RSP and Hiemenz, MC and Amler, C and Patel, J and Herbst, R and Reckamp, KL and Borghaei, H and Highleyman, L and Redman, MW and Pasquina, LW and Kozono, DE}, title = {A process to reanalyze clinical DNA sequencing data for biomarker matching in the Lung-MAP Master Protocol.}, journal = {The oncologist}, volume = {29}, number = {6}, pages = {e843-e847}, pmid = {38597608}, issn = {1549-490X}, mesh = {Humans ; *Lung Neoplasms/genetics/pathology ; *Biomarkers, Tumor/genetics ; Sequence Analysis, DNA/methods/standards ; Genomics/methods ; }, abstract = {For cancer clinical trials that require central confirmation of tumor genomic profiling, exhaustion of tissue from standard-of-care testing may prevent enrollment. For Lung-MAP, a master protocol that requires results from a defined centralized clinical trial assay to assign patients to a therapeutic substudy, we developed a process to repurpose existing commercial vendor raw genomic data for eligibility: genomic data reanalysis (GDR). Molecular results for substudy assignment were successfully generated for 369 of the first 374 patients (98.7%) using GDR for Lung-MAP, with a median time from request to result of 9 days. During the same period, 691 of 791 (87.4%) tissue samples received successfully yielded results, in a median of 14 days beyond sample acquisition. GDR is a scalable bioinformatic pipeline that expedites reanalysis of existing data for clinical trials in which validated integral biomarker testing is required for participation.}, }
@article {pmid38596455, year = {2024}, author = {Hotca, A and Sindhu, KK and Lehrer, EJ and Hartsell, WF and Vargas, C and Tsai, HK and Chang, JH and Apisarnthanarax, S and Nichols, RC and Chhabra, AM and Hasan, S and Press, RH and Lazarev, S and Hajj, C and Kabarriti, R and Rule, WG and Simone, CB and Choi, JI}, title = {Reirradiation With Proton Therapy for Recurrent Malignancies of the Esophagus and Gastroesophageal Junction: Results of the Proton Collaborative Group Multi-Institutional Prospective Registry Trial.}, journal = {Advances in radiation oncology}, volume = {9}, number = {5}, pages = {101459}, pmid = {38596455}, issn = {2452-1094}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: Treatment options for recurrent esophageal cancer (EC) previously treated with radiation therapy (RT) are limited. Reirradiation (reRT) with proton beam therapy (PBT) can offer lower toxicities by limiting doses to surrounding tissues. In this study, we present the first multi-institutional series reporting on toxicities and outcomes after reRT for locoregionally recurrent EC with PBT.<br><br>METHODS AND MATERIALS: Analysis of the prospective, multicenter, Proton Collaborative Group registry of patients with recurrent EC who had previously received photon-based RT and underwent PBT reRT was performed. Patient/tumor characteristics, treatment details, outcomes, and toxicities were collected. Local control (LC), distant metastasis-free survival (DMFS), and overall survival (OS) were estimated using the Kaplan-Meier method. Event time was determined from reRT start.<br><br>RESULTS: Between 2012 and 2020, 31 patients received reRT via uniform scanning/passive scattering (61.3%) or pencil beam scanning (38.7%) PBT at 7 institutions. Median prior RT, PBT reRT, and cumulative doses were 50.4 Gy (range, 37.5-110.4), 48.6 Gy (relative biological effectiveness) (25.2-72.1), and 99.9 Gy (79.1-182.5), respectively. Of these patients, 12.9% had 2 prior RT courses, and 67.7% received PBT with concurrent chemotherapy. Median follow-up was 7.2 months (0.9-64.7). Post-PBT, there were 16.7% locoregional only, 11.1% distant only, and 16.7% locoregional and distant recurrences. Six-month LC, DMFS, and OS were 80.5%, 83.4%, and 69.1%, respectively. One-year LC, DMFS, and OS were 67.1%, 83.4%, and 27%, respectively. Acute grade &#x2265;3 toxicities occurred in 23% of patients, with 1 acute grade 5 toxicity secondary to esophageal hemorrhage, unclear if related to reRT or disease progression. No grade &#x2265;3 late toxicities were reported.<br><br>CONCLUSIONS: In the largest report to date of PBT for reRT in patients with recurrent EC, we observed acceptable acute toxicities and encouraging rates of disease control. However, these findings are limited by the poor prognoses of these patients, who are at high risk of mortality. Further research is needed to better assess the long-term benefits and toxicities of PBT in this specific patient population.}, }
@article {pmid38593961, year = {2024}, author = {Irwin, T and Donlan, AW and Owens, L and Alvarez, R and Vakar-Lopez, F and Tretiakova, M}, title = {Enhancing upper tract urothelial carcinoma diagnosis: Utility of cytokeratin 17 and CK20/CD44/p53 immunohistochemical panel.}, journal = {Human pathology}, volume = {146}, number = {}, pages = {43-48}, doi = {10.1016/j.humpath.2024.04.001}, pmid = {38593961}, issn = {1532-8392}, mesh = {Humans ; *Biomarkers, Tumor/analysis ; Biopsy ; Carcinoma, Transitional Cell/diagnosis/pathology/metabolism ; Diagnosis, Differential ; *Hyaluronan Receptors/analysis/metabolism ; *Immunohistochemistry ; *Keratin-17/analysis ; *Keratin-20/analysis/metabolism ; Neoplasm Grading ; Predictive Value of Tests ; Reproducibility of Results ; *Tumor Suppressor Protein p53/analysis ; Urinary Bladder Neoplasms/diagnosis/pathology ; Urologic Neoplasms/diagnosis/pathology ; *Urothelium/pathology/chemistry ; }, abstract = {Upper tract urothelial carcinoma (UTUC) presents diagnostic challenges due to small biopsy specimen size, poor orientation, and technical obstacles that can yield equivocal diagnoses. This uncertainty often mandates repeated biopsies to evaluate the necessity of nephroureterectomy. Prior studies have suggested cytokeratin 17 (CK17) immunostain as an adjunctive tool for diagnosing bladder urothelial neoplasia in both urine cytology and tissue biopsy specimens. We evaluated the utility of CK17 in differentiating UTUC from benign urothelium and its ability to stratify low-grade from high-grade neoplasia. Our study involved a cohort of previously diagnosed cytology (n = 29) and tissue specimens from biopsies and resections (n = 85). We evaluated CK17 staining percentage in cytology and tissue samples and localization patterns in biopsy/resection samples. Our findings showed a statistically significant distinction (p < 0.05) between UTUC and benign tissue specimens based on full thickness localization pattern (odds ratio 8.8 [95% CI 1.53-67.4]). The percentage of CK17 staining failed to significantly differentiate neoplastic from non-neoplastic cases in cytology or tissue samples. Additionally, based on prior research showing the efficacy of CK20/CD44/p53 triple panel in bladder urothelial neoplasia, we utilized tissue microarrays to evaluate if these markers could distinguish UTUC from benign urothelium. We found that CK20/CD44/p53, individually or in combination, could not distinguish urothelial neoplasia from non-neoplasia. Full thickness CK17 urothelial localization by immunohistochemistry was highly reproducible with excellent interobserver agreement and may play a supplementary role in distinguishing upper tract urothelial neoplasia from benign urothelium.}, }
@article {pmid38593796, year = {2024}, author = {Cooper, L and Xu, H and Polmear, J and Kealy, L and Szeto, C and Pang, ES and Gupta, M and Kirn, A and Taylor, JJ and Jackson, KJL and Broomfield, BJ and Nguyen, A and Gago da Graça, C and La Gruta, N and Utzschneider, DT and Groom, JR and Martelotto, L and Parish, IA and O'Keeffe, M and Scharer, CD and Gras, S and Good-Jacobson, KL}, title = {Type I interferons induce an epigenetically distinct memory B cell subset in chronic viral infection.}, journal = {Immunity}, volume = {57}, number = {5}, pages = {1037-1055.e6}, pmid = {38593796}, issn = {1097-4180}, support = {R01 AI148471/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; *Interferon Type I/metabolism/immunology ; *Lymphocytic Choriomeningitis/immunology/virology ; Mice ; *Lymphocytic choriomeningitis virus/immunology ; *Memory B Cells/immunology ; *Epigenesis, Genetic ; Mice, Inbred C57BL ; Receptor, Interferon alpha-beta/genetics ; Immunologic Memory/immunology ; Chronic Disease ; B-Lymphocyte Subsets/immunology ; Single-Cell Analysis ; }, abstract = {Memory B cells (MBCs) are key providers of long-lived immunity against infectious disease, yet in chronic viral infection, they do not produce effective protection. How chronic viral infection disrupts MBC development and whether such changes are reversible remain unknown. Through single-cell (sc)ATAC-seq and scRNA-seq during acute versus chronic lymphocytic choriomeningitis viral infection, we identified a memory subset enriched for interferon (IFN)-stimulated genes (ISGs) during chronic infection that was distinct from the T-bet[+] subset normally associated with chronic infection. Blockade of IFNAR-1 early in infection transformed the chromatin landscape of chronic MBCs, decreasing accessibility at ISG-inducing transcription factor binding motifs and inducing phenotypic changes in the dominating MBC subset, with a decrease in the ISG subset and an increase in CD11c[+]CD80[+] cells. However, timing was critical, with MBCs resistant to intervention at 4 weeks post-infection. Together, our research identifies a key mechanism to instruct MBC identity during viral infection.}, }
@article {pmid38593233, year = {2024}, author = {Dadwal, SS and Bansal, R and Schuster, MW and Yared, JA and Myers, GD and Matzko, M and Adnan, S and McNeel, D and Ma, J and Gilmore, SA and Vasileiou, S and Leen, AM and Hill, JA and Young, JH}, title = {Final outcomes from a phase 2 trial of posoleucel in allogeneic hematopoietic cell transplant recipients.}, journal = {Blood advances}, volume = {8}, number = {17}, pages = {4740-4750}, pmid = {38593233}, issn = {2473-9537}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects/methods ; Middle Aged ; Female ; Male ; Adult ; *Transplantation, Homologous ; Virus Diseases ; Aged ; Treatment Outcome ; Graft vs Host Disease/etiology/prevention &amp; control ; }, abstract = {Allogeneic hematopoietic cell transplantation (allo-HCT) recipients are susceptible to viral infections. We conducted a phase 2 trial evaluating the safety and rate of clinically significant infections (CSIs; viremia requiring treatment or end-organ disease) after infusion of posoleucel, a partially HLA-matched, allogeneic, off-the-shelf, multivirus-specific T-cell investigational product for preventing CSIs with adenovirus, BK virus, cytomegalovirus, Epstein-Barr virus, human herpesvirus-6, or JC virus. This open-label trial enrolled allo-HCT recipients at high risk based on receiving grafts from umbilical cord blood, haploidentical, mismatched, or matched unrelated donors; post-HCT lymphocytes of <180/mm3; or use of T-cell depletion. Posoleucel dosing was initiated within 15 to 49 days of allo-HCT and subsequently every 14 days for up to 7 doses. The primary end point was the number of CSIs due to the 6 target viruses by week 14. Of the 26 patients enrolled, only 3 (12%) had a CSI by week 14, each with a single target virus. In vivo expansion of functional virus-specific T cells detected via interferon-γ enzyme-linked immunosorbent spot assay was associated with viral control. Persistence of posoleucel-derived T-cell clones for up to 14 weeks after the last infusion was confirmed by T-cell-receptor deep sequencing. Five patients (19%) had acute graft-versus-host disease grade 2 to 4. No patient experienced cytokine release syndrome. All 6 deaths were due to relapse or disease progression. allo-HCT recipients at high risk who received posoleucel had low rates of CSIs from 6 targeted viruses. Repeat posoleucel dosing was generally safe and well tolerated and associated with functional immune reconstitution. This trial was registered at www.ClinicalTrials.gov as #NCT04693637.}, }
@article {pmid38589034, year = {2024}, author = {Nuechterlein, N and Shelbourn, A and Szulzewsky, F and Arora, S and Casad, M and Pattwell, S and Merino-Galan, L and Sulman, E and Arowa, S and Alvinez, N and Jung, M and Brown, D and Tang, K and Jackson, S and Stoica, S and Chittaboina, P and Banasavadi-Siddegowda, YK and Wirsching, HG and Stella, N and Shapiro, L and Paddison, P and Patel, AP and Gilbert, MR and Abdullaev, Z and Aldape, K and Pratt, D and Holland, EC and Cimino, PJ}, title = {Haploinsufficiency of phosphodiesterase 10A activates PI3K/AKT signaling independent of PTEN to induce an aggressive glioma phenotype.}, journal = {Genes &amp; development}, volume = {38}, number = {5-6}, pages = {273-288}, pmid = {38589034}, issn = {1549-5477}, support = {K08 CA245037/CA/NCI NIH HHS/United States ; R01 NS119650/NS/NINDS NIH HHS/United States ; R35 CA253119/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Animals ; Mice ; *Glioblastoma/genetics ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/genetics/metabolism ; Haploinsufficiency ; *Glioma/genetics ; PTEN Phosphohydrolase/genetics ; Phosphoric Diester Hydrolases/genetics ; Cell Line, Tumor ; *Brain Neoplasms/genetics ; }, abstract = {Glioblastoma is universally fatal and characterized by frequent chromosomal copy number alterations harboring oncogenes and tumor suppressors. In this study, we analyzed exome-wide human glioblastoma copy number data and found that cytoband 6q27 is an independent poor prognostic marker in multiple data sets. We then combined CRISPR-Cas9 data, human spatial transcriptomic data, and human and mouse RNA sequencing data to nominate PDE10A as a potential haploinsufficient tumor suppressor in the 6q27 region. Mouse glioblastoma modeling using the RCAS/tv-a system confirmed that Pde10a suppression induced an aggressive glioma phenotype in vivo and resistance to temozolomide and radiation therapy in vitro. Cell culture analysis showed that decreased Pde10a expression led to increased PI3K/AKT signaling in a Pten-independent manner, a response blocked by selective PI3K inhibitors. Single-nucleus RNA sequencing from our mouse gliomas in vivo, in combination with cell culture validation, further showed that Pde10a suppression was associated with a proneural-to-mesenchymal transition that exhibited increased cell adhesion and decreased cell migration. Our results indicate that glioblastoma patients harboring PDE10A loss have worse outcomes and potentially increased sensitivity to PI3K inhibition.}, }
@article {pmid38588487, year = {2024}, author = {Nilius, H and Hamzeh-Cognasse, H and Hastings, J and Studt, JD and Tsakiris, DA and Greinacher, A and Mendez, A and Schmidt, A and Wuillemin, WA and Gerber, B and Vishnu, P and Graf, L and Kremer Hovinga, JA and Bakchoul, T and Cognasse, F and Nagler, M}, title = {Proteomic profiling for biomarker discovery in heparin-induced thrombocytopenia.}, journal = {Blood advances}, volume = {8}, number = {11}, pages = {2825-2834}, pmid = {38588487}, issn = {2473-9537}, mesh = {Humans ; *Heparin/adverse effects ; *Biomarkers ; Female ; *Proteomics/methods ; Male ; *Thrombocytopenia/chemically induced/diagnosis/blood ; Middle Aged ; Aged ; P-Selectin/blood ; Platelet Factor 4 ; Adult ; Platelet Activation ; }, abstract = {New analytical techniques can assess hundreds of proteins simultaneously with high sensitivity, facilitating the observation of their complex interplay and role in disease mechanisms. We hypothesized that proteomic profiling targeting proteins involved in thrombus formation, inflammation, and the immune response would identify potentially new biomarkers for heparin-induced thrombocytopenia (HIT). Four existing panels of the Olink proximity extension assay covering 356 proteins involved in thrombus formation, inflammation, and immune response were applied to randomly selected patients with suspected HIT (confirmed HIT, n = 32; HIT ruled out, n = 38; and positive heparin/platelet factor 4 [H/PF4] antibodies, n = 28). The relative difference in protein concentration was analyzed using a linear regression model adjusted for sex and age. To confirm the test results, soluble P-selectin was determined using enzyme-linked immunosorbent assay (ELISA) in above mentioned patients and an additional second data set (n = 49). HIT was defined as a positive heparin-induced platelet activation assay (washed platelet assay). Among 98 patients of the primary data set, the median 4Ts score was 5 in patients with HIT, 4 in patients with positive H/PF4 antibodies, and 3 in patients without HIT. The median optical density of a polyspecific H/PF4 ELISA were 3.0, 0.9, and 0.3. Soluble P-selectin remained statistically significant after multiple test adjustments. The area under the receiver operating characteristic curve was 0.81 for Olink and 0.8 for ELISA. Future studies shall assess the diagnostic and prognostic value of soluble P-selectin in the management of HIT.}, }
@article {pmid38586421, year = {2024}, author = {Rupert, PB and Buerger, M and Girard, EJ and Frutoso, M and Parrilla, D and Ng, K and Gooley, T and Groh, V and Strong, RK}, title = {Preclinical characterization of Pan-NKG2D ligand-binding NKG2D receptor decoys.}, journal = {Heliyon}, volume = {10}, number = {7}, pages = {e28583}, pmid = {38586421}, issn = {2405-8440}, abstract = {NKG2D and its ligands are critical regulators of protective immune responses controlling infections and cancer, defining a crucial immune signaling axis. Current therapeutic efforts targeting this axis almost exclusively aim at enhancing NKG2D-mediated effector functions. However, this axis can drive disease processes when dysregulated, in particular, driving stem-like cancer cell reprogramming and tumorigenesis through receptor/ligand self-stimulation on tumor cells. Despite complexities with its structure and biology, we developed multiple novel engineered proteins that functionally serve as axis-blocking NKG2D "decoys" and report biochemical, structural, in vitro, and in vivo evaluation of their functionality.}, }
@article {pmid38585982, year = {2024}, author = {Lichauco, C and Foss, EJ and Gatbonton-Schwager, T and Athow, NF and Lofts, B and Acob, R and Taylor, E and Marquez, JJ and Lao, U and Miles, S and Bedalov, A}, title = {Sir2 and Fun30 regulate ribosomal DNA replication timing via MCM helicase positioning and nucleosome occupancy.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38585982}, issn = {2692-8205}, support = {R01 GM117446/GM/NIGMS NIH HHS/United States ; }, abstract = {The association between late replication timing and low transcription rates in eukaryotic heterochromatin is well-known, yet the specific mechanisms underlying this link remain uncertain. In Saccharomyces cerevisiae, the histone deacetylase Sir2 is required for both transcriptional silencing and late replication at the repetitive ribosomal DNA arrays (rDNA). We have previously reported that in the absence of SIR2, a derepressed RNA PolII repositions MCM replicative helicases from their loading site at the ribosomal origin, where they abut well-positioned, high-occupancy nucleosomes, to an adjacent region with lower nucleosome occupancy. By developing a method that can distinguish activation of closely spaced MCM complexes, here we show that the displaced MCMs at rDNA origins have increased firing propensity compared to the nondisplaced MCMs. Furthermore, we found that both, activation of the repositioned MCMs and low occupancy of the adjacent nucleosomes critically depend on the chromatin remodeling activity of FUN30. Our study elucidates the mechanism by which Sir2 delays replication timing, and it demonstrates, for the first time, that activation of a specific replication origin in vivo relies on the nucleosome context shaped by a single chromatin remodeler.}, }
@article {pmid38583868, year = {2024}, author = {Feng, X and Zahed, H and Onwuka, J and Callister, MEJ and Johansson, M and Etzioni, R and Robbins, HA}, title = {Cancer Stage Compared With Mortality as End Points in Randomized Clinical Trials of Cancer Screening: A Systematic Review and Meta-Analysis.}, journal = {JAMA}, volume = {331}, number = {22}, pages = {1910-1917}, pmid = {38583868}, issn = {1538-3598}, support = {001/WHO_/World Health Organization/International ; R35 CA274442/CA/NCI NIH HHS/United States ; }, mesh = {Female ; Humans ; Male ; *Early Detection of Cancer ; Endpoint Determination ; Incidence ; *Neoplasm Staging ; *Neoplasms/mortality/pathology ; Prostatic Neoplasms/mortality/diagnosis ; *Randomized Controlled Trials as Topic ; }, abstract = {IMPORTANCE: Randomized clinical trials of cancer screening typically use cancer-specific mortality as the primary end point. The incidence of stage III-IV cancer is a potential alternative end point that may accelerate completion of randomized clinical trials of cancer screening.<br><br>OBJECTIVE: To compare cancer-specific mortality with stage III-IV cancer as end points in randomized clinical trials of cancer screening.<br><br>This meta-analysis included 41 randomized clinical trials of cancer screening conducted in Europe, North America, and Asia published through February 19, 2024. Data extracted included numbers of participants, cancer diagnoses, and cancer deaths in the intervention and comparison groups. For each clinical trial, the effect of screening was calculated as the percentage reduction between the intervention and comparison groups in the incidence of participants with cancer-specific mortality and stage III-IV cancer.<br><br>EXPOSURES: Randomization to a cancer screening test or to a comparison group in a clinical trial of cancer screening.<br><br>MAIN OUTCOMES AND MEASURES: End points of cancer-specific mortality and incidence of stage III-IV cancer were compared using Pearson correlation coefficients with 95% CIs, linear regression, and fixed-effects meta-analysis.<br><br>RESULTS: The included randomized clinical trials tested benefits of screening for breast (n&#x2009;=&#x2009;6), colorectal (n&#x2009;=&#x2009;11), lung (n&#x2009;=&#x2009;12), ovarian (n&#x2009;=&#x2009;4), prostate (n&#x2009;=&#x2009;4), and other cancers (n&#x2009;=&#x2009;4). Correlation between reductions in cancer-specific mortality and stage III-IV cancer varied by cancer type (I2&#x2009;=&#x2009;65%; P&#x2009;=&#x2009;.02). Correlation was highest for trials that screened for ovarian (Pearson &#x3c1;&#x2009;=&#x2009;0.99 [95% CI, 0.51-1.00]) and lung (Pearson &#x3c1;&#x2009;=&#x2009;0.92 [95% CI, 0.72-0.98]) cancers, moderate for breast cancer (Pearson &#x3c1;&#x2009;=&#x2009;0.70 [95% CI, -0.26 to 0.96]), and weak for colorectal (Pearson &#x3c1;&#x2009;=&#x2009;0.39 [95% CI, -0.27 to 0.80]) and prostate (Pearson &#x3c1;&#x2009;=&#x2009;-0.69 [95% CI, -0.99 to 0.81]) cancers. Slopes from linear regression were estimated as 1.15 for ovarian cancer, 0.75 for lung cancer, 0.40 for colorectal cancer, 0.28 for breast cancer, and -3.58 for prostate cancer, suggesting that a given magnitude of reduction in incidence of stage III-IV cancer produced different magnitudes of change in incidence of cancer-specific mortality (P for heterogeneity&#x2009;=&#x2009;.004).<br><br>CONCLUSIONS AND RELEVANCE: In randomized clinical trials of cancer screening, incidence of late-stage cancer may be a suitable alternative end point to cancer-specific mortality for some cancer types, but is not suitable for others. These results have implications for clinical trials of multicancer screening tests.}, }
@article {pmid38583802, year = {2024}, author = {Takahashi, T and Watkins, B and Bratrude, B and Neuberg, D and Hebert, K and Betz, K and Yu, A and Choi, SW and Davis, J and Duncan, C and Giller, R and Grimley, M and Harris, AC and Jacobsohn, D and Lalefar, N and Farhadfar, N and Pulsipher, MA and Shenoy, S and Petrovic, A and Schultz, KR and Yanik, GA and Blazar, BR and Horan, JT and Langston, A and Kean, LS and Qayed, M}, title = {The Adverse Event Landscape of Stem Cell Transplant: Evidence for aGVHD Driving Early Transplant Associated Toxicities.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2024.03.030}, pmid = {38583802}, issn = {2666-6367}, abstract = {Although unrelated-donor (URD) hematopoietic cell transplantation (HCT) is associated with many toxicities, a detailed analysis of adverse events, as defined by the Common Terminology Criteria for Adverse Events (CTCAE), has not previously been curated. This represents a major unmet need, especially as it relates to assessing the safety of novel agents. We analyzed a detailed AE database from the "ABA2" randomized, double-blind, placebo-controlled clinical trial of abatacept for acute graft-versus-host disease (aGVHD) prevention, for which the FDA mandated a detailed AE assessment through Day +180, and weekly neutrophil and platelet counts through Day +100. These were analyzed for their relationship to key transplant outcomes, with a major focus on the impact of aGVHD on the development/severity of AEs. A total of 2102 AEs and 1816 neutrophil/platelet counts were analyzed from 142 8/8-HLA-matched URD HCT recipients on ABA2 (placebo cohort, n = 69, abatacept cohort, n = 73). This analysis resulted in 2 major observations. (1) Among graft source, conditioning intensity, age, and Grade 2 to 4 aGVHD, only aGVHD impacted Grade 3 to 5 AE acquisition after the first month post-transplant. (2) The development of Grade 3 to 4 aGVHD was associated with thrombocytopenia. We have created a detailed resource for the transplant community by which to contextualize clinical toxicities after transplant. It has identified aGVHD as a major driver of post-HCT Grade 3 to 5 AEs, and underscored a link between aGVHD and thrombocytopenia. This establishes a critical safety framework upon which the impact of novel post-transplant aGVHD therapeutics should be evaluated. This trial was registered at www.clinicaltrials.gov (#NCT01743131).}, }
@article {pmid38580777, year = {2024}, author = {Zhang, X and Zhao, X and Chen, S and Hao, M and Zhang, L and Gong, M and Shi, Y and Wei, J and Zhang, P and Feng, S and He, Y and Jiang, E and Han, M}, title = {Addition of ruxolitinib to standard graft-versus-host disease prophylaxis for allogeneic stem cell transplantation in aplastic anemia patients.}, journal = {Bone marrow transplantation}, volume = {59}, number = {7}, pages = {997-1005}, pmid = {38580777}, issn = {1476-5365}, mesh = {Humans ; *Pyrazoles/therapeutic use ; *Nitriles/therapeutic use ; *Graft vs Host Disease/prevention &amp; control/etiology ; *Pyrimidines/therapeutic use ; Adult ; Male ; Female ; *Hematopoietic Stem Cell Transplantation/methods ; *Anemia, Aplastic/therapy ; Middle Aged ; Adolescent ; Retrospective Studies ; Young Adult ; Transplantation, Homologous/methods ; Allografts ; }, abstract = {Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers rapid hematopoietic and immune reconstitution for aplastic anemia (AA). As a non-malignant disorder, attenuation of GVHD remains a clinical priority in AA patients. Our study sought to investigate the safety and efficacy of the prophylactic use of ruxolitinib in allogeneic HSCT. A total of 35 AA patients were retrospectively consecutively treated with allo-HSCT whereby ruxolitinib was added to the standard GVHD prophylaxis regimen (rux group). The addition of peri-transplant ruxolitinib did not impact the engraftment and graft function, while better recovery of CD4+ Tregs in the rux group was observed. Interestingly, the rux group demonstrated significantly lower incidence of bacterial/fungal infections (17.14% vs 45.71%). Compared to the control group, the rux group exhibited significantly lower incidence of moderate to severe aGVHD (17.1% vs 48.6%) with a trend toward lower severe aGVHD (8.6% vs 20%) and cGVHD (26.2 vs 38.3). The rux group also demonstrated a trend toward higher GVHD and failure-free survival (GFFS: 85.7% vs 68.6%) and lower TRM (2.9% vs 14.3%). Addition of ruxolitinib to standard GVHD prophylaxis regimen, thus, represents a safe and highly efficient method for the attenuation of GVHD with better outcome of allo-HSCT.}, }
@article {pmid38580518, year = {2024}, author = {Pal, SK and Grivas, P and Gupta, S and Dizman, N and Zengin, Z and Valderrama, BP and Rodriguez-Vida, A and Roghmann, F and Sevillano Fernandez, E and Matin, SF and Loriot, Y and Sridhar, SS and Sonpavde, G and Fleming, MT and Lerner, SP and Bellmunt, J and Master, V and Tripathi, A and Davis, K and van Veenhuyzen, D and Weng, R and Daneshmand, S}, title = {Infigratinib Versus Placebo for Patients with High-risk Resected Urothelial Cancer Bearing an FGFR3 Genomic Alteration: Results from the PROOF302 Phase 3 Trial.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2024.03.023}, pmid = {38580518}, issn = {1873-7560}, }
@article {pmid38579280, year = {2024}, author = {Lankowski, A and Tollefson, D and Sánchez, H and Cabello, R and Hidalgo, J and Mathison, MN and Molina, Y and Duerr, A}, title = {Acceptability of venue-based HIV testing and prevention interventions for men who have sex with transgender women and transgender women in Lima, Perú: a formative, qualitative study.}, journal = {HIV research &amp; clinical practice}, volume = {25}, number = {1}, pages = {2331360}, pmid = {38579280}, issn = {2578-7470}, support = {P30 AI027757/AI/NIAID NIH HHS/United States ; T32 AI007140/AI/NIAID NIH HHS/United States ; }, mesh = {Male ; Humans ; Female ; *HIV Infections/diagnosis/prevention &amp; control/epidemiology ; *Transgender Persons ; Peru/epidemiology ; Prospective Studies ; HIV Testing ; Lubricants ; }, abstract = {BACKGROUND: Despite being at elevated risk for HIV, men who have sex with transgender women (MSTW) are an overlooked population in the global HIV response. Venue-based HIV interventions have previously had success reaching other HIV priority populations, including transgender women (TW). Similar approaches could be applied for MSTW.<br><br>OBJECTIVE: To evaluate the prospective acceptability of venue-based HIV testing and prevention interventions for MSTW and TW in Lima, Peru.<br><br>METHODS: In this exploratory qualitative study, we conducted in-depth interviews (IDI) and focus group discussions (FGD) with three types of participants: MSTW (7 IDIs, 1 FGD), TW (1 FGD), and owners of social venues frequented by MSTW/TW in Lima (2 IDIs). We elicited participants' attitudes and perceptions related to the following four hypothetical interventions delivered at social venues in Lima: rapid HIV testing; HIV self-test distribution; condom/lubricant distribution; and enrolment in a mobile app supporting HIV prevention. We performed a mixed deductive-inductive thematic analysis using the framework method, then applied the Theoretical Framework of Acceptability to classify the overall acceptability of each intervention.<br><br>RESULTS: Condom/lubricant distribution and app-based HIV prevention information were highly acceptable among all participant types. The two HIV testing interventions had relatively lower acceptability; however, participants suggested this could be overcome if such interventions focused on ensuring discretion, providing access to healthcare professionals, and offering appropriate incentives.<br><br>CONCLUSIONS: Overall, MSTW and TW shared similar favourable attitudes towards venue-based HIV interventions. Venue-based outreach warrants further exploration as a strategy for engaging MSTW and TW in HIV prevention activities.}, }
@article {pmid38579257, year = {2024}, author = {Lyu, Y and Wu, C and Sun, W and Li, Z}, title = {Regional analysis to delineate intrasample heterogeneity with RegionalST.}, journal = {Bioinformatics (Oxford, England)}, volume = {40}, number = {4}, pages = {}, pmid = {38579257}, issn = {1367-4811}, support = {R01 CA263494/CA/NCI NIH HHS/United States ; R01 GM105785/GM/NIGMS NIH HHS/United States ; R01 CA222833/CA/NCI NIH HHS/United States ; R03 CA270725/CA/NCI NIH HHS/United States ; U24 CA274212/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Software ; *Gene Expression Profiling/methods ; }, abstract = {MOTIVATION: Spatial transcriptomics has greatly contributed to our understanding of spatial and intra-sample heterogeneity, which could be crucial for deciphering the molecular basis of human diseases. Intra-tumor heterogeneity, e.g. may be associated with cancer treatment responses. However, the lack of computational tools for exploiting cross-regional information and the limited spatial resolution of current technologies present major obstacles to elucidating tissue heterogeneity.<br><br>RESULTS: To address these challenges, we introduce RegionalST, an efficient computational method that enables users to quantify cell type mixture and interactions, identify sub-regions of interest, and perform cross-region cell type-specific differential analysis for the first time. Our simulations and real data applications demonstrate that RegionalST is an efficient tool for visualizing and analyzing diverse spatial transcriptomics data, thereby enabling accurate and flexible exploration of tissue heterogeneity. Overall, RegionalST provides a one-stop destination for researchers seeking to delve deeper into the intricacies of spatial transcriptomics data.<br><br>The implementation of our method is available as an open-source R/Bioconductor package with a user-friendly manual available at https://bioconductor.org/packages/release/bioc/html/RegionalST.html.}, }
@article {pmid38579192, year = {2024}, author = {Park, JJ and Chu, A and Li, J and Ali, A and McKay, RR and Hwang, C and Labriola, MK and Jang, A and Kilari, D and Mo, G and Ravindranathan, D and Graham, LS and Sokolova, A and Tripathi, A and Pilling, A and Jindal, T and Ravindra, A and Cackowski, FC and Sweeney, PL and Thapa, B and Amery, TS and Heath, EI and Garje, R and Zakharia, Y and Koshkin, VS and Bilen, MA and Schweizer, MT and Barata, PC and Dorff, TB and Cieslik, M and Alva, AS and Armstrong, AJ}, title = {Repeat Next-Generation Sequencing Testing on Progression in Men With Metastatic Prostate Cancer Can Identify New Actionable Alterations.}, journal = {JCO precision oncology}, volume = {8}, number = {}, pages = {e2300567}, pmid = {38579192}, issn = {2473-4284}, support = {R01 CA233585/CA/NCI NIH HHS/United States ; }, mesh = {Male ; Humans ; Retrospective Studies ; *Prostatic Neoplasms/diagnosis/genetics/drug therapy ; *Circulating Tumor DNA/genetics ; *Antineoplastic Agents/therapeutic use ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; High-Throughput Nucleotide Sequencing/methods ; }, abstract = {PURPOSE: There are limited data available on the real-world patterns of molecular testing in men with advanced prostate cancer. We thus sought to evaluate next-generation sequencing (NGS) testing in the United States, focused on single versus serial NGS testing, the different disease states of testing (hormone-sensitive v castration-resistant, metastatic vs nonmetastatic), tissue versus plasma circulating tumor DNA (ctDNA) assays, and how often actionable data were found on each NGS test.<br><br>METHODS: The Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort clinical-genomic database was used for this retrospective analysis, including 1,597 patients across 15 institutions. Actionable NGS data were defined as including somatic alterations in homologous recombination repair genes, mismatch repair deficiency, microsatellite instability (MSI-high), or a high tumor mutational burden &#x2265;10 mut/MB.<br><br>RESULTS: Serial NGS testing (two or more NGS tests with specimens collected more than 60 days apart) was performed in 9% (n = 144) of patients with a median of 182 days in between test results. For the second NGS test and beyond, 82.1% (225 of 274) of tests were from ctDNA assays and 76.1% (217 of 285) were collected in the metastatic castration-resistant setting. New actionable data were found on 11.1% (16 of 144) of second NGS tests, with 3.5% (5 of 144) of tests detecting a new BRCA2 alteration or MSI-high. A targeted therapy (poly (ADP-ribose) polymerase inhibitor or immunotherapy) was given after an actionable result on the second NGS test in 31.3% (5 of 16) of patients.<br><br>CONCLUSION: Repeat somatic NGS testing in men with prostate cancer is infrequently performed in practice and can identify new actionable alterations not present with initial testing, suggesting the utility of repeat molecular profiling with tissue or blood of men with metastatic castration-resistant prostate cancer to guide therapy choices.}, }
@article {pmid38579004, year = {2024}, author = {Sunassee, ED and Deutsch, RJ and D'Agostino, VW and Castellano-Escuder, P and Siebeneck, EA and Ilkayeva, O and Crouch, BT and Madonna, MC and Everitt, J and Alvarez, JV and Palmer, GM and Hirschey, MD and Ramanujam, N}, title = {Optical imaging reveals chemotherapy-induced metabolic reprogramming of residual disease and recurrence.}, journal = {Science advances}, volume = {10}, number = {14}, pages = {eadj7540}, pmid = {38579004}, issn = {2375-2548}, support = {F99 CA284283/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Metabolic Reprogramming ; *Triple Negative Breast Neoplasms/drug therapy/genetics/pathology ; *Carcinoma, Hepatocellular/drug therapy ; *Liver Neoplasms/drug therapy ; *Antineoplastic Agents/pharmacology ; Optical Imaging ; Cell Line, Tumor ; }, abstract = {Fewer than 20% of triple-negative breast cancer patients experience long-term responses to mainstay chemotherapy. Resistant tumor subpopulations use alternative metabolic pathways to escape therapy, survive, and eventually recur. Here, we show in vivo, longitudinal metabolic reprogramming in residual disease and recurrence of triple-negative breast cancer xenografts with varying sensitivities to the chemotherapeutic drug paclitaxel. Optical imaging coupled with metabolomics reported an increase in non-glucose-driven mitochondrial metabolism and an increase in intratumoral metabolic heterogeneity during regression and residual disease in resistant MDA-MB-231 tumors. Conversely, sensitive HCC-1806 tumors were primarily reliant on glucose uptake and minimal changes in metabolism or heterogeneity were observed over the tumors' therapeutic life cycles. Further, day-matched resistant HCC-1806 tumors revealed a higher reliance on mitochondrial metabolism and elevated metabolic heterogeneity compared to sensitive HCC-1806 tumors. Together, metabolic flexibility, increased reliance on mitochondrial metabolism, and increased metabolic heterogeneity are defining characteristics of persistent residual disease, features that will inform the appropriate type and timing of therapies.}, }
@article {pmid38575647, year = {2024}, author = {Crist, SB and Azzag, K and Kiley, J and Coleman, I and Magli, A and Perlingeiro, RCR}, title = {The adult environment promotes the transcriptional maturation of human iPSC-derived muscle grafts.}, journal = {NPJ Regenerative medicine}, volume = {9}, number = {1}, pages = {16}, pmid = {38575647}, issn = {2057-3995}, support = {R01 AR078571/AR/NIAMS NIH HHS/United States ; R01 AR078624/AR/NIAMS NIH HHS/United States ; R01 AR081882/AR/NIAMS NIH HHS/United States ; T32 HL144472/HL/NHLBI NIH HHS/United States ; }, abstract = {Pluripotent stem cell (PSC)-based cell therapy is an attractive option for the treatment of multiple human disorders, including muscular dystrophies. While in vitro differentiating PSCs can generate large numbers of human lineage-specific tissue, multiple studies evidenced that these cell populations mostly display embryonic/fetal features. We previously demonstrated that transplantation of PSC-derived myogenic progenitors provides long-term engraftment and functional improvement in several dystrophic mouse models, but it remained unknown whether donor-derived myofibers mature to match adult tissue. Here, we transplanted iPAX7 myogenic progenitors into muscles of non-dystrophic and dystrophic mice and compared the transcriptional landscape of human grafts with respective in vitro-differentiated iPAX7 myotubes as well as human skeletal muscle biospecimens. Pairing bulk RNA sequencing with computational deconvolution of human reads, we were able to pinpoint key myogenic changes that occur during the in vitro-to-in vivo transition, confirm developmental maturity, and consequently evaluate their applicability for cell-based therapies.}, }
@article {pmid38574894, year = {2024}, author = {Malik, FS and Liese, AD and Ellyson, A and Reid, LA and Reboussin, BA and Sauder, KA and Frongillo, EA and Pihoker, C and Dabelea, D and Reynolds, K and Jensen, ET and Marcovina, S and Bowlby, DA and Mendoza, JA and , }, title = {Household food insecurity and associations with hemoglobin A1c and acute diabetes-related complications in youth and young adults with type 1 diabetes: The SEARCH for Diabetes in Youth study.}, journal = {Diabetes research and clinical practice}, volume = {212}, number = {}, pages = {111608}, pmid = {38574894}, issn = {1872-8227}, support = {HIR 10-001/HX/HSRD VA/United States ; UC4 DK108173/DK/NIDDK NIH HHS/United States ; U18 DP002710/DP/NCCDPHP CDC HHS/United States ; U18 DP006134/DP/NCCDPHP CDC HHS/United States ; U18 DP006138/DP/NCCDPHP CDC HHS/United States ; U18 DP002714/DP/NCCDPHP CDC HHS/United States ; U01 DP000248/DP/NCCDPHP CDC HHS/United States ; U01 DP000244/DP/NCCDPHP CDC HHS/United States ; EP-C-15-002/EPA/EPA/United States ; R01 DK117461/DK/NIDDK NIH HHS/United States ; U18 DP006139/DP/NCCDPHP CDC HHS/United States ; R01 DK127208/DK/NIDDK NIH HHS/United States ; U01 DP000250/DP/NCCDPHP CDC HHS/United States ; K23 DK119465/DK/NIDDK NIH HHS/United States ; U18 DP002708/DP/NCCDPHP CDC HHS/United States ; U01 DP000247/DP/NCCDPHP CDC HHS/United States ; P30 DK048520/DK/NIDDK NIH HHS/United States ; U18 DP006131/DP/NCCDPHP CDC HHS/United States ; U18 DP006136/DP/NCCDPHP CDC HHS/United States ; U18 DP002709/DP/NCCDPHP CDC HHS/United States ; U18 DP006133/DP/NCCDPHP CDC HHS/United States ; U01 DP000246/DP/NCCDPHP CDC HHS/United States ; U01 DP000254/DP/NCCDPHP CDC HHS/United States ; }, mesh = {Humans ; *Diabetes Mellitus, Type 1/blood/epidemiology/complications ; Male ; *Glycated Hemoglobin/analysis/metabolism ; Female ; *Food Insecurity ; Adolescent ; Young Adult ; Adult ; Hypoglycemia/epidemiology/blood ; Diabetic Ketoacidosis/epidemiology/etiology ; Cross-Sectional Studies ; Prevalence ; }, abstract = {AIMS: To examine, among youth and young adults (YYA) with type 1 diabetes (T1D), the association of household food insecurity (HFI) with: 1) HbA1c and 2) episodes of diabetic ketoacidosis (DKA) and severe hypoglycemia.<br><br>METHODS: HFI was assessed using the U.S. Household Food Security Survey Module in SEARCH for Diabetes in Youth participants with T1D between 2016 and 2019. Linear and logistic regression models adjusted for age, diabetes duration, sex, race, ethnicity, clinic site, parent/participant education, household income, health insurance, and diabetes technology use.<br><br>RESULTS: Of 1830 participants (mean age 20.8&#xa0;&#xb1;&#xa0;5.0&#xa0;years, 70.0&#xa0;% non-Hispanic White), HbA1c was collected for 1060 individuals (mean HbA1c 9.2&#xa0;% &#xb1; 2.0&#xa0;%). The prevalence of HFI was 16.4&#xa0;%. In the past 12&#xa0;months, 18.2&#xa0;% and 9.9&#xa0;% reported an episode of DKA or severe hypoglycemia, respectively. Compared to participants who were food secure, HFI was associated with a 0.33&#xa0;% (95&#xa0;% CI 0.003, 0.657) higher HbA1c level. Those with HFI had 1.58 (95&#xa0;% CI 1.13, 2.21) times the adjusted odds of an episode of DKA and 1.53 (95&#xa0;% CI 0.99, 2.37) times the adjusted odds of an episode of severe hypoglycemia as those without HFI.<br><br>CONCLUSIONS: HFI is associated with higher HbA1c levels and increased odds of DKA in YYA with T1D.}, }
@article {pmid38574299, year = {2024}, author = {Ledergor, G and Fan, Z and Wu, K and McCarthy, E and Hyrenius-Wittsten, A and Starzinski, A and Chang, H and Bridge, M and Kwek, S and Cheung, A and Bylsma, S and Hansen, E and Wolf, J and Wong, S and Shah, N and Roybal, KT and Martin, T and Ye, CJ and Fong, L}, title = {CD4+ CAR T-cell exhaustion associated with early relapse of multiple myeloma after BCMA CAR T-cell therapy.}, journal = {Blood advances}, volume = {8}, number = {13}, pages = {3562-3575}, pmid = {38574299}, issn = {2473-9537}, support = {P30 DK063720/DK/NIDDK NIH HHS/United States ; R35 CA253175/CA/NCI NIH HHS/United States ; S10 OD021822/OD/NIH HHS/United States ; }, mesh = {*Multiple Myeloma/therapy/immunology ; Humans ; *B-Cell Maturation Antigen/metabolism/immunology ; *Immunotherapy, Adoptive/methods ; *Receptors, Chimeric Antigen/immunology/metabolism ; *CD4-Positive T-Lymphocytes/immunology/metabolism ; Recurrence ; Male ; Female ; T-Cell Exhaustion ; }, abstract = {Multiple myeloma is characterized by frequent clinical relapses after conventional therapy. Recently, chimeric antigen receptor (CAR) T cells targeting B-cell maturation antigen (BCMA) has been established as a treatment option for patients with relapsed or refractory disease. However, although >70% of patients initially respond to this treatment, clinical relapse and disease progression occur in most cases. Recent studies showed persistent expression of BCMA at the time of relapse, indicating that immune-intrinsic mechanisms may contribute to this resistance. Although there were no preexisting T-cell features associated with clinical outcomes, we found that patients with a durable response to CAR T-cell treatment had greater persistence of their CAR T cells than patients with transient clinical responses. They also possessed a significantly higher proportion of CD8+ T-effector memory cells. In contrast, patients with short-lived responses to treatment have increased frequencies of cytotoxic CD4+ CAR T cells. These cells expand in vivo early after infusion but express exhaustion markers (hepatitis A virus cellular receptor 2 [HAVCR2] and T-cell immunoglobulin and mucin domain-containing-3 [TIGIT]) and remain polyclonal. Finally, we demonstrate that nonclassical monocytes are enriched in the myeloma niche and may induce CAR T-cell dysfunction through mechanisms that include transforming growth factor β. These findings shed new light on the role of cytotoxic CD4+ T cells in disease progression after CAR T-cell therapy.}, }
@article {pmid38573893, year = {2024}, author = {Schilsky, S and Green Howard, A and Moore, CC and Cuthbertson, CC and Parada, H and Lee, IM and Di, C and LaMonte, MJ and Buring, JE and Shiroma, EJ and LaCroix, AZ and Evenson, KR}, title = {Correlates of physical activity and sedentary behavior among cancer survivors and cancer-free women: The Women's Health Accelerometry Collaboration.}, journal = {PloS one}, volume = {19}, number = {4}, pages = {e0301233}, pmid = {38573893}, issn = {1932-6203}, mesh = {Humans ; Female ; Sedentary Behavior ; Overweight ; *Cancer Survivors ; Exercise ; Women's Health ; Obesity ; Accelerometry ; *Diabetes Mellitus ; *Neoplasms/epidemiology ; }, abstract = {BACKGROUND: Describing correlates of physical activity (PA) and sedentary behavior (SB) among postmenopausal cancer survivors can help identify risk profiles and can be used to support development of targeted interventions to improve PA and reduce SB in this population.<br><br>OBJECTIVE: To describe PA/SB and identify correlates of PA/SB among cancer and cancer-free post-menopausal women.<br><br>METHODS: Women from the Women's Health Study (N = 16,629) and Women's Health Initiative/Objective Physical Activity and Cardiovascular Health Study (N = 6,079) were asked to wear an accelerometer on the hip for 7 days. Multiple mixed-effects linear regression models were used to identify sociodemographic-, health-, and chronic condition-related correlates (independent variables) associated with PA and SB (dependent variables) among women with (n = 2,554) and without (n = 20,154) a history of cancer. All correlates were mutually adjusted for each other.<br><br>RESULTS: In unadjusted analyses, women with a history of cancer took fewer mean daily steps (4,572 (standard deviation 2557) vs 5,029 (2679) steps/day) and had lower mean moderate-to-vigorous PA (74.9 (45.0) vs. 81.6 (46.7) minutes/day) than cancer-free women. In adjusted analyses, for cancer and cancer-free women, age, diabetes, overweight, and obesity were inversely associated with all metrics of PA (average vector magnitude, time in moderate-to-vigorous PA, step volume, time at &#x2265;40 steps/minutes, and peak 30-minute step cadence). In unadjusted analyses, mean SB was similar for those with and without cancer (529.7 (98.1) vs. 521.7 (101.2) minutes/day). In adjusted analyses, for cancer and cancer-free women, age, diabetes, cardiovascular disease, current smoking, overweight, and obesity were positive correlates of SB, while Black or Hispanic race/ethnicity, weekly/daily alcohol intake, and excellent/very good/good self-rated health were inverse correlates of SB.<br><br>CONCLUSION: Several sociodemographic, health, and chronic conditions were correlates of PA/SB for postmenopausal women with and without cancer. Future studies should examine longitudinal relationships to gain insight into potential determinants of PA/SB.}, }
@article {pmid38573774, year = {2024}, author = {Owens, K and Esmaeili, S and Schiffer, JT}, title = {Heterogeneous SARS-CoV-2 kinetics due to variable timing and intensity of immune responses.}, journal = {JCI insight}, volume = {9}, number = {9}, pages = {}, pmid = {38573774}, issn = {2379-3708}, support = {R01 AI121129/AI/NIAID NIH HHS/United States ; R01 AI177512/AI/NIAID NIH HHS/United States ; T32 AI118690/AI/NIAID NIH HHS/United States ; }, mesh = {*COVID-19/immunology/virology ; Humans ; *SARS-CoV-2/immunology ; *Viral Load ; *Virus Shedding/immunology ; Kinetics ; Male ; COVID-19 Vaccines/immunology/administration &amp; dosage ; Reinfection/immunology/virology ; Adult ; Female ; Models, Theoretical ; }, abstract = {The viral kinetics of documented SARS-CoV-2 infections exhibit a high degree of interindividual variability. We identified 6 distinct viral shedding patterns, which differed according to peak viral load, duration, expansion rate, and clearance rate, by clustering data from 768 infections in the National Basketball Association cohort. Omicron variant infections in previously vaccinated individuals generally led to lower cumulative shedding levels of SARS-CoV-2 than other scenarios. We then developed a mechanistic mathematical model that recapitulated 1,510 observed viral trajectories, including viral rebound and cases of reinfection. Lower peak viral loads were explained by a more rapid and sustained transition of susceptible cells to a refractory state during infection as well as by an earlier and more potent late, cytolytic immune response. Our results suggest that viral elimination occurs more rapidly during Omicron infection, following vaccination, and following reinfection due to enhanced innate and acquired immune responses. Because viral load has been linked with COVID-19 severity and transmission risk, our model provides a framework for understanding the wide range of observed SARS-CoV-2 infection outcomes.}, }
@article {pmid38571886, year = {2024}, author = {Szulzewsky, F and Thirimanne, HN and Holland, EC}, title = {Meningioma: current updates on genetics, classification, and mouse modeling.}, journal = {Upsala journal of medical sciences}, volume = {129}, number = {}, pages = {}, pmid = {38571886}, issn = {2000-1967}, support = {R35 CA253119/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Humans ; Animals ; Mice ; *Meningioma/genetics/pathology ; *Meningeal Neoplasms/genetics/pathology/surgery ; Kruppel-Like Factor 4 ; Mutation ; Prognosis ; }, abstract = {Meningiomas, the most common primary brain tumors in adults, are often benign and curable by surgical resection. However, a subset is of higher grade, shows aggressive growth behavior as well as brain invasion, and often recurs even after several rounds of surgery. Increasing evidence suggests that tumor classification and grading primarily based on histopathology do not always accurately predict tumor aggressiveness and recurrence behavior. The underlying biology of aggressive treatment-resistant meningiomas and the impact of specific genetic aberrations present in these high-grade tumors is still only insufficiently understood. Therefore, an in-depth research into the biology of this tumor type is warranted. More recent studies based on large-scale molecular data such as whole exome/genome sequencing, DNA methylation sequencing, and RNA sequencing have provided new insights into the biology of meningiomas and have revealed new risk factors and prognostic subtypes. The most common genetic aberration in meningiomas is functional loss of NF2 and occurs in both low- and high-grade meningiomas, whereas NF2-wildtype meningiomas are enriched for recurrent mutations in TRAF7, KLF4, AKT1, PI3KCA, and SMO and are more frequently benign. Most meningioma mouse models are based on patient-derived xenografts and only recently have new genetically engineered mouse models of meningioma been developed that will aid in the systematic evaluation of specific mutations found in meningioma and their impact on tumor behavior. In this article, we review recent advances in the understanding of meningioma biology and classification and highlight the most common genetic mutations, as well as discuss new genetically engineered mouse models of meningioma.}, }
@article {pmid38571435, year = {2024}, author = {Stangis, MM and Chen, Z and Min, J and Glass, SE and Jackson, JO and Radyk, MD and Hoi, XP and Brennen, WN and Yu, M and Dinh, HQ and Coffey, RJ and Shrubsole, MJ and Chan, KS and Grady, WM and Yegnasubramanian, S and Lyssiotis, CA and Maitra, A and Halberg, RB and Dey, N and Lau, KS}, title = {The Hallmarks of Precancer.}, journal = {Cancer discovery}, volume = {14}, number = {4}, pages = {683-689}, pmid = {38571435}, issn = {2159-8290}, support = {U54 CA274367/CA/NCI NIH HHS/United States ; U54 CA274370/CA/NCI NIH HHS/United States ; R50 CA233042/CA/NCI NIH HHS/United States ; U54 CA274371/CA/NCI NIH HHS/United States ; U01 AG077920/AG/NIA NIH HHS/United States ; U54 CA274374/CA/NCI NIH HHS/United States ; U54 CA274375/CA/NCI NIH HHS/United States ; P50 CA236733/CA/NCI NIH HHS/United States ; R01 DK103831/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; *Precancerous Conditions/genetics/pathology ; Risk Factors ; }, abstract = {Research on precancers, as defined as at-risk tissues and early lesions, is of high significance given the effectiveness of early intervention. We discuss the need for risk stratification to prevent overtreatment, an emphasis on the role of genetic and epigenetic aging when considering risk, and the importance of integrating macroenvironmental risk factors with molecules and cells in lesions and at-risk normal tissues for developing effective intervention and health policy strategies.}, }
@article {pmid38571425, year = {2024}, author = {Lee, HY and Song, M and Stopsack, KH and Peng, C and Phipps, AI and Wang, M and Ogino, S and Sasamoto, N and Ugai, T}, title = {The Cancer Spectrum Theory.}, journal = {Cancer discovery}, volume = {14}, number = {4}, pages = {589-593}, doi = {10.1158/2159-8290.CD-23-1494}, pmid = {38571425}, issn = {2159-8290}, mesh = {Humans ; *Neoplasms/genetics/pathology ; Precision Medicine ; Medical Oncology ; }, abstract = {Biological characteristics of tumors are heterogeneous, forming spectra in terms of several factors such as age at onset, anatomic spatial localization, tumor subtyping, and the degree of tumor aggressiveness (encompassing a neoplastic property spectrum). Instead of blindly using dichotomized approaches, the application of the multicategorical and continuous analysis approaches to detailed cancer spectrum data can contribute to a better understanding of the etiology of cancer, ultimately leading to effective prevention and precision oncology. We provide examples of cancer spectra and emphasize the importance of integrating the cancer spectrum theory into large-scale population cancer research.}, }
@article {pmid38571307, year = {2024}, author = {Lundin, JI and Peters, U and Hu, Y and Ammous, F and Avery, CL and Benjamin, EJ and Bis, JC and Brody, JA and Carlson, C and Cushman, M and Gignoux, C and Guo, X and Haessler, J and Haiman, C and Joehanes, R and Kasela, S and Kenny, E and Lapalainien, T and Levy, D and Liu, C and Liu, Y and Loos, RJF and Lu, A and Matise, T and North, KE and Park, SL and Ratliff, SM and Reiner, A and Rich, SS and Rotter, JI and Smith, JA and Sotoodehnia, N and Tracy, R and Van den Berg, D and Xu, H and Ye, T and Zhao, W and Raffield, LM and Kooperberg, C and , }, title = {Methylation patterns associated with C-reactive protein in racially and ethnically diverse populations.}, journal = {Epigenetics}, volume = {19}, number = {1}, pages = {2333668}, pmid = {38571307}, issn = {1559-2308}, support = {U01 HL120393/HL/NHLBI NIH HHS/United States ; N01HC85081/HL/NHLBI NIH HHS/United States ; R01 HL103612/HL/NHLBI NIH HHS/United States ; 75N92020D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; HHSN268201500003C/HL/NHLBI NIH HHS/United States ; R01 HL143885/HL/NHLBI NIH HHS/United States ; HHSN268201800012C/HL/NHLBI NIH HHS/United States ; 75N92020D00005/HL/NHLBI NIH HHS/United States ; N01HC95160/HL/NHLBI NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; U54 HG003067/HG/NHGRI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; N01HC95163/HL/NHLBI NIH HHS/United States ; U01 HL080295/HL/NHLBI NIH HHS/United States ; HHSN268201500001C/HL/NHLBI NIH HHS/United States ; UL1 TR001079/TR/NCATS NIH HHS/United States ; HHSN268201800014I/HB/NHLBI NIH HHS/United States ; R01 HL092577/HL/NHLBI NIH HHS/United States ; U01 HL130114/HL/NHLBI NIH HHS/United States ; R01 HL087660/HL/NHLBI NIH HHS/United States ; HHSN268200800007C/HL/NHLBI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; 75N92020D00001/HL/NHLBI NIH HHS/United States ; N01HC95169/HL/NHLBI NIH HHS/United States ; R01 HL087652/HL/NHLBI NIH HHS/United States ; R01 HL076784/HL/NHLBI NIH HHS/United States ; N01HC95164/HL/NHLBI NIH HHS/United States ; UL1 TR000124/TR/NCATS NIH HHS/United States ; N01HC55222/HL/NHLBI NIH HHS/United States ; HHSN268201800014C/HL/NHLBI NIH HHS/United States ; N01HC95162/HL/NHLBI NIH HHS/United States ; N01HC85086/HL/NHLBI NIH HHS/United States ; 75N92020D00003/HL/NHLBI NIH HHS/United States ; R01 HL119443/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; N01HC95168/HL/NHLBI NIH HHS/United States ; K08 HL116640/HL/NHLBI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; P30 DK063491/DK/NIDDK NIH HHS/United States ; RC1 HL100185/HL/NHLBI NIH HHS/United States ; HHSN268201700002C/HL/NHLBI NIH HHS/United States ; HHSN268201200036C/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; HHSN268201700001I/HL/NHLBI NIH HHS/United States ; HHSN268201800013I/MD/NIMHD NIH HHS/United States ; U01 HL054457/HL/NHLBI NIH HHS/United States ; HHSN268201700004I/HL/NHLBI NIH HHS/United States ; N01HC95165/HL/NHLBI NIH HHS/United States ; HHSN268201600038C/HL/NHLBI NIH HHS/United States ; N01HC95159/HL/NHLBI NIH HHS/United States ; HHSN268201500001I/HL/NHLBI NIH HHS/United States ; HHSN268201800012I/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; N01HC95161/HL/NHLBI NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; 75N92020D00004/HL/NHLBI NIH HHS/United States ; U01 HL072515/HL/NHLBI NIH HHS/United States ; HHSN268201800011C/HL/NHLBI NIH HHS/United States ; 75N92020D00007/HL/NHLBI NIH HHS/United States ; HHSN268201500003I/HL/NHLBI NIH HHS/United States ; R01 HL133221/HL/NHLBI NIH HHS/United States ; 75N92021D00006/HL/NHLBI NIH HHS/United States ; HHSN268201700001C/HL/NHLBI NIH HHS/United States ; N01HC85082/HL/NHLBI NIH HHS/United States ; N01HC95167/HL/NHLBI NIH HHS/United States ; HHSN268201700003C/HL/NHLBI NIH HHS/United States ; N01HC85083/HL/NHLBI NIH HHS/United States ; N01HC25195/HL/NHLBI NIH HHS/United States ; HHSN268201800015I/HB/NHLBI NIH HHS/United States ; 75N92019D00031/HL/NHLBI NIH HHS/United States ; HHSN268201700004C/HL/NHLBI NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; HHSN268201700002I/HL/NHLBI NIH HHS/United States ; HHSN268201800010I/HB/NHLBI NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; 75N92020D00006/HL/NHLBI NIH HHS/United States ; N01HC85079/HL/NHLBI NIH HHS/United States ; N01HC95166/HL/NHLBI NIH HHS/United States ; R01 AG028321/AG/NIA NIH HHS/United States ; R01 AG023629/AG/NIA NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; HHSN268201800011I/HB/NHLBI NIH HHS/United States ; N01HC85080/HL/NHLBI NIH HHS/United States ; HHSN268201700003I/HL/NHLBI NIH HHS/United States ; R01 HG010297/HG/NHGRI NIH HHS/United States ; U01 CA164973/CA/NCI NIH HHS/United States ; R01 AG018728/AG/NIA NIH HHS/United States ; U01 GM074518/GM/NIGMS NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; R01 HL111089/HL/NHLBI NIH HHS/United States ; R01 HL116747/HL/NHLBI NIH HHS/United States ; R01 HL092111/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *DNA Methylation ; *C-Reactive Protein/genetics ; Epigenesis, Genetic ; DNA ; Inflammation/genetics ; Genome-Wide Association Study ; CpG Islands ; Intracellular Signaling Peptides and Proteins/genetics ; }, abstract = {Systemic low-grade inflammation is a feature of chronic disease. C-reactive protein (CRP) is a common biomarker of inflammation and used as an indicator of disease risk; however, the role of inflammation in disease is not completely understood. Methylation is an epigenetic modification in the DNA which plays a pivotal role in gene expression. In this study we evaluated differential DNA methylation patterns associated with blood CRP level to elucidate biological pathways and genetic regulatory mechanisms to improve the understanding of chronic inflammation. The racially and ethnically diverse participants in this study were included as 50% White, 41% Black or African American, 7% Hispanic or Latino/a, and 2% Native Hawaiian, Asian American, American Indian, or Alaska Native (total n = 13,433) individuals. We replicated 113 CpG sites from 87 unique loci, of which five were novel (CADM3, NALCN, NLRC5, ZNF792, and cg03282312), across a discovery set of 1,150 CpG sites associated with CRP level (p < 1.2E-7). The downstream pathways affected by DNA methylation included the identification of IFI16 and IRF7 CpG-gene transcript pairs which contributed to the innate immune response gene enrichment pathway along with NLRC5, NOD2, and AIM2. Gene enrichment analysis also identified the nuclear factor-kappaB transcription pathway. Using two-sample Mendelian randomization (MR) we inferred methylation at three CpG sites as causal for CRP levels using both White and Black or African American MR instrument variables. Overall, we identified novel CpG sites and gene transcripts that could be valuable in understanding the specific cellular processes and pathogenic mechanisms involved in inflammation.}, }
@article {pmid38570422, year = {2024}, author = {Leary, JB and Enright, T and Bakaloudi, DR and Basnet, A and Bratslavsky, G and Jacob, J and Spiess, PE and Li, R and Necchi, A and Kamat, AM and Pavlick, DC and Danziger, N and Huang, RSP and Lin, DI and Cheng, L and Ross, J and Talukder, R and Grivas, P}, title = {Frequency and Nature of Genomic Alterations in ERBB2-Altered Urothelial Bladder Cancer.}, journal = {Targeted oncology}, volume = {19}, number = {3}, pages = {447-458}, pmid = {38570422}, issn = {1776-260X}, mesh = {Humans ; *Urinary Bladder Neoplasms/genetics/pathology ; *Receptor, ErbB-2/metabolism ; Female ; Male ; Aged ; Mutation ; Middle Aged ; Genomics/methods ; Aged, 80 and over ; }, abstract = {BACKGROUND: Human epidermal growth factor-2 (HER2) overexpression is an oncogenic driver in many solid tumors, including urothelial bladder cancer (UBC). In addition, activating mutations in the ERBB2 gene have been shown to play an oncogenic role similar to ERBB2 amplification.<br><br>OBJECTIVE: To describe and compare the frequency and nature of genomic alterations (GA) of ERBB2-altered (mutations, amplification) and ERBB2 wild-type UBC.<br><br>PATIENTS AND METHODS: Using a hybrid capture-based comprehensive profiling assay, 9518 UBC cases were grouped by ERBB2 alteration and evaluated for all classes of genomic alterations (GA), tumor mutational burden (TMB), microsatellite instability (MSI), genome-wide loss of heterozygosity (gLOH), and genomic mutational signature. PD-L1 expression was measured by immunohistochemistry (Dako 22C3). Categorical statistical comparisons were performed using Fisher's exact tests.<br><br>RESULTS: A total of 602 (6.3%) UBC cases featured ERBB2 extracellular domain short variant (SV) GA (ECDmut+), 253 (2.7%) cases featured ERBB2 kinase domain SV GA (KDmut+), 866 (9.1%) cases had ERBB2 amplification (amp+), and 7797 (81.9%) cases were ERBB2 wild-type (wt). European genetic ancestry of ECDmut+ was higher than ERBB2wt. Numerous significant associations were observed when comparing GA by group. Notably among these, CDKN2A/MTAP loss were more frequent in ERBB2wt versus ECDmut+ and amp+. ERBB3 GA were more frequent in ECDmut+ and KDmut+ than ERBB2wt. TERT GA were more frequent in ECDmut+, KDmut+, and amp+ versus ERBB2wt. TOP2A amplification was significantly more common in ECDmut+ and amp+ versus ERBB2wt, and TP53 SV GA were significantly higher in ERBB2 amp+ versus ERBB2wt. Mean TMB levels were significantly higher in ECDmut+, KDmut+, and amp+ than in ERBB2wt. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptides (APOBEC) signature was more frequent in ECDmut+, KDmut+, and amp+ versus ERBB2wt. No significant differences were observed in PD-L1 status between groups, while gLOH-high status was more common in amp+ versus ERBB2wt. MSI-high status was more frequent in KDmut+ versus ERBB2wt, and in ERBB2wt than in amp+.<br><br>CONCLUSIONS: We noted important differences in co-occurring GA in ERBB2-altered (ECDmut+, KDmut+, amp+) versus ERBB2wt UBC, as well as higher mean TMB and higher APOBEC mutational signature in the ERBB2-altered groups. Our results can help refine future clinical trial designs and elucidate possible response and resistance mechanisms for ERBB2-altered UBC.}, }
@article {pmid38568971, year = {2024}, author = {Tran-Kiem, C and Bedford, T}, title = {Estimating the reproduction number and transmission heterogeneity from the size distribution of clusters of identical pathogen sequences.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {15}, pages = {e2305299121}, pmid = {38568971}, issn = {1091-6490}, support = {R35 GM119774/GM/NIGMS NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, mesh = {Humans ; Phylogeny ; *Communicable Diseases ; Contact Tracing ; }, abstract = {Quantifying transmission intensity and heterogeneity is crucial to ascertain the threat posed by infectious diseases and inform the design of interventions. Methods that jointly estimate the reproduction number R and the dispersion parameter k have however mainly remained limited to the analysis of epidemiological clusters or contact tracing data, whose collection often proves difficult. Here, we show that clusters of identical sequences are imprinted by the pathogen offspring distribution, and we derive an analytical formula for the distribution of the size of these clusters. We develop and evaluate an inference framework to jointly estimate the reproduction number and the dispersion parameter from the size distribution of clusters of identical sequences. We then illustrate its application across a range of epidemiological situations. Finally, we develop a hypothesis testing framework relying on clusters of identical sequences to determine whether a given pathogen genetic subpopulation is associated with increased or reduced transmissibility. Our work provides tools to estimate the reproduction number and transmission heterogeneity from pathogen sequences without building a phylogenetic tree, thus making it easily scalable to large pathogen genome datasets.}, }
@article {pmid38568688, year = {2024}, author = {Briercheck, EL and Wrigglesworth, JM and Garcia-Gonzalez, I and Scheepers, C and Ong, MC and Venkatesh, V and Stevenson, P and Annamalay, AA and Coffey, DG and Anderson, AB and Garcia-Gonzalez, P and Wagner, MJ}, title = {Treatment Access for Gastrointestinal Stromal Tumor in Predominantly Low- and Middle-Income Countries.}, journal = {JAMA network open}, volume = {7}, number = {4}, pages = {e244898}, pmid = {38568688}, issn = {2574-3805}, mesh = {Humans ; Male ; Middle Aged ; Child ; Adolescent ; Young Adult ; Adult ; Aged ; Aged, 80 and over ; *Gastrointestinal Stromal Tumors/drug therapy ; Sunitinib/therapeutic use ; Developing Countries ; Imatinib Mesylate/therapeutic use ; Cohort Studies ; Retrospective Studies ; Adjuvants, Immunologic ; *Neoplasms, Second Primary ; }, abstract = {IMPORTANCE: Gastrointestinal stromal tumor (GIST) is a rare cancer treated with the tyrosine kinase inhibitors imatinib mesylate or sunitinib malate. In general, in low- and middle-income countries (LMICs), access to these treatments is limited.<br><br>OBJECTIVE: To describe the demographic characteristics, treatment duration, and survival of patients with GIST in LMICs treated with imatinib and sunitinib through The Max Foundation programs.<br><br>This retrospective database cohort analysis included patients in 2 access programs administered by The Max Foundation: the Glivec International Patient Assistance Program (GIPAP), from January 1, 2001, to December 31, 2016, and the Max Access Solutions (MAS) program, January 1, 2017, to October 12, 2020. Sixty-six countries in which The Max Foundation facilitates access to imatinib and sunitinib were included. Participants consisted of patients with approved indications for imatinib, including adjuvant therapy in high-risk GIST by pathologic evaluation of resected tumor or biopsy-proven unresectable or metastatic GIST. All patients were reported to have tumors positive for CD117(c-kit) by treating physicians. A total of 9866 patients received treatment for metastatic and/or unresectable disease; 2100 received adjuvant imatinib; 49 received imatinib from another source and were only included in the sunitinib analysis; and 53 received both imatinib and sunitinib through The Max Foundation programs. Data were analyzed from October 13, 2020, to January 30, 2024.<br><br>MAIN OUTCOMES AND MEASURES: Demographic and clinical information was reported by treating physicians. Kaplan-Meier analysis was used to estimate time to treatment discontinuation (TTD) and overall survival (OS). An imputation-based informed censoring model estimated events for patients lost to follow-up after treatment with adjuvant imatinib. Patients who were lost to follow-up with metastatic or unresectable disease were presumed deceased.<br><br>RESULTS: A total of 12 015 unique patients were included in the analysis (6890 male [57.6%]; median age, 54 [range, 0-100] years). Of these, 2100 patients were treated with imatinib in the adjuvant setting (median age, 54 [range 8-88] years) and 9866 were treated with imatinib for metastatic or unresectable disease (median age, 55 [range, 0-100] years). Male patients comprised 5867 of 9866 patients (59.5%) with metastatic or unresectable disease and 1023 of 2100 patients (48.7%) receiving adjuvant therapy. The median OS with imatinib for unresectable or metastatic disease was 5.8 (95% CI, 5.6-6.1) years, and the median TTD was 4.2 (95% CI, 4.1-4.4) years. The median OS with sunitinib for patients with metastatic or unresectable GIST was 2.0 (95% CI, 1.5-2.5) years; the median TTD was 1.5 (95% CI, 1.0-2.1) years. The 10-year OS rate in the adjuvant setting was 73.8% (95% CI, 67.2%-81.1%).<br><br>CONCLUSIONS AND RELEVANCE: In this cohort study of patients with GIST who were predominantly from LMICs and received orally administered therapy through the GIPAP or MAS programs, outcomes were similar to those observed in high-resource countries. These findings underscore the feasibility and relevance of administering oral anticancer therapy to a molecularly defined population in LMICs, addressing a critical gap in cancer care.}, }
@article {pmid38567689, year = {2024}, author = {McConnell, KM and Shen, MJ}, title = {The need for multilevel supportive care infrastructure for cancer caregivers.}, journal = {Cancer}, volume = {130}, number = {11}, pages = {1913-1915}, doi = {10.1002/cncr.35303}, pmid = {38567689}, issn = {1097-0142}, support = {5P30CA008748//Vickers/ ; }, mesh = {Humans ; *Caregivers ; *Neoplasms/therapy ; Social Support ; }, }
@article {pmid38566558, year = {2024}, author = {VoPham, T and White, AJ and Jones, RR}, title = {Geospatial Science for the Environmental Epidemiology of Cancer in the Exposome Era.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {33}, number = {4}, pages = {451-460}, pmid = {38566558}, issn = {1538-7755}, support = {K01 DK125612/DK/NIDDK NIH HHS/United States ; L30 ES027668/ES/NIEHS NIH HHS/United States ; ZIA CP010125/ImNIH/Intramural NIH HHS/United States ; ZIA ES103332/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Humans ; *Exposome ; Environmental Exposure/adverse effects ; Geographic Information Systems ; Epidemiologic Studies ; *Neoplasms/epidemiology/etiology ; }, abstract = {Geospatial science is the science of location or place that harnesses geospatial tools, such as geographic information systems (GIS), to understand the features of the environment according to their locations. Geospatial science has been transformative for cancer epidemiologic studies through enabling large-scale environmental exposure assessments. As the research paradigm for the exposome, or the totality of environmental exposures across the life course, continues to evolve, geospatial science will serve a critical role in determining optimal practices for how to measure the environment as part of the external exposome. The objectives of this article are to provide a summary of key concepts, present a conceptual framework that illustrates how geospatial science is applied to environmental epidemiology in practice and through the lens of the exposome, and discuss the following opportunities for advancing geospatial science in cancer epidemiologic research: enhancing spatial and temporal resolutions and extents for geospatial data; geospatial methodologies to measure climate change factors; approaches facilitating the use of patient addresses in epidemiologic studies; combining internal exposome data and geospatial exposure models of the external exposome to provide insights into biological pathways for environment-disease relationships; and incorporation of geospatial data into personalized cancer screening policies and clinical decision making.}, }
@article {pmid38566051, year = {2024}, author = {Dahl, AM and Brown, CE and Brown, ER and O'Brien, MP and Barnabas, RV}, title = {Concordance between SARS-CoV-2 index individuals and their household contacts on index individual COVID-19 transmission cofactors: a comparison of self-reported and contact-reported information.}, journal = {BMC public health}, volume = {24}, number = {1}, pages = {950}, pmid = {38566051}, issn = {1471-2458}, support = {UM1 AI068619/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *COVID-19/epidemiology ; COVID-19 Drug Treatment ; Pandemics/prevention &amp; control ; Retrospective Studies ; SARS-CoV-2 ; Self Report ; }, abstract = {BACKGROUND: Following the outbreak of the COVID-19 pandemic, several clinical trials have evaluated postexposure prophylaxis (PEP) among close contacts of an index individual with a confirmed SARS-CoV-2 infection. Because index individuals do not directly inform the efficacy of prevention interventions, they are seldom enrolled in COVID-19 PEP studies. However, adjusting for prognostic covariates such as an index individual's COVID-19 illness and risk behaviors can increase precision in PEP efficacy estimates, so approaches to accurately collecting this information about the index individual are needed. This analysis aimed to assess whether surveying household contacts captures the same information as surveying the index individual directly.<br><br>METHODS: REGN 2069/CoVPN 3502, a randomized controlled trial of COVID-19 PEP, enrolled household contacts of SARS-CoV-2 index individuals. CoVPN 3502-01 retrospectively enrolled and surveyed the index individuals. We compared responses to seven similar questions about the index individuals' transmission cofactors that were asked in both studies. We estimated the percent concordance between index individuals and their household contacts on each question, with 50% concordance considered equivalent to random chance.<br><br>RESULTS: Concordance between index individuals and contacts was high on the most objective questions, approximately 97% (95% CI: 90-99%) for index individual age group and 96% (88-98%) for hospitalization. Concordance was moderate for symptoms, approximately 85% (75-91%). Concordance on questions related to the index individual's behavior was only slightly better or no better than random: approximately 62% (51-72%) for whether they received COVID-19 treatment, 68% (57-77%) for sharing a bedroom, 70% (59-79%) for sharing a common room, and 49% (39-60%) for mask wearing at home. However, while contacts were surveyed within 96&#xa0;h of the index individual testing positive for SARS-CoV-2, the median time to enrollment in CoVPN 3502-01 was 240 days, which may have caused recall bias in our results.<br><br>CONCLUSIONS: Our results suggest a need to survey index individuals directly in order to accurately capture their transmission cofactors, rather than relying on their household contacts to report on their behavior. The lag in enrolling participants into CoVPN 3502-01 also highlights the importance of timely enrollment to minimize recall bias.}, }
@article {pmid38565269, year = {2024}, author = {Singhvi, A and Shaham, S and Rapti, G}, title = {Glia Development and Function in the Nematode Caenorhabditis elegans.}, journal = {Cold Spring Harbor perspectives in biology}, volume = {16}, number = {12}, pages = {}, pmid = {38565269}, issn = {1943-0264}, support = {R01 NS114222/NS/NINDS NIH HHS/United States ; R35 NS105094/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Caenorhabditis elegans/physiology ; *Neuroglia/physiology ; Neurons/physiology ; Nervous System ; }, abstract = {The nematode Caenorhabditis elegans is a powerful experimental setting for uncovering fundamental tenets of nervous system organization and function. Its nearly invariant and simple anatomy, coupled with a plethora of methodologies for interrogating single-gene functions at single-cell resolution in vivo, have led to exciting discoveries in glial cell biology and mechanisms of glia-neuron interactions. Findings over the last two decades reinforce the idea that insights from C. elegans can inform our understanding of glial operating principles in other species. Here, we summarize the current state-of-the-art, and describe mechanistic insights that have emerged from a concerted effort to understand C. elegans glia. The remarkable acceleration in the pace of discovery in recent years paints a portrait of striking molecular complexity, exquisite specificity, and functional heterogeneity among glia. Glial cells affect nearly every aspect of nervous system development and function, from generating neurons, to promoting neurite formation, to animal behavior, and to whole-animal traits, including longevity. We discuss emerging questions where C. elegans is poised to fill critical knowledge gaps in our understanding of glia biology.}, }
@article {pmid38565249, year = {2024}, author = {Freie, B and Carroll, PA and Varnum-Finney, BJ and Ramsey, EL and Ramani, V and Bernstein, I and Eisenman, RN}, title = {A germline point mutation in the MYC-FBW7 phosphodegron initiates hematopoietic malignancies.}, journal = {Genes &amp; development}, volume = {38}, number = {5-6}, pages = {253-272}, pmid = {38565249}, issn = {1549-5477}, support = {DP2 HG012442/HG/NHGRI NIH HHS/United States ; P01 HL084205/HL/NHLBI NIH HHS/United States ; R35 CA231989/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, mesh = {Animals ; Mice ; Germ Cells/metabolism ; *Hematologic Neoplasms ; Hematopoietic Stem Cells/metabolism ; *Lymphoma ; Point Mutation ; *Proto-Oncogene Proteins c-myc/genetics/metabolism ; *F-Box-WD Repeat-Containing Protein 7/metabolism ; }, abstract = {Oncogenic activation of MYC in cancers predominantly involves increased transcription rather than coding region mutations. However, MYC-dependent lymphomas frequently acquire point mutations in the MYC phosphodegron, including at threonine 58 (T58), where phosphorylation permits binding via the FBW7 ubiquitin ligase triggering MYC degradation. To understand how T58 phosphorylation functions in normal cell physiology, we introduced an alanine mutation at T58 (T58A) into the endogenous c-Myc locus in the mouse germline. While MYC-T58A mice develop normally, lymphomas and myeloid leukemias emerge in ∼60% of adult homozygous T58A mice. We found that primitive hematopoietic progenitor cells from MYC-T58A mice exhibit aberrant self-renewal normally associated with hematopoietic stem cells (HSCs) and up-regulate a subset of MYC target genes important in maintaining stem/progenitor cell balance. In lymphocytes, genomic occupancy by MYC-T58A was increased at all promoters compared with WT MYC, while genes differentially expressed in a T58A-dependent manner were significantly more proximal to MYC-bound enhancers. MYC-T58A lymphocyte progenitors exhibited metabolic alterations and decreased activation of inflammatory and apoptotic pathways. Our data demonstrate that a single point mutation stabilizing MYC is sufficient to skew target gene expression, producing a profound gain of function in multipotential hematopoietic progenitors associated with self-renewal and initiation of lymphomas and leukemias.}, }
@article {pmid38564681, year = {2024}, author = {Unger, JM and Shulman, LN and Facktor, MA and Nelson, H and Fleury, ME}, title = {National Estimates of the Participation of Patients With Cancer in Clinical Research Studies Based on Commission on Cancer Accreditation Data.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {42}, number = {18}, pages = {2139-2148}, pmid = {38564681}, issn = {1527-7755}, mesh = {Humans ; *Neoplasms/therapy ; United States ; *Patient Participation/statistics &amp; numerical data ; *Accreditation ; *Clinical Trials as Topic/statistics &amp; numerical data ; Patient Selection ; Adult ; Biomedical Research ; Female ; Male ; Registries ; Quality of Life ; }, abstract = {PURPOSE: National estimates of cancer clinical trial participation are nearly two decades old and have focused solely on enrollment to treatment trials, which does not reflect the willingness of patients to contribute to other elements of clinical research. We determined inclusive, contemporary estimates of clinical trial participation for adults with cancer using a national sample of data from the Commission on Cancer (CoC).<br><br>METHODS: The data were obtained from accreditation information submitted by the 1,200 CoC programs, which represent more than 70% of all cancer cases diagnosed in the United States each year. Deidentified, institution-level aggregate counts of annual enrollment to treatment, biorepository, diagnostic, economic, genetic, prevention, quality-of-life (QOL), and registry studies were examined. Overall, study-type estimates for the period 2013-2017 were estimated. Multiple imputation by chained equations was used to account for missing data, with summary estimates calculated separately by type of program (eg, National Cancer Institute [NCI]-designated cancer centers) and pooled.<br><br>RESULTS: The overall estimated patient participation rate to cancer treatment trials was 7.1%. Patients with cancer participated in a wide variety of other studies, including biorepository (12.9%), registry (7.3%), genetic (3.6%), QOL (2.8%), diagnostic (2.5%), and economic (2.4%) studies. Treatment trial enrollment was 21.6% at NCI-designated comprehensive cancer centers, 5.4% at academic (non-NCI-designated) comprehensive cancer programs, 5.7% at integrated network cancer programs, and 4.1% at community programs. One in five patients (21.9%) participated in one or more cancer clinical research studies.<br><br>CONCLUSION: In a first-time use of national accreditation information from the CoC, enrollment to cancer treatment trials was 7.1%, higher than historical estimates of <5%. Patients participated in a diverse set of other study types. Contributions of adult patients with cancer to clinical research is more common than previously understood.}, }
@article {pmid38563600, year = {2024}, author = {Schoenfeld, AJ and Lee, SM and Doger de Spéville, B and Gettinger, SN and Häfliger, S and Sukari, A and Papa, S and Rodríguez-Moreno, JF and Graf Finckenstein, F and Fiaz, R and Catlett, M and Chen, G and Qi, R and Masteller, EL and Gontcharova, V and He, K}, title = {Lifileucel, an Autologous Tumor-Infiltrating Lymphocyte Monotherapy, in Patients with Advanced Non-Small Cell Lung Cancer Resistant to Immune Checkpoint Inhibitors.}, journal = {Cancer discovery}, volume = {14}, number = {8}, pages = {1389-1402}, pmid = {38563600}, issn = {2159-8290}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; P30 CA016058/CA/NCI NIH HHS/United States ; //Iovance Biotherapeutics (Lion Biotechnologies, Inc.)/ ; }, mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; *Carcinoma, Non-Small-Cell Lung/drug therapy/pathology ; Drug Resistance, Neoplasm ; *Immune Checkpoint Inhibitors/therapeutic use ; *Lung Neoplasms/drug therapy/pathology ; *Lymphocytes, Tumor-Infiltrating/immunology/transplantation ; }, abstract = {In this phase 2 multicenter study, we evaluated the efficacy and safety of lifileucel (LN-145), an autologous tumor-infiltrating lymphocyte cell therapy, in patients with metastatic non-small cell lung cancer (mNSCLC) who had received prior immunotherapy and progressed on their most recent therapy. The median number of prior systemic therapies was 2 (range, 1-6). Lifileucel was successfully manufactured using tumor tissue from different anatomic sites, predominantly lung. The objective response rate was 21.4% (6/28). Responses occurred in tumors with profiles typically resistant to immunotherapy, such as PD-L1-negative, low tumor mutational burden, and STK11 mutation. Two responses were ongoing at the time of data cutoff, including one complete metabolic response in a PD-L1-negative tumor. Adverse events were generally as expected and manageable. Two patients died of treatment-emergent adverse events: cardiac failure and multiple organ failure. Lifileucel is a potential treatment option for patients with mNSCLC refractory to prior therapy. Significance: Autologous tumor-infiltrating lymphocyte therapy lifileucel was administered to 28 patients with heavily pretreated metastatic non-small cell lung cancer (mNSCLC). Responses were observed in patients with driver mutations, and various tumor mutational burdens and PD-L1 expression, potentially addressing an unmet medical need in patients with mNSCLC refractory to prior therapy. See related commentary by Lotze et al., p. 1366.}, }
@article {pmid38562833, year = {2024}, author = {Erdmann, NB and Williams, WB and Walsh, SR and Grunenberg, N and Edlefsen, PT and Goepfert, PA and Cain, DW and Cohen, KW and Maenza, J and Mayer, KH and Tieu, HV and Sobieszczyk, ME and Swann, E and Lu, H and De Rosa, SC and Sagawa, Z and Moody, MA and Fox, CB and Ferrari, G and Edwards, RJ and Acharya, P and Alam, SM and Parks, R and Barr, M and Tomaras, GD and Montefiori, DC and Gilbert, PB and McElrath, MJ and Corey, L and Haynes, BF and Baden, LR and , }, title = {A HIV-1 Gp41 Peptide-Liposome Vaccine Elicits Neutralizing Epitope-Targeted Antibody Responses in Healthy Individuals.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {38562833}, support = {UM1 AI100645/AI/NIAID NIH HHS/United States ; U01 AI069470/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UL1 RR025758/RR/NCRR NIH HHS/United States ; UM1 AI144371/AI/NIAID NIH HHS/United States ; UM1 AI069412/AI/NIAID NIH HHS/United States ; UM1 AI069470/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: HIV-1 vaccine development is a global health priority. Broadly neutralizing antibodies (bnAbs) which target the HIV-1 gp41 membrane-proximal external region (MPER) have some of the highest neutralization breadth. An MPER peptide-liposome vaccine has been found to expand bnAb precursors in monkeys.<br><br>METHODS: The HVTN133 phase 1 clinical trial (NCT03934541) studied the MPER-peptide liposome immunogen in 24 HIV-1 seronegative individuals. Participants were recruited between 15 July 2019 and 18 October 2019 and were randomized in a dose-escalation design to either 500 mcg or 2000 mcg of the MPER-peptide liposome or placebo. Four intramuscular injections were planned at months 0, 2, 6, and 12.<br><br>RESULTS: The trial was stopped prematurely due to an anaphylaxis reaction in one participant ultimately attributed to vaccine-associated polyethylene glycol. The immunogen induced robust immune responses, including MPER+ serum and blood CD4+ T-cell responses in 95% and 100% of vaccinees, respectively, and 35% (7/20) of vaccine recipients had blood IgG memory B cells with MPER-bnAb binding phenotype. Affinity purification of plasma MPER+ IgG demonstrated tier 2 HIV-1 neutralizing activity in two of five participants after 3 immunizations.<br><br>CONCLUSIONS: MPER-peptide liposomes induced gp41 serum neutralizing epitope-targeted antibodies and memory B-cell responses in humans despite the early termination of the study. These results suggest that the MPER region is a promising target for a candidate HIV vaccine.}, }
@article {pmid38562829, year = {2024}, author = {Plender, EG and Prodanov, T and Hsieh, P and Nizamis, E and Harvey, WT and Sulovari, A and Munson, KM and Kaufman, EJ and O'Neal, WK and Valdmanis, PN and Marschall, T and Bloom, JD and Eichler, EE}, title = {Structural and genetic diversity in the secreted mucins, MUC5AC and MUC5B.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38562829}, issn = {2692-8205}, support = {R01 HG002385/HG/NHGRI NIH HHS/United States ; R01 HG010169/HG/NHGRI NIH HHS/United States ; U24 HG007497/HG/NHGRI NIH HHS/United States ; U41 HG007497/HG/NHGRI NIH HHS/United States ; }, abstract = {The secreted mucins MUC5AC and MUC5B play critical defensive roles in airway pathogen entrapment and mucociliary clearance by encoding large glycoproteins with variable number tandem repeats (VNTRs). These polymorphic and degenerate protein coding VNTRs make the loci difficult to investigate with short reads. We characterize the structural diversity of MUC5AC and MUC5B by long-read sequencing and assembly of 206 human and 20 nonhuman primate (NHP) haplotypes. We find that human MUC5B is largely invariant (5761-5762aa); however, seven haplotypes have expanded VNTRs (6291-7019aa). In contrast, 30 allelic variants of MUC5AC encode 16 distinct proteins (5249-6325aa) with cysteine-rich domain and VNTR copy number variation. We grouped MUC5AC alleles into three phylogenetic clades: H1 (46%, ~5654aa), H2 (33%, ~5742aa), and H3 (7%, ~6325aa). The two most common human MUC5AC variants are smaller than NHP gene models, suggesting a reduction in protein length during recent human evolution. Linkage disequilibrium (LD) and Tajima's D analyses reveal that East Asians carry exceptionally large MUC5AC LD blocks with an excess of rare variation (p<0.05). To validate this result, we used Locityper for genotyping MUC5AC haplogroups in 2,600 unrelated samples from the 1000 Genomes Project. We observed signatures of positive selection in H1 and H2 among East Asians and a depletion of the likely ancestral haplogroup (H3). In Africans and Europeans, H3 alleles show an excess of common variation and deviate from Hardy-Weinberg equilibrium, consistent with heterozygote advantage and balancing selection. This study provides a generalizable strategy to characterize complex protein coding VNTRs for improved disease associations.}, }
@article {pmid38562371, year = {2024}, author = {Atilla, E}, title = {Editorial: Hematopoietic stem cell transplantation: back to the future.}, journal = {Frontiers in medicine}, volume = {11}, number = {}, pages = {1390041}, pmid = {38562371}, issn = {2296-858X}, }
@article {pmid38562076, year = {2024}, author = {Verstovsek, S and Mesa, R and Talpaz, M and Kiladjian, JJ and Harrison, CN and Oh, ST and Vannucchi, AM and Rampal, R and Scott, BL and Buckley, SA and Craig, AR and Roman-Torres, K and Mascarenhas, JO}, title = {Erratum to: Retrospective analysis of pacritinib in patients with myelofibrosis and severe thrombocytopenia.}, journal = {Haematologica}, volume = {109}, number = {4}, pages = {3010}, pmid = {38562076}, issn = {1592-8721}, }
@article {pmid38561434, year = {2024}, author = {Tian, Y and Lin, Y and Qu, C and Arndt, V and Baurley, JW and Berndt, SI and Bien, SA and Bishop, DT and Brenner, H and Buchanan, DD and Budiarto, A and Campbell, PT and Carreras-Torres, R and Casey, G and Chan, AT and Chen, R and Chen, X and Conti, DV and Díez-Obrero, V and Dimou, N and Drew, DA and Figueiredo, JC and Gallinger, S and Giles, GG and Gruber, SB and Gunter, MJ and Harlid, S and Harrison, TA and Hidaka, A and Hoffmeister, M and Huyghe, JR and Jenkins, MA and Jordahl, KM and Joshi, AD and Keku, TO and Kawaguchi, E and Kim, AE and Kundaje, A and Larsson, SC and Marchand, LL and Lewinger, JP and Li, L and Moreno, V and Morrison, J and Murphy, N and Nan, H and Nassir, R and Newcomb, PA and Obón-Santacana, M and Ogino, S and Ose, J and Pardamean, B and Pellatt, AJ and Peoples, AR and Platz, EA and Potter, JD and Prentice, RL and Rennert, G and Ruiz-Narvaez, EA and Sakoda, LC and Schoen, RE and Shcherbina, A and Stern, MC and Su, YR and Thibodeau, SN and Thomas, DC and Tsilidis, KK and van Duijnhoven, FJB and Van Guelpen, B and Visvanathan, K and White, E and Wolk, A and Woods, MO and Wu, AH and Peters, U and Gauderman, WJ and Hsu, L and Chang-Claude, J}, title = {Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk.}, journal = {British journal of cancer}, volume = {130}, number = {10}, pages = {1687-1696}, pmid = {38561434}, issn = {1532-1827}, support = {U2C CA252971/CA/NCI NIH HHS/United States ; R01 CA263318/CA/NCI NIH HHS/United States ; 82204127//National Natural Science Foundation of China (National Science Foundation of China)/ ; 001/WHO_/World Health Organization/International ; K01 DK120742/DK/NIDDK NIH HHS/United States ; P01 CA196569/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Colorectal Neoplasms/genetics/epidemiology ; Middle Aged ; *Genetic Predisposition to Disease ; Case-Control Studies ; Risk Factors ; Aged ; Hormone Replacement Therapy/adverse effects ; Risk Assessment ; Menopause ; Postmenopause ; Estrogen Replacement Therapy/adverse effects ; }, abstract = {BACKGROUND: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk.<br><br>METHODS: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated.<br><br>RESULTS: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value&#x2009;=&#x2009;2.7 &#xd7;&#x2009;10[-8]). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%-4.0%) vs 6.1% (5.7%-6.5%) (difference 2.4%, P-value&#x2009;=&#x2009;1.83 &#xd7;&#x2009;10[-14]); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%-1.8%) vs 2.2% (1.9%-2.4%) (difference 0.6%, P-value&#x2009;=&#x2009;1.01 &#xd7;&#x2009;10[-3]), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk.<br><br>CONCLUSIONS: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.}, }
@article {pmid38561139, year = {2024}, author = {Salit, RB and Lee, SJ and Bhatt, NS and Carpenter, PA and Fan, X and Armstrong, A and Oshima, MU and Connelly-Smith, L and Krakow, E and Lee, CJ and Vo, P and Mehta, R and Syrjala, KL}, title = {Returning to Work Following Hematopoietic Cell Transplantation: The Survivor's Perspective.}, journal = {Transplantation and cellular therapy}, volume = {30}, number = {6}, pages = {612.e1-612.e12}, doi = {10.1016/j.jtct.2024.03.028}, pmid = {38561139}, issn = {2666-6367}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/psychology ; Middle Aged ; Adult ; Male ; Female ; *Return to Work/statistics &amp; numerical data ; Aged ; *Quality of Life/psychology ; *Survivors/psychology ; Adolescent ; Surveys and Questionnaires ; Young Adult ; }, abstract = {While curing a patient's underlying disease is the primary goal of physicians performing hematopoietic cell transplantation (HCT), the ultimate objective is to provide patients with optimal post-HCT quality of life. For many survivors, this includes returning to work (RTW). We conducted a survey of 1- to 5-yr post-HCT survivors at our center to evaluate their perspective on facilitators and barriers to RTW as well as to gauge interest in potentially useful RTW support interventions. Survivors aged 18 to 65 yrs (n = 994) were sent an annual survey that included 36 supplementary questions about post-HCT RTW. Survey questions were selected from published national cancer survivor surveys and then modified specifically for HCT survivors. Three hundred forty-four (35%) survivors with a mean age of 53 yrs completed the survey, of whom 272 (79%) had worked prior to their diagnosis. Of those 272 patients, 145 (53%) were working currently and another 22 (8%) had attempted to go back to work following HCT but were not presently working. We found that having had an allogeneic versus autologous HCT (P = .006) was associated with a decreased likelihood of currently working, whereas frequent employer communication (>once a month) (P = .070) and having a more supportive employer (P = .036) were associated with a greater chance of currently working. Of survivors currently working, 45% reported that they had made one or more changes to their work schedule (e.g., flexible schedule or part-time work) or environment (e.g., work from home) upon RTW. Ninety-five percent of responders reported that they could have benefited from RTW support provided by the transplant center, but only 13% indicated that they had received it. Education on RTW challenges, information on disability benefits, and access to physical therapy were among the most requested support interventions. To improve post-HCT quality of life for survivors open to assistance, providers should address work status and goals, recognize barriers to successful return, and offer RTW support including working directly with employers. Allogeneic HCT survivors are particularly vulnerable to failing attempts to RTW and should be the target of retention interventions. A previously published manuscript on RTW guidance for providers of stem cell transplant patients endorsed by the American Society of Transplant and Cellular Therapy is available in Open Access and can be used as a tool to counsel and support these patients.}, }
@article {pmid38559266, year = {2024}, author = {Razi, A and Lo, CC and Wang, S and Leek, JT and Hansen, KD}, title = {Genotype prediction of 336,463 samples from public expression data.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38559266}, issn = {2692-8205}, support = {U24 HG010263/HG/NHGRI NIH HHS/United States ; R01 GM121459/GM/NIGMS NIH HHS/United States ; R35 GM144128/GM/NIGMS NIH HHS/United States ; T32 GM148383/GM/NIGMS NIH HHS/United States ; R35 GM149323/GM/NIGMS NIH HHS/United States ; }, abstract = {Tens of thousands of RNA-sequencing experiments comprising hundreds of thousands of individual samples have now been performed. These data represent a broad range of experimental conditions, sequencing technologies, and hypotheses under study. The Recount project has aggregated and uniformly processed hundreds of thousands of publicly available RNA-seq samples. Most of these samples only include RNA expression measurements; genotype data for these same samples would enable a wide range of analyses including variant prioritization, eQTL analysis, and studies of allele specific expression. Here, we developed a statistical model based on the existing reference and alternative read counts from the RNA-seq experiments available through Recount3 to predict genotypes at autosomal biallelic loci in coding regions. We demonstrate the accuracy of our model using large-scale studies that measured both gene expression and genotype genome-wide. We show that our predictive model is highly accurate with 99.5% overall accuracy, 99.6% major allele accuracy, and 90.4% minor allele accuracy. Our model is robust to tissue and study effects, provided the coverage is high enough. We applied this model to genotype all the samples in Recount 3 and provide the largest ready-to-use expression repository containing genotype information. We illustrate that the predicted genotype from RNA-seq data is sufficient to unravel the underlying population structure of samples in Recount3 using Principal Component Analysis.}, }
@article {pmid38559244, year = {2024}, author = {Parino, F and Gustani-Buss, E and Bedford, T and Suchard, MA and Trovão, NS and Rambaut, A and Colizza, V and Poletto, C and Lemey, P}, title = {Integrating dynamical modeling and phylogeographic inference to characterize global influenza circulation.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {38559244}, support = {U19 AI135995/AI/NIAID NIH HHS/United States ; R01 AI153044/AI/NIAID NIH HHS/United States ; R35 GM119774/GM/NIGMS NIH HHS/United States ; R01 AI162611/AI/NIAID NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; }, abstract = {Global seasonal influenza circulation involves a complex interplay between local (seasonality, demography, host immunity) and global factors (international mobility) shaping recurrent epidemic patterns. No studies so far have reconciled the two spatial levels, evaluating the coupling between national epidemics, considering heterogeneous coverage of epidemiological and virological data, integrating different data sources. We propose a novel combined approach based on a dynamical model of global influenza spread (GLEAM), integrating high-resolution demographic and mobility data, and a generalized linear model of phylogeographic diffusion that accounts for time-varying migration rates. Seasonal migration fluxes across global macro-regions simulated with GLEAM are tested as phylogeographic predictors to provide model validation and calibration based on genetic data. Seasonal fluxes obtained with a specific transmissibility peak time and recurrent travel outperformed the raw air-transportation predictor, previously considered as optimal indicator of global influenza migration. Influenza A subtypes supported autumn-winter reproductive number as high as 2.25 and an average immunity duration of 2 years. Similar dynamics were preferred by influenza B lineages, with a lower autumn-winter reproductive number. Comparing simulated epidemic profiles against FluNet data offered comparatively limited resolution power. The multiscale approach enables model selection yielding a novel computational framework for describing global influenza dynamics at different scales - local transmission and national epidemics vs. international coupling through mobility and imported cases. Our findings have important implications to improve preparedness against seasonal influenza epidemics. The approach can be generalized to other epidemic contexts, such as emerging disease outbreaks to improve the flexibility and predictive power of modeling.}, }
@article {pmid38559108, year = {2024}, author = {Percival, ME and Zhang, M and Othus, M and McMillen, K and Erba, H and Garcia-Manero, G and Pagel, J and Sorror, M}, title = {Association between class III obesity and overall survival in previously untreated younger patients with acute myeloid leukemia enrolled on SWOG S1203.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {38559108}, issn = {2693-5015}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; U10 CA180819/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; }, abstract = {There has been ongoing debate on the association between obesity and outcomes in acute myeloid leukemia (AML). Currently there are few studies that have stratified outcomes by class I obesity, class II obesity, and class III obesity; and a more nuanced understanding is becoming increasingly important with the rising prevalence of obesity. We examined the association between body mass index (BMI) and outcomes in previously untreated AML in younger patients (age ≤60) enrolled in SWOG S1203 (n=729). Class III obesity was associated with an increased rate of early death (p=0.004) and worse overall survival (OS) in multivariate analysis (hazard ratio (HR) 2.48, 95% confidence interval (CI) 1.62-3.80 versus normal weight). Class III obesity was also associated with worse OS after allogeneic hematopoietic cell transplant (HR 2.37, 95% CI 1.24-4.54 versus normal weight). These findings highlight the unique risk of class III obesity in AML, and the importance of further investigation to better characterize this patient population.}, }
@article {pmid38559075, year = {2024}, author = {Henikoff, S and Henikoff, JG and Paranal, RM and Greene, JE and Zheng, Y and Russell, ZR and Szulzewsky, F and Kugel, S and Holland, EC and Ahmad, K}, title = {RNA Polymerase II hypertranscription in cancer FFPE samples.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38559075}, issn = {2692-8205}, support = {K99 HG012797/HG/NHGRI NIH HHS/United States ; R35 CA253119/CA/NCI NIH HHS/United States ; T32 CA009515/CA/NCI NIH HHS/United States ; }, abstract = {Hypertranscription is common in human cancers and predicts poor prognosis. However detection of hypertranscription is indirect, relying on accurately quantifying mRNA levels and estimating cell numbers. Previously, we introduced FFPE-CUTAC, a genome-wide method for mapping RNA Polymerase II (RNAPII) in formalin-fixed paraffin-embedded (FFPE) sections. Here we use FFPE-CUTAC to demonstrate genome-wide hypertranscription both in transgene-driven mouse gliomas and in assorted human tumors at active regulatory elements and replication-coupled histone genes with reduced mitochondrial DNA abundance. FFPE-CUTAC identified RNAPII-bound regulatory elements shared among diverse cancers and readily categorized human tumors despite using very small samples and low sequencing depths. Remarkably, RNAPII FFPE-CUTAC identified de novo and precisely mapped HER2 amplifications punctuated by likely selective sweeps including genes encoding direct positive regulators of RNAPII itself. Our results demonstrate that FFPE-CUTAC measurements of hypertranscription and classifications of tumors using small sections provides an affordable and sensitive genome-wide strategy for personalized medicine.}, }
@article {pmid38559053, year = {2024}, author = {Samorodnitsky, S and Campbell, K and Ribas, A and Wu, MC}, title = {A Spatial Omnibus Test (SPOT) for Spatial Proteomic Data.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38559053}, issn = {2692-8205}, support = {U10 CA180819/CA/NCI NIH HHS/United States ; }, abstract = {Spatial proteomics can reveal the spatial organization of immune cells in the tumor immune microenvironment. Relating measures of spatial clustering, such as Ripley's K or Besag's L, to patient outcomes may offer important clinical insights. However, these measures require pre-specifying a radius in which to quantify clustering, yet no consensus exists on the optimal radius which may be context-specific. We propose a SPatial Omnibus Test (SPOT) which conducts this analysis across a range of candidate radii. At each radius, SPOT evaluates the association between the spatial summary and outcome, adjusting for confounders. SPOT then aggregates results across radii using the Cauchy combination test, yielding an omnibus p-value characterizing the overall degree of association. Using simulations, we verify that the type I error rate is controlled and show SPOT can be more powerful than alternatives. We also apply SPOT to an ovarian cancer study. An R package and tutorial is provided at https://github.com/sarahsamorodnitsky/SPOT.}, }
@article {pmid38559000, year = {2024}, author = {Kubinski, HC and Despres, HW and Johnson, BA and Schmidt, MM and Jaffrani, SA and Mills, MG and Lokugamage, K and Dumas, CM and Shirley, DJ and Estes, LK and Pekosz, A and Crothers, JW and Roychoudhury, P and Greninger, AL and Jerome, KR and Di Genova, BM and Walker, DH and Ballif, BA and Ladinsky, MS and Bjorkman, PJ and Menachery, VD and Bruce, EA}, title = {Variant mutation in SARS-CoV-2 nucleocapsid enhances viral infection via altered genomic encapsidation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38559000}, issn = {2692-8205}, support = {P01 AI165075/AI/NIAID NIH HHS/United States ; P30 GM118228/GM/NIGMS NIH HHS/United States ; R01 AI153602/AI/NIAID NIH HHS/United States ; }, abstract = {The evolution of SARS-CoV-2 variants and their respective phenotypes represents an important set of tools to understand basic coronavirus biology as well as the public health implications of individual mutations in variants of concern. While mutations outside of Spike are not well studied, the entire viral genome is undergoing evolutionary selection, particularly the central disordered linker region of the nucleocapsid (N) protein. Here, we identify a mutation (G215C), characteristic of the Delta variant, that introduces a novel cysteine into this linker domain, which results in the formation of a disulfide bond and a stable N-N dimer. Using reverse genetics, we determined that this cysteine residue is necessary and sufficient for stable dimer formation in a WA1 SARS-CoV-2 background, where it results in significantly increased viral growth both in vitro and in vivo. Finally, we demonstrate that the N:G215C virus packages more nucleocapsid per virion and that individual virions are larger, with elongated morphologies.}, }
@article {pmid38558981, year = {2024}, author = {Schmid, S and Russell, ZR and Yamashita, AS and West, ME and Parrish, AG and Walker, J and Rudoy, D and Yan, JZ and Quist, DC and Gessesse, BN and Alvinez, N and Cimino, PJ and Kumasaka, DK and Parchment, RE and Holland, EC and Szulzewsky, F}, title = {ERK signaling promotes resistance to TRK kinase inhibition in NTRK fusion-driven glioma mouse models.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38558981}, issn = {2692-8205}, support = {R35 CA253119/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; U54 CA243125/CA/NCI NIH HHS/United States ; S10 OD026919/OD/NIH HHS/United States ; 75N91019D00024/CA/NCI NIH HHS/United States ; }, abstract = {Pediatric-type high-grade gliomas frequently harbor gene fusions involving receptor tyrosine kinase genes, including neurotrophic tyrosine kinase receptor (NTRK) fusions. Clinically, these tumors show high initial response rates to tyrosine kinase inhibition but ultimately recur due to the accumulation of additional resistance-conferring mutations. Here, we developed a series of genetically engineered mouse models of treatment-naïve and -experienced NTRK1/2/3 fusion-driven gliomas. Both the TRK kinase domain and the N-terminal fusion partners influenced tumor histology and aggressiveness. Treatment with TRK kinase inhibitors significantly extended survival of NTRK fusion-driven glioma mice in a fusion- and inhibitor-dependent manner, but tumors ultimately recurred due to the presence of treatment-resistant persister cells. Finally, we show that ERK activation promotes resistance to TRK kinase inhibition and identify MEK inhibition as a potential combination therapy. These models will be invaluable tools for preclinical testing of novel inhibitors and to study the cellular responses of NTRK fusion-driven gliomas to therapy.}, }
@article {pmid38557496, year = {2024}, author = {Eichholz, K and Fukazawa, Y and Peterson, CW and Haeseleer, F and Medina, M and Hoffmeister, S and Duell, DM and Varco-Merth, BD and Dross, S and Park, H and Labriola, CS and Axthelm, MK and Murnane, RD and Smedley, JV and Jin, L and Gong, J and Rust, BJ and Fuller, DH and Kiem, HP and Picker, LJ and Okoye, AA and Corey, L}, title = {Anti-PD-1 chimeric antigen receptor T cells efficiently target SIV-infected CD4+ T cells in germinal centers.}, journal = {The Journal of clinical investigation}, volume = {134}, number = {7}, pages = {}, pmid = {38557496}, issn = {1558-8238}, support = {P51 OD011092/OD/NIH HHS/United States ; }, mesh = {Animals ; *CD4-Positive T-Lymphocytes/immunology ; Germinal Center/immunology ; HIV Infections/therapy ; Macaca mulatta/metabolism ; Programmed Cell Death 1 Receptor ; *Receptors, Chimeric Antigen/genetics ; *Simian Acquired Immunodeficiency Syndrome/therapy ; *Simian Immunodeficiency Virus ; }, abstract = {Programmed cell death protein 1 (PD-1) is an immune checkpoint marker commonly expressed on memory T cells and enriched in latently HIV-infected CD4+ T cells. We engineered an anti-PD-1 chimeric antigen receptor (CAR) to assess the impact of PD-1 depletion on viral reservoirs and rebound dynamics in SIVmac239-infected rhesus macaques (RMs). Adoptive transfer of anti-PD-1 CAR T cells was done in 2 SIV-naive and 4 SIV-infected RMs on antiretroviral therapy (ART). In 3 of 6 RMs, anti-PD-1 CAR T cells expanded and persisted for up to 100 days concomitant with the depletion of PD-1+ memory T cells in blood and tissues, including lymph node CD4+ follicular helper T (TFH) cells. Loss of TFH cells was associated with depletion of detectable SIV RNA from the germinal center (GC). However, following CAR T infusion and ART interruption, there was a marked increase in SIV replication in extrafollicular portions of lymph nodes, a 2-log higher plasma viremia relative to controls, and accelerated disease progression associated with the depletion of CD8+ memory T cells. These data indicate anti-PD-1 CAR T cells depleted PD-1+ T cells, including GC TFH cells, and eradicated SIV from this immunological sanctuary.}, }
@article {pmid38557487, year = {2024}, author = {Zhang, P and Fleming, P and Andoniou, CE and Waltner, OG and Bhise, SS and Martins, JP and McEnroe, BA and Voigt, V and Daly, S and Kuns, RD and Ekwe, AP and Henden, AS and Saldan, A and Olver, S and Varelias, A and Smith, C and Schmidt, CR and Ensbey, KS and Legg, SR and Sekiguchi, T and Minnie, SA and Gradwell, M and Wagenaar, I and Clouston, AD and Koyama, M and Furlan, SN and Kennedy, GA and Ward, ES and Degli-Esposti, MA and Hill, GR and Tey, SK}, title = {IL-6-mediated endothelial injury impairs antiviral humoral immunity after bone marrow transplantation.}, journal = {The Journal of clinical investigation}, volume = {134}, number = {7}, pages = {}, pmid = {38557487}, issn = {1558-8238}, support = {R01 AI175535/AI/NIAID NIH HHS/United States ; }, mesh = {Antiviral Agents ; *Bone Marrow Transplantation/adverse effects ; *Cytomegalovirus Infections/immunology/metabolism ; *Immunity, Humoral ; Immunoglobulin G ; *Interleukin-6/metabolism ; Animals ; Mice ; }, abstract = {Endothelial function and integrity are compromised after allogeneic bone marrow transplantation (BMT), but how this affects immune responses broadly remains unknown. Using a preclinical model of CMV reactivation after BMT, we found compromised antiviral humoral responses induced by IL-6 signaling. IL-6 signaling in T cells maintained Th1 cells, resulting in sustained IFN-γ secretion, which promoted endothelial cell (EC) injury, loss of the neonatal Fc receptor (FcRn) responsible for IgG recycling, and rapid IgG loss. T cell-specific deletion of IL-6R led to persistence of recipient-derived, CMV-specific IgG and inhibited CMV reactivation. Deletion of IFN-γ in donor T cells also eliminated EC injury and FcRn loss. In a phase III clinical trial, blockade of IL-6R with tocilizumab promoted CMV-specific IgG persistence and significantly attenuated early HCMV reactivation. In sum, IL-6 invoked IFN-γ-dependent EC injury and consequent IgG loss, leading to CMV reactivation. Hence, cytokine inhibition represents a logical strategy to prevent endothelial injury, thereby preserving humoral immunity after immunotherapy.}, }
@article {pmid38554725, year = {2024}, author = {D'Angelo, SP and Araujo, DM and Abdul Razak, AR and Agulnik, M and Attia, S and Blay, JY and Carrasco Garcia, I and Charlson, JA and Choy, E and Demetri, GD and Druta, M and Forcade, E and Ganjoo, KN and Glod, J and Keedy, VL and Le Cesne, A and Liebner, DA and Moreno, V and Pollack, SM and Schuetze, SM and Schwartz, GK and Strauss, SJ and Tap, WD and Thistlethwaite, F and Valverde Morales, CM and Wagner, MJ and Wilky, BA and McAlpine, C and Hudson, L and Navenot, JM and Wang, T and Bai, J and Rafail, S and Wang, R and Sun, A and Fernandes, L and Van Winkle, E and Elefant, E and Lunt, C and Norry, E and Williams, D and Biswas, S and Van Tine, BA}, title = {Afamitresgene autoleucel for advanced synovial sarcoma and myxoid round cell liposarcoma (SPEARHEAD-1): an international, open-label, phase 2 trial.}, journal = {Lancet (London, England)}, volume = {403}, number = {10435}, pages = {1460-1471}, pmid = {38554725}, issn = {1474-547X}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Humans ; *Sarcoma, Synovial/drug therapy/genetics ; *Liposarcoma, Myxoid/etiology ; Cytokine Release Syndrome/etiology ; Ifosfamide ; *Thrombocytopenia/etiology ; *Anemia/etiology ; HLA-A Antigens ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; }, abstract = {BACKGROUND: Afamitresgene autoleucel (afami-cel) showed acceptable safety and promising efficacy in a phase 1 trial (NCT03132922). The aim of this study was to further evaluate the efficacy of afami-cel for the treatment of patients with HLA-A*02 and MAGE-A4-expressing advanced synovial sarcoma or myxoid round cell liposarcoma.<br><br>METHODS: SPEARHEAD-1 was an open-label, non-randomised, phase 2 trial done across 23 sites in Canada, the USA, and Europe. The trial included three cohorts, of which the main investigational cohort (cohort 1) is reported here. Cohort 1 included patients with HLA-A*02, aged 16-75 years, with metastatic or unresectable synovial sarcoma or myxoid round cell liposarcoma (confirmed by cytogenetics) expressing MAGE-A4, and who had received at least one previous line of anthracycline-containing or ifosfamide-containing chemotherapy. Patients received a single intravenous dose of afami-cel (transduced dose range 1&#xb7;0&#x2009;&#xd7;&#x2009;10[9]-10&#xb7;0&#x2009;&#xd7;&#x2009;10[9] T cells) after lymphodepletion. The primary endpoint was overall response rate in cohort 1, assessed by a masked independent review committee using Response Evaluation Criteria in Solid Tumours (version 1.1) in the modified intention-to-treat population (all patients who received afami-cel). Adverse events, including those of special interest (cytokine release syndrome, prolonged cytopenia, and neurotoxicity), were monitored and are reported for the modified intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT04044768; recruitment is closed and follow-up is ongoing for cohorts 1 and 2, and recruitment is open for cohort 3.<br><br>FINDINGS: Between Dec 17, 2019, and July 27, 2021, 52 patients with cytogenetically confirmed synovial sarcoma (n=44) and myxoid round cell liposarcoma (n=8) were enrolled and received afami-cel in cohort 1. Patients were heavily pre-treated (median three [IQR two to four] previous lines of systemic therapy). Median follow-up time was 32&#xb7;6 months (IQR 29&#xb7;4-36&#xb7;1). Overall response rate was 37% (19 of 52; 95% CI 24-51) overall, 39% (17 of 44; 24-55) for patients with synovial sarcoma, and 25% (two of eight; 3-65) for patients with myxoid round cell liposarcoma. Cytokine release syndrome occurred in 37 (71%) of 52 of patients (one grade 3 event). Cytopenias were the most common grade 3 or worse adverse events (lymphopenia in 50 [96%], neutropenia 44 [85%], leukopenia 42 [81%] of 52 patients). No treatment-related deaths occurred.<br><br>INTERPRETATION: Afami-cel treatment resulted in durable responses in heavily pre-treated patients with HLA-A*02 and MAGE-A4-expressing synovial sarcoma. This study shows that T-cell receptor therapy can be used to effectively target solid tumours and provides rationale to expand this approach to other solid malignancies.<br><br>FUNDING: Adaptimmune.}, }
@article {pmid38552671, year = {2024}, author = {van den Puttelaar, R and Nascimento de Lima, P and Knudsen, AB and Rutter, CM and Kuntz, KM and de Jonge, L and Escudero, FA and Lieberman, D and Zauber, AG and Hahn, AI and Inadomi, JM and Lansdorp-Vogelaar, I}, title = {Effectiveness and Cost-Effectiveness of Colorectal Cancer Screening With a Blood Test That Meets the Centers for Medicare &amp; Medicaid Services Coverage Decision.}, journal = {Gastroenterology}, volume = {167}, number = {2}, pages = {368-377}, pmid = {38552671}, issn = {1528-0012}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; U01 CA253913/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Colorectal Neoplasms/diagnosis/economics ; *Cost-Benefit Analysis ; Middle Aged ; Aged ; United States ; *Early Detection of Cancer/economics/methods ; *Occult Blood ; Female ; Male ; *Colonoscopy/economics/statistics &amp; numerical data ; Centers for Medicare and Medicaid Services, U.S. ; Quality-Adjusted Life Years ; Sensitivity and Specificity ; Predictive Value of Tests ; Feces/chemistry ; Computer Simulation ; Models, Economic ; }, abstract = {BACKGROUND &amp; AIMS: A blood-based colorectal cancer (CRC) screening test may increase screening participation. However, blood tests may be less effective than current guideline-endorsed options. The Centers for Medicare &amp; Medicaid Services (CMS) covers blood tests with sensitivity of at least 74% for detection of CRC and specificity of at least 90%. In this study, we investigate whether a blood test that meets these criteria is cost-effective.<br><br>METHODS: Three microsimulation models for CRC (MISCAN-Colon, CRC-SPIN, and SimCRC) were used to estimate the effectiveness and cost-effectiveness of triennial blood-based screening (from ages 45 to 75 years) compared to no screening, annual fecal immunochemical testing (FIT), triennial stool DNA testing combined with an FIT assay, and colonoscopy screening every 10 years. The CMS coverage criteria were used as performance characteristics of the hypothetical blood test. We varied screening ages, test performance characteristics, and screening uptake in a sensitivity analysis.<br><br>RESULTS: Without screening, the models predicted 77-88 CRC cases and 32-36 CRC deaths per 1000 individuals, costing $5.3-$5.8 million. Compared to no screening, blood-based screening was cost-effective, with an additional cost of $25,600-$43,700 per quality-adjusted life-year gained (QALYG). However, compared to FIT, triennial stool DNA testing combined with FIT, and colonoscopy, blood-based screening was not cost-effective, with both a decrease in QALYG and an increase in costs. FIT remained more effective (+5-24 QALYG) and less costly (-$3.2 to -$3.5 million) than blood-based screening even when uptake of blood-based screening was 20 percentage points higher than uptake of FIT.<br><br>CONCLUSION: Even with higher screening uptake, triennial blood-based screening, with the CMS-specified minimum performance sensitivity of 74% and specificity of 90%, was not projected to be cost-effective compared with established strategies for colorectal cancer screening.}, }
@article {pmid38552609, year = {2024}, author = {Swanton, C and Bernard, E and Abbosh, C and André, F and Auwerx, J and Balmain, A and Bar-Sagi, D and Bernards, R and Bullman, S and DeGregori, J and Elliott, C and Erez, A and Evan, G and Febbraio, MA and Hidalgo, A and Jamal-Hanjani, M and Joyce, JA and Kaiser, M and Lamia, K and Locasale, JW and Loi, S and Malanchi, I and Merad, M and Musgrave, K and Patel, KJ and Quezada, S and Wargo, JA and Weeraratna, A and White, E and Winkler, F and Wood, JN and Vousden, KH and Hanahan, D}, title = {Embracing cancer complexity: Hallmarks of systemic disease.}, journal = {Cell}, volume = {187}, number = {7}, pages = {1589-1616}, doi = {10.1016/j.cell.2024.02.009}, pmid = {38552609}, issn = {1097-4172}, support = {CGCATF-2021/100026/CRUK_/Cancer Research UK/United Kingdom ; }, mesh = {Humans ; Carcinogenesis ; Microbiota ; *Neoplasms/genetics/pathology/therapy ; Obesity/complications ; Quality of Life ; }, abstract = {The last 50 years have witnessed extraordinary developments in understanding mechanisms of carcinogenesis, synthesized as the hallmarks of cancer. Despite this logical framework, our understanding of the molecular basis of systemic manifestations and the underlying causes of cancer-related death remains incomplete. Looking forward, elucidating how tumors interact with distant organs and how multifaceted environmental and physiological parameters impinge on tumors and their hosts will be crucial for advances in preventing and more effectively treating human cancers. In this perspective, we discuss complexities of cancer as a systemic disease, including tumor initiation and promotion, tumor micro- and immune macro-environments, aging, metabolism and obesity, cancer cachexia, circadian rhythms, nervous system interactions, tumor-related thrombosis, and the microbiome. Model systems incorporating human genetic variation will be essential to decipher the mechanistic basis of these phenomena and unravel gene-environment interactions, providing a modern synthesis of molecular oncology that is primed to prevent cancers and improve patient quality of life and cancer outcomes.}, }
@article {pmid38552193, year = {2024}, author = {Kittai, AS and Bond, D and Huang, Y and Bhat, SA and Blyth, E and Byrd, JC and Chavez, JC and Davids, MS and Dela Cruz, JP and Dowling, MR and Duffy, C and Ho, C and Jacobson, C and Jaglowski, S and Jain, N and Lin, KH and Miller, C and McCarthy, C and Omer, Z and Parry, E and Rai, M and Rogers, KA and Saha, A and Schachter, L and Scott, H and Senapati, J and Shadman, M and Siddiqi, T and Stephens, DM and Vanguru, V and Wierda, W and Woyach, JA and Thompson, PA}, title = {Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy for Richter Transformation: An International, Multicenter, Retrospective Study.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {42}, number = {17}, pages = {2071-2079}, doi = {10.1200/JCO.24.00033}, pmid = {38552193}, issn = {1527-7755}, support = {P30 CA016672/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Retrospective Studies ; Male ; Middle Aged ; Aged ; Adult ; Female ; *Antigens, CD19/therapeutic use/immunology ; *Immunotherapy, Adoptive/adverse effects/methods ; Aged, 80 and over ; *Receptors, Chimeric Antigen/therapeutic use/immunology ; Leukemia, Lymphocytic, Chronic, B-Cell/therapy/immunology/mortality ; Progression-Free Survival ; }, abstract = {PURPOSE: Outcomes for Richter transformation (RT) are poor with current therapies. The efficacy and safety of anti-CD19 chimeric antigen receptor T-cell therapy (CAR-T) for RT are not established.<br><br>METHODS: We performed an international multicenter retrospective study of patients with RT who received CAR-T. Patient, disease, and treatment characteristics were summarized using descriptive statistics, and modeling analyses were used to determine association with progression-free survival (PFS) and overall survival (OS). PFS and OS were estimated from the date of CAR-T infusion.<br><br>RESULTS: Sixty-nine patients were identified. The median age at CAR-T infusion was 64 years (range, 27-80). Patients had a median of four (range, 1-15) previous lines of therapy for CLL and/or RT, including previous Bruton tyrosine kinase inhibitor and/or BCL2 inhibitor therapy in 58 (84%) patients. The CAR-T product administered was axicabtagene ciloleucel in 44 patients (64%), tisagenlecleucel in 17 patients (25%), lisocabtagene maraleucel in seven patients (10%), and brexucabtagene autoleucel in one patient (1%). Eleven patients (16%) and 25 patients (37%) experienced grade &#x2265;3 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, respectively. The overall response rate was 63%, with 46% attaining a complete response (CR). After a median follow-up of 24 months, the median PFS was 4.7 months (95% CI, 2.0 to 6.9); the 2-year PFS was 29% (95% CI, 18 to 41). The median OS was 8.5 months (95% CI, 5.1 to 25.4); the 2-year OS was 38% (95% CI, 26 to 50). The median duration of response was 27.6 months (95% CI, 14.5 to not reached) for patients achieving CR.<br><br>CONCLUSION: CAR-T demonstrates clinical efficacy for patients with RT.}, }
@article {pmid38550531, year = {2024}, author = {MacKay, EJ and Talham, CJ and Zhang, B and Brown, CR and Groeneveld, PW and Desai, ND and Augoustides, JG}, title = {Testing clinical selection criteria for intraoperative transoesophageal echocardiography in isolated coronary artery bypass graft surgery.}, journal = {BJA open}, volume = {10}, number = {}, pages = {100278}, pmid = {38550531}, issn = {2772-6096}, support = {K23 HL166964/HL/NHLBI NIH HHS/United States ; }, abstract = {BACKGROUND: There is a lack of evidence associating intraoperative transoesophageal echocardiography (TOE) use with improved outcomes among coronary artery bypass graft (CABG) surgery subpopulations.<br><br>METHODS: This matched retrospective cohort study used a US private claims dataset to compare outcomes among different CABG surgery patient populations with vs without TOE. Statistical analyses involved exact matching on pre-selected subgroups (congestive heart failure, single vessel, and multivessel CABG) and used fine and propensity-score balanced techniques to conduct multiple matched comparisons and sensitivity analyses.<br><br>RESULTS: Of 42 249 patients undergoing isolated CABG surgery, 24 919 (59.0%) received and 17 330 (41.0%) did not receive TOE. After matching, intraoperative TOE was significantly associated with a lower, 30-day mortality: 2.63% vs 3.20% (odds ratio [OR]: 0.81; 95% confidence interval [CI]: 0.71-0.92; P=0.002). In the subgroup matched comparisons, intraoperative TOE was significantly associated with a lower, 30-day mortality rate among those with congestive heart failure: 4.20% vs 5.26% (OR: 0.78; 95% CI: 0.66-0.94; P=0.007) and among those undergoing multivessel CABG with congestive heart failure: 4.23% vs 5.24% (OR: 0.80; 95% CI: 0.65-0.97; P=0.025), but not among those undergoing multivessel CABG without congestive heart failure: 1.83% vs 2.15% (OR: 0.85; 95% CI: 0.70-1.02; P=0.089, nor any of the remaining three subgroups.<br><br>CONCLUSIONS: Among US adults undergoing isolated CABG surgery, intraoperative TOE was associated with improved outcomes in patients with congestive heart failure (vs without) and among patients undergoing multivessel (vs single vessel) CABG. These findings support prioritised TOE allocation to these patient populations at centres with limited TOE capabilities.}, }
@article {pmid38548700, year = {2024}, author = {Dalapati, T and Williams, CA and Giorgi, EE and Hurst, JH and Herbek, S and Chen, JL and Kosman, C and Rotta, AT and Turner, NA and Pulido, N and Aquino, JN and Pfeiffer, TS and Rodriguez, J and Fouda, GG and Permar, SR and Kelly, MS}, title = {Immunogenicity of Monovalent mRNA-1273 and BNT162b2 Vaccines in Children &lt;5 Years of Age.}, journal = {Pediatrics}, volume = {153}, number = {6}, pages = {}, pmid = {38548700}, issn = {1098-4275}, support = {K01 AI173398/AI/NIAID NIH HHS/United States ; K23 AI135090/AI/NIAID NIH HHS/United States ; R01 AI161008/AI/NIAID NIH HHS/United States ; T32 GM007171/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *BNT162 Vaccine/immunology/administration &amp; dosage ; Infant ; *2019-nCoV Vaccine mRNA-1273/immunology ; Child, Preschool ; Male ; *Antibodies, Neutralizing/blood ; Prospective Studies ; Female ; *Immunogenicity, Vaccine/immunology ; *COVID-19/prevention &amp; control/immunology ; *Antibodies, Viral/blood ; SARS-CoV-2/immunology ; COVID-19 Vaccines/immunology/administration &amp; dosage ; Cohort Studies ; Spike Glycoprotein, Coronavirus/immunology ; }, abstract = {BACKGROUND AND OBJECTIVES: The messenger RNA (mRNA)-based coronavirus disease 2019 vaccines approved for use in children <5 years of age have different antigen doses and administration schedules that could affect vaccine immunogenicity and effectiveness. We sought to compare the strength and breadth of serum binding and neutralizing antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) elicited by monovalent mRNA-based coronavirus disease 2019 vaccines in young children.<br><br>METHODS: We conducted a prospective cohort study of children 6 months to 4 years of age who completed primary series vaccination with monovalent mRNA-1273 or BNT162b2 vaccines. Serum was collected 1 month after primary vaccine series completion for the measurement of SARS-CoV-2-specific humoral immune responses, including antibody binding responses to Spike proteins from an ancestral strain (D614G) and major variants of SARS-CoV-2 and antibody neutralizing activity against D614G and Omicron&#xa0;subvariants (BA.1, BA.4/5).<br><br>RESULTS: Of 75 participants, 40 (53%) received mRNA-1273 and 35 (47%) received BNT162b2. Children receiving either primary vaccine series developed robust and broad SARS-CoV-2-specific binding and neutralizing antibodies, including to Omicron&#xa0;subvariants. Children with a previous history of SARS-CoV-2 infection developed significantly higher antibody binding responses and neutralization titers to Omicron&#xa0;subvariants, which is consistent with the occurrence of identified infections during the circulation of Omicron&#xa0;subvariants in the region.<br><br>CONCLUSIONS: Monovalent mRNA-1273 and BNT162b2 elicited similar antibody responses 1 month after vaccination in young children. In addition, previous infection significantly enhanced the strength of antibody responses to Omicron&#xa0;subvariants. The authors of future studies should evaluate incorporation of these vaccines into the standard childhood immunization schedule.}, }
@article {pmid38548552, year = {2024}, author = {Markey, KA}, title = {Lipocalin-2: a novel potential therapy for GVHD.}, journal = {Trends in immunology}, volume = {45}, number = {4}, pages = {231-233}, doi = {10.1016/j.it.2024.03.004}, pmid = {38548552}, issn = {1471-4981}, mesh = {Animals ; Mice ; Transplantation, Homologous ; Lipocalin-2 ; *Graft vs Host Disease/therapy ; *Hematopoietic Stem Cell Transplantation ; }, abstract = {Czech et al. used mouse models of allogeneic hematopoietic stem cell transplantation (allo-HCT) to investigate the role of lipocalin-2 (LCN2) as a newfound regulator of intestinal graft-versus-host disease (GVHD). Administration of recombinant LCN2 protein after disease onset prevented GVHD progression, suggesting that it may play a role in reversing tissue damage that has already begun.}, }
@article {pmid38547892, year = {2024}, author = {Layman, RM and Han, HS and Rugo, HS and Stringer-Reasor, EM and Specht, JM and Dees, EC and Kabos, P and Suzuki, S and Mutka, SC and Sullivan, BF and Gorbatchevsky, I and Wesolowski, R}, title = {Gedatolisib in combination with palbociclib and endocrine therapy in women with hormone receptor-positive, HER2-negative advanced breast cancer: results from the dose expansion groups of an open-label, phase 1b study.}, journal = {The Lancet. Oncology}, volume = {25}, number = {4}, pages = {474-487}, doi = {10.1016/S1470-2045(24)00034-2}, pmid = {38547892}, issn = {1474-5488}, mesh = {Female ; Humans ; Adolescent ; Adult ; *Breast Neoplasms/drug therapy/genetics/metabolism ; Receptor, ErbB-2/metabolism ; Disease-Free Survival ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; TOR Serine-Threonine Kinases ; *Morpholines ; *Piperazines ; *Pyridines ; *Triazines ; }, abstract = {BACKGROUND: The PI3K-mTOR pathway is frequently dysregulated in breast cancer. Combining an inhibitor targeting all class I PI3K isoforms and mTOR complex 1 (mTORC1)-mTOR complex 2 (mTORC2) with endocrine therapy and a CDK4/6 inhibitor might provide more effective tumour control than standard-of-care therapy. To evaluate this hypothesis, gedatolisib, a pan-PI3K-mTOR inhibitor, was assessed in a phase 1b trial combined with palbociclib and endocrine therapy in patients with hormone receptor-positive, HER2-negative, advanced breast cancer. Results from the dose expansion portion of this trial are reported herein.<br><br>METHODS: This multicentre, open-label, phase 1b study recruited female patients aged at least 18 years from 17 sites across the USA with hormone-receptor-positive, HER2-negative, advanced breast cancer and an Eastern Cooperative Oncology Group performance status of 0-1. Four patient groups were studied in the dose expansion portion of the study: treatment-naive in the advanced setting (first line; group A), progression on 1-2 lines of endocrine therapy but CDK4/6 inhibitor-naive (group B); and one or more previous lines (second-line and higher) of therapy, including a CDK4/6 inhibitor (groups C and D). Gedatolisib 180 mg was administered intravenously weekly in 28-day treatment cycles for groups A-C, and on days 1, 8, and 15 for group D. Letrozole (group A), fulvestrant (groups B-D), and palbociclib (all groups) were administered at standard doses and schedules. The primary endpoint was investigator-assessed objective response rate per RECIST version 1.1 in the evaluable analysis set. This trial is completed and registered with ClinicalTrials.gov, NCT02684032.<br><br>FINDINGS: Between Dec 19, 2017, and June 19, 2019, 103 female participants were enrolled in the dose expansion groups A (n=31), B (n=13), C (n=32), and D (n=27). Median follow-up was 16&#xb7;6 months (IQR 5&#xb7;7-48&#xb7;4) for group A, 11&#xb7;0 months (7&#xb7;6-16&#xb7;9) for group B, 3&#xb7;6 months (1&#xb7;8-7&#xb7;5) for group C, and 9&#xb7;4 months (5&#xb7;3-16&#xb7;7) for group D for the primary endpoint. Gedatolisib, palbociclib, and endocrine therapy induced an objective response in 23 (85&#xb7;2%; 90% CI 69&#xb7;2-94&#xb7;8) of 27 evaluable first-line participants (group A). In the second-line and higher setting, an objective response was observed in eight (61&#xb7;5%; 90% CI 35&#xb7;5-83&#xb7;4) of 13 evaluable group B participants, seven (25&#xb7;0%; 12&#xb7;4-41&#xb7;9) of 28 evaluable group C participants, and 15 (55&#xb7;6%; 38&#xb7;2-72&#xb7;0) of 27 evaluable group D participants; this included participants with both wild-type and mutated PIK3CA tumours. The most common grade 3-4 treatment-related adverse events were neutropenia (65 [63%] of 103), stomatitis (28 [27%]), and rash (21 [20%]). Grade 3-4 hyperglycaemia was reported in six (6%) participants. 23 (22%) of 103 participants had a treatment-related serious adverse event, and there were no treatment-related deaths. Nine (9%) participants discontinued treatment because of a treatment-emergent adverse event.<br><br>INTERPRETATION: Gedatolisib plus palbociclib and endocrine therapy showed a promising objective response rate compared with the published results for standard-of-care therapies and had an acceptable safety profile.<br><br>FUNDING: Pfizer and Celcuity.}, }
@article {pmid38547425, year = {2024}, author = {Budde, LE and Assouline, S and Sehn, LH and Schuster, SJ and Yoon, SS and Yoon, DH and Matasar, MJ and Bosch, F and Kim, WS and Nastoupil, LJ and Flinn, IW and Shadman, M and Diefenbach, C and Cheah, CY and Ma, CY and Huang, H and Kwan, A and Wei, MC and Yin, S and Bartlett, NL}, title = {Durable Responses With Mosunetuzumab in Relapsed/Refractory Indolent and Aggressive B-Cell Non-Hodgkin Lymphomas: Extended Follow-Up of a Phase I/II Study.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {42}, number = {19}, pages = {2250-2256}, pmid = {38547425}, issn = {1527-7755}, mesh = {Humans ; *Lymphoma, B-Cell/drug therapy ; Follow-Up Studies ; *Antibodies, Bispecific/therapeutic use/administration &amp; dosage/adverse effects ; Middle Aged ; Male ; Female ; Aged ; Adult ; Neoplasm Recurrence, Local/drug therapy ; Antineoplastic Agents, Immunological/therapeutic use/adverse effects ; }, abstract = {Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Mosunetuzumab is a CD20xCD3 T-cell-engaging bispecific antibody administered as an off-the-shelf, fixed-duration treatment in an outpatient setting. We report an updated analysis of the durability of response, by investigator assessment, after an overall median follow-up of 3.5 years in patients with relapsed/refractory indolent or aggressive B-cell non-Hodgkin lymphoma (iNHL/aNHL) from the dose-escalation stage of a phase I/II study of mosunetuzumab (ClinicalTrials.gov identifier: NCT02500407). Across dose levels, 65.7% of patients with iNHL and 36.4% with aNHL achieved a complete or partial response to mosunetuzumab. Median duration of response (DoR) in patients with iNHL for all responders was 23.2 months (95% CI, 13.8 to not estimable [NE]), but was not reached in complete responders (95% CI, 21.0 to NE). After a median time on study of 38.9 months, no relapses were observed beyond 26 months in complete responders. In patients with aNHL, median DoR for all responders was 7.8 months (95% CI, 4.6 to 22.8). Among 12 complete responders who progressed postmosunetuzumab treatment and were retreated with mosunetuzumab, 83.3% had an objective response and 58.3% achieved a second complete response. Our study reports the longest follow-up using bispecific antibodies in patients with B-cell non-Hodgkin lymphoma and demonstrates that mosunetuzumab can mediate durable remissions with time-limited treatment.}, }
@article {pmid38547246, year = {2024}, author = {Wang, Z and Peters, BA and Yu, B and Grove, ML and Wang, T and Xue, X and Thyagarajan, B and Daviglus, ML and Boerwinkle, E and Hu, G and Mossavar-Rahmani, Y and Isasi, CR and Knight, R and Burk, RD and Kaplan, RC and Qi, Q}, title = {Gut Microbiota and Blood Metabolites Related to Fiber Intake and Type 2 Diabetes.}, journal = {Circulation research}, volume = {134}, number = {7}, pages = {842-854}, pmid = {38547246}, issn = {1524-4571}, support = {R01 DK120870/DK/NIDDK NIH HHS/United States ; R01 DK119268/DK/NIDDK NIH HHS/United States ; N01HC65236/HL/NHLBI NIH HHS/United States ; N01HC65235/HL/NHLBI NIH HHS/United States ; N01HC65234/HL/NHLBI NIH HHS/United States ; K01 HL169019/HL/NHLBI NIH HHS/United States ; R01 DK134672/DK/NIDDK NIH HHS/United States ; N01HC65237/HL/NHLBI NIH HHS/United States ; R01 HL140976/HL/NHLBI NIH HHS/United States ; R01 HL136266/HL/NHLBI NIH HHS/United States ; R01 DK126698/DK/NIDDK NIH HHS/United States ; R01 MD011389/MD/NIMHD NIH HHS/United States ; R01 HL170904/HL/NHLBI NIH HHS/United States ; N01HC65233/HL/NHLBI NIH HHS/United States ; K01 HL129892/HL/NHLBI NIH HHS/United States ; P30 DK111022/DK/NIDDK NIH HHS/United States ; R01 HL060712/HL/NHLBI NIH HHS/United States ; UM1 HG008898/HG/NHGRI NIH HHS/United States ; }, mesh = {Humans ; *Gastrointestinal Microbiome ; *Diabetes Mellitus, Type 2/diagnosis/microbiology ; Diet ; Bacteria ; Dietary Fiber ; }, abstract = {BACKGROUND: Consistent evidence suggests diabetes-protective effects of dietary fiber intake. However, the underlying mechanisms, particularly the role of gut microbiota and host circulating metabolites, are not fully understood. We aimed to investigate gut microbiota and circulating metabolites associated with dietary fiber intake and their relationships with type 2 diabetes (T2D).<br><br>METHODS: This study included up to 11&#x2005;394 participants from the HCHS/SOL (Hispanic Community Health Study/Study of Latinos). Diet was assessed with two 24-hour dietary recalls at baseline. We examined associations of dietary fiber intake with gut microbiome measured by shotgun metagenomics (350 species/85 genera and 1958 enzymes; n=2992 at visit 2), serum metabolome measured by untargeted metabolomics (624 metabolites; n=6198 at baseline), and associations between fiber-related gut bacteria and metabolites (n=804 at visit 2). We examined prospective associations of serum microbial-associated metabolites (n=3579 at baseline) with incident T2D over 6 years.<br><br>RESULTS: We identified multiple bacterial genera, species, and related enzymes associated with fiber intake. Several bacteria (eg, Butyrivibrio, Faecalibacterium) and enzymes involved in fiber degradation (eg, xylanase EC3.2.1.156) were positively associated with fiber intake, inversely associated with prevalent T2D, and favorably associated with T2D-related metabolic traits. We identified 159 metabolites associated with fiber intake, 47 of which were associated with incident T2D. We identified 18 of these 47 metabolites associated with the identified fiber-related bacteria, including several microbial metabolites (eg, indolepropionate and 3-phenylpropionate) inversely associated with the risk of T2D. Both Butyrivibrio and Faecalibacterium were associated with these favorable metabolites. The associations of fiber-related bacteria, especially Faecalibacterium and Butyrivibrio, with T2D were attenuated after further adjustment for these microbial metabolites.<br><br>CONCLUSIONS: Among United States Hispanics/Latinos, dietary fiber intake was associated with favorable profiles of gut microbiota and circulating metabolites for T2D. These findings advance our understanding of the role of gut microbiota and microbial metabolites in the relationship between diet and T2D.}, }
@article {pmid38546646, year = {2024}, author = {Hershman, DL and Vaidya, R and Till, C and Barlow, W and LeBlanc, M and Ramsey, S and Unger, JM}, title = {Socioeconomic Deprivation and Health Care Use in Patients Enrolled in SWOG Cancer Clinical Trials.}, journal = {JAMA network open}, volume = {7}, number = {3}, pages = {e244008}, pmid = {38546646}, issn = {2574-3805}, support = {UG1 CA189974/CA/NCI NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Cohort Studies ; Delivery of Health Care ; Medicaid ; *Medicare ; *Neoplasms/epidemiology/therapy ; Socioeconomic Factors ; United States/epidemiology ; Black or African American ; White ; }, abstract = {IMPORTANCE: Reducing acute care use is an important strategy for improving value. Patients with cancer are at risk for unplanned emergency department (ED) visits and hospital stays (HS). Clinical trial patients have homogeneous treatment; despite this, structural barriers to care may independently impact acute care use.<br><br>OBJECTIVE: To examine whether ED visits and HS within 12 months of trial enrollment are more common among Medicare enrollees who live in areas of socioeconomic deprivation or have Medicaid insurance.<br><br>This cohort study included patients with cancer who were 65 years or older and treated in SWOG Cancer Research Network trials from 1999 to 2018 using data linked to Medicare claims. Data were collected from 1999 to 2019 and analyzed from 2022 to 2024.<br><br>MAIN OUTCOMES AND MEASURES: Outcomes were ED visits, HS, and costs in the first year following enrollment. Neighborhood socioeconomic deprivation was measured using patients' zip code linked to the Area Deprivation Index (ADI), measured on a 0 to 100 scale for increasing deprivation and categorized into tertiles (T1 to T3). Type of insurance was classified as Medicare with or without commercial insurance vs dual Medicare and Medicaid. Demographic, clinical, and prognostic factors were captured from trial records. Multivariable regression was used, and the association of ADI and insurance with each outcome was considered separately.<br><br>RESULTS: In total, 3027 trial participants were analyzed. The median (range) age was 71 (65-98) years, 1280 (32.3%) were female, 221 (7.3%) were Black patients, 2717 (89.8%) were White patients, 90 (3.0%) had Medicare and Medicaid insurance, and 660 (22.3%) were in the areas of highest deprivation (ADI-T3). In all, 1094 patients (36.1%) had an ED visit and 983 patients (32.4%) had an HS. In multivariable generalized estimating equation, patients living in areas categorized as ADI-T3 were more likely to have an ED visit (OR, 1.34; 95% CI, 1.10-1.62; P&#x2009;=&#x2009;.004). A similar but nonsignificant pattern was observed for HS (OR, 1.36; 95% CI, 0.96-1.93; P&#x2009;=&#x2009;.08). Patients from areas with the highest deprivation had a 62% increase in risk of either an ED visit or HS (OR, 1.62; 95% CI, 1.25-2.09; P&#x2009;<&#x2009;.001). Patients with Medicare and Medicaid were 96% more likely to have an ED visit (OR, 1.96; 95% CI, 1.56-2.46; P&#x2009;<&#x2009;.001).<br><br>CONCLUSIONS AND RELEVANCE: In this cohort of older patients enrolled in clinical trials, neighborhood deprivation and economic disadvantage were associated with an increase in ED visits and HS. Efforts are needed to ensure adequate resources to prevent unplanned use of acute care in socioeconomically vulnerable populations.}, }
@article {pmid38546022, year = {2024}, author = {Buchheit, SF and Collins, JM and Anthony, KM and Love, SM and Stewart, JD and Gondalia, R and Huang, DY and Manson, JE and Reiner, AP and Schwartz, GG and Vitolins, MZ and Schumann, RR and Smith, RL and Whitsel, EA}, title = {Radon Exposure and Incident Stroke Risk in the Women's Health Initiative.}, journal = {Neurology}, volume = {102}, number = {4}, pages = {e209143}, doi = {10.1212/WNL.0000000000209143}, pmid = {38546022}, issn = {1526-632X}, support = {R01 ES034050/ES/NIEHS NIH HHS/United States ; R01 HL148565/HL/NHLBI NIH HHS/United States ; }, mesh = {Middle Aged ; Humans ; Female ; United States/epidemiology ; Aged ; Prospective Studies ; *Stroke/epidemiology/etiology ; *Radon/adverse effects/analysis ; *Hemorrhagic Stroke ; Women's Health ; Risk Factors ; Incidence ; }, abstract = {BACKGROUND AND OBJECTIVES: Little is known about the role of radon in the epidemiology of stroke among women. We therefore examined the association between home radon exposure and risk of stroke among middle-aged and older women in the United States.<br><br>METHODS: We conducted a prospective cohort study of postmenopausal women aged 50-79 years at baseline (1993-1998) in the Women's Health Initiative. We measured exposures as 2-day, indoor, lowest living-level average radon concentrations in picocuries per liter (pCi/L) as estimated in 1993 by the US Geological Survey and reviewed by the Association of American State Geologists under the Indoor Radon Abatement Act. We used Cox proportional hazards models to estimate risk of incident, neurologist-adjudicated stroke during follow-up through 2020 as a hazard ratio and 95% CI, adjusting for study design and participant demographic, social, behavioral, and clinical characteristics.<br><br>RESULTS: Among 158,910 women without stroke at baseline (mean age 63.2 years; 83% white), 6,979 incident strokes were identified over follow-up (mean 13.4 years). Incidence rates were 333, 343, and 349 strokes per 100,000 woman-years at radon concentrations of <2, 2-4, and >4 pCi/L, respectively. Compared with women living at concentrations <2 pCi/L, those at 2-4 and >4 pCi/L had higher covariate-adjusted risks of incident stroke: hazard ratio (95% CI) 1.06 (0.99-1.13) and 1.14 (1.05-1.22). Using nonlinear spline functions to model radon, stroke risk was significantly elevated at concentrations ranging from 2 to 4 pCi/L (p = 0.0004), that is, below the United States Environmental Protection Agency Radon Action Level for mitigation (4 pCi/L). Associations were slightly stronger for ischemic (especially cardioembolic, small vessel occlusive, and large artery atherosclerotic) than hemorrhagic stroke, but otherwise robust in sensitivity analyses.<br><br>DISCUSSION: Radon exposure is associated with moderately increased stroke risk among middle-aged and older women in the United States, suggesting that promulgation of a lower Radon Action Level may help reduce the domestic impact of cerebrovascular disease on public health.}, }
@article {pmid38544800, year = {2024}, author = {Liu, M and Liu, Y and Hsu, L and He, Q}, title = {TCRpred: incorporating T-cell receptor repertoire for clinical outcome prediction.}, journal = {Frontiers in genetics}, volume = {15}, number = {}, pages = {1345559}, pmid = {38544800}, issn = {1664-8021}, abstract = {T-cell receptor (TCR) plays critical roles in recognizing antigen peptides and mediating adaptive immune response against disease. High-throughput technologies have enabled the sequencing of TCR repertoire at the single nucleotide level, allowing researchers to characterize TCR sequences with high resolutions. The TCR sequences provide important information about patients' adaptive immune system, and have the potential to improve clinical outcome prediction. However, it is challenging to incorporate the TCR repertoire data for prediction, because the data is unstructured, highly complex, and TCR sequences vary widely in their compositions and abundances across different individuals. We introduce TCRpred, an analytic tool for incorporating TCR repertoire for clinical outcome prediction. The TCRpred is able to utilize features that can be extracted from the TCR amino acid sequences, as well as features that are hidden in the TCR amino acid sequences and are hard to extract. Simulation studies show that the proposed approach has a good performance in predicting clinical outcome and tends to be more powerful than potential alternative approaches. We apply the TCRpred to real cancer datasets and demonstrate its practical utility in clinical outcome prediction.}, }
@article {pmid38543894, year = {2024}, author = {Hensley, C and Roier, S and Zhou, P and Schnur, S and Nyblade, C and Parreno, V and Frazier, A and Frazier, M and Kiley, K and O'Brien, S and Liang, Y and Mayer, BT and Wu, R and Mahoney, C and McNeal, MM and Petsch, B and Rauch, S and Yuan, L}, title = {mRNA-Based Vaccines Are Highly Immunogenic and Confer Protection in the Gnotobiotic Pig Model of Human Rotavirus Diarrhea.}, journal = {Vaccines}, volume = {12}, number = {3}, pages = {}, pmid = {38543894}, issn = {2076-393X}, support = {INV-020846 and INV-027499/GATES/Bill &amp; Melinda Gates Foundation/United States ; }, abstract = {Human rotavirus (HRV) is still a leading cause of severe dehydrating gastroenteritis globally, particularly in infants and children. Previously, we demonstrated the immunogenicity of mRNA-based HRV vaccine candidates expressing the viral spike protein VP8* in rodent models. In the present study, we assessed the immunogenicity and protective efficacy of two mRNA-based HRV trivalent vaccine candidates, encoding VP8* of the genotypes P[8], P[6], or P[4], in the gnotobiotic (Gn) pig model of Wa (G1P[8]) HRV infection and diarrhea. Vaccines either encoded VP8* alone fused to the universal T-cell epitope P2 (P2-VP8*) or expressed P2-VP8* as a fusion protein with lumazine synthase (LS-P2-VP8*) to allow the formation and secretion of protein particles that present VP8* on their surface. Gn pigs were randomly assigned into groups and immunized three times with either P2-VP8* (30 µg) or LS-P2-VP8* (30 µg or 12 µg). A trivalent alum-adjuvanted P2-VP8* protein vaccine or an LNP-formulated irrelevant mRNA vaccine served as the positive and negative control, respectively. Upon challenge with virulent Wa HRV, a significantly shortened duration and decreased severity of diarrhea and significant protection from virus shedding was induced by both mRNA vaccine candidates compared to the negative control. Both LS-P2-VP8* doses induced significantly higher VP8*-specific IgG antibody titers in the serum after immunizations than the negative as well as the protein control. The P[8] VP8*-specific IgG antibody-secreting cells in the ileum, spleen, and blood seven days post-challenge, as well as VP8*-specific IFN-γ-producing T-cell numbers increased in all three mRNA-vaccinated pig groups compared to the negative control. Overall, there was a clear tendency towards improved responses in LS-P2-VP8* compared to the P2-VP8*mRNA vaccine. The demonstrated strong humoral immune responses, priming for effector T cells, and the significant reduction of viral shedding and duration of diarrhea in Gn pigs provide a promising proof of concept and may provide guidance for the further development of mRNA-based rotavirus vaccines.}, }
@article {pmid38542739, year = {2024}, author = {Schenk, JM and Boynton, A and Kulik, P and Zyuzin, A and Neuhouser, ML and Kristal, AR}, title = {The Use of Three-Dimensional Images and Food Descriptions from a Smartphone Device Is Feasible and Accurate for Dietary Assessment.}, journal = {Nutrients}, volume = {16}, number = {6}, pages = {}, pmid = {38542739}, issn = {2072-6643}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P30 DK035816/DK/NIDDK NIH HHS/United States ; 261201400052C/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Smartphone ; *Nutrition Assessment ; Imaging, Three-Dimensional ; Diet Records ; Energy Intake ; Meals ; Reproducibility of Results ; }, abstract = {Technology-assisted dietary assessment has the potential to improve the accuracy of self-reported dietary intake. This study evaluates MealScan3D (MS3D), a mobile device-based food recording system, which uses three-dimensional images to obtain food volumes and an application to capture algorithm-driven food intake data. Participants (n = 179) were randomly assigned and trained to record three meals using either MS3D or a written food record (WFR). Generous amounts of standardized meals were provided, and participants self-selected portions for each food. The weights of provided and uneaten/leftover foods were used to determine true intake. For total energy intake (three meals combined), validity (Pearson correlation) was significantly higher for MS3D vs. the WFR (p < 0.001); when interpreted as the percentage of variance in energy intake explained, MS3D explained 84.6% of true variance, a 25.3% absolute and 42.6% relative increase over the 59.3% explained by the WFR. For 9 of 15 individual foods, the Pearson correlations between true and reported portion size estimates were significantly larger for MS3D than the WFR. Bias was smaller (intercepts were closer to the means) for 9 of 15 foods and the regression coefficients for 10 of 15 foods were significantly closer to 1.0 in the MS3D arm. MS3D is feasible for dietary assessment and may provide improvements in accuracy compared to WFRs.}, }
@article {pmid38538798, year = {2024}, author = {Radko-Juettner, S and Yue, H and Myers, JA and Carter, RD and Robertson, AN and Mittal, P and Zhu, Z and Hansen, BS and Donovan, KA and Hunkeler, M and Rosikiewicz, W and Wu, Z and McReynolds, MG and Roy Burman, SS and Schmoker, AM and Mageed, N and Brown, SA and Mobley, RJ and Partridge, JF and Stewart, EA and Pruett-Miller, SM and Nabet, B and Peng, J and Gray, NS and Fischer, ES and Roberts, CWM}, title = {Targeting DCAF5 suppresses SMARCB1-mutant cancer by stabilizing SWI/SNF.}, journal = {Nature}, volume = {628}, number = {8007}, pages = {442-449}, pmid = {38538798}, issn = {1476-4687}, support = {F31 CA261150/CA/NCI NIH HHS/United States ; R01 CA273455/CA/NCI NIH HHS/United States ; RF1 AG068581/AG/NIA NIH HHS/United States ; R01 CA113794/CA/NCI NIH HHS/United States ; P30 CA021765/CA/NCI NIH HHS/United States ; K22 CA258805/CA/NCI NIH HHS/United States ; R01 CA262188/CA/NCI NIH HHS/United States ; R01 CA172152/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Female ; Humans ; Male ; Mice ; Cell Line, Tumor ; CRISPR-Cas Systems ; Gene Editing ; *Mutation ; *Neoplasms/genetics/metabolism ; *SMARCB1 Protein/deficiency/genetics/metabolism ; Tumor Suppressor Proteins/deficiency/genetics/metabolism ; *Multiprotein Complexes/chemistry/metabolism ; Proteolysis ; Ubiquitin/metabolism ; }, abstract = {Whereas oncogenes can potentially be inhibited with small molecules, the loss of tumour suppressors is more common and is problematic because the tumour-suppressor proteins are no longer present to be targeted. Notable examples include SMARCB1-mutant cancers, which are highly lethal malignancies driven by the inactivation of a subunit of SWI/SNF (also known as BAF) chromatin-remodelling complexes. Here, to generate mechanistic insights into the consequences of SMARCB1 mutation and to identify vulnerabilities, we contributed 14 SMARCB1-mutant cell lines to a near genome-wide CRISPR screen as part of the Cancer Dependency Map Project[1-3]. We report that the little-studied gene DDB1-CUL4-associated factor 5 (DCAF5) is required for the survival of SMARCB1-mutant cancers. We show that DCAF5 has a quality-control function for SWI/SNF complexes and promotes the degradation of incompletely assembled SWI/SNF complexes in the absence of SMARCB1. After depletion of DCAF5, SMARCB1-deficient SWI/SNF complexes reaccumulate, bind to target loci and restore SWI/SNF-mediated gene expression to levels that are sufficient to reverse the cancer state, including in vivo. Consequently, cancer results not from the loss of SMARCB1 function per se, but rather from DCAF5-mediated degradation of SWI/SNF complexes. These data indicate that therapeutic targeting of ubiquitin-mediated quality-control factors may effectively reverse the malignant state of some cancers driven by disruption of tumour suppressor complexes.}, }
@article {pmid38538157, year = {2024}, author = {Menacho, L and Konda, KA and Lecca, L and Cabello, R and Lankowski, A and Benites, C and Gallardo-Cartagena, JA and Duerr, A and Sánchez, J and Galea, JT}, title = {Optimising PrEP uptake and use in Peru: no time to lose!.}, journal = {The lancet. HIV}, volume = {11}, number = {4}, pages = {e204-e206}, doi = {10.1016/S2352-3018(24)00038-9}, pmid = {38538157}, issn = {2352-3018}, mesh = {Humans ; Male ; *HIV Infections/epidemiology/prevention &amp; control/drug therapy ; Peru/epidemiology ; Homosexuality, Male ; *Anti-HIV Agents/therapeutic use ; *Pre-Exposure Prophylaxis ; }, }
@article {pmid38537574, year = {2024}, author = {Ferjan Ramírez, N and Hippe, DS}, title = {Estimating infants' language exposure: A comparison of random and volume sampling from daylong recordings collected in a bilingual community.}, journal = {Infant behavior &amp; development}, volume = {75}, number = {}, pages = {101943}, doi = {10.1016/j.infbeh.2024.101943}, pmid = {38537574}, issn = {1934-8800}, mesh = {Humans ; Male ; Infant ; Female ; *Multilingualism ; Language Development ; Speech/physiology ; Child Language ; Adult ; }, abstract = {In North America, the characteristics of a child's language environment predict language outcomes. For example, differences in bilingual language exposure, exposure to electronic media, and exposure to child-directed speech (CDS) relate to children's language growth. Recently, these predictors have been studied through the use of daylong recordings, followed by manual annotation of audio samples selected from these recordings. Using a dataset of daylong recordings collected from bilingually raised infants in the United States as an example, we ask whether two of the most commonly used sampling methods, random sampling and sampling based on high adult speech, differ from each other with regard to estimating the frequencies of specific language behaviors. Daylong recordings from 37 Spanish-English speaking families with infants between 4 and 22 months of age were analyzed. From each child's recording, samples were extracted in two ways (at random/based on high adult speech) and then annotated for Language (Spanish/English/Mixed), CDS, Electronic Media, Social Context, Turn-Taking, and Infant Babbling. Correlation and agreement analyses were performed, in addition to paired sample t-tests, to assess how the choice of one or the other sampling method may affect the estimates. For most behaviors studied, correlation and agreement between the two sampling methods was high (Pearson r values between 0.79 and 0.99 for 16 of 17 measures; Intraclass Correlation Coefficient values between 0.78 and 0.99 for 13 of 17 measures). However, interesting between-sample differences also emerged: the degree of language mixing, the amount of CDS, and the number of conversational turns were all significantly higher when sampling was performed based on high adult speech compared to random sampling. By contrast, the presence of electronic media and one-on-one social contexts was higher when sampling was performed at random. We discuss advantages of choosing one sampling technique over the other, depending on the research question and variables at hand.}, }
@article {pmid38537419, year = {2024}, author = {Okoye, F and Gadzinski, AJ and Sekar, R and Abarro, I and Grivas, P and Tykodi, SS and Liao, J and Chen, J and Zeng, J and Wright, J and Gore, JL}, title = {Telemedicine for Multidisciplinary Urologic Cancer Care: A Prospective Single Institution Study.}, journal = {Clinical genitourinary cancer}, volume = {22}, number = {3}, pages = {102058}, doi = {10.1016/j.clgc.2024.02.009}, pmid = {38537419}, issn = {1938-0682}, mesh = {Humans ; *Telemedicine ; Male ; Female ; Prospective Studies ; *COVID-19/epidemiology ; Aged ; Middle Aged ; *Urologic Neoplasms/therapy ; Patient Satisfaction ; Aged, 80 and over ; Patient Reported Outcome Measures ; SARS-CoV-2 ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: We rapidly implemented a telemedicine Multidisciplinary Urologic Cancer Clinic (MDUCC) at the University of Washington/Seattle Cancer Care Alliance during the peak of the COVID-19 Public Health Emergency to maintain our ability to provide multidisciplinary cancer care. We report our experiences though assessment of patient-reported outcomes from our telemedicine MDUCC.<br><br>METHODS: Video visits with a urologic oncologist, medical oncologist, and radiation oncologist were conducted in the same format as our in-person MDUCC. We prospectively collected patient demographic and clinical data. Patients were invited to complete a post-visit survey that assessed satisfaction, provider trust, travel time, and costs of the telemedicine visit. We estimated travel distances and times from each patient's home to our clinic.<br><br>RESULTS: Among invited patients, twenty-four patients completed a survey after their telemedicine MDUCC visit. Twenty patients (83%) were at home during the visit. Most (85%) were men, Caucasian (79%), and were being seen in our Bladder Cancer MDUCC (83%). All twenty-four patients responded that they would be willing to have future appointments via telemedicine; eighteen patients (75%) strongly agreed that the encounter was high quality; 19 patients strongly agreed that they were satisfied with their visit. Patients saved an estimated average one-way travel distance of 145 miles and one-way travel time of 179 minutes to convene a telemedicine visit.<br><br>CONCLUSIONS: Telemedicine MDUCCs are feasible and effective in providing access to multidisciplinary urologic cancer care. Patient satisfaction was high, and many patients were spared a substantial travel burden. Telemedicine may continue to be leveraged to improve access to multidisciplinary urologic cancer care.}, }
@article {pmid38537158, year = {2024}, author = {Xiao, H and Vaidya, R and Hershman, DL and Unger, JM}, title = {Impact of Broadening Trial Eligibility Criteria on the Inclusion of Patients With Brain Metastases in Cancer Clinical Trials: Time Series Analyses for 2012-2022.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {42}, number = {16}, pages = {1953-1960}, doi = {10.1200/JCO.23.01777}, pmid = {38537158}, issn = {1527-7755}, mesh = {Humans ; *Brain Neoplasms/secondary ; *Patient Selection ; *Clinical Trials as Topic ; Eligibility Determination ; United States ; Interrupted Time Series Analysis ; Female ; }, abstract = {PURPOSE: In October 2017, an ASCO, Friends of Cancer Research (FoCR), and US Food and Drug Administration (ASCO/FoCR/FDA) task force recommended that common eligibility criteria be modified to make trials more inclusive. We examined whether patterns of exclusions regarding patients with brain metastases changed over time in relation to these recommendations.<br><br>METHODS: Trial eligibility criteria were abstracted from ClinicalTrials.gov for phase I-III US-based interventional clinical trials for patients with advanced breast, colorectal, lung, or melanoma cancers from January 2012 to December 2022. Trials were examined to determine whether patients with brain metastases were not excluded, conditionally excluded (ie, excluded in some circumstances), or wholly excluded. An interrupted time series analysis with multinomial logistic regression was used to determine whether the ASCO/FoCR/FDA recommendations were associated with changes in brain metastases criteria.<br><br>RESULTS: We evaluated N = 3,077 trials. Patients with brain metastases were not excluded in 506 trials (16.4%), conditionally excluded in 2,263 trials (73.5%), and wholly excluded in 308 trials (10.0%). In the postrecommendation period, we estimated a 68% increase in the odds of brain metastases not excluded compared with conditionally excluded (odds ratio, 1.68 [95% CI, 1.06 to 2.66], P = .03). The proportion of trials in which patients with brain metastases were not excluded increased (from 11.5% v 17.3%) and conditionally excluded decreased (from 82.3% to 75.2%, P = .03). We found no difference in the proportion of trials in which patients with brain metastases were wholly excluded (7.5% v 6.2%, P = .42).<br><br>CONCLUSION: The ASCO/FoCR/FDA task force recommendations were associated with a shift in patterns of brain metastases exclusion criteria from conditionally excluded to not excluded. These findings demonstrate that the cancer clinical trial community has begun to change the way trials are written to be more inclusive.}, }
@article {pmid38537062, year = {2024}, author = {Sadowska-Klasa, A and Özkök, S and Xie, H and Leisenring, W and Zamora, D and Seo, S and Sheldon, J and Lee, SJ and Jerome, KR and Green, ML and Boeckh, M}, title = {Late cytomegalovirus disease after hematopoietic cell transplantation: significance of novel transplantation techniques.}, journal = {Blood advances}, volume = {8}, number = {14}, pages = {3639-3651}, pmid = {38537062}, issn = {2473-9537}, support = {K23 AI097234/AI/NIAID NIH HHS/United States ; K24 HL093294/HL/NHLBI NIH HHS/United States ; F31 CA157045/CA/NCI NIH HHS/United States ; K23 AI163343/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects/methods ; *Cytomegalovirus Infections/etiology/prevention &amp; control/epidemiology ; Male ; Female ; Middle Aged ; Adult ; Risk Factors ; Retrospective Studies ; Antiviral Agents/therapeutic use ; Aged ; Cytomegalovirus ; Graft vs Host Disease/etiology/prevention &amp; control ; Adolescent ; Incidence ; Young Adult ; }, abstract = {Preemptive therapy (PET) and letermovir prophylaxis are effective in preventing cytomegalovirus (CMV) disease within the first 100 days after allogeneic hematopoietic cell transplantation (HCT) but are associated with late-onset CMV disease. We retrospectively examined the clinical manifestations, risk factors, prevention algorithm, and outcome of late CMV disease in CMV seropositive day 100 survivors transplanted between 2001-2017 (PET cohort) and 2018-2021 (letermovir cohort). There were 203 episodes of late CMV disease among 2469 day 100 survivors, and the estimated cumulative incidence of first late CMV disease was 7.2% (95% confidence interval [CI], 6.2-8.3) with no difference between the PET (7.4%; 95% CI, 6.4-8.6) and the letermovir group (5.4%; 95% CI, 3.2-8.3). Thirty-seven patients (1.5%) had a second episode of CMV disease. In multivariable Cox regression models, posttransplant cyclophosphamide was associated with an increased risk of gastrointestinal CMV disease. CMV viremia or disease detected before day 100, corticosteroid treatment after day 100 at dose ≥1 mg/kg, acute and chronic graft-versus-host disease, lymphopenia, HLA-mismatched related donor status, were also associated with late CMV disease. HLA-mismatched donor status and late use of corticosteroids (≥1 mg/kg) were risk factors for late CMV disease recurrence. Late CMV disease occurred most frequently in a setting of prolonged low-level untreated viremia and was independently associated with death by 2 years after HCT. In summary, late CMV disease continues to occur in the present era. Improved prevention strategies for late CMV disease are needed.}, }
@article {pmid38532709, year = {2024}, author = {Sale, JE and Stoddard, BL}, title = {CRISPR in Nucleic Acids Research: the sequel.}, journal = {Nucleic acids research}, volume = {52}, number = {7}, pages = {3489-3492}, pmid = {38532709}, issn = {1362-4962}, mesh = {*CRISPR-Cas Systems ; *Gene Editing/methods ; Humans ; Clustered Regularly Interspaced Short Palindromic Repeats ; Nucleic Acids/genetics ; }, }
@article {pmid38532279, year = {2024}, author = {Bjornard, K and Close, A and Burns, K and Chavez, J and Chow, EJ and Meacham, LR}, title = {Fertility preservation in pediatric solid tumors: A report from the Children's Oncology Group.}, journal = {Pediatric blood &amp; cancer}, volume = {71}, number = {6}, pages = {e30960}, pmid = {38532279}, issn = {1545-5017}, support = {U10 CA180886/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; UG1 CA189955/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Fertility Preservation/methods ; *Neoplasms/therapy ; Child ; Female ; Male ; Adolescent ; }, abstract = {Treatment for childhood solid tumors may lead to an increased risk for gonadal dysfunction/infertility. Discussion of risk should occur at diagnosis, any changes in therapy, and during survivorship. Gonadotoxic therapies were abstracted from 32 Children's Oncology Group (COG) phase III, frontline solid tumor protocols, in use from 2000 to 2022. Risk for gonadal dysfunction/infertility was assessed based on gonadotoxic therapies, sex, and pubertal status and assigned as minimal, significant, and high following the Oncofertility Consortium Pediatric Initiative Network (PIN) risk stratification. Most protocols (65.6%, 21/32) contained at least one therapeutic arm with a high level of increased risk. Solid tumor therapies present challenges in risk stratification due to response-adjusted therapy and the need to account for radiation field in the risk assessment. This guide hopes to serve as a tool to assist in standardizing gonadotoxic risk assessments across disciplines and improve referral for fertility services and reproductive health counseling for patients receiving COG-based solid tumor therapy. Internationally, many solid tumor therapies follow similar paradigms to COG studies, and risk stratifications may be generalizable to similar styles of therapy. In addition, this model may be applied to other international groups with the goal of standardizing fertility assessments.}, }
@article {pmid38531685, year = {2024}, author = {Kim, AE and Bennett, JC and Luiten, K and O'Hanlon, JA and Wolf, CR and Magedson, A and Han, PD and Acker, Z and Regelbrugge, L and McCaffrey, KM and Stone, J and Reinhart, D and Capodanno, BJ and Morse, SS and Bedford, T and Englund, JA and Boeckh, M and Starita, LM and Uyeki, TM and Carone, M and Weil, A and Chu, HY}, title = {Comparative Diagnostic Utility of SARS-CoV-2 Rapid Antigen and Molecular Testing in a Community Setting.}, journal = {The Journal of infectious diseases}, volume = {230}, number = {2}, pages = {363-373}, doi = {10.1093/infdis/jiae150}, pmid = {38531685}, issn = {1537-6613}, support = {//University of Washington/ ; }, mesh = {Humans ; *COVID-19/diagnosis ; *Sensitivity and Specificity ; *SARS-CoV-2/immunology/isolation &amp; purification/genetics ; Prospective Studies ; Longitudinal Studies ; Male ; Female ; Middle Aged ; Adult ; *COVID-19 Serological Testing/methods ; Antigens, Viral/analysis ; COVID-19 Nucleic Acid Testing/methods ; Aged ; Washington ; Young Adult ; Adolescent ; }, abstract = {BACKGROUND: SARS-CoV-2 antigen-detection rapid diagnostic tests (Ag-RDTs) have become widely utilized but longitudinal characterization of their community-based performance remains incompletely understood.<br><br>METHODS: This prospective longitudinal study at a large public university in Seattle, WA utilized remote enrollment, online surveys, and self-collected nasal swab specimens to evaluate Ag-RDT performance against real-time reverse transcription polymerase chain reaction (rRT-PCR) in the context of SARS-CoV-2 Omicron. Ag-RDT sensitivity and specificity within 1 day of rRT-PCR were evaluated by symptom status throughout the illness episode and Orf1b cycle threshold (Ct).<br><br>RESULTS: From February to December 2022, 5757 participants reported 17 572 Ag-RDT results and completed 12 674 rRT-PCR tests, of which 995 (7.9%) were rRT-PCR positive. Overall sensitivity and specificity were 53.0% (95% confidence interval [CI], 49.6%-56.4%) and 98.8% (95% CI, 98.5%-99.0%), respectively. Sensitivity was comparatively higher for Ag-RDTs used 1 day after rRT-PCR (69.0%), 4-7 days after symptom onset (70.1%), and Orf1b Ct &#x2264;20 (82.7%). Serial Ag-RDT sensitivity increased with repeat testing &#x2265;2 (68.5%) and &#x2265;4 (75.8%) days after an initial Ag-RDT-negative result.<br><br>CONCLUSIONS: Ag-RDT performance varied by clinical characteristics and temporal testing patterns. Our findings support recommendations for serial testing following an initial Ag-RDT-negative result, especially among recently symptomatic persons or those at high risk for SARS-CoV-2 infection.}, }
@article {pmid38530853, year = {2024}, author = {Paredes, MI and Perofsky, AC and Frisbie, L and Moncla, LH and Roychoudhury, P and Xie, H and Bakhash, SAM and Kong, K and Arnould, I and Nguyen, TV and Wendm, ST and Hajian, P and Ellis, S and Mathias, PC and Greninger, AL and Starita, LM and Frazar, CD and Ryke, E and Zhong, W and Gamboa, L and Threlkeld, M and Lee, J and Stone, J and McDermot, E and Truong, M and Shendure, J and Oltean, HN and Viboud, C and Chu, H and Müller, NF and Bedford, T}, title = {Local-scale phylodynamics reveal differential community impact of SARS-CoV-2 in a metropolitan US county.}, journal = {PLoS pathogens}, volume = {20}, number = {3}, pages = {e1012117}, pmid = {38530853}, issn = {1553-7374}, support = {R00 AI147029/AI/NIAID NIH HHS/United States ; R35 GM119774/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; SARS-CoV-2/genetics ; *COVID-19/epidemiology ; Washington/epidemiology ; *Epidemics ; }, abstract = {SARS-CoV-2 transmission is largely driven by heterogeneous dynamics at a local scale, leaving local health departments to design interventions with limited information. We analyzed SARS-CoV-2 genomes sampled between February 2020 and March 2022 jointly with epidemiological and cell phone mobility data to investigate fine scale spatiotemporal SARS-CoV-2 transmission dynamics in King County, Washington, a diverse, metropolitan US county. We applied an approximate structured coalescent approach to model transmission within and between North King County and South King County alongside the rate of outside introductions into the county. Our phylodynamic analyses reveal that following stay-at-home orders, the epidemic trajectories of North and South King County began to diverge. We find that South King County consistently had more reported and estimated cases, COVID-19 hospitalizations, and longer persistence of local viral transmission when compared to North King County, where viral importations from outside drove a larger proportion of new cases. Using mobility and demographic data, we also find that South King County experienced a more modest and less sustained reduction in mobility following stay-at-home orders than North King County, while also bearing more socioeconomic inequities that might contribute to a disproportionate burden of SARS-CoV-2 transmission. Overall, our findings suggest a role for local-scale phylodynamics in understanding the heterogeneous transmission landscape.}, }
@article {pmid38530700, year = {2024}, author = {Dalal, PJ and Giro, P and Rasmussen-Torvik, LJ and Yancy, CW and Shah, SJ and Reiner, AP and Haring, B and Martin, LW and Wells, GL and Manson, JE and Kooperberg, C and Eaton, CB and Patel, RB}, title = {Heart Failure Risk Among African-American Women With an ICAM1 Missense Variant.}, journal = {JACC. Heart failure}, volume = {12}, number = {9}, pages = {1614-1624}, doi = {10.1016/j.jchf.2024.02.002}, pmid = {38530700}, issn = {2213-1787}, support = {KL2 TR001424/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; Female ; *Heart Failure/genetics/ethnology ; *Black or African American/genetics ; Aged ; Middle Aged ; *Mutation, Missense ; *Hospitalization/statistics &amp; numerical data ; *Intercellular Adhesion Molecule-1/genetics ; *Stroke Volume/physiology ; United States/epidemiology ; Risk Factors ; Aged, 80 and over ; }, abstract = {BACKGROUND: A common genetic variant of ICAM1 among African-American individuals (rs5491; p.K56M) is associated with heart failure (HF) hospitalization, but whether this risk is specific to heart failure with preserved ejection fraction (HFpEF) remains unclear. Older women are at high risk for HFpEF, and the relationship between rs5491 and HFpEF across the age spectrum is unknown.<br><br>OBJECTIVES: This study assessed risk of HF and its subtypes conferred by ICAM1 p.K56M (rs5491).<br><br>METHODS: Associations of rs5491 with risk of HF and its subtypes were estimated among African American individuals in WHI (Women's Health Initiative). The study evaluated whether the association between rs5491 and HF hospitalizations was modified by baseline age. Subsequently, African-American women in WHI and MESA (Multi-Ethnic Study of Atherosclerosis) were pooled and analyses were repeated.<br><br>RESULTS: Among 8,401 women in WHI, the minor allele frequency of rs5491 was 20.7%, and 731 HF hospitalizations occurred over 19.2 years. The rs5491 variant was not associated with HF or its subtypes across WHI. Interaction analyses suggested that age as a continuous variable modified the association of rs5491 with HFpEF hospitalization (interaction P&#xa0;= 0.04). Upon categorizing women into age decades, rs5491 conferred increased risk of HFpEF among women &#x2265;70&#xa0;years (HR per additional rs5491 allele: 1.82 [95%&#xa0;CI: 1.25-2.65]; P = 0.002) but was not associated with HFpEF risk among women&#xa0;<70 years. Pooling African-American women in WHI (n&#xa0;=&#xa0;8,401) and MESA (n&#xa0;=&#xa0;856) demonstrated that the effect modification by&#xa0;age on the association of rs5491 with HFpEF became more significant (interaction P = 0.009), with consistent HFpEF risk effect estimates among women&#xa0;&#x2265;70 years.<br><br>CONCLUSIONS: ICAM1 p.K56M (rs5491) is associated with HFpEF among African-American women&#xa0;&#x2265;70 years.}, }
@article {pmid38530690, year = {2024}, author = {Ekwe, AP and Au, R and Zhang, P and McEnroe, BA and Tan, ML and Saldan, A and Henden, AS and Hutchins, CJ and Henderson, A and Mudie, K and Kerr, K and Fuery, M and Kennedy, GA and Hill, GR and Tey, SK}, title = {Clinical grade multiparametric cell sorting and gene-marking of regulatory T cells.}, journal = {Cytotherapy}, volume = {26}, number = {7}, pages = {719-728}, doi = {10.1016/j.jcyt.2024.02.023}, pmid = {38530690}, issn = {1477-2566}, mesh = {*T-Lymphocytes, Regulatory/immunology ; Humans ; *Flow Cytometry/methods ; *Forkhead Transcription Factors/metabolism/genetics ; Cell Separation/methods ; Genetic Vectors/genetics ; }, abstract = {BACKGROUND AIMS: Regulatory T cells (Tregs) are the main mediators of peripheral tolerance. Treg-directed therapy has shown promising results in preclinical studies of diverse immunopathologies. At present, the clinical applicability of adoptive Treg transfer is limited by difficulties in generating Tregs at sufficient cell dose and purity.<br><br>METHODS: We developed a Good Manufacturing Practice (GMP) compliant method based on closed-system multiparametric Fluorescence-Activated Cell Sorting (FACS) to purify Tregs, which are then expanded in vitro and gene-marked with a clinical grade retroviral vector to enable in vivo fate tracking. Following small-scale optimization, we conducted four clinical-scale processing runs.<br><br>RESULTS: We showed that Tregs could be enriched to 87- 92% purity following FACS-sorting, and expanded and transduced to yield clinically relevant cell dose of 136-732&#xd7;10[6] gene-marked cells, sufficient for a cell dose of at least 2 &#xd7; 10[6] cells/kg. The expanded Tregs were highly demethylated in the FOXP3 Treg-specific demethylated region (TSDR), consistent with bona fide natural Tregs. They were suppressive in vitro, but a small percentage could secrete proinflammatory cytokines, including interferon-&#x3b3; and interleukin-17A.<br><br>CONCLUSIONS: This study demonstrated the feasibility of isolating, expanding and gene-marking Tregs in clinical scale, thus paving the way for future phase I trials that will advance knowledge about the in vivo fate of transferred Tregs and its relationship with concomitant Treg-directed pharmacotherapy and clinical response.}, }
@article {pmid38530681, year = {2024}, author = {Ball, A and Hadland, S and Rodean, J and Hall, M and Mendoza, J and Ahrens, K}, title = {Trends in Substance-Related Visits Among Youth to US Children's Hospitals, 2016-2021: An Analysis of the Pediatric Health Information System Database.}, journal = {The Journal of adolescent health : official publication of the Society for Adolescent Medicine}, volume = {75}, number = {1}, pages = {76-84}, doi = {10.1016/j.jadohealth.2024.02.016}, pmid = {38530681}, issn = {1879-1972}, mesh = {Humans ; Adolescent ; Female ; Male ; United States/epidemiology ; Cross-Sectional Studies ; *Substance-Related Disorders/epidemiology ; Child ; *Hospitals, Pediatric ; *COVID-19/epidemiology ; Young Adult ; Databases, Factual ; SARS-CoV-2 ; }, abstract = {PURPOSE: This study evaluates recent trends in substance-related visits among youth visiting children's hospitals.<br><br>METHODS: We conducted a cross-sectional study of substance-related visits to pediatric hospitals within the Pediatric Health Information System database of youth aged 12-21 years from 2016 through 2021. Substance-related visits were defined as acute visits for International Classification of Diseases, 10th Revision Clinical Modification codes related to substance 'use', dependence, or overdoses for alcohol, cannabis, nicotine, opioids, sedatives, stimulants, hallucinogens, or other substances. Cumulative growth rate and stratified substance-related trends were calculated using generalized estimating equations. Predicted number of visits during the COVID-19 pandemic was generated using an auto-regressive time series analysis.<br><br>RESULTS: There were 106,793 substance-related visits involving 84,632 youth. From 2016 to 2021, substance-related visits increased by 47.9% and increased across all ages, demographics, regions, and payors. Visits of Hispanic youth experienced the greatest percentage growth (63.3%, p < .05) when compared to Non-Hispanic (NH) White (46.2%) or NH Black (49.8%) youth. All substances except sedatives experienced an increase in growth in visits. Cannabis accounted for the largest percentage of visits (52.2%) and experienced the greatest percentage growth during the study period (82.4%, p < .001). During the pandemic, publicly insured, female, NH Black, and Hispanic youth experienced a greater-than-predicted number of substance-related visits.<br><br>DISCUSSION: Substance-related visits to children's hospitals are increasing for all demographics and nearly all substances. There were substantial increases in visits for most minoritized youth with a disproportionate rise among Hispanic youth. Visits over the pandemic were concentrated among publicly insured, female, NH Black, and Hispanic youth. Equitable large-scale investment is needed to address the rising morbidity of substance use among adolescents.}, }
@article {pmid38530310, year = {2024}, author = {Larsen, EL and Nilius, H and Studt, JD and Tsakiris, DA and Greinacher, A and Mendez, A and Schmidt, A and Wuillemin, WA and Gerber, B and Vishnu, P and Graf, L and Kremer Hovinga, JA and Goetze, JP and Bakchoul, T and Nagler, M}, title = {Accuracy of Diagnosing Heparin-Induced Thrombocytopenia.}, journal = {JAMA network open}, volume = {7}, number = {3}, pages = {e243786}, pmid = {38530310}, issn = {2574-3805}, mesh = {Humans ; Male ; Aged ; Female ; Prospective Studies ; *Thrombocytopenia/chemically induced/diagnosis ; Heparin/adverse effects ; Algorithms ; Germany ; }, abstract = {IMPORTANCE: Heparin-induced thrombocytopenia (HIT) is a life-threatening condition that requires urgent diagnostic clarification. However, knowledge of the diagnostic utility of the recommended diagnostic tests is limited in clinical practice.<br><br>OBJECTIVE: To evaluate the current diagnostic practice for managing the suspicion of HIT.<br><br>This prospective diagnostic study was conducted from January 2018 to May 2021 among consecutive patients with suspected HIT from 11 study centers in Switzerland, Germany, and the United States. Detailed clinical data and laboratory information were recorded. Platelet factor 4/heparin antibodies were quantified using an automated chemiluminescent immunoassay (CLIA). A washed-platelet heparin-induced platelet activation (HIPA) test was used as a reference standard to define HIT.<br><br>EXPOSURES: Suspicion of HIT.<br><br>MAIN OUTCOMES AND MEASURES: The primary outcome was the diagnostic accuracy of the 4Ts score, the CLIA, and the recommended algorithm serially combining both tests.<br><br>RESULTS: Of 1448 patients included between 2018 and 2021, 1318 were available for the current analysis (median [IQR] age, 67 [57-75] years; 849 [64.6%] male). HIPA was positive in 111 patients (prevalence, 8.4%). The most frequent setting was intensive care unit (487 [37.0%]) or cardiovascular surgery (434 [33.0%]). The 4Ts score was low risk in 625 patients (46.8%). By 2&#x2009;&#xd7;&#x2009;2 table, the numbers of patients with false-negative results were 10 (9.0%; 4Ts score), 5 (4.5%; CLIA), and 15 (13.5%; recommended diagnostic algorithm). The numbers of patients with false-positive results were 592 (49.0%; 4Ts score), 73 (6.0%; CLIA), and 50 (4.1%; recommended diagnostic algorithm), respectively.<br><br>CONCLUSIONS AND RELEVANCE: In this diagnostic study of patients suspected of having HIT, when the recommended diagnostic algorithm was used in clinical practice, antibody testing was required in half the patients. A substantial number of patients were, however, still misclassified, which could lead to delayed diagnosis or overtreatment. Development of improved diagnostic algorithms for HIT diagnosis should be pursued.}, }
@article {pmid38527998, year = {2024}, author = {Uechi, L and Vasudevan, S and Vilenski, D and Branciamore, S and Frankhouser, D and O'Meally, D and Meshinchi, S and Marcucci, G and Kuo, YH and Rockne, R and Kravchenko-Balasha, N}, title = {Transcriptome free energy can serve as a dynamic patient-specific biomarker in acute myeloid leukemia.}, journal = {NPJ systems biology and applications}, volume = {10}, number = {1}, pages = {32}, pmid = {38527998}, issn = {2056-7189}, support = {P30 CA033572/CA/NCI NIH HHS/United States ; U01 CA250046/CA/NCI NIH HHS/United States ; U01CA250067 S1//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; 1961/19//Israel Science Foundation (ISF)/ ; }, mesh = {Adult ; Animals ; Mice ; Humans ; Child ; *Transcriptome/genetics ; Gene Expression Profiling ; *Leukemia, Myeloid, Acute/genetics ; Biomarkers, Tumor/genetics ; Phenotype ; }, abstract = {Acute myeloid leukemia (AML) is prevalent in both adult and pediatric patients. Despite advances in patient categorization, the heterogeneity of AML remains a challenge. Recent studies have explored the use of gene expression data to enhance AML diagnosis and prognosis, however, alternative approaches rooted in physics and chemistry may provide another level of insight into AML transformation. Utilizing publicly available databases, we analyze 884 human and mouse blood and bone marrow samples. We employ a personalized medicine strategy, combining state-transition theory and surprisal analysis, to assess the RNA transcriptome of individual patients. The transcriptome is transformed into physical parameters that represent each sample's steady state and the free energy change (FEC) from that steady state, which is the state with the lowest free energy.We found the transcriptome steady state was invariant across normal and AML samples. FEC, representing active molecular processes, varied significantly between samples and was used to create patient-specific barcodes to characterize the biology of the disease. We discovered that AML samples that were in a transition state had the highest FEC. This disease state may be characterized as the most unstable and hence the most therapeutically targetable since a change in free energy is a thermodynamic requirement for disease progression. We also found that distinct sets of ongoing processes may be at the root of otherwise similar clinical phenotypes, implying that our integrated analysis of transcriptome profiles may facilitate a personalized medicine approach to cure AML and restore a steady state in each patient.}, }
@article {pmid38523017, year = {2024}, author = {Parikh, M and Tangen, C and Hussain, MHA and Gupta, S and Callis, S and Jo, Y and Harzstark, A and Paller, CJ and George, S and Zibelman, MR and Cheng, HH and Maughan, BL and Zhang, J and Pachynski, RK and Bryce, AH and Lin, DW and Quinn, DI and Lerner, SP and Thompson, IM and Dorff, TB and Lara, PN and Agarwal, N}, title = {Three- and Seven-month Prostate-specific Antigen Levels as Prognostic Markers for Overall Survival in Metastatic Hormone-sensitive Prostate Cancer: Results from SWOG S1216, a Phase 3 Randomized Trial of Androgen Deprivation Plus Orteronel or Bicalutamide.}, journal = {European urology oncology}, volume = {7}, number = {5}, pages = {1097-1104}, doi = {10.1016/j.euo.2024.03.001}, pmid = {38523017}, issn = {2588-9311}, mesh = {Humans ; Male ; *Prostate-Specific Antigen/blood ; *Tosyl Compounds/therapeutic use ; *Anilides/therapeutic use ; *Nitriles/therapeutic use ; *Prostatic Neoplasms/drug therapy/mortality/pathology/blood ; *Androgen Antagonists/therapeutic use ; Aged ; Prognosis ; Middle Aged ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Biomarkers, Tumor/blood ; Neoplasm Metastasis ; Aged, 80 and over ; }, abstract = {BACKGROUND: A robust decrease in prostate-specific antigen (PSA) in response to androgen deprivation therapy (ADT) has been evaluated as a prognostic factor in patients with metastatic hormone-sensitive prostate cancer (mHSPC) since 2006, but the treatment of mHSPC has since evolved to include intensified therapy.<br><br>OBJECTIVE: We assessed the association of PSA levels at 3 (PSA-3mo) and 7 (PSA-7mo) mo with overall survival (OS) in patients with mHSPC treated with ADT combined with either bicalutamide or orteronel in the S1216 phase 3 clinical trial.<br><br>PSA responses to treatment of patients in the S1216 trial were categorized as: complete response (CR) if PSA was &#x2264;0.2&#xa0;ng/ml, partial response if PSA was >0.2 and &#x2264;4&#xa0;ng/ml, and no response (NR) if PSA was >4&#xa0;ng/ml.<br><br>A Cox analysis (adjusted for treatment arm and three stratification factors: performance status, severity of disease, and early vs late induction) was used for OS association. While PSA-7mo association was a prespecified objective, PSA-3mo association was also evaluated.<br><br>RESULTS AND LIMITATIONS: A total of 1251 and 1231 patients from the S1216 study were evaluable for PSA-3mo and PSA-7mo, respectively. A PSA-7mo CR was associated with improved OS compared with NR (HR: 0.20; p&#xa0;<&#xa0;0.0001). A PSA-3mo CR showed a similar association to NR (HR: 0.34; p&#xa0;<&#xa0;0.0001). The association of a PSA response with survival did not differ by treatment arm at either time point.<br><br>CONCLUSIONS: The PSA-3mo and PSA-7mo responses were strongly associated with OS; taken with other emerging prognostic biomarkers, these markers may allow for early identification of patients at the highest risk of death, aid with counseling in clinical practice, and permit design of future clinical trials targeting these patients.<br><br>PATIENT SUMMARY: A low prostate-specific antigen level at 3 or 7 mo after starting treatment for metastatic hormone-sensitive prostate cancer predicts longer survival regardless of the first treatment given with androgen deprivation therapy.}, }
@article {pmid38521653, year = {2024}, author = {Tomasin, R and Ghajar, CM}, title = {Poised epigenetic states dictate metastatic fitness.}, journal = {Trends in cancer}, volume = {10}, number = {4}, pages = {275-276}, doi = {10.1016/j.trecan.2024.03.001}, pmid = {38521653}, issn = {2405-8025}, mesh = {Humans ; *Epigenesis, Genetic ; }, abstract = {Seeking to define early events that regulate disseminated tumor cell (DTC) fate upon their arrival to the lung, Jakab et al. reach the surprising conclusion that dormancy is determined by a cell autonomous poised epigenetic state that renders DTCs responsive to angiocrine Wnt signaling.}, }
@article {pmid38521640, year = {2024}, author = {Banerjee, R and Cowan, AJ and Ortega, M and Missimer, C and Carpenter, PA and Oshima, MU and Salit, RB and Vo, PT and Lee, CJ and Mehta, RS and Kuderer, NM and Shankaran, V and Lee, SJ and Su, CT}, title = {Financial Toxicity, Time Toxicity, and Quality of Life in Multiple Myeloma.}, journal = {Clinical lymphoma, myeloma &amp; leukemia}, volume = {24}, number = {7}, pages = {446-454.e3}, pmid = {38521640}, issn = {2152-2669}, support = {K12 CA076930/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Multiple Myeloma/drug therapy ; *Quality of Life ; Male ; Female ; Middle Aged ; Cross-Sectional Studies ; Aged ; Adult ; }, abstract = {BACKGROUND: Patients with multiple myeloma (MM) may be on therapy for years, which can lead to financial toxicity (FinTox) or time toxicity (TimeTox). The prevalence, predictors, and quality of life (QOL) impacts of FinTox and TimeTox during different phases of MM treatment have not been characterized.<br><br>PATIENTS AND METHODS: We conducted a single-center cross-sectional survey of patients with MM who had undergone transplantation. FinTox+ was defined as a COST-FACIT score <23, TimeTox+ as MM-related interactions (including phone calls) &#x2265;1x weekly or &#x2265;1x monthly in-person among far-residing patients, QOL using PROMIS Global Health, and functional status using patient-reported Karnofsky performance status (KPS).<br><br>RESULTS: Of 252 patients, 22% and 40% met FinTox+ and TimeTox+ criteria respectively. Respective FinTox+ and TimeTox+ proportions were 22%/37% for patients on maintenance, 22%/82% with active therapy, and 20%/14% with observation. FinTox+ predictors included annual income (P < .01) and out-of-pocket costs (P < .01). TimeTox+ predictors included disease status (P < .001), caregiver status (P = .01), far-residing status (P < .001), and out-of-pocket costs (P = .03). FinTox+ was associated with a clinically meaningful decrease in mental QOL, while TimeTox+ patients were more likely to have KPS &#x2264; 80.<br><br>CONCLUSIONS: In our large study, monetary status but not disease status predicted FinTox. Over a third of patients on maintenance reported TimeTox. FinTox+ was associated with decreased mental health, while TimeTox+ was associated with worse performance status. These two toxicities may negatively impact patient wellbeing, and studies of strategies to mitigate their impact are in development.}, }
@article {pmid38520765, year = {2024}, author = {Ho, CC and Naresh, K and Liu, Y and Wu, Y and Gopal, AK and Eckel, AM}, title = {Assessment for 11q and other chromosomal aberrations in large B-cell/high-grade B cell lymphomas of germinal center phenotype lacking BCL2 expression.}, journal = {Cancer genetics}, volume = {284-285}, number = {}, pages = {30-33}, doi = {10.1016/j.cancergen.2024.03.001}, pmid = {38520765}, issn = {2210-7762}, mesh = {Humans ; *Lymphoma, Large B-Cell, Diffuse/genetics/pathology ; *Chromosomes, Human, Pair 11/genetics ; *Proto-Oncogene Proteins c-bcl-2/genetics ; *Germinal Center/pathology ; Adult ; Middle Aged ; Female ; *Chromosome Aberrations ; Male ; Aged ; *Phenotype ; Young Adult ; Aged, 80 and over ; In Situ Hybridization, Fluorescence ; Adolescent ; }, abstract = {The WHO classifications of hematolymphoid malignancies have recognized several distinct entities within the large B cell lymphomas, including the more recently described high-grade B cell lymphoma with 11q aberration (HGBCL-11q). We utilized genomic array to assess for chromosome 11q abnormalities in a broad set of aggressive B cell lymphomas from 27 patients with a focus on younger adults. The findings suggest more frequent alterations of 11q in diffuse large B cell lymphoma (DLBCL)/HGBCL-GC BCL2-, in comparison to cases of Burkitt lymphoma (BL) or DLBCL-GC BCL2+, and confirm a low genomic complexity score of BL. Variability identified in patterns of 11q alterations suggests genomic array studies may afford value over FISH testing as we continue to understand HGBCL-11q as a distinct entity, and interrogate cases of DLBCL/HGBCL-GC BCL2-.}, }
@article {pmid38520075, year = {2024}, author = {Konecny, AJ and Huang, Y and Setty, M and Prlic, M}, title = {Signals that control MAIT cell function in healthy and inflamed human tissues.}, journal = {Immunological reviews}, volume = {323}, number = {1}, pages = {138-149}, doi = {10.1111/imr.13325}, pmid = {38520075}, issn = {1600-065X}, support = {R01 AI123323/AI/NIAID NIH HHS/United States ; R56 DE032009/DE/NIDCR NIH HHS/United States ; R01AI123323 R56DE032009 T32CA080416/HI/NHLBI NIH HHS/United States ; R01AI123323 R56DE032009 T32CA080416/HI/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Mucosal-Associated Invariant T Cells/immunology/metabolism ; *Signal Transduction ; Animals ; Inflammation/immunology ; Lymphocyte Activation/immunology ; Histocompatibility Antigens Class I/metabolism/immunology ; Minor Histocompatibility Antigens/metabolism/immunology ; Receptors, Antigen, T-Cell/metabolism ; }, abstract = {Mucosal-associated invariant T (MAIT) cells have a semi-invariant T-cell receptor that allows recognition of antigen in the context of the MHC class I-related (MR1) protein. Metabolic intermediates of the riboflavin synthesis pathway have been identified as MR1-restricted antigens with agonist properties. As riboflavin synthesis occurs in many bacterial species, but not human cells, it has been proposed that the main purpose of MAIT cells is antibacterial surveillance and protection. The majority of human MAIT cells secrete interferon-gamma (IFNg) upon activation, while some MAIT cells in tissues can also express IL-17. Given that MAIT cells are present in human barrier tissues colonized by a microbiome, MAIT cells must somehow be able to distinguish colonization from infection to ensure effector functions are only elicited when necessary. Importantly, MAIT cells have additional functional properties, including the potential to contribute to restoring tissue homeostasis by expression of CTLA-4 and secretion of the cytokine IL-22. A recent study provided compelling data indicating that the range of human MAIT